Current Medical Diagnosis & Treatment 2015

13

Blood Disorders

Lloyd E. Damon, MD
Charalambos Andreadis, MD

ANEMIAS

 General Approach to Anemias

Anemia is present in adults if the hematocrit is < 41% (hemoglobin < 13.5 g/dL [135 g/L]) in males or < 36% (hemoglobin < 12 g/dL [120 g/L]) in females. Congenital anemia is suggested by the patient’s personal and family history. The most common cause of anemia is iron deficiency. Poor diet may result in folic acid deficiency and contribute to iron deficiency, but bleeding is the most common cause of iron deficiency in adults. Physical examination demonstrates pallor. Attention to physical signs of primary hematologic diseases (lymphadenopathy; hepatosplenomegaly; or bone tenderness, especially in the sternum or anterior tibia) is important. Mucosal changes such as a smooth tongue suggest megaloblastic anemia.

Anemias are classified according to their pathophysiologic basis, ie, whether related to diminished production (relative or absolute reticulocytopenia) or to increased production due to accelerated loss of red blood cells (reticulocytosis) (Table 13–1), and according to red blood cell size (Table 13–2). A reticulocytosis occurs in one of three pathophysiologic states: acute blood loss, recent replacement of a missing erythropoietic nutrient, or reduced red blood cell survival (ie, hemolysis). A severely microcytic anemia (mean corpuscular volume [MCV] < 70 fL) is due either to iron deficiency or thalassemia, while a severely macrocytic anemia (MCV < 125 fL) is almost always due to either megaloblastic anemia or to cold agglutinins in blood analyzed at room temperature. A bone marrow biopsy is generally needed to complete the evaluation of anemia when the laboratory evaluation fails to reveal an etiology, when there are additional cytopenias present, or when an underlying primary or secondary bone marrow process is suspected.

Table 13–1. Classification of anemia by pathophysiology.

Table 13–2. Classification of anemia by mean red blood cell volume (MCV).

IRON DEFICIENCY ANEMIAS

 ESSENTIAL INQUIRIES

 Iron deficiency is present if serum ferritin < 12 ng/mL (27 pmol/L) or < 30 ng/mL (67 pmol/L) if also anemic.

 Caused by bleeding unless proved otherwise.

 Responds to iron therapy.

 General Considerations

Iron deficiency is the most common cause of anemia worldwide. The causes are listed in Table 13–3. Aside from circulating red blood cells, the major location of iron in the body is the storage pool as ferritin or as hemosiderin in macrophages.

Table 13–3. Causes of iron deficiency.

The average American diet contains 10–15 mg of iron per day. About 10% of this amount is absorbed in the stomach, duodenum, and upper jejunum under acidic conditions. Dietary iron present as heme is efficiently absorbed (10–20%) but nonheme iron less so (1–5%), largely because of interference by phosphates, tannins, and other food constituents. The major iron transporter from the diet across the intestinal lumen is ferroportin, which also facilitates the transport of iron to apotransferrin in macrophages for delivery to erythroid cells prepared to synthesize hemoglobin. Hepcidin, produced during inflammation, negatively regulates iron transport by promoting the degradation of ferroportin. Small amounts of iron—approximately 1 mg/d—are normally lost through exfoliation of skin and mucosal cells.

Menstrual blood loss plays a major role in iron metabolism. The average monthly menstrual blood loss is approximately 50 mL but may be five times greater in some individuals. To maintain adequate iron stores, women with heavy menstrual losses must absorb 3–4 mg of iron from the diet each day. This strains the upper limit of what may reasonably be absorbed, and women with menorrhagia of this degree will almost always become iron deficient without iron supplementation.

In general, iron metabolism is balanced between absorption of 1 mg/d and loss of 1 mg/d. Pregnancy and lactation upset the iron balance, since requirements increase to 2–5 mg of iron per day. Normal dietary iron cannot supply these requirements, and medicinal iron is needed during pregnancy and lactation. Decreased iron absorption can also cause iron deficiency, such as in people affected with celiac disease, and it commonly occurs after surgical resection of the stomach or bypass of the jejunum.

The most important cause of iron deficiency anemia in adults is chronic blood loss, especially gastrointestinal blood loss. Prolonged aspirin use, or the use of other anti-inflammatory drugs, may cause it even without a documented structural lesion. Iron deficiency demands a search for a source of gastrointestinal bleeding if other sites of blood loss (menorrhagia, other uterine bleeding, and repeated blood donations) are excluded. Celiac disease (gluten enteropathy), even when asymptomatic, is an occult cause of iron deficiency through poor absorption in the gastrointestinal tract and should be considered when blood loss is not evident. Zinc deficiency is another cause of poor iron absorption. Chronic hemoglobinuria may lead to iron deficiency, but this is uncommon; traumatic hemolysis due to a prosthetic cardiac valve and other causes of intravascular hemolysis (eg, paroxysmal nocturnal hemoglobinuria) should also be considered. The cause of iron deficiency is not found in up to 5% of cases.

 Clinical Findings

  1. Symptoms and Signs

The primary symptoms of iron deficiency anemia are those of the anemia itself (easy fatigability, tachycardia, palpitations, and dyspnea on exertion). Severe deficiency causes skin and mucosal changes, including a smooth tongue, brittle nails, spooning of nails (koilonychia), and cheilosis. Dysphagia due to the formation of esophageal webs (Plummer–Vinson syndrome) may occur in severe iron deficiency. Many iron-deficient patients develop pica, craving for specific foods (ice chips, etc) often not rich in iron.

  1. Laboratory Findings

Iron deficiency develops in stages. The first is depletion of iron stores without anemia followed by anemia with a normal red blood cell size (normal MCV) followed by anemia with reduced red blood cell size (low MCV). The reticulocyte count is low or inappropriately normal. Ferritin is a measure of total body iron stores. A ferritin value < 12 ng/mL (< 27 pmol/L) (in the absence of scurvy) is a highly reliable indicator of depletion of iron stores. Note that the lower limit of normal for ferritin generally is below 12 ng/mL (< 27 pmol/L) in women due to the fact that the normal range is generated by including healthy menstruating women who are iron deficient but not anemic. However, because serum ferritin levels may rise in response to inflammation or other stimuli, a normal or elevated ferritin level does not exclude a diagnosis of iron deficiency. A ferritin level of < 30 ng/mL (67 pmol/L) almost always indicates iron deficiency in anyone who is anemic. As iron deficiency progresses, serum iron values decline to < 30 mcg/dL (67 pmol/L) and transferrin levels rise to compensate, leading to transferrin saturations of < 15%. Low transferrin saturation is also seen in anemia of inflammation, so caution in the interpretation of this test is warranted. Isolated iron deficiency anemia has a low hepcidin level, not yet a clinically available test. As the MCV falls (ie, microcytosis), the blood smear shows hypochromic microcytic cells. With further progression, anisocytosis (variations in red blood cell size) and poikilocytosis (variation in shape of red cells) develop. Severe iron deficiency will produce a bizarre peripheral blood smear, with severely hypochromic cells, target cells, and pencil-shaped or cigar-shaped cells. Bone marrow biopsy for evaluation of iron stores is rarely performed. If the biopsy is done, it shows the absence of iron in erythroid progenitor cells by Prussian blue staining. The platelet count is commonly increased, but it usually remains < 800,000/mcL (800 × 109/L).

 Differential Diagnosis

Other causes of microcytic anemia include anemia of chronic disease (specifically, anemia of inflammation), thalassemia, lead poisoning, and congenital X-linked sideroblastic anemia. Anemia of chronic disease is characterized by normal or increased iron stores in bone marrow macrophages and a normal or elevated ferritin level; the serum iron and transferrin saturation are low, often drastically so, and the total iron-binding capacity (TIBC) and transferrin are either normal or low. Thalassemia produces a greater degree of microcytosis for any given level of anemia than does iron deficiency and, unlike virtually every other cause of anemia, has a normal or elevated (rather than a low) red blood cell count as well as a reticulocytosis. In thalassemia, red blood cell morphology on the peripheral smear resembles severe iron deficiency.

 Treatment

The diagnosis of iron deficiency anemia can be made either by the laboratory demonstration of an iron-deficient state or by evaluating the response to a therapeutic trial of iron replacement. Since the anemia itself is rarely life-threatening, the most important part of management is identification of the cause—especially a source of occult blood loss.

  1. Oral Iron

Ferrous sulfate, 325 mg three times daily on an empty stomach, which provides 180 mg of iron daily of which up to 10 mg is absorbed, is the preferred therapy. Nausea and constipation limit compliance with ferrous sulfate. Extended-release ferrous sulfate with mucoprotease is the best tolerated oral preparation. Compliance is improved by introducing the medicine slowly in gradually escalating doses. Taking ferrous sulfate with food reduces side effects and but also its absorption. An appropriate response is a return of the hematocrit level halfway toward normal within 3 weeks with full return to baseline after 2 months. Iron therapy should continue for 3–6 months after restoration of normal hematologic values to replenish iron stores. Failure of response to iron therapy is usually due to noncompliance, although occasional patients may absorb iron poorly, particularly if the stomach is achlorhydric. Such patients may benefit from concomitant administration of oral ascorbic acid. Other reasons for failure to respond include incorrect diagnosis (anemia of chronic disease, thalassemia), celiac disease, and ongoing gastrointestinal blood loss that exceeds the rate of new erythropoiesis.

  1. Parenteral Iron

The indications are intolerance to oral iron, refractoriness to oral iron, gastrointestinal disease (usually inflammatory bowel disease) precluding the use of oral iron, and continued blood loss that cannot be corrected, such as chronic hemodialysis. Parenteral iron preparations coat the iron in protective carbohydrate shells. Historical parenteral iron preparations, such as iron dextran, were problematic due to long infusion times (hours), polyarthralgia, and hypersensitivity reactions, including anaphylaxis. Current preparations are safe and can be infused in less than 5 minutes. Iron oxide coated with polyglucose sorbitol carboxymethyl-ether can be given in doses up to 510 mg by intravenous bolus over 20 seconds, with no test dose required.

The iron defi cit is calculated by determining the decrement in red cell volume from normal, recognizing there is 1 mg of iron in each milliliter of red blood cells. Total body iron ranges between 2 g and 4 g: approximately 50 mg/kg in men and 35 mg/kg in women. Most (70 – 95%) of the iron is present in hemoglobin in circulating red blood cells. In men, red blood cell volume is approximately 30 mL/kg; in women, it is about 27 mL/kg. Thus, a 50-kg woman whose hemoglobin is 9 g/dL (75% of normal) has an iron deficit of 0.25 × 27 mL/kg × 50 kg = 337.5 mL of red blood cells (or 337.5 mg of iron). The p arenteral iron dose is the iron deficit plus (usually) 1 extra gram to replenish iron stores and anticipate further iron loses, so in this case 1.4 g.

 When to Refer

Patients should be referred to a hematologist if the suspected diagnosis is not confirmed or if they are not responsive to oral iron therapy.

Auerbach M et al. Clinical use of intravenous iron: administration, efficacy, and safety. Hematology Am Soc Hematol Educ Program. 2010;2010:338–47. [PMID: 21239816]

Cancelo-Hildago MJ et al. Tolerability of different oral iron supplements: a systematic review. Curr Med Res Opin. 2013 Apr;29(4):291–303. [PMID: 23252877]

Goodnough LT. Iron deficiency syndromes and iron-restricted erythropoiesis (CME). Transfusion. 2012 Jul;52(7):1584–92. [PMID: 22211566]

Short MW et al. Iron deficiency anemia: evaluation and management. Am Fam Physician. 2013 Jan 15;87(2):98–104. [PMID: 23317073]

ANEMIA OF CHRONIC DISEASE

 ESSENTIAL INQUIRIES

 Mild or moderate normocytic or microcytic anemia.

 Normal or increased ferritin and normal or reduced transferrin.

 Underlying chronic disease.

 General Considerations

Many chronic systemic diseases are associated with mild or moderate anemia. The anemias of chronic disease are characterized according to etiology and pathophysiology. First, the anemia of inflammation is associated with chronic inflammatory states (such as inflammatory bowel disease, rheumatoid arthritis, chronic infections, and malignancy) and is mediated through hepcidin (a negative regulator of ferroportin), resulting in reduced iron uptake in the gut and reduced iron transfer from macrophages to erythroid progenitor cells in the bone marrow. This is referred to as iron-restricted erythropoiesis since the patient is iron replete. There is also reduced responsiveness to erythropoietin, the elaboration of hemolysins that shorten red blood cell survival, and the production of inflammatory cytokines that dampen red cell production. The serum iron is low in the anemia of inflammation. Second, the anemia of organ failure can occur with kidney disease, hepatic failure, and in endocrine gland failure; erythropoietin is reduced and the red blood cell mass decreases in response to a diminished signal for red blood cell production; the serum iron is normal. Third, the anemia of the elderly is present in up to 20% of individuals over age 85 years and a thorough evaluation for an etiology of anemia is negative. The anemia of the elderly is a consequence of relative red blood cell production resistance to erythropoietin, a decrease in erythropoietin production relative to the nephron mass in older people, and the negative erythropoietic influence of low levels of chronic inflammatory cytokines in this age group; the serum iron is normal.

 Clinical Findings

  1. Symptoms and Signs

The clinical features are those of the causative condition. The diagnosis should be suspected in patients with known chronic diseases. In cases of significant anemia, coexistent iron deficiency or folic acid deficiency should be suspected. Decreased dietary intake of folic acid or iron is common in chronically ill patients, and many will also have ongoing gastrointestinal blood losses. Patients undergoing hemodialysis regularly lose both iron and folic acid during dialysis.

  1. Laboratory Findings

The hematocrit rarely falls below 60% of baseline (except in kidney failure). The MCV is usually normal or slightly reduced. Red blood cell morphology is usually normal, and the reticulocyte count is mildly decreased or normal. In the anemia of inflammation, serum iron and transferrin values are low, and transferrin saturation may be extremely low, leading to an erroneous diagnosis of iron deficiency. In contrast to iron deficiency, serum ferritin values should be normal or increased. A serum ferritin value of < 30 ng/mL (67 pmol/L) indicates coexistent iron deficiency. Classic anemia of inflammation has elevated hepcidin levels; however, no clinical test is yet available. In the anemias of organ failure and of the elderly, the iron studies are generally normal. The anemia of the elderly is a diagnosis of exclusion in a patient with anemia who is over age 65 years.

A particular challenge is the diagnosis of iron deficiency in the setting of the anemia of inflammation in which the serum ferritin can be as high as 200 ng/mL (450 pmol/L). The gold standard for diagnosis is a bone marrow biopsy with iron stain. Absent iron staining indicates iron deficiency, and iron localized in marrow macrophages indicates pure anemia of inflammation. Bone marrow biopsies are rarely done for this purpose. Three other tests may help make this distinction: a reticulocyte hemoglobin concentration of < 28 pg; a soluble serum transferrin receptor (units: mg/L) to log ferritin (units: mcg/L) ratio of 1–8; or a normal hepcidin level all support iron deficiency in the setting of inflammation. A functional test is hemoglobin response to oral or parenteral iron in the setting of inflammation when iron deficiency is suspected. A note of caution: certain circumstances of iron-restricted erythropoiesis (such as malignancy) will partially respond to parenteral iron infusion even when the iron stores are replete due to the immediate distribution of iron to erythropoietic progenitor cells after the infusion.

 Treatment

In most cases, no treatment is necessary and the primary management is to address the condition causing the anemia of chronic disease. When the anemia is severe or is adversely affecting the quality of life or functional status, then treatment involves either red blood cell transfusions or parenteral recombinant erythropoietin (epoetin alfa or darbepoetin). The indications for recombinant erythropoietin are hemoglobin < 10 g/dL and anemia due to rheumatoid arthritis, inflammatory bowel disease, hepatitis C, the administration of zidovudine in HIV-infected patients, myelosuppressive chemotherapy in patients with solid malignancy (treated with palliative intent only), or chronic kidney disease (estimated glomerular filtration rate of < 60 mL/min). The dosing and schedule of recombinant erythropoietin are individualized to maintain the hemoglobin between 10 g/dL (100 g/L) and 12 g/dL (120 g/L). The use of recombinant erythropoietin is associated with an increased risk of venothromboembolism and arterial thrombotic episodes, especially if the hemoglobin rises to > 12 g/dL (120 g/L). There is controversy about whether recombinant erythropoietin is associated with reduced survival in patients with malignancy. For patients with end-stage renal disease receiving recombinant erythropoietin who are on hemodialysis, the anemia of chronic kidney disease can be more effectively corrected by adding soluble ferric pyrophosphate to their dialysate than by administering intravenous iron supplementation.

 When to Refer

Referral to a hematologist is not necessary.

Cheng PP et al. Hepcidin expression in anemia of chronic disease and concomitant iron-deficiency anemia. Clin Exp Med. 2011 Mar;11(1):33–42. [PMID: 20499129]

Roy CN. Anemia of inflammation. Hematology Am Soc Hematol Educ Program. 2010;2010:276–80. [PMID: 21239806]

Sun CC et al. Targeting the hepcidin-ferroportin axis to develop new treatment strategies for anemia of chronic disease and anemia of inflammation. Am J Hematol. 2012 Apr;87(4):392–400. [PMID: 22290531]

Vanasse GJ et al. Anemia in elderly patients: an emerging problem for the 21st century. Hematology Am Soc Hematol Educ Program. 2010;2010:271–5. [PMID: 21239805]

THE THALASSEMIAS

 ESSENTIAL INQUIRIES

 Microcytosis disproportionate to the degree of anemia.

 Positive family history or lifelong personal history of microcytic anemia.

 Normal or elevated red blood cell count.

 Abnormal red blood cell morphology with microcytes, hypochromia, acanthocytes, and target cells.

 In beta-thalassemia, elevated levels of hemoglobin A2 or F.

 General Considerations

The thalassemias are hereditary disorders characterized by reduction in the synthesis of globin chains (alpha or beta). Reduced globin chain synthesis causes reduced hemoglobin synthesis and a hypochromic microcytic anemia because of defective hemoglobinization of red blood cells. Thalassemias can be considered among the hyperproliferative hemolytic anemias, the anemias related to abnormal hemoglobin, and the hypoproliferative anemias, since all of these factors play a role in pathogenesis. The hallmark laboratory features are small and pale red blood cells (low MCV and mean corpuscular hemoglobin [MCH]), anemia, and a normal to elevated red blood cell count (ie, a large number of small red blood cells are being produced). Although patients often exhibit an elevated reticulocyte count, generally the degree of reticulocyte output is inadequate to meet the degree of red blood cell destruction (hemolysis) and the patients remain anemic.

Normal adult hemoglobin is primarily hemoglobin A, which represents approximately 98% of circulating hemoglobin. Hemoglobin A is formed from a tetramer of two alpha chains and two beta chains—and can be designated alpha2beta2. Two copies of the alpha-globin gene are located on each chromosome 16, and there is no substitute for alpha-globin in the formation of adult hemoglobin. One copy of the beta-globin gene resides on each chromosome 11 adjacent to genes encoding the beta-like globins delta and gamma (the so-called beta-globin gene cluster region). The tetramer of alpha2delta2 forms hemoglobin A 2, which normally comprises 1–3% of adult hemoglobin. The tetramer alpha2gamma2 forms hemoglobin F, which is the major hemoglobin of fetal life but which comprises < 1% of normal adult hemoglobin.

The thalassemias are described as “trait” when there are laboratory features without significant clinical impact, “intermedia” when there is an occasional red blood cell transfusion requirement or other moderate clinical impact, and “major” when the disorder is life-threatening and the patient is transfusion-dependent. Most patients with thalassemia major die of the consequences of iron overload.

Alpha-thalassemia is due primarily to gene deletions causing reduced alpha-globin chain synthesis (Table 13–4). Each alpha-globin gene produces one-quarter of the total alpha-globin quantity, so there is a predictable proportionate decrease in alpha-globin output with each lost alpha-globin gene. Since all adult hemoglobins are alpha containing, alpha-thalassemia produces no change in the proportions of hemoglobins A, A 2, and F on hemoglobin electrophoresis. In severe forms of alpha-thalassemia, excess beta chains may form a beta-4 tetramer called hemoglobin H. In the presence of reduced alpha chains, the excess beta chains are unstable and precipitate, leading to damage of red blood cell membranes. This leads to both intramedullary (bone marrow) and peripheral blood hemolysis.

Table 13–4. Alpha-thalassemia syndromes.

Beta-thalassemias are usually caused by point mutations rather than deletions (Table 13–5). These mutations result in premature chain termination or in problems with transcription of RNA and ultimately result in reduced or absent beta-globin chain synthesis. The molecular defects leading to beta-thalassemia are numerous and heterogeneous but run true within families. Defects that result in absent beta-globin chain expression are termed beta 0, whereas those causing reduced but not absent synthesis are termed beta +. In beta + thalassemia, the degree of reduction of beta-globin synthesis is consistent within families but is quite variable between families. The reduced beta-globin chain synthesis in beta-thalassemia results in a relative increase in the proportions of hemoglobins A 2 and F compared to hemoglobin A on hemoglobin electrophoresis, as the beta-like globins (delta and gamma) substitute for the missing beta chains. In the presence of reduced beta chains, the excess alpha chains are unstable and precipitate, leading to damage of red blood cell membranes. This leads to both intramedullary (bone marrow) and peripheral blood hemolysis. The bone marrow demonstrates erythroid hyperplasia under the stimuli of anemia and ineffective erythropoiesis (intramedullary destruction of the developing erythroid cells). In cases of severe thalassemia, the marked expansion of the erythroid element in the bone marrow may cause severe bony deformities, osteopenia, and pathologic fractures.

Table 13–5. Beta-thalassemia syndromes.

 Clinical Findings

  1. Symptoms and Signs

The alpha-thalassemia syndromes are seen primarily in persons from southeast Asia and China, and, less commonly, in blacks and persons of Mediterranean origin (Table 13–4). Normally, adults have four copies of the alpha-globin chain. When three alpha-globin genes are present, the patient is hematologically normal (silent carrier). When two alpha-globin genes are present, the patient is said to have alpha-thalassemia trait, one form of thalassemia minor. In alpha-thalassemia-1 trait, the alpha gene deletion is heterozygous (alpha –/alpha –) and affects mainly those of Asian descent. In alpha-thalassemia-2 trait, the alpha gene deletion is homozygous (alpha alpha/– –) and affects mainly blacks. These patients are clinically normal and have a normal life expectancy and performance status, with a mild microcytic anemia. When only one alpha globin chain is present (alpha –/– –), the patient has hemoglobin H disease. This is a chronic hemolytic anemia of variable severity (thalassemia minor or intermedia). Physical examination might reveal pallor and splenomegaly. Affected individuals usually do not need transfusions; however, they may be required during transient periods of hemolytic exacerbation caused by infection or other stressors or during periods of erythropoietic shutdown caused by certain viruses (“aplastic crisis”). When all four alpha-globin genes are deleted, no normal hemoglobin is produced and the affected fetus is stillborn (hydrops fetalis). In hydrops fetalis, the only hemoglobin species gamma made is called hemoglobin Bart’s (gamma4).

Beta-thalassemia primarily affects persons of Mediterranean origin (Italian, Greek) and to a lesser extent Asians and blacks (Table 13–5). Patients homozygous for beta-thalassemia (beta 0/beta 0 or beta+/beta +) have thalassemia major (Cooley anemia). Affected children are normal at birth but after 6 months, when hemoglobin synthesis switches from hemoglobin F to hemoglobin A, severe anemia requiring transfusion develops. Numerous clinical problems ensue, including stunted growth, bony deformities (abnormal facial structure, pathologic fractures), hepatosplenomegaly, jaundice due to gallstones or hepatitis-related cirrhosis (or both), and thrombophilia. The clinical course is modified significantly by transfusion therapy, but transfusional iron overload (hemosiderosis) results in a clinical picture similar to hemochromatosis, with heart failure, cardiac arrhythmias, cirrhosis, endocrinopathies, and pseudoxanthoma elasticum (calcification and fragmentation of the elastic fibers of the skin, retina, and cardiovascular system), usually after more than 100 units of red blood cells have been transfused. Iron loading occurs because the human body has no active iron excretory mechanism. Before the application of allogeneic stem cell transplantation and the development of more effective forms of iron chelation, death from iron overload usually occurred between the ages of 20 and 30 years.

Patients homozygous for a milder form of beta-thalassemia (beta +/beta +, but allowing a higher rate of beta-globin synthesis) have thalassemia intermedia. These patients have chronic hemolytic anemia but do not require transfusions except under periods of stress or during aplastic crises. They also may develop iron overload because of periodic transfusion. They survive into adult life but with hepatosplenomegaly and bony deformities. Patients heterozygous for beta-thalassemia (beta/beta 0 or beta/beta +) have thalassemia minor and a clinically insignificant microcytic anemia.

Prenatal diagnosis is available, and genetic counseling should be offered and the opportunity for prenatal diagnosis discussed.

  1. Laboratory Findings
  2. Alpha-thalassemia trait—These patients have mild anemia, with hematocrits between 28% and 40%. The MCV is strikingly low (60–75 fL) despite the modest anemia, and the red blood count is normal or increased. The peripheral blood smear shows microcytes, hypochromia, occasional target cells, and acanthocytes (cells with irregularly spaced spiked projections). The reticulocyte count and iron parameters are normal. Hemoglobin electrophoresis is normal. Alpha-thalassemia trait is thus usually diagnosed by exclusion. Genetic testing to demonstrate alpha-globin gene deletion is available only in a limited number of laboratories.
  3. Hemoglobin H disease—These patients have a more marked anemia, with hematocrits between 22% and 32%. The MCV is remarkably low (60–70 fL) and the peripheral blood smear is markedly abnormal, with hypochromia, microcytosis, target cells, and poikilocytosis. The reticulocyte count is elevated and the red blood cell count is normal or elevated. Hemoglobin electrophoresis will show a fast migrating hemoglobin (hemoglobin H), which comprises 10–40% of the hemoglobin. A peripheral blood smear can be stained with supravital dyes to demonstrate the presence of hemoglobin H.
  4. Beta-thalassemia minor—These patients have a modest anemia with hematocrit between 28% and 40%. The MCV ranges from 55 fL to 75 fL, and the red blood cell count is normal or increased. The reticulocyte count is normal or slightly elevated. The peripheral blood smear is mildly abnormal, with hypochromia, microcytosis, and target cells. In contrast to alpha-thalassemia, basophilic stippling is present. Hemoglobin electrophoresis shows an elevation of hemoglobin A2to 4–8% and occasional elevations of hemoglobin F to 1–5%.
  5. Beta-thalassemia intermedia—These patients have a modest anemia with hematocrit between 17% and 33%. The MCV ranges from 55 fL to 75 fL, and the red blood cell count is normal or increased. The reticulocyte count is elevated. The peripheral blood smear is abnormal with hypochromia, microcytosis, basophilic stippling, and target cells. Hemoglobin electrophoresis shows up to 30% hemoglobin A and an elevation of hemoglobin A2up to 10% and elevation of hemoglobin F from 6% to 100%.
  6. Beta-thalassemia major—These patients have severe anemia, and without transfusion the hematocrit may fall to < 10%. The peripheral blood smear is bizarre, showing severe poikilocytosis, hypochromia, microcytosis, target cells, basophilic stippling, and nucleated red blood cells. Little or no hemoglobin A is present. Variable amounts of hemoglobin A2are seen, and the predominant hemoglobin present is hemoglobin F.

 Differential Diagnosis

Mild forms of thalassemia must be differentiated from iron deficiency. Compared to iron deficiency anemia, patients with thalassemia have a lower MCV, a normal or elevated red blood cell count, a more abnormal peripheral blood smear at modest levels of anemia, and usually a reticulocytosis. Iron studies are normal or the transferrin saturation or ferritin (or both) are elevated. Severe forms of thalassemia may be confused with other hemoglobinopathies. The diagnosis of beta-thalassemia is made by the above findings and hemoglobin electrophoresis showing elevated levels of hemoglobins A 2 and F (provided the patient is replete in iron), but the diagnosis of alpha-thalassemia is made by exclusion since there is no change in the proportion of the normal adult hemoglobin species. The only other microcytic anemia with a normal or elevated red blood cell count is iron deficiency in a patient with polycythemia vera.

 Treatment

Patients with mild thalassemia (alpha-thalassemia trait or beta-thalassemia minor) require no treatment and should be identified so that they will not be subjected to repeated evaluations and treatment for iron deficiency. Patients with hemoglobin H disease should take folic acid supplementation (1 mg/d orally) and avoid medicinal iron and oxidative drugs such as sulfonamides. Patients with severe thalassemia are maintained on a regular transfusion schedule and receive folic acid supplementation. Splenectomy is performed if hypersplenism causes a marked increase in the transfusion requirement or refractory symptoms. Patients with regular transfusion requirements should be treated with iron chelation (such as oral deferasirox 20–30 mg/kg/d) in order to prevent life-limiting organ damage from iron overload.

Allogeneic stem cell transplantation is the treatment of choice for beta-thalassemia major and the only available cure. Children who have not yet experienced iron overload and chronic organ toxicity do well, with long-term survival in more than 80% of cases.

 When to Refer

All patients with severe thalassemia should be referred to a hematologist. Any patient with an unexplained microcytic anemia should be referred to help establish a diagnosis. Patients with thalassemia minor or intermedia should be referred for genetic counseling because offspring of thalassemic couples are at risk for inheriting thalassemia major.

Angelucci E. Hematopoietic stem cell transplantation in thalassemia. Hematology Am Soc Hematol Educ Program. 2010;2010:456–62. [PMID: 21239835]

Borgna-Pignatti C et al. Complications of thalassemia major and their treatment. Expert Rev Hematol. 2011 Jun;4(3):353–66. [PMID: 21668399]

Forget BG et al. Classification of the disorders of hemoglobin. Cold Spring Harb Perspect Med. 2013 Feb 1;3(2):a011684. [PMID: 23378597]

Higgs DR et al. Thalassaemia. Lancet. 2012 Jan 28;379(9813):373–83. [PMID: 21908035]

Schoorl M et al. Efficacy of advanced discriminating algorithms for screening on iron deficiency anemia and beta thalassemia trait: a multicenter evaluation. Am J Clin Pathol. 2012 Aug;138(2):300–4. [PMID: 22904143]

VITAMIN B 12 DEFICIENCY

 ESSENTIAL INQUIRIES

 Macrocytic anemia.

 Megaloblastic blood smear (macro-ovalocytes and hypersegmented neutrophils).

 Low serum vitamin B 12 level.

 General Considerations

Vitamin B 12 belongs to the family of cobalamins and serves as a cofactor for two important reactions in humans. As methylcobalamin, it is a cofactor for methionine synthetase in the conversion of homocysteine to methionine, and as adenosylcobalamin for the conversion of methylmalonyl-coenzyme A (CoA) to succinyl-CoA. These enzymatic steps are critical for annealing Okazaki fragments during DNA synthesis, particularly in erythroid progenitor cells. Vitamin B 12 comes from the diet and is present in all foods of animal origin. The daily absorption of vitamin B 12 is 5 mcg.

The liver contains 2–5 mg of stored vitamin B 12. Since daily utilization is 3–5 mcg, the body usually has sufficient stores of vitamin B 12 so that it takes more than 3 years for vitamin B 12 deficiency to occur if all intake or absorption immediately ceases.

Since vitamin B 12 is present in foods of animal origin, dietary vitamin B 12 deficiency is extremely rare but is seen in vegans—strict vegetarians who avoid all dairy products as well as meat and fish (Table 13–6). Pernicious anemia is an autoimmune illness whereby autoantibodies destroy gastric parietal cells (that produce intrinsic factor) and cause atrophic gastritis or bind to and neutralize intrinsic factor, or both. Abdominal surgery may lead to vitamin B 12 deficiency in several ways. Gastrectomy will eliminate the site of intrinsic factor production; blind loop syndrome will cause competition for vitamin B 12 by bacterial overgrowth in the lumen of the intestine; and surgical resection of the ileum will eliminate the site of vitamin B 12 absorption. Rare causes of vitamin B 12 deficiency include fish tapeworm (Diphyllobothrium latum) infection, in which the parasite uses luminal vitamin B 12; pancreatic insufficiency (with failure to inactivate competing cobalamin-binding proteins); and severe Crohn disease, causing sufficient destruction of the ileum to impair vitamin B 12 absorption.

Table 13–6. Causes of vitamin B12 deficiency.

 Clinical Findings

  1. Symptoms and Signs

Vitamin B 12 deficiency causes a moderate to severe anemia of slow onset; patients may have few symptoms relative to the degree of anemia. In advanced cases, the anemia may be severe, with hematocrits as low as 10–15%, and may be accompanied by leukopenia and thrombocytopenia. The deficiency also produces changes in mucosal cells, leading to glossitis, as well as other vague gastrointestinal disturbances such as anorexia and diarrhea. Vitamin B 12 deficiency also leads to a complex neurologic syndrome. Peripheral nerves are usually affected first, and patients complain initially of paresthesias. As the posterior columns of the spinal cord become impaired, patients complain of difficulty with balance or proprioception, or both. In more advanced cases, cerebral function may be altered as well, and on occasion dementia and other neuropsychiatric abnormalities may be present. It is critical to recognize that the non-hematologic manifestations of vitamin B 12 deficiency can be manifest despite a completely normal complete blood count.

Patients are usually pale and may be mildly icteric or sallow. Typically later in the disease course, neurologic examination may reveal decreased vibration and position sense or memory disturbance (or both).

  1. Laboratory Findings

The diagnosis of vitamin B 12 deficiency is made by finding a low serum vitamin B 12 (cobalamin) level. Whereas the normal vitamin B 12 level is > 210 pg/mL (> 155 pmol/L), most patients with overt vitamin B 12 deficiency have serum levels < 170 pg/mL (< 126 pmol/L), with symptomatic patients usually having levels < 100 pg/mL (< 74 pmol/L). The diagnosis of vitamin B 12 deficiency in low or low-normal values (level of 170–210 pg/mL [126–155 pmol/L]) is best confirmed by finding an elevated level of serum methylmalonic acid (> 1000 nmol/L) or homocysteine. Of note, elevated levels of serum methylmalonic acid can be due to kidney disease.

The anemia of vitamin B 12 deficiency is typically moderate to severe with the MCV quite elevated (110–140 fL). However, it is possible to have vitamin B 12 deficiency with a normal MCV. Occasionally, the normal MCV may be explained by coexistent thalassemia or iron deficiency, but in other cases the reason is obscure. Patients with neurologic symptoms and signs that suggest possible vitamin B 12 deficiency should be evaluated for that deficiency despite a normal MCV or the absence of anemia. The peripheral blood smear is megaloblastic, defined as red blood cells that appear as macro-ovalocytes, (although other shape changes are usually present) and neutrophils that are hypersegmented (mean neutrophil lobe counts greater than four or the finding of six [or greater]-lobed neutrophils). The reticulocyte count is reduced. Because vitamin B 12 deficiency can affect all hematopoietic cell lines, the white blood cell count and the platelet count are reduced in severe cases.

Other laboratory abnormalities include elevated serum lactate dehydrogenase (LD) and a modest increase in indirect bilirubin. These two findings are a reflection of intramedullary destruction of developing abnormal erythroid cells and are similar to those observed in peripheral hemolytic anemias.

Bone marrow morphology is characteristically abnormal. Marked erythroid hyperplasia is present as a response to defective red blood cell production (ineffective erythropoiesis). Megaloblastic changes in the erythroid series include abnormally large cell size and asynchronous maturation of the nucleus and cytoplasm—ie, cytoplasmic maturation continues while impaired DNA synthesis causes retarded nuclear development. In the myeloid series, giant bands and meta-myelocytes are characteristically seen.

 Differential Diagnosis

Vitamin B 12 deficiency should be differentiated from folic acid deficiency, the other common cause of megaloblastic anemia, in which red blood cell folic acid is low while vitamin B 12 levels are normal. The bone marrow findings of vitamin B 12 deficiency are sometimes mistaken for a myelodysplastic syndrome or even acute erythrocytic leukemia. The distinction between vitamin B 12 deficiency and myelodysplasia is based on the characteristic morphology and the low vitamin B 12 and elevated methylmalonic acid levels.

 Treatment

Patients with vitamin B 12 deficiency have historically been treated with parenteral therapy. Intramuscular or subcutaneous injections of 100 mcg of vitamin B 12 are adequate for each dose. Replacement is usually given daily for the first week, weekly for the first month, and then monthly for life. The vitamin deficiency will recur if patients discontinue their therapy. Oral or sublingual methylcobalamin (1 mg/d) may be used instead of parenteral therapy once initial correction of the deficiency has occurred. Oral or sublingual replacement is effective, even in pernicious anemia, since approximately 1% of the dose is absorbed in the intestine via passive diffusion in the absence of active transport. It must be continued indefinitely and serum vitamin B 12 levels must be monitored to ensure adequate replacement. For patients with neurologic symptoms caused by B 12 deficiency, long-term parenteral vitamin B 12 therapy is prudent. Because many patients are concurrently folic acid deficient from intestinal mucosal atrophy, simultaneous folic acid replacement (1 mg daily) is recommended for the first several months of vitamin B 12 replacement.

Patients respond to therapy with an immediate improvement in their sense of well-being. Hypokalemia may complicate the first several days of therapy, particularly if the anemia is severe. A brisk reticulocytosis occurs in 5–7 days, and the hematologic picture normalizes in 2 months. Central nervous system symptoms and signs are reversible if they are of relatively short duration (< 6 months) but are likely permanent if of longer duration. Red blood cell transfusions are rarely needed despite the severity of anemia, but when given, diuretics are also recommended to avoid heart failure because this anemia developed slowly and the plasma volume is increased.

 When to Refer

Referral to a hematologist is not usually necessary.

Langan RC et al. Update on vitamin B 12 deficiency. Am Fam Physician. 2011 Jun 15;83(12):1425–30. [PMID: 21671542]

Stabler SP. Clinical practice. Vitamin B 12 deficiency. N Engl J Med. 2013 Jan 10;368(2):149–60. [PMID: 23301732]

FOLIC ACID DEFICIENCY

 ESSENTIAL INQUIRIES

 Macrocytic anemia.

 Megaloblastic blood smear (macro-ovalocytes and hypersegmented neutrophils).

 Reduced folic acid levels in red blood cells or serum.

 Normal serum vitamin B 12 level.

 General Considerations

Folic acid is the term commonly used for pteroylmonoglutamic acid. Folic acid is present in most fruits and vegetables (especially citrus fruits and green leafy vegetables). Daily dietary requirements are 50–100 mcg. Total body stores of folic acid are approximately 5 mg, enough to supply requirements for 2–3 months.

The most common cause of folic acid deficiency is inadequate dietary intake (Table 13–7). Alcoholic or anorectic patients, persons who do not eat fresh fruits and vegetables, and those who overcook their food are candidates for folic acid deficiency. Reduced folic acid absorption is rarely seen, since absorption occurs from the entire gastrointestinal tract. However, drugs such as phenytoin, trimethoprim-sulfamethoxazole, or sulfasalazine may interfere with its absorption. Folic acid absorption is poor in some patients with vitamin B 12 deficiency due to gastrointestinal mucosal atrophy. Folic acid requirements are increased in pregnancy, hemolytic anemia, and exfoliative skin disease, and in these cases the increased requirements (five to ten times normal) may not be met by a normal diet.

Table 13–7. Causes of folic acid deficiency.

 Clinical Findings

  1. Symptoms and Signs

The clinical features are similar to those of vitamin B 12 deficiency. However, when there is isolated folic acid deficiency, there are none of the neurologic abnormalities associated with vitamin B 12deficiency.

  1. Laboratory Findings

Megaloblastic anemia is identical to anemia resulting from vitamin B 12 deficiency (see above). A red blood cell folic acid level of < 150 ng/mL (< 340 nmol/L) is diagnostic of folic acid deficiency. The red blood cell folic acid level is preferred over the serum folic acid level because the former reflects body stores over the life span of the red blood cell, while the latter reflects immediate labile serum levels rather than body stores, although the clinical application of this principle is controversial. Usually the serum vitamin B 12 level is normal and should always be measured when folic acid deficiency is suspected. In some instances, folic acid deficiency is a consequence of the gastrointestinal mucosal disturbances from vitamin B 12 deficiency.

 Differential Diagnosis

The megaloblastic anemia of folic acid deficiency should be differentiated from vitamin B 12 deficiency by the finding of a normal vitamin B 12 level and a reduced red blood cell folic acid or serum folic acid level. Alcoholic patients, who often have nutritional deficiency, may also have anemia of liver disease. Anemia of liver disease causes a macrocytic anemia but does not produce megaloblastic morphologic changes in the peripheral blood; rather, target cells are present. Hypothyroidism is associated with mild macrocytosis and also with pernicious anemia.

 Treatment

Folic acid deficiency is treated with daily oral folic acid (1 mg). The response is similar to that seen in the treatment of vitamin B 12 deficiency, with rapid improvement and a sense of well-being, reticulocytosis in 5–7 days, and total correction of hematologic abnormalities within 2 months. Large doses of folic acid may produce hematologic responses in cases of vitamin B 12 deficiency but permit neurologic damage to progress, hence knowing the vitamin B 12 status in suspected folic acid deficiency is paramount.

 When to Refer

Referral to a hematologist is not usually necessary.

Farrell CJ et al. Red cell or serum folate: what to do in clinical practice. Clin Chem Lab Med. 2013 Mar 1;51(3):555–69. [PMID: 23449524]

Green R. Indicators for assessing folate and vitamin B-12 status and for monitoring the efficacy of intervention strategies. Am J Clin Nutr. 2011 Aug;94(2):666S–72S. [PMID: 21733877]

Sanghvi TG et al. Maternal iron-folic acid supplementation programs: evidence of impact and implementation. Food Nutr Bull. 2010 Jun;31(2 Suppl):S100–7. [PMID: 20715594]

HEMOLYTIC ANEMIAS

The hemolytic anemias are a group of disorders in which red blood cell survival is reduced, either episodically or continuously. The bone marrow has the ability to increase erythroid production up to eightfold in response to reduced red cell survival, so anemia will be present only when the ability of the bone marrow to compensate is outstripped. This will occur when red cell survival is extremely short or when the ability of the bone marrow to compensate is impaired.

Hemolytic disorders are generally classified according to whether the defect is intrinsic to the red cell or due to some external factor (Table 13–8). Intrinsic defects have been described in all components of the red blood cell, including the membrane, enzyme systems, and hemoglobin; most of these disorders are hereditary. Hemolytic anemias due to external factors are the immune and microangiopathic hemolytic anemias and infections of red blood cells.

Table 13–8. Classification of hemolytic anemias.

Certain laboratory features are common to all the hemolytic anemias. Haptoglobin, a normal plasma protein that binds and clears free hemoglobin released into plasma, may be depressed in hemolytic disorders. However, the haptoglobin level is influenced by many factors and is not a reliable indicator of hemolysis, particularly in the setting of end-stage liver disease (its site of synthesis). When intravascular hemolysis occurs, transient hemoglobinemia occurs. Hemoglobin is filtered through the glomerulus and is usually reabsorbed by tubular cells. Hemoglobinuria will be present only when the capacity for reabsorption of hemoglobin by renal tubular cells is exceeded. In its absence, evidence for prior intravascular hemolysis is the presence of hemosiderin in shed renal tubular cells (positive urine hemosiderin). With severe intravascular hemolysis, hemoglobinemia and methemalbuminemia may be present. Hemolysis increases the indirect bilirubin, and the total bilirubin may rise to 4 mg/dL (68 mcmol/L). Bilirubin levels higher than this may indicate some degree of hepatic dysfunction. Serum LD levels are strikingly elevated in cases of microangiopathic hemolysis (thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome) and may be elevated in other hemolytic anemias.

PAROXYSMAL NOCTURNAL HEMOGLOBINURIA

 ESSENTIAL INQUIRIES

 Episodic hemoglobinuria.

 Thrombosis is common.

 Suspect in confusing cases of hemolytic anemia or pancytopenia.

 Flow cytometry demonstrates deficiencies of CD55 and CD59.

 General Considerations

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal hematopoietic stem cell disorder that results in abnormal sensitivity of the red blood cell membrane to lysis by complement. The underlying cause is an acquired defect in the gene for phosphatidylinositol class A (PIG-A), which results in a deficiency of the glycosylphosphatidylinositol (GPI) anchor for cellular membrane proteins. In particular, the complement-regulating proteins CD55 and CD59 are deficient, which permits unregulated formation of the complement membrane attack complex on red cell membranes and intravascular hemolysis. Free hemoglobin is released into the blood that scavenges nitric oxide and promotes esophageal spasms, male erectile dysfunction, renal damage, and thrombosis. Patients with significant PNH live 10–15 years; thrombosis is the primary cause of death.

 Clinical Findings

  1. Symptoms and Signs

Classically, patients report episodic hemoglobinuria resulting in reddish brown urine. Hemoglobinuria is most often noticed in the first morning urine due to the drop in blood pH while sleeping that facilitates this hemolysis. Besides anemia, these patients are prone to thrombosis, especially within mesenteric and hepatic veins, central nervous system veins (sagittal vein), and skin vessels (with formation of painful nodules). As this is a hematopoietic stem cell disorder, PNH may appear de novo or arise in the setting of aplastic anemia with possible progression to myelodysplasia or acute myeloid leukemia (AML).

  1. Laboratory Findings

Anemia is of variable severity and frequency, so reticulocytosis may or may not be present at any given time. Abnormalities on the blood smear are nondiagnostic and may include macro-ovalocytes and polychromasia. Since the episodic hemolysis is mainly intravascular, the finding of urine hemosiderin is a useful test. Serum LD is characteristically elevated. Iron deficiency is commonly present and is related to chronic iron loss from hemoglobinuria.

The white blood cell count and platelet count may be decreased and are always decreased in the setting of aplastic anemia. The best screening test is flow cytometry of blood granulocytes to demonstrate deficiency of CD55 and CD59. The FLAER assay (fluorescein-labeled proaerolysin) by flow cytometry is even more sensitive. Bone marrow morphology is variable and may show either generalized hypoplasia or erythroid hyperplasia or both. The bone marrow karyotype may be either normal or demonstrate a clonal abnormality.

 Treatment

Most patients with PNH have mild disease not requiring intervention. In severe cases and in those occurring in the setting of aplastic anemia or myelodysplasia, allogeneic hematopoietic stem cell transplantation has been used. In patients with severe hemolysis (usually requiring red cell transfusions), or thrombosis, treatment with eculizumab is warranted. Eculizumab is a humanized monoclonal antibody against complement protein C5—binding C5 prevents its cleavage so the membrane attack complex cannot assemble. Eculizumab improves quality of life and reduces hemolysis, transfusion requirements, and thrombosis risk. Eculizumab is expensive and increases the risk of Neisseria meningitidis infections; patients receiving the antibody must undergo meningococcal vaccination. Iron replacement is indicated for treatment of iron deficiency when present, which may improve the anemia while also causing a transient increase in hemolysis. For unclear reasons, corticosteroids are effective in decreasing hemolysis.

 When to Refer

Most patients with PNH should be under the care of a hematologist.

Hill A et al. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood. 2013 Jan 20;121(25):4985–96. [PMID: 23610373]

Keating GM et al. Eculizumab: a guide to its use in paroxysmal nocturnal hemoglobinuria. BioDrugs. 2012 Apr 1;26(2):125–30. [PMID: 22350448]

Luzzatto L et al. Management of paroxysmal nocturnal haemoglobinuria: a personal view. Br J Haematol. 2011 Jun;153(6):709–20. [PMID: 21517820]

Parker CJ. Paroxysmal nocturnal hemoglobinuria. Curr Opin Hematol. 2012 May;19(3):141–8. [PMID: 22395662]

Pu JJ et al. Paroxysmal nocturnal hemoglobinuria from bench to bedside. Clin Transl Sci. 2011 Jun;4(3):219–24. [PMID: 21707954]

GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY

 ESSENTIAL INQUIRIES

 X-linked recessive disorder seen commonly in American black men.

 Episodic hemolysis in response to oxidant drugs or infection.

 Bite cells and blister cells on the peripheral blood smear.

 Reduced levels of glucose-6-phosphate dehydrogenase between hemolytic episodes.

 General Considerations

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a hereditary enzyme defect that causes episodic hemolytic anemia because of the decreased ability of red blood cells to deal with oxidative stresses. G6PD deficiency leads to excess oxidized glutathione (hence, inadequate levels of reduced glutathione) that forces hemoglobin to denature and form precipitants called Heinz bodies. Heinz bodies cause red blood cell membrane damage, which leads to premature removal of these red blood cells by reticuloendothelial cells within the spleen (extravascular hemolysis).

Numerous G6PD isoenzymes have been described. The usual isoenzyme found in whites is designated G6PD-B and that in American blacks is designated G6PD-A, both of which have normal function and stability and therefore no hemolytic anemia. Ten to 15 percent of American blacks have the variant G6PD isoenzyme designated A–, in which there is both a reduction in normal enzyme activity and a reduction in stability. The A– isoenzyme activity declines rapidly as the red blood cell ages past 40 days, a fact that explains the clinical findings in this disorder. More than 150 G6PD isoenzyme variants have been described, including some Mediterranean, Ashkenazi Jewish, and Asian variants with extremely low enzyme activity, episodic hemolysis, and exacerbations due to oxidizing substances including fava beans (class II G6PD activity). The other classes of G6PD isoenzyme activity are class I, extremely low activity with associated chronic, severe hemolysis; class III, 10–60% activity with episodic hemolysis (includes the American black A– isoform); class IV, 60–150% activity (normal); and class V, >150% activity. Patients with G6PD deficiency seem to be protected from malaria parasitic infection, have less coronary artery disease, and possibly have fewer cancers and greater longevity.

 Clinical Findings

G6PD deficiency is an X-linked disorder affecting 10–15% of American hemizygous black males and rare female homozygotes. Female carriers are rarely affected—only when an unusually high percentage of cells producing the normal enzyme are X-inactivated.

  1. Symptoms and Signs

Patients are usually healthy, without chronic hemolytic anemia or splenomegaly. Hemolysis occurs episodically as a result of oxidative stress on the red blood cells, generated either by infection or exposure to certain drugs. Seven drugs initiate hemolysis and should be avoided: dapsone, methylthioninium chloride (methylene blue), phenazopyridine, primaquine, rasburicase, tolonium chloride (toluidine blue), and nitrofurantoin. Other drugs, such as sulfonamides, have been implicated but are less certain as offenders since they are often given during infections. Even with continuous use of the offending drug, the hemolytic episode is self-limited because older red blood cells (with low enzyme activity) are removed and replaced with a population of young red blood cells (reticulocytes) with adequate functional levels of G6PD. Severe G6PD deficiency (as in Mediterranean variants) may produce a chronic hemolytic anemia.

  1. Laboratory Findings

Between hemolytic episodes, the blood is normal. During episodes of hemolysis, the hemoglobin rarely falls below 8 g/dL (80 g/L), and there is reticulocytosis and increased serum indirect bilirubin. The peripheral blood cell smear often reveals a small number of “bite” cells—cells that appear to have had a bite taken out of their periphery, or “blister” cells. This indicates pitting of precipitated membrane hemoglobin aggregates by the spleen. Heinz bodies may be demonstrated by staining a peripheral blood smear with cresyl violet; they are not visible on the usual Wright–Giemsa–stained blood smear. Specific enzyme assays for G6PD reveal a low level but may be falsely normal if they are performed during or shortly after a hemolytic episode during the period of reticulocytosis. In these cases, the enzyme assays should be repeated weeks after hemolysis has resolved. In severe cases of G6PD deficiency, enzyme levels are always low.

 Treatment

No treatment is necessary except to avoid known oxidant drugs.

Manganelli G et al. Glucose-6-phosphate dehydrogenase deficiency: disadvantages and possible benefits. Cardiovasc Hematol Disord Drug Targets. 2013 Mar 1;13(1):73–82. [PMID: 23534950]

Youngster I et al. Medications and glucose-6-phosphate dehydrogenase deficiency. An evidence-based review. Drug Saf. 2010 Sep 1;33(9):713–26. [PMID: 20701405]

SICKLE CELL ANEMIA & RELATED SYNDROMES

 ESSENTIAL INQUIRIES

 Recurrent pain episodes.

 Positive family history and lifelong history of hemolytic anemia.

 Irreversibly sickled cells on peripheral blood smear.

 Hemoglobin S is the major hemoglobin seen on electrophoresis.

 General Considerations

Sickle cell anemia is an autosomal recessive disorder in which an abnormal hemoglobin leads to chronic hemolytic anemia with numerous clinical consequences. A single DNA base change leads to an amino acid substitution of valine for glutamine in the sixth position on the beta-globin chain. The abnormal beta chain is designated betas and the tetramer of alpha-2betas-2 is designated hemoglobin S. Hemoglobin S is unstable and polymerizes in the setting of various stressors, including hypoxemia and acidosis, leading to the formation of sickled red blood cells. Sickled cells result in hemolysis and the release of ATP, which is converted to adenosine. Adenosine binds to its receptor (A2B) resulting in the production of 2,3-biphosphoglycerate and the induction of more sickling and to its receptor (A2A) on natural killer cells resulting to pulmonary inflammation. The free hemoglobin from hemolysis scavenges nitric oxide causing endothelial dysfunction, vascular injury, and pulmonary hypertension.

The rate of sickling is influenced by the intracellular concentration of hemoglobin S and by the presence of other hemoglobins within the cell. Hemoglobin F cannot participate in polymer formation, and its presence markedly retards sickling. Factors that increase sickling are red cell dehydration and factors that lead to formation of deoxyhemoglobin S, eg, acidosis and hypoxemia, either systemic or locally in tissues. Hemolytic crises may be related to splenic sequestration of sickled cells (primarily in childhood before the spleen has been infarcted as a result of repeated sickling) or with coexistent disorders such as G6PD deficiency.

The beta S gene is carried in 8% of American blacks, and 1 of 400 American black children will be born with sickle cell anemia. Prenatal diagnosis is available for couples at risk for producing a child with sickle cell anemia. Genetic counseling should be made available to such couples.

 Clinical Findings

  1. Symptoms and Signs

The disorder has its onset during the first year of life, when hemoglobin F levels fall as a signal is sent to switch from production of gamma-globin to beta-globin. Chronic hemolytic anemia produces jaundice, pigment (calcium bilirubinate) gallstones, splenomegaly (early in life), and poorly healing ulcers over the lower tibia. Life-threatening severe anemia can occur during hemolytic or aplastic crises, the latter generally associated with viral or other infection or by folic acid deficiency causing reduced erythropoiesis.

Acute painful episodes due to acute vaso-occlusion from clusters of sickled red cells may occur spontaneously or be provoked by infection, dehydration, or hypoxia. Common sites of acute painful episodes include the bones (especially the back and long bones) and the chest. These episodes last hours to days and may produce low-grade fever. Acute vaso-occlusion may cause strokes due to sagittal sinus thrombosis or to bland or hemorrhagic arterial ischemia and may also cause priapism. Vaso-occlusive episodes are not associated with increased hemolysis.

Repeated episodes of vascular occlusion especially affect the heart, lungs, and liver. Ischemic necrosis of bone occurs, rendering the bone susceptible to osteomyelitis due to salmonellae and (somewhat less commonly) staphylococci. Infarction of the papillae of the renal medulla causes renal tubular concentrating defects and gross hematuria, more often encountered in sickle cell trait than in sickle cell anemia. Retinopathy similar to that noted in diabetes mellitus is often present and may lead to visual impairment. Pulmonary hypertension may develop and is associated with a poor prognosis.

These patients are prone to delayed puberty. An increased incidence of infection is related to hyposplenism as well as to defects in the alternative pathway of complement.

On examination, patients are often chronically ill and jaundiced. There is hepatomegaly, but the spleen is not palpable in adult life. The heart is enlarged, with a hyperdynamic precordium and systolic murmurs. Nonhealing ulcers of the lower leg and retinopathy may be present.

Sickle cell anemia becomes a chronic multisystem disease, with death from organ failure. With improved supportive care, average life expectancy is now between 40 and 50 years of age.

  1. Laboratory Findings

Chronic hemolytic anemia is present. The hematocrit is usually 20–30%. The peripheral blood smear is characteristically abnormal, with irreversibly sickled cells comprising 5–50% of red cells. Other findings include reticulocytosis (10–25%), nucleated red blood cells, and hallmarks of hyposplenism such as Howell–Jolly bodies and target cells. The white blood cell count is characteristically elevated to12,000–15,000/mcL, and reactive thrombocytosis may occur. Indirect bilirubin levels are high.

After a screening test for sickle cell hemoglobin, the diagnosis of sickle cell anemia is confirmed by hemoglobin electrophoresis (Table 13–9). Hemoglobin S will usually comprise 85–98% of hemoglobin. In homozygous S disease, no hemoglobin A will be present. Hemoglobin F levels are variably increased, and high hemoglobin F levels are associated with a more benign clinical course. Patients with S-beta +-thalassemia and SS alpha-thalassemia also have a more benign clinical course than sickle cell anemia.

Table 13–9. Hemoglobin distribution in sickle cell syndromes.

 Treatment

When allogeneic hematopoietic stem cell transplantation is performed before the onset of significant end-organ damage, it can cure more than 80% of children with sickle cell anemia who have suitable HLA-matched donors. Transplantation remains investigational in adults. Other therapies modulate disease severity: cytotoxic agents, such as hydroxyurea, increase hemoglobin F levels epigenetically. Hydroxyurea (500–750 mg orally daily) reduces the frequency of painful crises in patients whose quality of life is disrupted by frequent pain crises. Long-term follow-up of patients taking hydroxyurea demonstrate it improves overall survival and quality of life with little evidence for secondary malignancy. The use of omega-3 (n-3) fatty acid supplementation may reduce vaso-occlusive episodes and reduce transfusion needs in patients with sickle cell anemia.

Supportive care is the mainstay of treatment for sickle cell anemia. Patients are maintained on folic acid supplementation (1 mg orally daily) and given transfusions for aplastic or hemolytic crises. When acute painful episodes occur, precipitating factors should be identified and infections treated if present. The patient should be kept well hydrated, given generous analgesics, and supplied oxygen if hypoxic. Pneumococcal vaccination reduces the incidence of infections with this pathogen.

Severe acute vaso-occlusive crises can be treated with exchange transfusion. Exchange transfusions are primarily indicated for the treatment of intractable pain crises, acute chest syndrome, priapism, and stroke. Long-term transfusion therapy has been shown to be effective in reducing the risk of recurrent stroke in children.

 When to Refer

Patients with sickle cell anemia should have their care coordinated with a hematologist and should be referred to a Comprehensive Sickle Cell Center if one is available.

 When to Admit

Patients should be admitted for management of acute chest crises, for aplastic crisis, or for painful episodes that do not respond to outpatient care.

Daak AA et al. Effect of omega-3 (n-3) fatty acid supplementation in patients with sickle cell anemia: randomized, double-blind, placebo-controlled trial. Am J Clin Nutr. 2013 Jan;97(1):37–44. [PMID: 23193009]

Darbari DS et al. What is the evidence that hydroxyurea improves health-related quality of life in patients with sickle cell disease? Hematology Am Soc Hematol Educ Program. 2012;2012:290–1. [PMID: 23233594]

Gillis VL et al. Management of an acute painful sickle cell episode in hospital: summary of NICE guidance. BMJ. 2012 Jun 27;344:e4063. [PMID: 22740566]

Kassim AA et al. Sickle cell disease, vasculopathy, and therapeutics. Annu Rev Med. 2013;64:451–66. [PMID: 23190149]

McCavit TL. Sickle cell disease. Pediatr Rev. 2012 May;33(5):195–204. [PMID: 22550263]

Tisdale JF et al. HCT for nonmalignant disorders. Biol Blood Marrow Transplant. 2013 Jan;19(1 Suppl):S6–9. [PMID: 23104188]

SICKLE CELL TRAIT

People with the heterozygous genotype (AS) have sickle cell trait. These persons are hematologically normal, with no anemia and normal red blood cells on peripheral blood smear. A screening test for sickle hemoglobin will be positive, and hemoglobin electrophoresis will reveal that approximately 40% of hemoglobin is hemoglobin S (Table 13–9). People with sickle cell trait may experience sudden cardiac death and rhabdomyolysis during vigorous exercise, especially at high altitudes. They may also be at increased risk for venothromboembolism. Chronic sickling of red blood cells in the acidotic renal medulla results in microscopic and gross hematuria, hyposthenuria (poor urine concentrating ability), and possibly chronic kidney disease.

No treatment is necessary. Genetic counseling is recommended.

Key NS et al. Sickle-cell trait: novel clinical significance. Hematology Am Soc Hematol Educ Program. 2010;2010:418–22. [PMID: 21239829]

Tripette J et al. Exercise-related complications in sick cell trait. Clin Hemorheol Microcirc. 2013 Jan 1;55(1):29–37. [PMID: 23478224]

SICKLE THALASSEMIA

Patients with homozygous sickle cell anemia and alpha-thalassemia have less vigorous hemolysis and run higher hemoglobins than SS patients due to reduced red blood cell sickling related to a lower hemoglobin concentration within the red blood cell and higher hemoglobin F levels (Table 13–9). The MCV is low, and the red cells are hypochromic.

Patients who are compound heterozygotes for beta s and beta-thalassemia are clinically affected with sickle cell syndromes. Sickle beta 0-thalassemia is clinically very similar to homozygous SS disease. Vaso-occlusive crises may be somewhat less severe, and the spleen is not always infarcted. The MCV is low, in contrast to the normal MCV of sickle cell anemia. Hemoglobin electrophoresis reveals no hemoglobin A but will show an increase in hemoglobins A 2 and F (Table 13–9).

Sickle beta +-thalassemia is a milder disorder than homozygous SS disease, with fewer crises. The spleen is usually palpable. The hemolytic anemia is less severe, and the hematocrit is usually 30–38%, with reticulocytes of 5–10%. Hemoglobin electrophoresis shows the presence of some hemoglobin A and elevated hemoglobins A 2 and F (Table 13–9). The MCV is low.

Sankaran VG et al. Modifier genes in Mendelian disorders: the example of hemoglobin disorders. Ann NY Acad Sci. 2010 Dec;1214:47–56. [PMID: 21039591]

Steinberg MH et al. Genetic modifiers of sickle cell disease. Am J Hematol. 2012 Aug;87(8):795–803. [PMID: 22641398]

AUTOIMMUNE HEMOLYTIC ANEMIA

 ESSENTIAL INQUIRIES

 Acquired hemolytic anemia caused by IgG autoantibody.

 Spherocytes and reticulocytosis on peripheral blood smear.

 Positive antiglobulin (Coombs) test.

 General Considerations

Autoimmune hemolytic anemia is an acquired disorder in which an IgG autoantibody is formed that binds to the red blood cell membrane and does so most avidly at body temperature (ie, a “warm” autoantibody). The antibody is most commonly directed against a basic component of the Rh system present on most human red blood cells. When IgG antibodies coat the red blood cell, the Fc portion of the antibody is recognized by macrophages present in the spleen and other portions of the reticuloendothelial system. The interaction between splenic macrophages and the antibody-coated red blood cell results in removal of red blood cell membrane and the formation of a spherocyte due to the decrease in surface-to-volume ratio of the surviving red blood cell. These spherocytic cells have decreased deformability and are unable to squeeze through the 2-mcm fenestrations of splenic sinusoids and become trapped in the red pulp of the spleen. When large amounts of IgG are present on red blood cells, complement may be fixed. Direct complement lysis of cells is rare, but the presence of C3b on the surface of red blood cells allows Kupffer cells in the liver to participate in the hemolytic process via C3b receptors. The destruction of red blood cells in the spleen and liver designates this as extravascular hemolysis.

Approximately one-half of all cases of autoimmune hemolytic anemia are idiopathic. The disorder may also be seen in association with systemic lupus erythematosus, CLL, or lymphomas. It must be distinguished from drug-induced hemolytic anemia. When penicillin (or other drugs, especially cefotetan, ceftriaxone, and piperacillin) coats the red blood cell membrane, the antibody is directed against the membrane–drug complex. Fludarabine, an antineoplastic, causes autoimmune hemolytic anemia through its immunosuppression effects resulting in defective self- vs non-self immune surveillance permitting the escape of a B-cell clone, which produces the offending autoantibody.

 Clinical Findings

  1. Symptoms and Signs

Autoimmune hemolytic anemia typically produces an anemia of rapid onset that may be life threatening. Patients complain of fatigue and dyspnea and may present with angina pectoris or heart failure. On examination, jaundice and splenomegaly are usually present.

  1. Laboratory Findings

The anemia is of variable severity but may be very severe, with hematocrit of < 10%. Reticulocytosis is present, and spherocytes are seen on the peripheral blood smear. In cases of severe hemolysis, the stressed bone marrow may also release nucleated red blood cells. As with other hemolytic disorders, the serum indirect bilirubin is increased and the haptoglobin is low. Approximately 10% of patients with autoimmune hemolytic anemia have coincident immune thrombocytopenia (Evans syndrome).

The antiglobulin (Coombs) test (DAT) forms the basis for diagnosis. The Coombs reagent is a rabbit IgM antibody raised against human IgG or human complement. The direct antiglobulin (Coombs) test is performed by mixing the patient’s red blood cells with the Coombs reagent and looking for agglutination, which indicates the presence of antibody or complement or both on the red blood cell surface. The indirect antiglobulin (Coombs) test is performed by mixing the patient’s serum with a panel of type O red blood cells. After incubation of the test serum and panel red blood cells, the Coombs reagent is added. Agglutination in this system indicates the presence of free antibody in the patient’s serum.

The direct antiglobulin test is positive (for IgG, complement, or both) in about 90% of patients with autoimmune hemolytic anemia. The indirect antiglobulin test may or may not be positive. A positive indirect antiglobulin test indicates the presence of a large amount of autoantibody that has saturated binding sites in the red blood cell and consequently appears in the serum. Because the patient’s serum usually contains the autoantibody, it may be difficult to obtain a “compatible” cross-match with homologous red blood cells to be used for transfusion.

 Treatment

Initial treatment consists of prednisone, 1–2 mg/kg/d orally in divided doses. Patients with DAT-negative and DAT-positive autoimmune hemolysis respond equally well to corticosteroids. Transfused red blood cells will survive similarly to the patient’s own red blood cells. Because of difficulty in performing the cross-match, “incompatible” blood may need to be given. Decisions regarding transfusions should be made in consultation with a hematologist and a blood bank specialist. If prednisone is ineffective or if the disease recurs on tapering the dose, splenectomy should be considered. Splenectomy may cure the disorder. Death from cardiovascular collapse can occur in the setting of rapid hemolysis. In patients with rapid hemolysis, therapeutic plasmapheresis should be performed early in management to physically unload autoantibodies. Patients with autoimmune hemolytic anemia refractory to prednisone and splenectomy may be treated with a variety of agents. Treatment with rituximab, a monoclonal antibody against the B cell antigen CD20, is effective in some cases. The suggested dose is 375 mg/m 2 intravenously weekly for 4 weeks. Danazol, 400–800 mg/d orally, is less often effective than in immune thrombocytopenia but is well suited for long-term use because of its low toxicity profile. Immunosuppressive agents, including cyclophosphamide, azathioprine, mycophenolate mofetil, alemtuzumab (an anti-CD52 antibody), or cyclosporine, may also be used. High-dose intravenous immune globulin (1 g/kg daily for 2 days) may be effective in controlling hemolysis. The benefit is short-lived (1–3 weeks), and the drug is very expensive. The long-term prognosis for patients with this disorder is good, especially if there is no other underlying autoimmune disorder or lymphoproliferative disorder. Treatment of an associated lymphoproliferative disorder will also treat the hemolytic anemia.

 When to Refer

Patients with autoimmune hemolytic anemia should be referred to a hematologist for confirmation of the diagnosis and subsequent care.

 When to Admit

Patients should be hospitalized for symptomatic anemia or rapidly falling hemoglobin levels.

Barros MM et al. Warm autoimmune hemolytic anemia: recent progress in understanding the immunobiology and the treatment. Transfus Med Rev. 2010 Jul;24(3):195–210. [PMID: 20656187]

Garratty G. Immune hemolytic anemia associated with drug therapy. Blood Rev. 2010 July–Sep;24(4–5):143–50. [PMID: 20650555]

Jaime-Pérez JC et al. Current approaches for the treatment of autoimmune hemolytic anemia. Arch Immunol Ther Exp (Warsz). 2013 Oct;61(5):385–95. [PMID: 23689532]

Kamesaki T et al. Characterization of direct antiglobulin test-negative autoimmune hemolytic anemia: a study of 154 cases. Am J Hematol. 2013 Feb;88(2):93–6. [PMID: 23169533]

Lechner K et al. How I treat autoimmune hemolytic anemias in adults. Blood. 2010 Sept 16;116(11):1821–8. [PMID: 20548093]

Zeerleder S. Autoimmune haemolytic anaemia—a practical guide to cope with a diagnostic and therapeutic challenge. Neth J Med. 2011 Apr;69(4):177–84. [PMID: 21527804]

COLD AGGLUTININ DISEASE

 ESSENTIAL INQUIRIES

 Increased reticulocytes on peripheral blood smear.

 Antiglobulin (Coombs) test positive only for complement.

 Positive cold agglutinin titer.

 General Considerations

Cold agglutinin disease is an acquired hemolytic anemia due to an IgM autoantibody (called a cold agglutinin) usually directed against the I/i antigen on red blood cells. These IgM autoantibodies characteristically will not react with cells at 37°C but only at lower temperatures, most avidly at 0–4°C (ie, “cold” autoantibody). Since the blood temperature (even in the most peripheral parts of the body) rarely goes lower than 20°C, only antibodies reactive at relatively higher temperatures will produce clinical effects. Hemolysis results indirectly from attachment of IgM, which in the cooler parts of the circulation (fingers, nose, ears) binds and fixes complement. When the red blood cell returns to a warmer temperature, the IgM antibody dissociates, leaving complement on the cell. Lysis of red blood cells rarely occurs. Rather, C3b, present on the red blood cells, is recognized by Kupffer cells (which have receptors for C3b), and red blood cell sequestration and destruction in the liver ensues. In some cases, the complement membrane attack complex forms, lysing the red blood cells (intravascular hemolysis).

Most cases of chronic cold agglutinin disease are idiopathic. Others occur in association with Waldenström macroglobulinemia, lymphoma, or CLL, in which a monoclonal IgM paraprotein is produced. Acute postinfectious cold agglutinin disease occurs following mycoplasmal pneumonia or viral infection (infectious mononucleosis, measles, mumps, or cytomegalovirus (CMV) with antibody directed against antigen i rather than I).

 Clinical Findings

  1. Symptoms and Signs

In chronic cold agglutinin disease, symptoms related to red blood cell agglutination occur on exposure to cold, and patients may complain of mottled or numb fingers or toes, acrocyanosis, episodic low back pain, and dark colored urine. Hemolytic anemia is rarely severe, but episodic hemoglobinuria may occur on exposure to cold. The hemolytic anemia in acute postinfectious syndromes is rarely severe.

  1. Laboratory Findings

Mild anemia is present with reticulocytosis and rarely spherocytes. The blood smear made at room temperature shows agglutinated red blood cells (there is no agglutination on a blood smear made at body temperature). The direct antiglobulin (Coombs) test will be positive for complement only. Serum cold agglutinin titer will semi-quantitate the autoantibody. A monoclonal IgM is often found on serum protein electrophoresis and confirmed by serum immunoelectrophoresis. There is indirect hyperbilirubinemia and the haptoglobin is low during periods of hemolysis.

 Treatment

Treatment is largely symptomatic, based on avoiding exposure to cold. Splenectomy and prednisone are usually ineffective (except when associated with a lymphoproliferative disorder) since hemolysis takes place in the liver and blood stream. Rituximab is the treatment of choice. The dose is 375 mg/m 2 intravenously weekly for 4 weeks. Relapses may be effectively re-treated. High-dose intravenous immunoglobulin (2 g/kg) may be effective temporarily, but it is rarely used because of the high cost and short duration of benefit. Patients with severe disease may be treated with cytotoxic agents, such as cyclophosphamide, fludarabine, or bortezomib, or with immunosuppressive agents, such as cyclosporine. As in warm IgG-mediated autoimmune hemolysis, it may be difficult to find compatible blood for transfusion. Red blood cells should be transfused through an in-line blood warmer.

Berentsen S et al. Diagnosis and treatment of cold agglutinin mediated autoimmune hemolytic anemia. Blood Rev. 2012 May;26(3):107–15. [PMID: 22330255]

Swiecicki PL et al. Cold agglutinin disease. Blood. 2013 Aug 15;122(7):1114–21. [PMID: 23757733]

APLASTIC ANEMIA

 ESSENTIAL INQUIRIES

 Pancytopenia.

 No abnormal hematopoietic cells seen in blood or bone marrow.

 Hypocellular bone marrow.

 General Considerations

Aplastic anemia is a condition of bone marrow failure that arises from suppression of or injury to the hematopoietic stem cell. The bone marrow becomes hypoplastic, fails to produce mature blood cells, and pancytopenia develops.

There are a number of causes of aplastic anemia (Table 13–10). Direct hematopoietic stem cell injury may be caused by radiation, chemotherapy, toxins, or pharmacologic agents. Systemic lupus erythematosus may rarely cause suppression of the hematopoietic stem cell by an IgG autoantibody directed against the hematopoietic stem cell. However, the most common pathogenesis of aplastic anemia appears to be autoimmune suppression of hematopoiesis by a T–cell-mediated cellular mechanism, so called “idiopathic” aplastic anemia. In some cases of “idiopathic” aplastic anemia, defects in maintenance of the hematopoietic stem cell telomere length (dyskeratosis congenita) or in DNA repair pathways (Fanconi anemia) have been identified and are likely linked to both the initiation of bone marrow failure and the propensity to later progress to myelodysplasia, PNH, or AML. Complex detrimental immune responses to viruses can also cause aplastic anemia.

Table 13–10. Causes of aplastic anemia.

 Clinical Findings

  1. Symptoms and Signs

Patients come to medical attention because of the consequences of bone marrow failure. Anemia leads to symptoms of weakness and fatigue, neutropenia causes vulnerability to bacterial or fungal infections, and thrombocytopenia results in mucosal and skin bleeding. Physical examination may reveal signs of pallor, purpura, and petechiae. Other abnormalities such as hepatosplenomegaly, lymphadenopathy, or bone tenderness should not be present, and their presence should lead to questioning the diagnosis.

  1. Laboratory Findings

The hallmark of aplastic anemia is pancytopenia. However, early in the evolution of aplastic anemia, only one or two cell lines may be reduced.

Anemia may be severe and is always associated with reticulocytopenia. Red blood cell morphology is unremarkable, but there may be mild macrocytosis (increased MCV). Neutrophils and platelets are reduced in number, and no immature or abnormal forms are seen on the blood smear. The bone marrow aspirate and the bone marrow biopsy appear hypocellular, with only scant amounts of morphologically normal hematopoietic progenitors. The bone marrow karyotype should be normal (or germline if normal variant).

 Differential Diagnosis

Aplastic anemia must be differentiated from other causes of pancytopenia (Table 13–11). Hypocellular forms of myelodysplasia or acute leukemia may occasionally be confused with aplastic anemia. These are differentiated by the presence of cellular morphologic abnormalities or increased blasts, or by the presence of an abnormal karyotype in bone marrow cells. Hairy cell leukemia has been misdiagnosed as aplastic anemia and should be recognized by the presence of splenomegaly and by abnormal lymphoid cells in a hypocellular bone marrow biopsy. Pancytopenia with a normocellular bone marrow may be due to systemic lupus erythematosus, disseminated infection, hypersplenism, nutritional deficiency (eg, vitamin B 12 or folate), or myelodysplasia. Isolated thrombocytopenia may occur early as aplastic anemia develops and may be confused with immune thrombocytopenia.

Table 13–11. Causes of pancytopenia.

 Treatment

Mild cases of aplastic anemia may be treated with supportive care, including erythropoietic (epoetin or darbepoetin) or myeloid (filgrastim or sargramostim) growth factors, or both. Red blood cell transfusions and platelet transfusions are given as necessary, and antibiotics are used to treat infections.

Severe aplastic anemia is defined by a neutrophil count of < 500/mcL, platelets < 20,000/mcL, reticulocytes < 1%, and bone marrow cellularity < 20%. The treatment of choice for young adults (under age 40 years) who have an HLA-matched sibling is allogeneic bone marrow transplantation. Children or young adults may also benefit from allogeneic bone marrow transplantation using an unrelated donor. Because of the increased risks associated with unrelated donor allogeneic bone marrow transplantation relative to sibling donors, this treatment is usually reserved for patients who have not responded to immunosuppressive therapy.

For adults over age 40 years or those without HLA-matched donors, the treatment of choice for severe aplastic anemia is immunosuppression with equine antithymocyte globulin (ATG) plus cyclosporine. Equine ATG is given in the hospital in conjunction with transfusion and antibiotic support. A proven regimen is equine ATG 40 mg/kg/d intravenously for 4 days in combination with cyclosporine, 6 mg/kg orally twice daily. Equine ATG is superior to rabbit ATG, resulting in a higher response rate and better survival. ATG should be used in combination with corticosteroids (prednisone or methylprednisolone 1–2 mg/kg/d orally for 1 week, followed by a taper over 2 weeks) to avoid ATG infusion reactions and serum sickness. Responses usually occur in 1–3 months and are usually only partial, but the blood counts rise high enough to give patients a safe and transfusion-free life. The full benefit of immunosuppression is generally assessed at 4 months post-equine ATG. Cyclosporine is maintained at full dose for 6 months and then stopped in responding patients. Androgens (such as fluoxymesterone 10–20 mg/d orally in divided doses) have been widely used in the past, with a low response rate, and may be considered in mild cases. Androgens appear to partially correct telomere length maintenance defects and increase the production of endogenous erythropoietin. The thrombopoietin mimetic, eltrombopag, may help increase platelets (and also red blood cells and white blood cells) in patients with refractory aplastic anemia.

 Course & Prognosis

Patients with severe aplastic anemia have a rapidly fatal illness if left untreated. Allogeneic bone marrow transplant from a HLA-matched sibling donor produces survival rates over 80% in recipients under 20 years old and about 65–70% in those 20- to 50-years-old. Respective survival rates drop 10–15% when the donor is HLA-matched but unrelated. Equine ATG-cyclosporine immunosuppressive treatment leads to a response in approximately 70% of patients. Up to one-third of patients will relapse with aplastic anemia after ATG-based therapy. Clonal hematologic disorders, such as PNH, AML, or myelodysplasia, may develop in one-quarter of patients treated with immunosuppressive therapy after 10 years of follow-up. Factors that predict response to ATG-cyclosporine therapy are patient’s age, reticulocyte count, lymphocyte count, and age-adjusted telomere length of leukocytes at the time of diagnosis.

 When to Refer

All patients should be referred to a hematologist.

 When to Admit

Admission is necessary for treatment of neutropenic infection, the administration of ATG, or allogeneic bone marrow transplantation.

Dezern AE et al. Clinical management of aplastic anemia. Expert Rev Hematol. 2011 Apr;4(2):221–30. [PMID: 21495931]

Eapen M. Allogeneic transplantation for aplastic anemia. Hematology. 2012 Apr;17(Suppl 1):S15–7. [PMID: 22507769]

Olnes MJ et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med. 2012 Jul 5;367(1):11–19. [PMID: 22762314]

Rauff B et al. Hepatitis associated aplastic anemia: a review. Virol J. 2011 Feb 28;8:87–92. [PMID: 21352606]

Scheinberg P et al. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med. 2011 Aug 4;365(5):430–8. [PMID: 21812672]

Scheinberg P et al. How I treat acquired aplastic anemia. Blood. 2012 Aug 9;120(6):1185–96. [PMID: 22517900]

NEUTROPENIA

 ESSENTIAL INQUIRIES

 Neutrophils < 1800/mcL (< 1.8 × 10 9/L).

 Severe neutropenia if neutrophils < 500/mcL (< 0.5 × 10 9/L).

 General Considerations

Neutropenia is present when the absolute neutrophil count is < 1800/mcL (< 1.8 × 10 9/L), although blacks, Asians, and other specific ethnic groups may have normal neutrophil counts as low as 1200/mcL (< 1.2 × 10 9/L). The neutropenic patient is increasingly vulnerable to infection by gram-positive and gram-negative bacteria and by fungi. The risk of infection is related to the severity of neutropenia. The risk of serious infection rises sharply with neutrophil counts < 500/mcL (< 0.5 × 10 9/L), and neutrophil counts < 100/mcL (< 0.1 × 10 9/L) (“profound neutropenia”) are associated with a high risk of infection within days. Patients with “chronic benign neutropenia” are free of infection despite very low stable neutrophil levels; they seem to respond adequately to infections and inflammatory stimuli with an appropriate neutrophil release from the bone marrow. In contrast, the neutrophil count of patients with cyclic neutropenia periodically oscillate (usually in 21-day cycles) between normal and low, with infections occurring during the nadirs. Both cyclic neutropenia and congenital neutropenia represent problems in mutations in the neutrophil elastase genes ELA-2 or ELANE.

A variety of bone marrow disorders and nonmarrow conditions may cause neutropenia (Table 13–12). All of the causes of aplastic anemia (Table 13–10) and pancytopenia (Table 13–11) may cause neutropenia. The new onset of an isolated neutropenia is most often due to an idiosyncratic reaction to a drug, and agranulocytosis (complete absence of neutrophils in the peripheral blood) is almost always due to a drug reaction. In these cases, examination of the bone marrow shows an almost complete absence of granulocyte precursors with other cell lines undisturbed. This marrow finding is also seen in pure white blood cell aplasia, an autoimmune attack on marrow granulocyte precursors. Neutropenia in the presence of a normal bone marrow may be due to immunologic peripheral destruction (autoimmune neutropenia), sepsis, or hypersplenism. The presence in the serum of antineutrophil antibodies supports the diagnosis of autoimmune neutropenia. Felty syndrome is an immune neutropenia associated with seropositive nodular rheumatoid arthritis and splenomegaly. Severe neutropenia may be associated with clonal disorders of T lymphocytes, often with the morphology of large granular lymphocytes, referred to as CD3-positive T-cell large granular lymphoproliferative disorder. Isolated neutropenia is an uncommon presentation of hairy cell leukemia or a myelodysplastic syndrome. By its nature, myelosuppressive cytotoxic chemotherapy causes neutropenia in a predictable manner.

Table 13–12. Causes of neutropenia.

 Clinical Findings

Neutropenia results in stomatitis and in infections due to gram-positive or gram-negative aerobic bacteria or to fungi such as Candida or Aspergillus. The most common infections are septicemia, cellulitis, pneumonia, and neutropenic fever of unknown origin. Fever should always be initially assumed to be of infectious origin until proven otherwise.

 Treatment

Treatment of neutropenia depends on its cause. Potential causative drugs should be discontinued. Myeloid growth factors (filgrastim or sargramostim) help facilitate neutrophil recovery after offending drugs are stopped. Chronic myeloid growth factor administration (daily or every other day) is effective at dampening the neutropenia seen in cyclic or congenital neutropenia. When Felty syndrome leads to repeated bacterial infections, splenectomy has been the treatment of choice, but sustained use of myeloid growth factors is effective and provides a nonsurgical alternative. Patients with autoimmune neutropenia often respond to immunosuppression with corticosteroids, with splenectomy held in reserve for corticosteroid failure. Patients with true pure white blood cell aplasia need immunosuppression with ATG and cyclosporine, as in aplastic anemia. The neutropenia associated with large granular lymphoproliferative disorder may respond to therapy with either low-dose methotrexate or cyclosporine.

Fevers during neutropenia should be considered as infectious until proven otherwise. Febrile neutropenia is a life-threatening circumstance. Enteric gram-negative bacteria are of primary concern and often empirically treated with fluoroquinolones or third- or fourth-generation cephalosporins. For protracted neutropenia, fungal infections are problematic and empiric coverage with azoles (fluconazole for yeast and voriconazole, itraconazole, or posaconazole for molds) or echinocandins is recommended. The neutropenia following myelosuppressive chemotherapy is predictable and is largely ameliorated by the use of myeloid growth factors. For patients with acute leukemia undergoing intense chemotherapy or patients with solid cancer undergoing high-dose chemotherapy, the prophylactic use of antimicrobial agents and the myeloid growth factors is recommended.

 When to Refer

Refer to a hematologist if neutrophils are persistently and unexplainably < 1000/mcL (< 1.0 × 10 9/L).

 When to Admit

Neutropenia by itself is not an indication for hospitalization. However, most patients with severe neutropenia have a serious underlying disease that may require inpatient treatment. Most patients with febrile neutropenia require hospitalization to treat infection.

Andres E et al. The role of haematopoietic growth factors granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor in the management of drug-induced agranulocytosis. Br J Haematol. 2010 Jul;150(1):3–8. [PMID: 20151980]

Flowers CR et al. Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2013 Feb 20;31(6):794–810. [PMID: 23319691]

Legrand M et al. Survival in neutropenic patients with severe sepsis or septic shock. Crit Care Med. 2012 Jan;40(1):43–9. [PMID: 21926615]

Newberger PE et al. Evaluation and management of patients with isolated neutropenia. Semin Hematol. 2013 Jul;50(3):198–206. [PMID: 23953336]

LEUKEMIAS & OTHER MYELOPROLIFERATIVE NEOPLASMS

Myeloproliferative disorders are due to acquired clonal abnormalities of the hematopoietic stem cell. Since the stem cell gives rise to myeloid, erythroid, and platelet cells, qualitative and quantitative changes are seen in all these cell lines. Classically, the myeloproliferative disorders produce characteristic syndromes with well-defined clinical and laboratory features (Tables 13–13 and 13–14). However, these disorders are grouped together because they may evolve from one into another and because hybrid disorders are commonly seen. All of the myeloproliferative disorders may progress to AML.

Table 13–13. Classification of myeloproliferative disorders.

Table 13–14. Laboratory features of myeloproliferative neoplasms.

The Philadelphia chromosome seen in chronic myeloid leukemia (CML) was the first recurrent cytogenetic abnormality to be described in a human malignancy. Since that time, there has been tremendous progress in elucidating the genetic nature of these disorders, with identification of mutations in JAK2MPL, TET2, IDH1/2, DNMT3A, and other genes.

POLYCYTHEMIA VERA

 ESSENTIAL INQUIRIES

 JAK2 V617F mutation.

 Increased red blood cell mass.

 Splenomegaly.

 Normal arterial oxygen saturation.

 Usually elevated white blood count and platelet count.

 General Considerations

Polycythemia vera is an acquired myeloproliferative disorder that causes overproduction of all three hematopoietic cell lines, most prominently the red blood cells. Erythroid production is independent of erythropoietin, and the serum erythropoietin level is low. A mutation in exon 14 of JAK2 (V617F), a signaling molecule, has been demonstrated in 95% of cases. Additional JAK2 mutations have been identified (exon 12) and suggest that JAK2 is involved in the pathogenesis of this disease and is a potential therapeutic target.

True erythrocytosis, with an elevated red blood cell mass, should be distinguished from spurious erythrocytosis caused by a constricted plasma volume. Primary polycythemia (polycythemia vera) is a bone marrow disorder characterized by autonomous overproduction of erythroid cells.

 Clinical Findings

  1. Symptoms and Signs

Headache, dizziness, tinnitus, blurred vision, and fatigue are common complaints related to expanded blood volume and increased blood viscosity. Generalized pruritus, especially following a warm shower or bath, is related to histamine release from the basophilia. Epistaxis is probably related to engorgement of mucosal blood vessels in combination with abnormal hemostasis due to qualitative abnormalities in platelet function. Sixty percent of patients are men, and the median age at presentation is 60 years. Polycythemia rarely occurs in persons under age 40 years.

Physical examination reveals plethora and engorged retinal veins. The spleen is palpable in 75% of cases but is nearly always enlarged when imaged.

Thrombosis is the most common complication of polycythemia vera and the major cause of morbidity and death in this disorder. Thrombosis appears to be related both to increased blood viscosity and abnormal platelet function. Uncontrolled polycythemia leads to a very high incidence of thrombotic complications of surgery, and elective surgery should be deferred until the condition has been treated. Paradoxically, in addition to thrombosis, increased bleeding can also occur. There is a high incidence of peptic ulcer disease.

  1. Laboratory Findings

The hallmark of polycythemia vera is a hematocrit (at sea level) that exceeds 54% in males or 51% in females. Red blood cell morphology is normal (Table 13–14). By definition, the red blood cell mass is elevated, but this is now rarely measured. The white blood count is usually elevated to 10,000–20,000/mcL and the platelet count is variably increased, sometimes to counts exceeding 1,000,000/mcL. Platelet morphology is usually normal. White blood cells are usually normal, but basophilia and eosinophilia are frequently present. Erythropoietin levels are suppressed and are usually low. The diagnosis should be confirmed with JAK2 mutation screening. The absence of a mutation should lead the clinician to question the diagnosis.

The bone marrow is hypercellular, with panhyperplasia of all hematopoietic elements, but bone marrow examination is not necessary to establish the diagnosis. Iron stores are usually absent from the bone marrow, having been transferred to the increased circulating red blood cell mass. Iron deficiency may also result from chronic gastrointestinal blood loss. Bleeding may lower the hematocrit to the normal range (or lower), creating diagnostic confusion, and may lead to a situation with significant microcytosis with a normal hematocrit.

Vitamin B 12 levels are strikingly elevated because of increased levels of transcobalamin III (secreted by white blood cells). Overproduction of uric acid may lead to hyperuricemia.

Although red blood cell morphology is usually normal at presentation, microcytosis, hypochromia, and poikilocytosis may result from iron deficiency following treatment by phlebotomy (see below). Progressive hypersplenism may also lead to elliptocytosis.

 Differential Diagnosis

Spurious polycythemia, in which an elevated hematocrit is due to contracted plasma volume rather than increased red cell mass, may be related to diuretic use or may occur without obvious cause.

A secondary cause of polycythemia should be suspected if splenomegaly is absent and the high hematocrit is not accompanied by increases in other cell lines. Secondary causes of polycythemia include hypoxia and smoking; carboxyhemoglobin levels may be elevated in smokers (Table 13–15). A renal CT scan or sonogram may be considered to look for an erythropoietin-secreting cyst or tumor. A positive family history should lead to investigation for congenital high-oxygen-affinity hemoglobin. An absence of a mutation in JAK2 suggests a different diagnosis. However, JAK2 mutations are also commonly found in the myeloproliferative disorders essential thrombocytosis and myelofibrosis.

Table 13–15. Causes of polycythemia.

Polycythemia vera should be differentiated from other myeloproliferative disorders (Table 13–14). Marked elevation of the white blood count (above 30,000/mcL) suggests CML. Abnormal red blood cell morphology and nucleated red blood cells in the peripheral blood are seen in myelofibrosis. Essential thrombocytosis is suggested when the platelet count is strikingly elevated.

 Treatment

The treatment of choice is phlebotomy. One unit of blood (approximately 500 mL) is removed weekly until the hematocrit is < 45%; the hematocrit is maintained at < 45% by repeated phlebotomy as necessary. Patients for whom phlebotomy is problematic (because of poor venous access or logistical reasons) may be managed primarily with hydroxyurea (see below). Because repeated phlebotomy intentionally produces iron deficiency, the requirement for phlebotomy should gradually decrease. It is important to avoid medicinal iron supplementation, as this can thwart the goals of a phlebotomy program. Maintaining the hematocrit at normal levels has been shown to decrease the incidence of thrombotic complications. A diet low in iron also is not necessary but will increase the intervals between phlebotomies.

Occasionally, myelosuppressive therapy is indicated. Indications include a high phlebotomy requirement, thrombocytosis, and intractable pruritus. There is evidence that reduction of the platelet count to < 600,000/mcL will reduce the risk of thrombotic complications. Alkylating agents have been shown to increase the risk of conversion of this disease to acute leukemia and should be avoided. Hydroxyurea is widely used when myelosuppressive therapy is indicated. The usual dose is 500–1500 mg/d orally, adjusted to keep platelets < 500,000/mcL without reducing the neutrophil count to < 2000/mcL. Anagrelide may be substituted or added when hydroxyurea is not well tolerated, but it is not the preferred initial agent. Low-dose aspirin (75–81 mg/d orally) has been shown to reduce the risk of thrombosis without excessive bleeding, and should be part of therapy for all patients without contraindications to aspirin. Studies of pegylated alfa-2 interferon have demonstrated considerable efficacy, with hematologic response rates > 80%, as well as molecular responses in 20% (as measured by JAK2 mutations). Patients failing to achieve molecular responses had a higher frequency of mutations outside theJAK2 pathway and were more likely to acquire new mutations during therapy. Side effects were generally acceptable and much less significant than with nonpe gylated forms of interferon. Studies with selective JAK2 inhibitors are ongoing.

Allopurinol 300 mg orally daily may be indicated for hyperuricemia. Antihistamine therapy with diphenhydramine or other H 1-blockers and, rarely, selective serotonin reuptake inhibitors are used to manage pruritus.

 Prognosis

Polycythemia is an indolent disease with median survival of over 15 years. The major cause of morbidity and mortality is arterial thrombosis. Over time, polycythemia vera may convert to myelofibrosis or to CML. In approximately 5% of cases, the disorder progresses to AML, which is usually refractory to therapy.

 When to Refer

Patients with polycythemia vera should be referred to a hematologist.

 When to Admit

Inpatient care is rarely required.

Marchioli R et al; CYTO-PV Collaborative Group. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013 Jan 3;368(1):22–33. [PMID: 23216616]

Passamonti F. How I treat polycythemia vera. Blood. 2012 Jul 12;120(2):275–84. [PMID: 22611155]

Quintás-Cardama A et al. Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera. J Clin Oncol. 2009 Nov 10;27(32):5418–24. [PMID: 19826111]

Vainchenker W et al. New mutations and pathogenesis of myeloproliferative neoplasms. Blood. 2011 Aug 18;118(7):1723–35. [PMID: 21653328]

ESSENTIAL THROMBOCYTOSIS

 ESSENTIAL INQUIRIES

 Elevated platelet count in absence of other causes.

 Normal red blood cell mass.

 Absence of bcr/abl gene (Philadelphia chromosome).

 General Considerations

Essential thrombocytosis is an uncommon myeloproliferative disorder of unknown cause in which marked proliferation of the megakaryocytes in the bone marrow leads to elevation of the platelet count. As with polycythemia vera, the finding of a high frequency of mutations of JAK2 and others in these patients promises to advance the understanding of this disorder.

 Clinical Findings

  1. Symptoms and Signs

The median age at presentation is 50–60 years, and there is a slightly increased incidence in women. The disorder is often suspected when an elevated platelet count is found. Less frequently, the first sign is thrombosis, which is the most common clinical problem. The risk of thrombosis rises with age. Venous thromboses may occur in unusual sites such as the mesenteric, hepatic, or portal vein. Some patients experience erythromelalgia, painful burning of the hands accompanied by erythema; this symptom is reliably relieved by aspirin. Bleeding, typically mucosal, is less common and is related to a concomitant qualitative platelet defect. Splenomegaly is present in at least 25% of patients.

  1. Laboratory Findings

An elevated platelet count is the hallmark of this disorder, and may be over 2,000,000/mcL (2000 × 10 9/L) (Table 13–14). The white blood cell count is often mildly elevated, usually not above 30,000/mcL (30 × 10 9/L), but with some immature myeloid forms. The hematocrit is normal. The peripheral blood smear reveals large platelets, but giant degranulated forms seen in myelofibrosis are not observed. Red blood cell morphology is normal.

The bone marrow shows increased numbers of megakaryocytes but no other morphologic abnormalities. The Philadelphia chromosome is absent but should be assayed by molecular testing of peripheral blood for the bcr/abl fusion gene in all suspected cases to differentiate the disorder from CML.

 Differential Diagnosis

Essential thrombocytosis must be distinguished from secondary causes of an elevated platelet count. In reactive thrombocytosis, the platelet count seldom exceeds 1,000,000/mcL (1000 × 10 9/L). Inflammatory disorders such as rheumatoid arthritis and ulcerative colitis cause significant elevations of the platelet count, as may chronic infection. The thrombocytosis of iron deficiency is observed only when anemia is significant. The platelet count is temporarily elevated after splenectomy. JAK2 mutations are found in 50% of cases. MPL and TET2 mutations have also been described in a subset of patients with essential thrombocytosis.

Regarding other myeloproliferative disorders, the lack of erythrocytosis distinguishes it from polycythemia vera. Unlike myelofibrosis, red blood cell morphology is normal, nucleated red blood cells are absent, and giant degranulated platelets are not seen. In CML, the Philadelphia chromosome (or bcr/abl by molecular testing) establishes the diagnosis.

 Treatment

Patients are considered at high risk for thrombosis if they are older than 60 years, have a leukocyte count ≥ 11 × 10 9/L, or have a previous history of thrombosis. They also have a higher risk for bleeding. The risk of thrombosis can be reduced by control of the platelet count, which should be kept at < 500,000/mcL (500 × 10 9/L). The treatment of choice is oral hydroxyurea in a dose of 500–1000 mg/d. In cases in which hydroxyurea is not well tolerated because of anemia, low doses of anagrelide, 1–2 mg/d orally, may be added. Higher doses of anagrelide can be complicated by headache, peripheral edema, and heart failure. As with polycythemia vera, trials of pegylated interferon alfa-2 have demonstrated significant hematologic responses, but its role in management has not yet been established. Strict control of coexistent cardiovascular risk factors is mandatory for all patients.

Vasomotor symptoms such as erythromelalgia and paresthesias respond rapidly to aspirin, and its long-term low-dose use (81 mg/d orally) may reduce the risk of thrombotic complications in low-risk patients. In the unusual event of severe bleeding, the platelet count can be lowered rapidly with plateletpheresis.

 Course & Prognosis

Essential thrombocytosis is an indolent disorder and allows long-term survival. Average survival is longer than 15 years from diagnosis, and the survival of patients younger than 50 years does not appear different from matched controls. The major source of morbidity—thrombosis—can be reduced by appropriate platelet control. Late in the course of the disease, the bone marrow may become fibrotic, and massive splenomegaly may occur, sometimes with splenic infarction. There is a 10–15% risk of progression to myelofibrosis after 15 years, and a 1–5% risk of transformation to acute leukemia over 20 years.

 When to Refer

Patients with essential thrombocytosis should be referred to a hematologist.

Casini A et al. Thrombotic complications of myeloproliferative neoplasms: risk assessment and risk-guided management. J Thromb Haemost. 2013 Jul;11(7):1215–27. [PMID: 23601811]

Tefferi A. Polycythemia vera and essential thrombocythemia: 2013 update on diagnosis, risk-stratification, and management. Am J Hematol. 2013 Jun;88(6):507–16. [PMID: 23695894]

PRIMARY MYELOFIBROSIS

 ESSENTIAL INQUIRIES

 Striking splenomegaly.

 Teardrop poikilocytosis on peripheral smear.

 Leukoerythroblastic blood picture; giant abnormal platelets.

 Initially hypercellular, then hypocellular bone marrow with reticulin or collagen fibrosis.

 General Considerations

Primary myelofibrosis (myelofibrosis with myeloid metaplasia, agnogenic myeloid metaplasia, idiopathic myelofibrosis) is a myeloproliferative disorder characterized by fibrosis of the bone marrow, splenomegaly, and a leukoerythroblastic peripheral blood picture with teardrop poikilocytosis. Myelofibrosis can also occur as a secondary process following the other myeloproliferative disorders (eg, polycythemia vera, essential thrombocytosis). It is believed that fibrosis occurs in response to increased secretion of platelet-derived growth factor (PDGF) and possibly other cytokines. In response to bone marrow fibrosis, extramedullary hematopoiesis takes place in the liver, spleen, and lymph nodes. In these sites, mesenchymal cells responsible for fetal hematopoiesis can be reactivated. As with other myeloproliferative diseases, abnormalities of JAK2 and MPL may be involved in the pathogenesis.

 Clinical Findings

  1. Symptoms and Signs

Primary myelofibrosis develops in adults over age 50 years and is usually insidious in onset. Patients most commonly present with fatigue due to anemia or abdominal fullness related to splenomegaly. Uncommon presentations include bleeding and bone pain. On examination, splenomegaly is almost invariably present and is commonly massive. The liver is enlarged in more than 50% of cases.

Later in the course of the disease, progressive bone marrow failure takes place as it becomes increasingly more fibrotic. Progressive thrombocytopenia leads to bleeding. The spleen continues to enlarge, which leads to early satiety. Painful episodes of splenic infarction may occur. The patient becomes cachectic and may experience severe bone pain, especially in the upper legs. Hematopoiesis in the liver leads to portal hypertension with ascites, esophageal varices, and occasionally transverse myelitis caused by myelopoiesis in the epidural space.

  1. Laboratory Findings

Patients are almost invariably anemic at presentation. The white blood count is variable—either low, normal, or elevated—and may be increased to 50,000/mcL (50 × 10 9/L). The platelet count is variable. The peripheral blood smear is dramatic, with significant poikilocytosis and numerous teardrop forms in the red cell line. Nucleated red blood cells are present and the myeloid series is shifted, with immature forms including a small percentage of promyelocytes or myeloblasts. Platelet morphology may be bizarre, and giant degranulated platelet forms (megakaryocyte fragments) may be seen. The triad of teardrop poikilocytosis, leukoerythroblastic blood, and giant abnormal platelets is highly suggestive of myelofibrosis.

The bone marrow usually cannot be aspirated (dry tap), though early in the course of the disease it is hypercellular, with a marked increase in megakaryocytes. Fibrosis at this stage is detected by a silver stain demonstrating increased reticulin fibers. Later, biopsy reveals more severe fibrosis, with eventual replacement of hematopoietic precursors by collagen. There is no characteristic chromosomal abnormality. JAK2 is mutated in ~65% of cases, and MPL is mutated in ~40% of cases.

 Differential Diagnosis

A leukoerythroblastic blood picture from other causes may be seen in response to severe infection, inflammation, or infiltrative bone marrow processes. However, teardrop poikilocytosis and giant abnormal platelet forms will not be present. Bone marrow fibrosis may be seen in metastatic carcinoma, Hodgkin lymphoma, and hairy cell leukemia. These disorders are diagnosed by characteristic morphology of involved tissues.

Of the other myeloproliferative disorders, CML is diagnosed when there is marked leukocytosis, normal red blood cell morphology, and the presence of the bcr/abl fusion gene. Polycythemia vera is characterized by an elevated hematocrit. Essential thrombocytosis shows predominant platelet count elevations.

 Treatment

Patients with mild forms of the disease may require no therapy or occasional transfusion support. Anemic patients are supported with transfusion. Anemia can also be controlled with androgens, prednisone, thalidomide, or lenalidomide. First-line therapy for myelofibrosis-associated splenomegaly is hydroxyurea, which is effective in reducing spleen size by half in approximately 40% of patients. Both thalidomide and lenalidomide may improve splenomegaly and thrombocytopenia in some patients. Splenectomy is not routinely performed but is indicated for medication-refractory splenic enlargement causing recurrent painful episodes, severe thrombocytopenia, or an unacceptable transfusion requirement. Perioperative complications can occur in 28% of patients and include infections, abdominal vein thrombosis, and bleeding. Radiation therapy has a role for painful sites of extramedullary hematopoiesis, pulmonary hypertension, or severe bone pain. Transjugular intrahepatic portosystemic shunt might also be considered to alleviate symptoms of portal hypertension.

Several newer agents have shown activity in this disease. The immunomodulatory medications, lenalidomide and pomalidomide, result in control of anemia in 25% and thrombocytopenia in ~58% of cases, without significant reduction in splenic size. There are several JAK2 inhibitors in development. Ruxolitinib, a JAK2 inhibitor, has been approved by the US Food and Drug Administration for myelofibrosis. Even though treatment with ruxolitinib can exacerbate cytopenias, it results in reduction of spleen size, improvement of constitutional symptoms, and may lead to an overall survival benefit in patients with an intermediate- or high-risk disease. The only potentially curative option for this disease is allogeneic stem cell transplantation in selected patients.

 Course & Prognosis

The median survival from time of diagnosis is approximately 5 years. The Dynamic International Prognostic Scoring system is associated with overall survival. Therapies with biologic agents and the application of reduced-intensity allogeneic stem cell transplantation appear to offer the possibility of improving the outcome for many patients. End-stage myelofibrosis is characterized by generalized asthenia liver failure, and bleeding from thrombocytopenia, with some cases terminating in AML.

 When to Refer

Patients in whom myelofibrosis is suspected should be referred to a hematologist.

 When to Admit

Admission is not usually necessary.

Tefferi A. Primary myelofibrosis: 2013 update on diagnosis, risk-stratification, and management. Am J Hematol. 2013 Feb;88(2):141–50. Erratum in: Am J Hematol.2013 May;88(5):437–45. [PMID: 23349007]

Verstovsek S et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012 Mar 1;366(9):799–807. [PMID: 22375971]

CHRONIC MYELOID LEUKEMIA

 ESSENTIAL INQUIRIES

 Elevated white blood count.

 Markedly left-shifted myeloid series but with a low percentage of promyelocytes and blasts.

 Presence of bcr/abl gene (Philadelphia chromosome).

 General Considerations

CML is a myeloproliferative disorder characterized by overproduction of myeloid cells. These myeloid cells continue to differentiate and circulate in increased numbers in the peripheral blood.

CML is characterized by a specific chromosomal abnormality and specific molecular abnormality. The Philadelphia chromosome is a reciprocal translocation between the long arms of chromosomes 9 and 22. The portion of 9q that is translocated contains abl, a protooncogene that is the cellular homolog of the Ableson murine leukemia virus. The abl gene is received at a specific site on 22q, the break point cluster (bcr). The fusion gene bcr/abl produces a novel protein that differs from the normal transcript of the abl gene in that it possesses tyrosine kinase activity. This disorder is the first example of tyrosine kinase “addiction” by cancer cells.

Early CML (“chronic phase”) does not behave like a malignant disease. Normal bone marrow function is retained, white blood cells differentiate and, despite some qualitative abnormalities, the neutrophils combat infection normally. However, untreated CML is inherently unstable, and without treatment the disease progresses to an accelerated and then acute blast phase, which is morphologically indistinguishable from acute leukemia. Remarkable advances in therapy have changed the natural history of the disease, and the relentless progression to more advanced stages of disease is at least greatly delayed, if not eliminated.

 Clinical Findings

  1. Symptoms and Signs

CML is a disorder of middle age (median age at presentation is 55 years). Patients usually complain of fatigue, night sweats, and low-grade fevers related to the hypermetabolic state caused by overproduction of white blood cells. Patients may also complain of abdominal fullness related to splenomegaly. In some cases, an elevated white blood count is discovered incidentally. Rarely, the patient will present with a clinical syndrome related to leukostasis with blurred vision, respiratory distress, or priapism. The white blood count in these cases is usually < 500,000/mcL (500 × 10 9/L).

On examination, the spleen is enlarged (often markedly so), and sternal tenderness may be present as a sign of marrow overexpansion. In cases discovered during routine laboratory monitoring, these findings are often absent.

Acceleration of the disease is often associated with fever in the absence of infection, bone pain, and splenomegaly.

  1. Laboratory Findings

CML is characterized by an elevated white blood count; the median white blood count at diagnosis is 150,000/mcL (150 × 10 9/L), although in some cases the white blood cell count is only modestly increased (Table 13–14). The peripheral blood is characteristic. The myeloid series is left shifted, with mature forms dominating and with cells usually present in proportion to their degree of maturation. Blasts are usually < 5%. Basophilia and eosinophilia of granulocytes may be present. At presentation, the patient is usually not anemic. Red blood cell morphology is normal, and nucleated red blood cells are rarely seen. The platelet count may be normal or elevated (sometimes to strikingly high levels).

The bone marrow is hypercellular, with left-shifted myelopoiesis. Myeloblasts comprise < 5% of marrow cells.

The hallmark of the disease is that the bcr/abl gene is detected by the polymerase chain reaction (PCR) test in the peripheral blood. A bone marrow examination is not necessary for diagnosis, although it is useful for prognosis and for detecting other chromosomal abnormalities in addition to the Philadelphia chromosome.

With progression to the accelerated and blast phases, progressive anemia and thrombocytopenia occur, and the percentage of blasts in the blood and bone marrow increases. Blast phase CML is diagnosed when blasts comprise more than 20% of bone marrow cells.

 Differential Diagnosis

Early CML must be differentiated from the reactive leukocytosis associated with infection. In such cases, the white blood count is usually < 50,000/mcL (< 50 × 10 9/L), splenomegaly is absent, and thebcr/abl gene is not present.

CML must be distinguished from other myeloproliferative disease (Table 13–14). The hematocrit should not be elevated, the red blood cell morphology is normal, and nucleated red blood cells are rare or absent. Definitive diagnosis is made by finding the bcr/abl gene.

 Treatment

Treatment is usually not emergent even with white blood counts over 200,000/mcL (200 × 10 9/L), since the majority of circulating cells are mature myeloid cells that are smaller and more deformable than primitive leukemic blasts. In the rare instances in which symptoms result from extreme hyperleukocytosis (priapism, respiratory distress, visual blurring, altered mental status), emergent leukapheresis is performed in conjunction with myelosuppressive therapy.

In chronic-phase CML, the goal of therapy is normalization of the hematologic abnormalities and suppression of the malignant, bcr/abl-expressing clone. The treatment of choice consists of a tyrosine kinase inhibitor targeting the aberrantly active abl kinase. It is expected that a hematologic complete remission, with normalization of blood counts and splenomegaly will occur within 3 months of treatment initiation. Second, a major cytogenetic response should be achieved, ideally within 3 months but certainly within 6 months. A major cytogenetic response is identified when < 35% of metaphases contain the Philadelphia chromosome. Lastly, a major molecular response is desired within 12 months and is defined as a 3-log reduction of the bcr/abl transcript as measured by quantitative PCR. This roughly corresponds to a bcr/abl ratio (compared to abl) of < 0.01. Patients who achieve this level of molecular response have an excellent prognosis, with 100% of such patients remaining free of progression at 8 years. On the other hand, patients who do not achieve these targets or subsequently lose their cytogenetic or molecular response or patients in whom new mutations or cytogenetic abnormalities develop are considered high-risk.

Imatinib mesylate was the first tyrosine kinase inhibitor to be approved and it results in nearly universal (98%) hematologic control of chronic phase disease at a dose of 400 mg/d. The rate of a major molecular response with imatinib in chronic-phase disease is ~30% at 1 year. The second-generation tyrosine kinase inhibitors, dasatinib and nilotinib, have also been approved for use as front-line therapy and have been shown to significantly increase the rate of achievement of a major molecular response compared to imatinib (71% for nilotinib at 300–400 mg twice daily by 2 years, 64% for dasatinib at 100 mg/d by 2 years) and result in a lower rate of progression to advanced-stage disease. However, these agents can also salvage 90% of patients who do not respond to treatment with imatinib and may therefore be reserved for use in that setting. A dual bcr/abl tyrosine kinase inhibitor, bosutinib, was approved in 2012 for patients who are resistant or intolerant to the other tyrosine kinase inhibitors. The complete cytogenetic response rate to bosutinib is 25% but it is not active against the T315I mutation.

Patients taking tyrosine kinase inhibitors should be monitored with a quantitative PCR assay. Those with a consistent increase in bcr/abl transcript or those with a suboptimal molecular response as defined above should undergo abl mutation testing and then switched to an alternative tyrosine kinase inhibitor. The T315I mutation in abl is specifically resistant to therapy with imatinib, dasatinib, nilotinib, and bosutinib but appears to be sensitive to the third-generation agent ponatinib. However, use of ponatinib is associated with a high rate of vascular thrombotic complications. Patients who cannot achieve a good molecular response to any of these agents or progress following therapy should be considered for treatment with allogeneic transplantation.

Patients with advanced-stage disease (accelerated phase or myeloid/lymphoid blast crisis) should be treated with a tyrosine kinase inhibitor alone or in combination with myelosuppressive chemotherapy. The doses of tyrosine kinase inhibitors in that setting are usually higher than those appropriate for chronic-phase disease. Since the duration of response to tyrosine kinase inhibitors in this setting is limited, these patients should ultimately be considered for allogeneic stem cell transplantation.

Thus, allogeneic stem cell transplantation should be considered for patients in whom disease is not well controlled with tyrosine kinase inhibitor therapy, or for those who have accelerated or blast phase disease.

 Course & Prognosis

Since the introduction of imatinib therapy in 2001, and with the development of molecular targeted agents, more than 80% of patients remain alive and without disease progression at 9 years. Patients with good molecular responses to tyrosine kinase inhibitor therapy have an excellent prognosis, with essentially 100% survival at 9 years, and it is likely that some fraction of these patients will be cured. Small studies suggest that some patients with complete molecular responses (undetectable bcr/abl) lasting more than 2 years can stop drug therapy without disease recurrence, but these findings are being confirmed in prospective studies.

 When to Refer

All patients with CML should be referred to a hematologist.

 When to Admit

Hospitalization is rarely necessary and should be reserved for symptoms of leukostasis at diagnosis or for transformation to acute leukemia.

Baccarani M et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013 Aug 8;122(6):872–84. [PMID: 23803709]

Cortes J et al. How I treat newly diagnosed chronic phase CML. Blood. 2012 Aug 16;120(7):1390–7. [PMID: 22613793]

O’Brien S et al. NCCN Task Force report: tyrosine kinase inhibitor therapy selection in the management of patients with chronic myelogenous leukemia. J Natl Compr Canc Netw. 2011 Feb;9(Suppl 2):S1–25. [PMID: 21335443]

Soverini S et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood. 2011 Aug 4;118(5):1208–15. [PMID: 21562040]

MYELODYSPLASTIC SYNDROMES

 ESSENTIAL INQUIRIES

 Cytopenias with a hypercellular bone marrow.

 Morphologic abnormalities in two or more hematopoietic cell lines.

 General Considerations

The myelodysplastic syndromes are a group of acquired clonal disorders of the hematopoietic stem cell. They are characterized by the constellation of cytopenias, a usually hypercellular marrow, and a number of morphologic and cytogenetic abnormalities. The disorders are usually idiopathic but may be caused by prior exposure to cytotoxic chemotherapy or radiation or both. Ultimately, the disorder may evolve into AML, and the term “preleukemia” has been used in the past to describe these disorders.

Myelodysplasia encompasses several heterogeneous syndromes. Those without excess bone marrow blasts are termed “refractory anemia,” with or without ringed sideroblasts. Patients with the 5q– syndrome, which is characterized by the cytogenetic finding of loss of part of the long arm of chromosome 5, comprise an important subgroup of patients with refractory anemia. The diagnosis “refractory anemia with excess blasts” (RAEB 1 with 5–9% blasts and RAEB 2 with 10–19% blasts) is made in those with excess blasts. Patients with a proliferative syndrome including sustained peripheral blood monocytosis > 1000/mcL (1.0 × 10 9/L) are termed “chronic myelomonocytic leukemia” (CMML), a disorder that shares features of myelodysplastic and myeloproliferative disorders. An International Prognostic Scoring System (IPSS) classifies patients by risk status based on the percentage of bone marrow blasts, cytogenetics, and the severity of cytopenias. The IPSS is associated with the rate of progression to AML as well as overall survival, which can range from a median of 6 years for the low-risk group to 5 months for the high-risk patients.

 Clinical Findings

  1. Symptoms and Signs

Patients are usually over age 60 years. Many patients are asymptomatic when the diagnosis is made because of the finding of abnormal blood counts. Fatigue, infection, or bleeding related to bone marrow failure are usually the presenting symptoms and signs. The course may be indolent, and the disease may present as a wasting illness with fever, weight loss, and general debility. On examination, splenomegaly may be present in combination with pallor, bleeding, and various signs of infection. Myelodysplastic syndromes can also be accompanied by a variety of paraneoplastic syndromes that can occur prior to or following this diagnosis.

  1. Laboratory Findings

Anemia may be marked and may require transfusion support. The MCV is normal or increased, and macro-ovalocytes may be seen on the peripheral blood smear. The white blood cell count is usually normal or reduced, and neutropenia is common. The neutrophils may exhibit morphologic abnormalities, including deficient numbers of granules or deficient segmentation of the nucleus, especially a bilobed nucleus (Pelger–Huet abnormality). The myeloid series may be left shifted, and small numbers of promyelocytes or blasts may be seen. The platelet count is normal or reduced, and hypogranular platelets may be present.

The bone marrow is characteristically hypercellular but occasionally may be hypocellular. Erythroid hyperplasia is common, and signs of abnormal erythropoiesis include megaloblastic features, nuclear budding, or multinucleated erythroid precursors. The Prussian blue stain may demonstrate ringed sideroblasts. The myeloid series is often left shifted, with variable increases in blasts. Deficient or abnormal granules may be seen. A characteristic abnormality is the presence of dwarf megakaryocytes with a unilobed nucleus. Although no single specific chromosomal abnormality is seen in myelodysplasia, there are frequently abnormalities involving the long arm of chromosome 5 as well as deletions of chromosomes 5 and 7. Some patients with an indolent form of the disease have an isolated partial deletion of chromosome 5 (5q– syndrome). The presence of other abnormalities such as monosomy 7 or complex abnormalities is associated with more aggressive disease.

 Differential Diagnosis

Myelodysplastic syndromes should be distinguished from megaloblastic anemia, aplastic anemia, myelofibrosis, HIV-associated cytopenias, and acute or chronic drug effect. In subtle cases, cytogenetic evaluation of the bone marrow may help distinguish this clonal disorder from other causes of cytopenias. As the number of blasts increases in the bone marrow, myelodysplasia is arbitrarily separated from AML by the presence of < 20% blasts.

 Treatment

Myelodysplasia is a very heterogeneous disease, and the appropriate treatment depends on a number of factors. For patients with anemia who have a low serum EPO level (≤ 500 mU/mL), erythropoiesis-stimulating agents may raise the hematocrit and reduce the red cell transfusion requirement in 40%. Addition of intermittent granulocyte colony-stimulating factor (G-CSF) therapy may augment the erythroid response to epoetin. Unfortunately, the patients with the highest transfusion requirements are the least likely to respond. Patients who remain dependent on red blood cell transfusion and who do not have immediately life-threatening disease should receive iron chelation in order to prevent serious iron overload; the dose of oral agent deferasirox is 20 mg/kg/d. Patients affected primarily with severe neutropenia may benefit from the use of myeloid growth factors such as G-CSF. Oral thrombopoietin analogues such as romiplostim and eltrombopag that stimulate platelet production by binding the thrombopoietin receptor have shown effectiveness in raising the platelet count in myelodysplasia. Finally, occasional patients can benefit from immunosuppressive therapy including ATG. Predictors of response to ATG include age < 60 years, absence of 5q–, and presence of HLA DR15.

For patients who do not respond to these interventions, there are several therapeutic options available. Lenalidomide is approved for the treatment of transfusion-dependent anemia due to myelodysplasia. It is the treatment of choice in patients with the 5q– syndrome, with significant responses in 70% of patients, and with responses typically lasting longer than 2 years. In addition, nearly half of these patients enter a cytogenetic remission with clearing of the abnormal 5q– clone, leading to the hope that lenalidomide may change the natural history of the disease. The recommended initial dose is 10 mg/d orally. The most common side effects are neutropenia and thrombocytopenia, but venous thrombosis is also seen and warrants prophylaxis with aspirin, 325 mg/d orally. Azacitidine is the treatment of choice for patients with high-risk myelodysplasia and can improve both symptoms and blood counts and prolong both overall survival and the time to conversion to acute leukemia. It is used at a dose of 75 mg/m 2daily for 5–7 days every 28 days and it may require six cycles of therapy to achieve a response. Azacitidine combined with lenalidomide has shown preliminary promise in patients with high-risk disease. A related hypomethylating agent, decitabine, can produce similar hematologic responses but has not demonstrated a benefit in overall survival compared to supportive care alone. Allogeneic stem cell transplantation is the only curative therapy for myelodysplasia, but its role is limited by the advanced age of many patients and the indolent course of disease in some subsets of patients. The optimal use and timing of allogeneic transplantation are controversial, but the use of reduced-intensity preparative regimens for transplantation has expanded the role of this therapy, using both family and matched unrelated donors.

 Course & Prognosis

Myelodysplasia is an ultimately fatal disease, and allogeneic transplantation is the only curative therapy, with cure rates of 30–60% depending primarily on the risk status of the disease. Patients most commonly die of infections or bleeding. Patients with 5q– syndrome have a favorable prognosis, with 5-year survival over 90%. Other patients with low-risk disease (with absence of both excess blasts and adverse cytogenetics) may also do well, with similar survival. Those with excess blasts or CMML have a higher (30–50%) risk of developing acute leukemia, and short survival (< 2 years) without allogeneic transplantation.

 When to Refer

All patients with myelodysplasia should be referred to a hematologist.

 When to Admit

Hospitalization is needed only for specific complications, such as severe infection.

Fenaux P et al. How we treat lower-risk myelodysplastic syndromes. Blood. 2013 May 23;121(21):4280–6. [PMID: 23575446]

Foran JM et al. Clinical presentation, diagnosis, and prognosis of myelodysplastic syndromes. Am J Med. 2012 Jul;125(7 Suppl):S6–13. [PMID: 22735753]

Kröger N. Allogeneic stem cell transplantation for elderly patients with myelodysplastic syndrome. Blood. 2012 Jun 14;119(24):5632–9. [PMID: 22504927]

Lyons RM. Myelodysplastic syndromes: therapy and outlook. Am J Med. 2012 Jul;125(7 Suppl):S18–23. [PMID: 22735747]

ACUTE LEUKEMIA

 ESSENTIAL INQUIRIES

 Short duration of symptoms, including fatigue, fever, and bleeding.

 Cytopenias or pancytopenia.

 More than 20% blasts in the bone marrow.

 Blasts in peripheral blood in 90% of patients.

 General Considerations

Acute leukemia is a malignancy of the hematopoietic progenitor cell. These cells proliferate in an uncontrolled fashion and replace normal bone marrow elements. Most cases arise with no clear cause. However, radiation and some toxins (benzene) are leukemogenic. In addition, a number of chemotherapeutic agents (especially cyclophosphamide, melphalan, other alkylating agents, and etoposide) may cause leukemia. The leukemias seen after toxin or chemotherapy exposure often develop from a myelodysplastic prodrome and are often associated with abnormalities in chromosomes 5 and 7. Those related to etoposide may have abnormalities in chromosome 11q23 (MLL locus).

Acute promyelocytic leukemia (APL) is characterized by chromosomal translocation t(15;17), which produces the fusion gene PML-RAR-alpha which interacts with the retinoic acid receptor to produce a block in differentiation that can be overcome with pharmacologic doses of retinoic acid (see below).

Most of the clinical findings in acute leukemia are due to replacement of normal bone marrow elements by the malignant cells. Less common manifestations result from organ infiltration (skin, gastrointestinal tract, meninges). Acute leukemia is potentially curable with combination chemotherapy.

The lymphoblastic subtype of acute leukemia, ALL, comprises 80% of the acute leukemias of childhood. The peak incidence is between 3 and 7 years of age. It is also seen in adults, causing approximately 20% of adult acute leukemias. The myeloblastic subtype, AML, is primarily an adult disease with a median age at presentation of 60 years and an increasing incidence with advanced age.

 Classification of the Leukemias

  1. Acute Lymphoblastic Leukemia (ALL)

ALL is most usefully classified by immunologic phenotype as follows: common, early B lineage, and T cell. Hyperdiploidy (with more than 50 chromosomes), especially of chromosomes 4, 10 and 17, and translocation t(12;21) (TEL-AML1), is associated with a better prognosis. Unfavorable cytogenetics are hypodiploidy (less than 44 chromosomes), the Philadelphia chromosome t(9;22), the t(4;11) translocation, which has fusion genes involving the MLL gene at 11q23, and a complex karyotype with more than five chromosomal abnormalities.

  1. Acute Myeloid Leukemia (AML)

AML has been characterized in several ways. The World Health Organization (WHO) has sponsored a classification of the leukemias and other hematologic malignancies that incorporates cytogenetic, molecular, and immunophenotype information. The most important baseline prognostic factor is tumor genetics. This comprises cytogenetic abnormalities identified on traditional karyotyping or metaphase FISH and molecular abnormalities identified by either targeted or genome-wide sequencing of tumor DNA. Favorable cytogenetics such as t(8;21) producing a chimeric RUNX1/RUNX1T1 protein and inv(16)(p13;q22) are seen in 15% of cases and are termed the “core-binding factor” leukemias because of common genetic lesions affecting DNA-binding elements. These patients have a higher chance of achieving both short- and long-term disease control. Unfavorable cytogenetics confer a very poor prognosis. These consist of isolated monosomy 5 or 7, the presence of two or more monosomies, or three or more separate cytogenetic abnormalities. The majority of cases of AML are of intermediate risk by traditional cytogenetics and have either a normal karyotype or chromosomal abnormalities that do not confer strong prognostic significance. However, there are several recurrent genetic mutations with prognostic significance in this subgroup. On the one hand, internal tandem duplication in the gene FLT3occurs in ~30% of AML and is associated with a very poor prognosis. Other mutations conferring a poor prognosis occur in TET2MLL-PTD, and ASXL1. On the other hand, a relatively favorable group of patients has been defined that includes mutations of nucleophosmin 1 (NPM1) and lacks the internal tandem duplication of the FLT3 gene. Other mutations conferring a favorable prognosis occur in IDH1or IDH2.

  1. Acute Promyelocytic Leukemia (APL)

In considering the various types of AML, APL is discussed separately because of its unique biologic features and unique response to non-chemotherapy treatments. APL is characterized by the cytogenetic finding of t(15;17) and the fusion gene PML-RAR-alpha.

  1. Acute Leukemia of Ambiguous Lineage

These leukemias consist of blasts that lack differentiation along the lymphoid or myeloid lineage or blasts that express both myeloid and lymphoid lineage-specific antigens (ie, mixed phenotype acute leukemias). This group is considered very high risk and has a poor prognosis.

 Clinical Findings

  1. Symptoms and Signs

Most patients have been ill only for days or weeks. Bleeding (usually due to thrombocytopenia) occurs in the skin and mucosal surfaces, with gingival bleeding, epistaxis, or menorrhagia. Less commonly, widespread bleeding is seen in patients with disseminated intravascular coagulation (DIC) (in APL and monocytic leukemia). Infection is due to neutropenia, with the risk of infection rising as the neutrophil count falls below 500/mcL (0.5 × 10 9/L). The most common pathogens are gram-negative bacteria (Escherichia coli, Klebsiella, Pseudomonas) or fungi (Candida, Aspergillus). Common presentations include cellulitis, pneumonia, and perirectal infections; death within a few hours may occur if treatment with appropriate antibiotics is delayed.

Patients may also seek medical attention because of gum hypertrophy and bone and joint pain. The most dramatic presentation is hyperleukocytosis, in which a markedly elevated circulating blast count (total white blood count > 100,000/mcL) leads to impaired circulation, presenting as headache, confusion, and dyspnea. Such patients require emergent chemotherapy with adjunctive leukapheresis as mortality approaches 40% in the first 48 hours.

On examination, patients appear pale and have purpura and petechiae; signs of infection may not be present. Stomatitis and gum hypertrophy may be seen in patients with monocytic leukemia, as may rectal fissures. There is variable enlargement of the liver, spleen, and lymph nodes. Bone tenderness may be present, particularly in the sternum, tibia, and femur.

  1. Laboratory Findings

The hallmark of acute leukemia is the combination of pancytopenia with circulating blasts. However, blasts may be absent from the peripheral smear in as many as 10% of cases (“aleukemic leukemia”). The bone marrow is usually hypercellular and dominated by blasts. More than 20% marrow blasts are required to make a diagnosis of acute leukemia.

Hyperuricemia may be seen. If DIC is present, the fibrinogen level will be reduced, the prothrombin time prolonged, and fibrin degradation products or fibrin D-dimers present. Patients with ALL (especially T cell) may have a mediastinal mass visible on chest radiograph. Meningeal leukemia will have blasts present in the spinal fluid, seen in approximately 5% of cases at diagnosis; it is more common in monocytic types of AML and can be seen with ALL.

The Auer rod, an eosinophilic needle-like inclusion in the cytoplasm, is pathognomonic of AML and, if seen, secures the diagnosis. The phenotype of leukemia cells is usually demonstrated by flow cytometry or immunohistochemistry. AML cells usually express myeloid antigens such as CD 13 or CD 33 and myeloperoxidase. ALL cells of B lineage will express CD19, common to all B cells, and most cases will express CD10, formerly known as the “common ALL antigen.” ALL cells of T lineage will usually not express mature T-cell markers, such as CD 3, 4, or 8, but will express some combination of CD 2, 5, and 7 and do not express surface immunoglobulin. Almost all ALL cells express terminal deoxynucleotidyl transferase (TdT). The uncommon Burkitt type of ALL has a “lymphoma” phenotype, expressing CD19, CD20, and surface immunoglobulin but not TdT and is best treated with aggressive lymphoma regimens.

 Differential Diagnosis

AML must be distinguished from other myeloproliferative disorders, CML, and myelodysplastic syndromes. Acute leukemia may also resemble a left-shifted bone marrow recovering from a previous toxic insult. If the diagnosis is in doubt, a bone marrow study should be repeated in several days to see if maturation has taken place. ALL must be separated from other lymphoproliferative disease such as CLL, lymphomas, and hairy cell leukemia. It may also be confused with the atypical lymphocytosis of mononucleosis and pertussis.

 Treatment

Most patients up to age 60 with acute leukemia are treated with the objective of cure. The first step in treatment is to obtain complete remission, defined as normal peripheral blood with resolution of cytopenias, normal bone marrow with no excess blasts, and normal clinical status. The type of initial chemotherapy depends on the subtype of leukemia.

  1. AML—Most patients with AML are treated with a combination of an anthracycline (daunorubicin or idarubicin) plus cytarabine, either alone or in combination with other agents. This therapy will produce complete remissions in 80–90% of patients under age 60 years and in 50–60% of older patients (seeTable 39–5). Older patients with AML who are not candidates for traditional chemotherapy may be given 5-azacitidine or decitabine initially with acceptable outcomes. APL is treated differently from other forms of AML. Induction therapy for APL should include all-trans-retinoic acid (ATRA) with or without arsenic trioxide with or without chemotherapy. With this approach 90–95% of patients will achieve complete remission.

Once a patient has entered remission, post-remission therapy should be given with curative intent whenever possible. Options include standard chemotherapy and stem cell transplantation (either autologous or allogeneic). The optimal treatment strategy depends on the patient’s age and clinical status, and the risk factor profile of the leukemia. With the use of all-trans retinoic acid and arsenic trioxide with or without chemotherapy, 90% of patients with APL remain in long-term remission. Patients with a favorable genetic profile can be treated with chemotherapy alone or with autologous transplant with cure rates of 60–80%. Patients who do not enter remission (primary induction failure) or those with high-risk genetics have cure rates of less than 10% with chemotherapy alone and are referred for allogeneic stem cell transplantation. For intermediate-risk patients with AML, cure rates are 35–40% with chemotherapy, 40–50% with autologous transplantation, and 50–60% with allogeneic transplantation. Targeted therapeutics with FLT3 inhibitors are in development and have preliminarily shown activity in patients with FLT3-positive AML. Patients over age 60 have had a poor prognosis, even in first remission, when treated with standard chemotherapy approaches, and only 10–20% become long-term survivors. The use of reduced-intensity allogeneic transplant appears to be improving the outcome for such patients, with initial studies suggesting that up to 40% of selected patients may be cured.

Once leukemia has recurred after initial chemotherapy, the prognosis is poor. For patients in second remission, transplantation (autologous or allogeneic) offers a 20–30% chance of cure. For those patients with APL who relapse, arsenic trioxide can produce second remissions in 90% of cases.

  1. ALL—Adults with ALL are treated with combination chemotherapy, including daunorubicin, vincristine, prednisone, and asparaginase. This treatment produces complete remissions in 90% of patients. Those patients with Philadelphia chromosome-positive ALL (orbcr-ablpositive ALL) should have a tyrosine kinase inhibitor, such as dasatinib, added to their initial chemotherapy. Older patients (over age 60) may be treated with a tyrosine kinase inhibitor–based regimen, and 90% can enter initial remission.

Remission induction therapy for ALL is less myelosuppressive than treatment for AML and does not necessarily produce marrow aplasia. After achieving complete remission, patients receive central nervous system prophylaxis so that meningeal sequestration of leukemic cells does not develop. As with AML, patients may be treated with either additional cycles of chemotherapy or high-dose chemotherapy and stem cell transplantation. Treatment decisions are made based on patient age and risk factors of the disease. Adults younger than 39 years have uniformly better outcomes when treated under pediatric protocols. Low-risk patients with ALL may be treated with chemotherapy alone with a 70% chance of cure. Intermediate-risk patients have a 30–50% chance of cure with chemotherapy, and high-risk patients are rarely cured with chemotherapy alone. High-risk patients with adverse cytogenetics or poor responses to chemotherapy are best treated with allogeneic transplantation. Minimal residual disease testing may help guide treatment decisions following induction therapy in the future.

 Prognosis

Approximately 70–80% of adults with AML under age 60 years achieve complete remission and ~50% are cured using risk-adapted post-remission therapy. Older adults with AML achieve complete remission in up to 50% of instances. The cure rates for older patients with AML have been very low (approximately 10–20%) even if they achieve remission and are able to receive post-remission chemotherapy. The use of reduced-intensity allogeneic transplantation is being explored in order to improve on these outcomes.

 When to Refer

All patients should be referred to a hematologist.

 When to Admit

Most patients with acute leukemia will be admitted for treatment.

Bassan R et al. Modern therapy of acute lymphoblastic leukemia. J Clin Oncol. 2011 Feb 10;29(5):532–43. [PMID: 21220592]

Fernandez HF. New trends in the standard of care for initial therapy of acute myeloid leukemia. Hematology Am Soc Hematol Educ Program. 2010;2010:56–61. [PMID: 21239771]

Gupta V et al. Allogeneic hematopoietic cell transplantation for adults with acute myeloid leukemia: myths, controversies, and unknowns. Blood. 2011 Feb 24;117(8):2307–18. [PMID: 21098397]

Lo-Coco F et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111–21. [PMID: 23841729]

Patel JP et al. How do novel molecular genetic markers influence treatment decisions in acute myeloid leukemia? Hematology Am Soc Hematol Educ Program. 2012;2012:28–34. [PMID: 23233557]

Peyrade F et al. Treatment decisions for elderly patients with haematological malignancies: a dilemma. Lancet Oncol. 2012 Aug;13(8):e344–52. [PMID: 22846839]

CHRONIC LYMPHOCYTIC LEUKEMIA

 ESSENTIAL INQUIRIES

 B-cell lymphocytosis > 5000/mcL.

 Coexpression of CD19, CD5 on lymphocytes.

 General Considerations

CLL is a clonal malignancy of B lymphocytes. The disease is usually indolent, with slowly progressive accumulation of long-lived small lymphocytes. These cells are immune-incompetent and respond poorly to antigenic stimulation.

CLL is manifested clinically by immunosuppression, bone marrow failure, and organ infiltration with lymphocytes. Immunodeficiency is also related to inadequate antibody production by the abnormal B cells. With advanced disease, CLL may cause damage by direct tissue infiltration.

Information about CLL is evolving rapidly, with new findings in biology and new treatment options, and outcomes are improving significantly.

 Clinical Findings

  1. Symptoms and Signs

CLL is a disease of older patients, with 90% of cases occurring after age 50 years and a median age at presentation of 70 years. Many patients will be incidentally discovered to have lymphocytosis. Others present with fatigue or lymphadenopathy. On examination, 80% of patients will have lymphadenopathy and 50% will have enlargement of the liver or spleen.

The long-standing Rai classification system remains prognostically useful: stage 0, lymphocytosis only; stage I, lymphocytosis plus lymphadenopathy; stage II, organomegaly (spleen, liver); stage III, anemia; stage IV, thrombocytopenia. These stages can be collapsed in to low-risk (stages 0–I), intermediate risk (stage II) and high-risk (stages III–IV).

CLL usually pursues an indolent course, but some subtypes behave more aggressively; a variant, prolymphocytic leukemia, is more aggressive. The morphology of the latter is different, characterized by larger and more immature cells. In 5–10% of cases, CLL may be complicated by autoimmune hemolytic anemia or autoimmune thrombocytopenia. In approximately 5% of cases, while the systemic disease remains stable, an isolated lymph node transforms into an aggressive large cell lymphoma (Richter syndrome).

  1. Laboratory Findings

The hallmark of CLL is isolated lymphocytosis. The white blood count is usually > 20,000/mcL (20 × 10 9/L) and may be markedly elevated to several hundred thousand. Usually 75–98% of the circulating cells are lymphocytes. Lymphocytes appear small and mature, with condensed nuclear chromatin, and are morphologically indistinguishable from normal small lymphocytes, but smaller numbers of larger and activated lymphocytes may be seen. The hematocrit and platelet count are usually normal at presentation. The bone marrow is variably infiltrated with small lymphocytes. The immunophenotype of CLL demonstrates coexpression of the B lymphocyte lineage marker CD19 with the T lymphocyte marker CD5; this finding is commonly observed only in CLL and mantle cell lymphoma. CLL is distinguished from mantle cell lymphoma by the expression of CD23, low expression of surface immunoglobulin and CD20, and the absence of a translocation or overexpression of cyclin D1. Patients whose CLL cells have mutated forms of the immunoglobulin gene (IgVH somatic mutation) have a more indolent form of disease; these cells typically express low levels of the surface antigen CD38 and do not express the zeta-associated protein (ZAP-70). Conversely, patients whose cells have unmutated IgVH genes and high levels of ZAP-70 expression do less well and require treatment sooner. The assessment of genomic changes by fluorescence in-situ hybridization (FISH) provides important prognostic information. The finding of deletion of chromosome 17p (TP53) confers the worst prognosis, while deletion of 11q (ATM) confers an inferior prognosis to the average genotype, and isolated deletion of 13q has a more favorable outcome.

Hypogammaglobulinemia is present in 50% of patients and becomes more common with advanced disease. In some, a small amount of IgM paraprotein is present in the serum.

 Differential Diagnosis

Few syndromes can be confused with CLL. Viral infections producing lymphocytosis should be obvious from the presence of fever and other clinical findings; however, fever may occur in CLL from concomitant bacterial infection. Pertussis may cause a particularly high total lymphocyte count. Other lymphoproliferative diseases such as Waldenström macroglobulinemia, hairy cell leukemia, or lymphoma (especially mantle cell) in the leukemic phase are distinguished on the basis of the morphology and immunophenotype of circulating lymphocytes and bone marrow. Monoclonal B-cell lymphocytosis is a disorder characterized by < 5000/mcL B-cells and is considered a precursor to B-CLL.

 Treatment

Most cases of early indolent CLL require no specific therapy, and the standard of care for early stage disease has been observation. Indications for treatment include progressive fatigue, symptomatic lymphadenopathy, anemia, or thrombocytopenia. These patients have either symptomatic and progressive Rai stage II disease or stage III/IV disease. The initial treatment of choice for patients younger than 70 years old without significant comorbidities is the combination of fludarabine plus rituximab, with or without the addition of cyclophosphamide (see Table 39–15). The addition of cyclophosphamide appears to have greater antileukemic effectiveness, especially in patients with deletions of 11q, but also increases the risk of treatment-related infection. The combination of bendamustine with rituximab is another reasonable choice of therapy in this patient population. This combination has shown activity as the front-line therapy (88% overall response rate) and as treatment for relapsed setting (59% overall response rate), including for patients who had previously not responded to treatment with fludarabine.

For older or frail patients, chlorambucil, 0.6–1 mg/kg, a well-tolerated agent given orally every 3 weeks for approximately 6 months, has been the standard therapy. The novel monoclonal antibody, obinutuzumab, in combination with chlorambucil produces a significant number of responses (75%) including elimination of disease at the molecular level (in 17%) and offers another well-tolerated choice in this patient population. The oral agent ibrutinib, an inhibitor of Bruton’s tyrosine kinase, a key component in the B-cell receptor signaling pathway, has shown very high activity in patients with relapsed/refractory CLL and in those with deletion of 17p. As a single agent, it produces a 75% response rate with significant reduction in lymphadenopathy but initial therapy can be associated with marked lymphocytosis due to release of tumor cells from the lymph nodes into the peripheral blood. In patients with 17p deletion, the median duration of response can exceed 2 years, which is considered a breakthrough in this disease. Last, lenalidomide has been shown to be effective in refractory cases of CLL. However, this agent can induce a “flare” reaction with marked swelling of involved lymph nodes that appears to be caused by an infiltration of reactive T cells.

Associated autoimmune hemolytic anemia or immune thrombocytopenia may require treatment with rituximab, prednisone, or splenectomy. Fludarabine should be avoided in patients with autoimmune hemolytic anemia since it may exacerbate it, and rituximab, in patients with past HBV infection since HBV reactivation, fulminant, and rarely, death can occur. Patients with recurrent bacterial infections and hypogammaglobulinemia benefit from prophylactic infusions of gamma globulin (0.4 g/kg/month), but this treatment is very expensive and can be justified only when these infections are severe. Patients undergoing therapy with a nucleoside analogue (fludarabine, pentostatin) should receive anti-infective prophylaxis for Pneumocystis jirovecii pneumonia, herpes viruses, and invasive fungal infections until there is evidence of T-cell recovery.

Allogeneic transplantation offers potentially curative treatment for patients with CLL, but it should be used only in patients whose disease cannot be controlled by standard therapies. Nonmyeloablative allogeneic transplant has produced encouraging results in CLL. Some subtypes of CLL with genomic abnormalities such as 17p deletions have a sufficiently poor prognosis with standard therapies that early intervention with allogeneic transplant is being studied to assess whether it can improve outcomes.

 Prognosis

Therapies have changed the prognosis of CLL. In the past, median survival was approximately 6 years, and only 25% of patients lived more than 10 years. Patients with stage 0 or stage I disease have a median survival of 10–15 years, and these patients may be reassured that they can live a normal life for many years. Patients with stage III or stage IV disease had a median survival of < 2 years in the past, but with fludarabine-based combination therapies, 2-year survival is now > 90% and the long-term outlook appears to be substantially changed. For patients with high-risk and resistant forms of CLL, there is evidence that allogeneic transplantation can overcome risk factors and lead to long-term disease control.

 When to Refer

All patients with CLL should be referred to a hematologist.

 When to Admit

Hospitalization is rarely needed.

Byrd JC et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013 Jul 4;369(1):32–42. [PMID: 23782158]

Dreger P et al. Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL 3XX trial. Blood. 2010 Oct 7;116(14):2438–47. [PMID: 20595516]

Hallek M et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Center Institute-Working Group 1996 guidelines. Blood. 2008 Jun 15;111(12):5446–56. [PMID: 18216293]

Morrison VA. Infectious complications in patients with chronic lymphocytic leukemia: pathogenesis, spectrum of infection, and approaches to prophylaxis. Clin Lymphoma Myeloma. 2009 Oct;9(5):365–70. [PMID: 19858055]

HAIRY CELL LEUKEMIA

 ESSENTIAL INQUIRIES

 Pancytopenia.

 Splenomegaly, often massive.

 Hairy cells present on blood smear and especially in bone marrow biopsy.

 General Considerations

Hairy cell leukemia is a rare malignancy of hematopoietic stem cells differentiated as mature B-lymphocytes with hairy cytoplasmic projections.

 Clinical Findings

  1. Symptoms and Signs

The disease characteristically presents in middle-aged men. The median age at presentation is 55 years, and there is a striking 5:1 male predominance. Most patients present with gradual onset of fatigue, others complain of symptoms related to markedly enlarged spleen, and some come to attention because of infection.

Splenomegaly is almost invariably present and may be massive. The liver is enlarged in 50% of cases; lymphadenopathy is uncommon.

Hairy cell leukemia is usually an indolent disorder whose course is dominated by pancytopenia and recurrent infections, including mycobacterial infections.

  1. Laboratory Findings

The hallmark of hairy cell leukemia is pancytopenia. Anemia is nearly universal, and 75% of patients have thrombocytopenia and neutropenia. The “hairy cells” are usually present in small numbers on the peripheral blood smear and have a characteristic appearance with numerous cytoplasmic projections. The bone marrow is usually inaspirable (dry tap), and the diagnosis is made by characteristic morphology on bone marrow biopsy. The hairy cells have a characteristic histochemical staining pattern with tartrate-resistant acid phosphatase (TRAP). On immunophenotyping, the cells coexpress the antigens CD11c, CD20, CD22, CD25, CD103, and CD123. Pathologic examination of the spleen shows marked infiltration of the red pulp with hairy cells. This is in contrast to the usual predilection of lymphomas to involve the white pulp of the spleen. The identification of BRAF V600E mutation by sequencing hairy cells from affected patients offers a new diagnostic tool and potential treatment target.

 Differential Diagnosis

Hairy cell leukemia should be distinguished from other lymphoproliferative diseases such as Waldenström macroglobulinemia and non-Hodgkin lymphomas. It also may be confused with other causes of pancytopenia, including hypersplenism due to any cause, aplastic anemia, and paroxysmal nocturnal hemoglobinuria.

 Treatment

The treatment of choice is intravenous cladribine (2-chlorodeoxyadenosine; CdA), 0.1 mg/kg daily for 7 days. This is a relatively nontoxic drug that produces benefit in 95% of cases and complete remission in more than 80%. Responses are long lasting, with few patients relapsing in the first few years. Treatment with intravenous pentostatin produces similar results, but that drug is more cumbersome to administer. Rituximab is sometimes given for minimal residual disease after cladribine or pentostatin.

 Course & Prognosis

The development of new therapies has changed the prognosis of this disease. Formerly, median survival was 6 years, and only one-third of patients survived longer than 10 years. More than 95% of patients with hairy cell leukemia now live longer than 10 years.

Cawley JC et al. The biology of hairy-cell leukaemia. Curr Opin Hematol. 2010 Jul;17(4):341–9. [PMID: 20375887]

Ravandi F. Chemo-immunotherapy for hairy cell leukemia. Leuk Lymphoma. 2011 Jun;52(Suppl 2):72–4. [PMID: 21417822]

Tiacci E et al. BRAF mutations in hairy-cell leukemia. N Engl J Med. 2011 Jun 16;364(24):2305–15. [PMID: 21663470]

LYMPHOMAS

NON-HODGKIN LYMPHOMAS

 ESSENTIAL INQUIRIES

 Often present with painless lymphadenopathy.

 Pathologic diagnosis of lymphoma is made by pathologic examination of tissue.

 General Considerations

The non-Hodgkin lymphomas are a heterogeneous group of cancers of lymphocytes usually presenting as enlarged lymph nodes. The disorders vary in clinical presentation and course from indolent to rapidly progressive.

Molecular biology has provided clues to the pathogenesis of these disorders, often a matter of balanced chromosomal translocations whereby an oncogene becomes juxtaposed next to either an immunoglobulin gene (B-cell lymphoma) or the T-cell receptor gene or related gene (T-cell lymphoma). The net result is oncogene overexpression and the development of lymphoma. The best-studied example is Burkitt lymphoma, in which a characteristic cytogenetic abnormality of translocation between the long arms of chromosomes 8 and 14 has been identified. The protooncogene c-myc is translocated from its normal position on chromosome 8 to the immunoglobulin heavy chain locus on chromosome 14. Overexpression of c-myc is related to malignant transformation through excess B-cell proliferation. In the follicular lymphomas, the t(14;18) translocation is characteristic and bcl-2 is overexpressed, resulting in protection against apoptosis, the usual mechanism of B-cell death.

Classification of the lymphomas is a dynamic area still undergoing evolution. The most recent grouping (Table 13–16) separates diseases based on both clinical and pathologic features. Eighty-five percent of non-Hodgkin lymphomas are B-cell and 15% are T-cell or NK-cell in origin. Even though non-Hodgkin lymphomas represent a very diverse group of diseases, they are historically divided in two categories based on clinical behavior and pathology: the indolent (low-grade) and the aggressive (intermediate or higher-grade).

Table 13–16. World Health Organization classification of non-Hodgkin lymphomas (most common).

 Clinical Findings

  1. Symptoms and Signs

Patients with non-Hodgkin lymphomas usually present with lymphadenopathy, which may be isolated or widespread. Involved lymph nodes may be present peripherally or centrally (in the retroperitoneum, mesentery, and pelvis). The indolent lymphomas are usually disseminated at the time of diagnosis, and bone marrow involvement is frequent. Many patients with lymphoma have constitutional symptoms such as fever, drenching night sweats, and weight loss of >10% of prior body weight (referred to as “B” symptoms).

On examination, lymphadenopathy may be isolated or diffuse, and extranodal sites of disease (such as the skin, gastrointestinal tract, liver, and bone marrow) may be found. Patients with Burkitt lymphoma are noted to have abdominal pain or abdominal fullness because of the predilection of the disease for the abdomen.

Once a pathologic diagnosis is established, staging is done using a whole body PET/CT scan, a bone marrow biopsy and, in patients with high-grade lymphoma or intermediate-grade lymphoma with high-risk features, a lumbar puncture.

  1. Laboratory Findings

The peripheral blood is usually normal even with extensive bone marrow involvement by lymphoma. Circulating lymphoma cells in the blood are not commonly seen.

Bone marrow involvement is manifested as paratrabecular monoclonal lymphoid aggregates. In some high-grade lymphomas, the meninges are involved and malignant cells are found with cerebrospinal fluid cytology. The serum LD has been shown to be a useful prognostic marker and is now incorporated in risk stratification of treatment.

The diagnosis of lymphoma is made by tissue biopsy. Needle aspiration may yield evidence for non-Hodgkin lymphoma, but a lymph node biopsy (or biopsy of involved extranodal tissue) is required for accurate diagnosis and classification.

 Treatment

  1. Indolent Lymphomas

The most common lymphomas in this group are follicular lymphoma, marginal zone lymphomas, and small lymphocytic lymphoma (CLL). The treatment of indolent lymphomas depends on the stage of disease and the clinical status of the patient. A small number of patients have limited disease with only one or two contiguous abnormal lymph node groups and may be treated with localized irradiation with curative intent. However, most patients (85%) with indolent lymphoma have disseminated disease at the time of diagnosis and are not considered curable. Historically, treatment of these patients has not affected overall survival; therefore, treatment is only offered when symptoms develop or for high tumor bulk. Following each treatment response, patients will experience a relapse at traditionally shorter intervals. Some patients will have temporary spontaneous remissions. There are an increasing number of reasonable treatment options for indolent lymphomas, but no consensus has emerged on the best strategy. Treatment with rituximab (375 mg/m 2 intravenously weekly for 4 weeks) is commonly used either alone or in combination with chemotherapy and may be the only agent to affect overall survival in these disorders. Patients should be screened for hepatitis B because rare cases of fatal fulminant hepatitis have been described with the use of anti-CD20 monoclonal therapies. Common rituximab-chemotherapy regimens include bendamustine; cyclophosphamide, vincristine, and prednisone (R-CVP); and cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) (see Table 39–12). Radioimmunoconjugates that fuse anti-B cell monoclonal antibodies with radioactive nuclides produce higher response rates compared to antibody alone, and two such agents (yttrium-90 ibritumomab tiuxetan and iodine-131 tositumomab) are in use. Some patients with clinically aggressive low-grade lymphomas may be appropriate candidates for allogeneic stem cell transplantation with curative intent. The role of autologous hematopoietic stem cell transplantation remains uncertain, but some patients with recurrent disease appear to have prolonged remissions without the expectation of cure.

Patients with mucosal associated lymphoid tumors of the stomach may be appropriately treated with combination antibiotics directed against Helicobacter pylori and with acid blockade but require frequent endoscopic monitoring. Alternatively, MALT confined to the stomach can also be cured with whole-stomach radiotherapy.

  1. Aggressive Lymphomas

Patients with diffuse large B-cell lymphoma are treated with curative intent. Those with localized disease may receive short-course immunochemotherapy (such as three courses of R-CHOP) plus localized involved-field radiation or six cycles of immunochemotherapy without radiation. Most patients who have more advanced disease are treated with six cycles of immunochemotherapy such as R-CHOP (seeTable 39–12). Patients with diffuse large B-cell lymphoma who relapse after initial chemotherapy can still be cured by autologous hematopoietic stem cell transplantation if their disease remains responsive to chemotherapy.

Mantle cell lymphoma is not effectively treated with standard immunochemotherapy regimens. Intensive initial immunochemotherapy including autologous hematopoietic stem cell transplantation has been shown to improve outcomes. Reduced-intensity allogeneic stem cell transplantation offers curative potential for selected patients. Ibrutinib is active in relapsed or refractory patients with mantle cell lymphoma. For primary central nervous system lymphoma, repetitive cycles of high-dose intravenous methotrexate with rituximab early in the treatment course produce better results than whole brain radiotherapy and with less cognitive impairment.

Patients with high-grade lymphomas (Burkitt or lymphoblastic) require urgent, intense, cyclic chemotherapy in the hospital similar to that given for ALL, and they also require intrathecal chemotherapy as central nervous system prophylaxis.

Patients with peripheral T-cell lymphomas usually have advanced stage nodal and extranodal disease and typically have inferior response rates to therapy compared to patients with aggressive B-cell disease. Autologous stem cell transplantation is often incorporated in first-line therapy. The antibody-drug conjugate brentuximab vedotin has significant activity in patients with relapsed CD30 positive peripheral T-cell lymphomas, such as anaplastic large cell lymphoma.

 Prognosis

The median survival of patients with indolent lymphomas is 10–15 years. These diseases ultimately become refractory to chemotherapy. This often occurs at the time of histologic progression of the disease to a more aggressive form of lymphoma.

The International Prognostic Index is widely used to categorize patients with aggressive lymphoma into risk groups. Factors that confer adverse prognosis are age over 60 years, elevated serum LD, stage III or stage IV disease, more than one extranodal site of disease, and poor performance status. Cure rates range from > 80% for low-risk patients (zero risk factors) to < 50% for high-risk patients (four or more risk factors).

For patients who relapse after initial chemotherapy, the prognosis depends on whether the lymphoma is still responsive to chemotherapy. If the lymphoma remains responsive to chemotherapy, autologous hematopoietic stem cell transplantation offers a 50% chance of long-term lymphoma-free survival.

The treatment of older patients with lymphoma has been difficult because of poorer tolerance of aggressive chemotherapy. The use of myeloid growth factors and prophylactic antibiotics to reduce neutropenic complications may improve outcomes.

Molecular profiling techniques using gene array technology and immunophenotyping have defined subsets of lymphomas with different biologic features and prognoses are being studied in clinical trials to determine choice of therapy.

 When to Refer

All patients with lymphoma should be referred to a hematologist or an oncologist.

 When to Admit

Admission is necessary only for specific complications of lymphoma or its treatment and for the treatment of all high-grade lymphomas.

Foss FM et al. Peripheral T-cell lymphoma. Blood. 2011 Jun 23;117(25):6756–67. [PMID: 21493798]

Pérez-Galán P et al. Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era. Blood. 2011 Jan 6;117(1):26–38. [PMID: 20940415]

Shankland KR et al. Non-Hodgkin lymphoma. Lancet. 2012 Sep 1;380(9844):848–57. [PMID: 22835603]

Vidal L et al. Immunotherapy for patients with follicular lymphoma: the contribution of systematic reviews. Acta Haematol. 2011;125(1–2):23–31. [PMID: 21150184]

HODGKIN LYMPHOMA

 ESSENTIAL INQUIRIES

 Often painless lymphadenopathy.

 Constitutional symptoms may or may not be present.

 Pathologic diagnosis by lymph node biopsy.

 General Considerations

Hodgkin lymphoma is characterized by Reed–Sternberg cells in an appropriate reactive cellular background. The malignant cell is derived from B lymphocytes of germinal center origin.

 Clinical Findings

There is a bimodal age distribution, with one peak in the 20s and a second over age 50 years. Most patients seek medical attention because of a painless mass, commonly in the neck. Others may seek medical attention because of constitutional symptoms such as fever, weight loss, or drenching night sweats, or because of generalized pruritus. An unusual symptom of Hodgkin lymphoma is pain in an involved lymph node following alcohol ingestion.

An important feature of Hodgkin lymphoma is its tendency to arise within single lymph node areas and spread in an orderly fashion to contiguous areas of lymph nodes. Late in the course of the disease, vascular invasion leads to widespread hematogenous dissemination.

Hodgkin lymphoma is divided into two subtypes: classic Hodgkin (nodular sclerosis, mixed cellularity, lymphocyte rich, and lymphocyte depleted) and non-classic Hodgkin (nodular lymphocyte predominant). Hodgkin lymphoma should be distinguished pathologically from other malignant lymphomas and may occasionally be confused with reactive lymph nodes seen in infectious mononucleosis, cat-scratch disease, or drug reactions (eg, phenytoin).

Patients undergo a staging evaluation to determine the extent of disease, including serum chemistries, whole body PET/CT scan, and bone marrow biopsy. The staging nomenclature (Ann Arbor) is as follows: stage I, one lymph node region involved; stage II, involvement of two or more lymph node regions on one side of the diaphragm; stage III, lymph node regions involved on both sides of the diaphragm; and stage IV, disseminated disease with extranodal involvement. Disease staging is further categorized as “A” if patients lack constitutional symptoms or as “B” if patients have 10% weight loss over 6 months, fever, or drenching night sweats (or some combination thereof).

 Treatment

Chemotherapy is the mainstay of treatment for Hodgkin lymphoma and ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) remains the standard first-line regimen. Even though others such as Stanford V or escalated BEACOPP may improve response rates and reduce the need for consolidative radiotherapy, they are usually associated with increased toxicity and lack a definitive overall survival advantage. Low-risk patients are those with stage I or II disease without bulky lymphadenopathy or evidence of systemic inflammation. They traditionally receive a combination of short course chemotherapy with involved-field radiotherapy or a full course of chemotherapy alone (see Table 39–12). However, ongoing studies are aiming to eliminate the radiotherapy or to abbreviate the chemotherapy in patients who achieve an interim negative PET/CT scan. High-risk patients are those with stage III or IV disease or with stage II disease and a large mediastinal or other bulky mass. These patients are treated with a full course of ABVD for six cycles. End-of-treatment PET/CT scan may identify patients with stage II bulky disease who can avoid traditional involved-field radiotherapy. Pulmonary toxicity can unfortunately occur following either chemotherapy (bleomycin) or radiation and should be treated aggressively in these patients, since it can lead to permanent fibrosis and death.

Classic Hodgkin lymphoma relapsing after initial treatment may be treatable with high-dose chemotherapy and autologous hematopoietic stem cell transplantation. This offers a 35–50% chance of cure when disease is still chemotherapy responsive. The antibody-drug conjugate brentuximab vedotin has shown impressive activity in patients relapsing after autologous stem cell transplantation (ORR: 75%; CR: 34%) and has been approved by the US Food and Drug Administration for this indication. It is now being studied in front-line therapy, replacing the bleomycin in ABVD.

 Prognosis

All patients should be treated with curative intent. Prognosis in advanced stage Hodgkin lymphoma is influenced by seven features: stage, age, gender, hemoglobin, albumin, white blood count, and lymphocyte count. The cure rate is 75% if zero to two risk features are present and 55% when three or more risk features are present. The prognosis of patients with stage IA or IIA disease is excellent, with 10-year survival rates in excess of 90%. Patients with advanced disease (stage III or IV) have 10-year survival rates of 50–60%. Poorer results are seen in patients who are older, those who have bulky disease, and those with lymphocyte depletion or mixed cellularity on histologic examination. Non-classic Hodgkin lymphoma (nodular lymphocyte predominant) is highly curable with radiotherapy alone for early-stage disease; however, for high-stage disease, it is characterized by long survival with repetitive relapses after chemotherapy.

 When to Refer

  • All patients should be sent to an oncologist or hematologist.
  • Secondary referral to a radiation oncologist might be appropriate.

 When to Admit

Patients should be admitted for complications of the disease or its treatment.

Engert A et al. Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med. 2010 Aug 12;363(7):640–52. [PMID: 20818855]

Meyer RM et al. ABVD alone versus radiation-based therapy in limited-stage Hodgkin’s lymphoma. N Engl J Med. 2012 Feb 2;366(5):399–408. [PMID: 22149921]

Meyer RM et al. Point/counterpoint: early-stage Hodgkin lymphoma and the role of radiation therapy. Blood. 2012 Nov 29;120(23):4488–95. [PMID: 22821764]

Viviani S et al. ABVD versus BEACOPP for Hodgkin’s lymphoma when high-dose salvage is planned. N Engl J Med. 2011 Jul 21;365(3):203–12. [PMID: 21774708]

Younes A et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med. 2010 Nov 4;363(19):1812–21. [PMID: 21047225]

MULTIPLE MYELOMA

 ESSENTIAL INQUIRIES

 Bone pain, often in the spine, ribs, or proximal long bones.

 Monoclonal paraprotein by serum or urine protein electrophoresis or immunofixation.

 Clonal plasma cells in the bone marrow or in a tissue biopsy, or both.

 Organ damage due to plasma cells (eg, bones, kidneys, hypercalcemia, anemia).

 General Considerations

Multiple myeloma is a malignancy of hematopoietic stem cells terminally differentiated as plasma cells characterized by replacement of the bone marrow, bone destruction, and paraprotein formation. The diagnosis is established when monoclonal plasma cells (either kappa or lambda light chain restricted) in the bone marrow (any percentage) or as a tumor (plasmacytoma), or both, are associated with end organ damage (such as bone disease [lytic lesions, osteopenia], anemia [hemoglobin < 10 g/dL {100 g/L}], hypercalcemia [calcium > 11.5 mg/dL {2.9 mmol/L}], or renal failure [creatinine > 2 mg/dL {176.8 mcmol/L}]) with or without paraprotein elaboration. Smoldering myeloma is defined as ≥ 10% clonal plasma cells in the bone marrow, a serum paraprotein level ≥ 3 g/dL (30 g/L), or both, without plasma cell–related end-organ damage.

Malignant plasma cells can form tumors (plasmacytomas) that may cause spinal cord compression or other soft-tissue problems. Bone disease is common and due to excessive osteoclast activation mediated largely by the interaction of the receptor activator of NF-kappa-B (RANK) with its ligand (RANKL). In multiple myeloma, osteoprotegerin (a decoy receptor for RANKL) is underproduced, thus promoting the binding of RANK with RANKL with consequent excessive bone resorption. Other soluble factors contributing to osteoclast hyperactivation include interleukin-1, interleukin-6, tissue necrosis factor-alpha, macrophage inhibitor protein-1-alpha, and macrophage colony stimulating factor, all of which might prove eventual therapeutic targets.

The paraproteins (monoclonal immunoglobulins) secreted by the malignant plasma cells may cause problems in their own right. Very high paraprotein levels (either IgG or IgA) may cause hyperviscosity, although this is more often common with the IgM in Waldenström macroglobulinemia. The light chain component of the immunoglobulin often leads to kidney failure (frequently aggravated by hypercalcemia or hyperuricemia, or both). Light chain components may be deposited in tissues as amyloid, resulting in kidney failure with albuminuria and a vast array of systemic symptoms.

Myeloma patients are prone to recurrent infections for a number of reasons, including neutropenia, the underproduction of normal immunoglobulins and the immunosuppressive effects of chemotherapy. Myeloma patients are especially prone to infections with encapsulated organisms such as Streptococcus pneumoniae and Haemophilus influenzae.

 Clinical Findings

  1. Symptoms and Signs

Myeloma is a disease of older adults (median age, 65 years). The most common presenting complaints are those related to anemia, bone pain, kidney disease, and infection. Bone pain is most common in the back, hips, or ribs or may present as a pathologic fracture, especially of the femoral neck or vertebrae. Patients may also come to medical attention because of spinal cord compression or the hyperviscosity syndrome (mucosal bleeding, vertigo, nausea, visual disturbances, alterations in mental status). Many patients are diagnosed because of laboratory findings of hypercalcemia, proteinuria, elevated sedimentation rate, or abnormalities on serum protein electrophoresis obtained for symptoms or in routine screening studies. A few patients come to medical attention because of organ dysfunction due to amyloidosis.

Examination may reveal pallor, bone tenderness, and soft tissue masses. Patients may have neurologic signs related to neuropathy or spinal cord compression. Patients with primary amyloidosis may have an enlarged tongue, peripheral or autonomic neuropathy, heart failure, or hepatomegaly. Splenomegaly is absent unless amyloidosis is present. Fever occurs mainly with infection. Acute oliguric or nonoliguric renal failure may be present due to hypercalcemia, hyperuricemia, light-chain cast injury, or primary amyloidosis.

  1. Laboratory Findings

Anemia is nearly universal. Red blood cell morphology is normal, but rouleaux formation is common and may be marked. The absence of rouleaux formation, however, excludes neither multiple myeloma nor the presence of a serum paraprotein. The neutrophil and platelet counts are usually normal at presentation. Only rarely will plasma cells be visible on peripheral blood smear (plasma cell leukemia).

The hallmark of myeloma is the finding of a paraprotein on serum or urine protein electrophoresis (PEP) or immunofixation electrophoresis (IFE). The majority of patients will have a monoclonal spike visible in the gamma- or beta-globulin region of the PEP. The semi-quantification of the paraprotein on the PEP is referred to as the M-protein, and IFE will reveal this to be a monoclonal immunoglobulin. Approximately 15% of patients will have no demonstrable paraprotein in the serum because their myeloma cells produce only light chains and not intact immunoglobulin, and the light chains pass rapidly through the glomerulus into the urine. Urine PEP and IFE will demonstrate the light chain paraprotein in this setting. The free light chain assay will sometimes demonstrate excess monoclonal light chains in serum and urine, and in a small proportion of patients, will be the only means to identify and quantify the paraprotein being produced. Overall, the paraprotein is IgG (60%), IgA (20%), or light chain only (15%) in multiple myeloma, with the remainder being rare cases of IgD, IgM, or biclonal gammopathy. In sporadic cases, no paraprotein is present (“nonsecretory myeloma”); these patients have particularly aggressive disease.

The bone marrow will be infiltrated by variable numbers of monoclonal plasma cells. The plasma cells may be morphologically abnormal often demonstrating multi-nucleation and vacuolization. The plasma cells will display marked skewing of the normal kappa to lambda light chain ratio, which will indicate their clonality. Many benign processes can result in bone marrow plasmacytosis, but the presence of atypical plasma cells, light chain restriction, and effacement of normal bone marrow elements helps distinguish myeloma.

  1. Imaging

Bone radiographs are important in establishing the diagnosis of myeloma. Lytic lesions are most commonly seen in the axial skeleton: skull, spine, proximal long bones, and ribs. At other times, only generalized osteoporosis is seen. The radionuclide bone scan is not useful in detecting bone lesions in myeloma, since there is usually no osteoblastic component. Magnetic resonance imaging (MRI) and positron emission tomography (PET) scans will demonstrate significantly more disease than is shown in plain radiographs, and these imaging studies are common practice in the evaluation of patients with known or suspected multiple myeloma.

 Differential Diagnosis

When a patient is discovered to have a paraprotein, the distinction between multiple myeloma or another lymphoproliferative malignancy with a paraprotein (CLL, Waldenström macroglobulinemia, non-Hodgkin lymphoma, primary amyloid, cryoglobulinemia) and monoclonal gammopathy of undetermined significance (MGUS) must be made. MGUS is present in 1% of all adults, (3% of those over age 50 years and more than 5% in those over age 70 years). Thus, among all patients with paraproteins, MGUS is far more common than multiple myeloma. MGUS is defined as bone marrow monoclonal plasma cells < 10% in the setting of a paraprotein (serum M-protein < 3 g/dL [ < 30 g/L]) and the absence of end-organ damage. In approximately one-quarter of cases, MGUS progresses to overt malignant disease in a median of one decade. The transformation of MGUS to multiple myeloma is approximately 1% per year. Smoldering multiple myeloma is defined as a serum M-protein > 3 g/dL (> 30 g/L) or bone marrow monoclonal plasma cells ≥ 10% in the absence of end-organ damage. Multiple myeloma, smoldering multiple myeloma, and MGUS must be distinguished from reactive (benign) polyclonal hypergammaglobulinemia (which is commonly seen in cirrhosis).

 Treatment

Patients with MGUS are observed without treatment. Patients with smoldering myeloma treated with lenalidomide and dexamethasone take longer to progress to symptomatic myeloma and live longer than when simply observed. Most patients with multiple myeloma require treatment at diagnosis because of bone pain or other symptoms and complications related to the disease. The initial treatment generally involves at a minimum an immunomodulatory drug, such as thalidomide or lenalidomide, in combination with moderate- or high-dose dexamethasone. The major side effects of lenalidomide are neutropenia and thrombocytopenia, venothromboembolism, and peripheral neuropathy. Bortezomib, a proteosome inhibitor, is also highly active and has the advantages of producing rapid responses and of being effective in poor-prognosis multiple myeloma. The major side effect of bortezomib is neuropathy (both peripheral and autonomic), which is largely ameliorated when given subcutaneously rather than intravenously. A common regimen for initial treatment is RVD (lenalidomide, bortezomib, and dexamethasone). The combination of bortezomib, dexamethasone, and liposomal doxorubicin is also effective. Carfilzomib, a second-generation proteosome inhibitor, produces responses in patients for whom bortezomib treatment fails and does not cause neuropathy.

After initial therapy, many patients under age 76 years are consolidated with autologous hematopoietic stem cell transplantation. Autologous hematopoietic stem cell transplantation prolongs both duration of remission and overall survival, and has the advantage of providing long treatment-free intervals. Lenalidomide or thalidomide prolong remission and survival when given as posttransplant maintenance therapy. There is emerging concern about an elevated rate of secondary malignancies associated with use of immunomodulatory drugs as maintenance therapy. Allogeneic stem cell transplantation is potentially curative in multiple myeloma, but its role has been limited because of the unusually high treatment-related mortality rate (40–50%) in myeloma patients.

Localized radiotherapy may be useful for palliation of bone pain or for eradicating tumor at the site of pathologic fracture. Vertebral collapse with its attendant pain and mechanical disturbance can be treated with vertebroplasty or kyphoplasty. Hypercalcemia and hyperuricemia should be treated aggressively and immobilization and dehydration avoided. The bisphosphonates (pamidronate 90 mg or zoledronic acid 4 mg intravenously monthly) reduce pathologic fractures in patients with bone disease and are an important adjunct in this subset of patients. The bisphosphonates are also used to treat malignant hypercalcemia. However, long-term bisphosphonates, especially zoledronic acid, have been associated with a risk of osteonecrosis of the jaw and other bony areas so treated patients must be monitored for this complication.

 Prognosis

The outlook for patients with myeloma has been steadily improving for the past decade. The median survival of patients is more than 5 years. Patients with low-stage disease who lack high-risk genomic changes respond very well to treatment and derive significant benefit from autologous hematopoietic stem cell transplantation and have survivals approaching a decade. The International Staging Systemfor myeloma relies on two factors: beta-2-microglobulin and albumin. Stage 1 patients have both beta-2-microglobulin < 3.5 mg/L and albumin > 3.5 g/dL (survival > 5 years). Stage 3 is established when beta-2-microglobulin > 5.5 mg/L (survival < 2 years). Stage 2 is established with values in between. The other laboratory finding of important adverse prognostic significance on a bone marrow sample is genetic abnormalities established by FISH involving the immunoglobulin heavy chain locus at chromosome 14q32 (such as the finding of t[4;14] or t[14;16]). Abnormalities of chromosome 17p also confer a particularly poor prognosis.

 When to Refer

All patients with multiple myeloma should be referred to a hematologist or an oncologist.

 When to Admit

Hospitalization is indicated for treatment of acute kidney failure, hypercalcemia, or suspicion of spinal cord compression, for certain chemotherapy regimens, or for hematopoietic stem cell transplantation.

Kyle RA et al. Management of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Oncology (Williston Park). 2011 Jun;25(7):578–86. [PMID: 21888255]

Longo V et al. Therapeutic approaches to myeloma bone disease: an evolving story. Cancer Treat Rev. 2012 Oct;38(6):787–97. [PMID: 22494965]

Mateos MV et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438–47. [PMID: 23902483]

McCarthy PL et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012 May10;366(19):1770–81. [PMID: 22571201]

Palumbo A et al. Multiple myeloma. N Engl J Med. 2011 Mar 17;364(11):1046–60. [PMID: 21410373]

Smith D et al. Multiple myeloma. BMJ. 2013 Jun 26;346:f3863. [PMID: 23803862]

Yaqub S et al. Frontline therapy for multiple myeloma: a concise review of the evidence based on randomized clinical trials. Cancer Invest. 2013 Oct;31(8):529–37. [PMID: 24083815]

WALDENSTRÖM MACROGLOBULINEMIA

 ESSENTIAL INQUIRIES

 Monoclonal IgM paraprotein.

 Infiltration of bone marrow by plasmacytic lymphocytes.

 Absence of lytic bone disease.

 General Considerations

Waldenström macroglobulinemia is a syndrome of IgM hypergammaglobulinemia that occurs in the setting of a low-grade non-Hodgkin lymphoma characterized by B-cells that are morphologically a hybrid of lymphocytes and plasma cells. These cells characteristically secrete the IgM paraprotein, and many clinical manifestations of the disease are related to this macroglobulin.

 Clinical Findings

  1. Symptoms and Signs

This disease characteristically develops insidiously in patients in their 60s or 70s. Patients usually present with fatigue related to anemia. Hyperviscosity of serum may be manifested in a number of ways. Mucosal and gastrointestinal bleeding is related to engorged blood vessels and platelet dysfunction. Other complaints include nausea, vertigo, and visual disturbances. Alterations in consciousness vary from mild lethargy to stupor and coma. The IgM paraprotein may also cause symptoms of cold agglutinin disease (hemolysis) or chronic demyelinating peripheral neuropathy.

On examination, there may be hepatosplenomegaly or lymphadenopathy. The retinal veins are engorged. Purpura may be present. There should be no bone tenderness.

  1. Laboratory Findings

Anemia is nearly universal, and rouleaux formation is common although the red blood cells are agglutinated when the blood smear is prepared at room temperature. The anemia is related in part to expansion of the plasma volume by 50–100% due to the presence of the paraprotein. Other blood counts are usually normal. The abnormal plasmacytic lymphocytes may appear in small numbers on the peripheral blood smear. The bone marrow is characteristically infiltrated by the plasmacytic lymphocytes.

The hallmark of macroglobulinemia is the presence of a monoclonal IgM spike seen on serum PEP in the beta-globulin region. The serum viscosity is usually increased above the normal of 1.4–1.8 times that of water. Symptoms of hyperviscosity usually develop when the serum viscosity is over four times that of water, and marked symptoms usually arise when the viscosity is over six times that of water. Because paraproteins vary in their physicochemical properties, there is no strict correlation between the concentration of paraprotein and serum viscosity.

The IgM paraprotein may cause a positive antiglobulin (Coombs) test for complement and have cold agglutinin or cryoglobulin properties. If macroglobulinemia is suspected but the serum PEP shows only hypogammaglobulinemia, the test should be repeated while taking special measures to maintain the blood at 37°C, since the paraprotein may precipitate out at room temperature. Bone radiographs are normal, and there is no evidence of kidney failure.

 Differential Diagnosis

Waldenström macroglobulinemia is differentiated from MGUS by the finding of bone marrow infiltration with monoclonal malignant cells. It is distinguished from CLL by bone marrow morphology, the absence of CD5 expression and the absence of lymphocytosis and from multiple myeloma by bone marrow morphology and the finding of the characteristic IgM paraprotein and the absence of bone disease.

 Treatment

Patients with marked hyperviscosity syndrome (stupor, coma, pulmonary edema) should be treated on an emergency basis with plasmapheresis. On a chronic basis, some patients can be managed with periodic plasmapheresis alone. As with other indolent malignant lymphoid diseases, rituximab (375 mg/m 2 intravenously weekly for 4–8 weeks) has significant activity. However, a word of caution: the IgM often rises first after rituximab therapy before it falls. Combination therapy is recommended for advanced disease (see Table 39–12). Bortezomib, thalidomide, lenalidomide, and bendamustine have all been shown to have activity in this disease. Autologous hematopoietic stem cell transplantation is reserved for relapsed or refractory patients.

 Prognosis

Waldenström macroglobulinemia is an indolent disease with a median survival rate of 5 years, and 10% of patients are alive at 15 years.

 When to Refer

All patients should be referred to a hematologist or an oncologist.

 When to Admit

Patients should be admitted for treatment of hyperviscosity syndrome.

Gertz MA. Waldenström macroglobulinemia: 2013 update on diagnosis, risk stratification, and management. Am J Hematol. 2013 Aug;88(8):703–11. [PMID: 23784973]

Stone MJ. Waldenström’s macroglobulinemia: hyperviscosity syndrome and cryoglobulinemia. Clin Lymphoma Myeloma. 2009 Mar;9(1):97–9. [PMID: 19362986]

Treon SP. How I treat Waldenström macroglobulinemia. Blood. 2009 Sep 17;114(12):2375–85. [PMID: 19617573]

PRIMARY AMYLOIDOSIS

 ESSENTIAL INQUIRIES

 Congo red positive amyloid protein on tissue biopsy.

 Amyloid protein is kappa or lambda immunoglobulin light chain.

 Serum or urine (or both) light chain paraprotein.

 General Considerations

Amyloidosis is an uncommon condition whereby a protein abnormally deposits in tissue resulting in organ dysfunction. The propensity of a protein to be amyloidogenic is a consequence of disturbed translational or posttranslational protein folding. The input of amyloid protein into tissues far exceeds its output, so amyloid build up inexorably proceeds to organ dysfunction and ultimately organ failure and premature death.

Amyloidosis is classified according to the type of amyloid protein deposited. The five main categories are primary (immunoglobulin light chain [AL]), secondary (serum protein A, produced in inflammatory conditions [AA]), hereditary (mutated transthyretin [TTR]; others), senile (wild-type TTR; atrial natriuretic peptide; others), and renal failure type (beta-2-microglobulin, not filtered out by dialysis membranes [Abeta-2M]). Amyloidosis is further classified as localized (amyloid deposits only in a single tissue type or organ) or, most common, systemic (widespread amyloid deposition).

 Clinical Findings

  1. Symptoms and Signs

Patients with localized amyloidosis have symptoms and signs related to the affected single organ, such as hoarseness (vocal cords) or proptosis and visual disturbance (orbits). Patients with systemic amyloidosis have symptoms and signs of unexplained medical syndromes, including heart failure (infiltrative/restrictive cardiomyopathy), nephrotic syndrome, malabsorption and weight loss, hepatic dysfunction, autonomic insufficiency, carpal tunnel syndrome (often bilateral), and sensorimotor peripheral neuropathy. Other symptoms and signs include an enlarged tongue; waxy, rough plaques on skin; contusions (including the periorbital areas); cough or dyspnea; and disturbed deglutition. These symptoms and signs arise insidiously, and the diagnosis of amyloidosis is generally made late in the disease process.

  1. Laboratory Findings

The diagnosis of amyloid protein requires a tissue biopsy that demonstrates deposition of a pink substance in the tissue with the H&E stain. This protein stains red with Congo Red and becomes an apple-green color when the light is polarized. Amyloid is a triple-stranded fibril composed of the amyloid protein, amyloid protein P, and glycosaminoglycan. The amyloid fibrils form beta-pleated sheets as demonstrated by electron microscopy. In primary amyloidosis, the amyloid protein is either the kappa or lambda immunoglobulin light chain.

When systemic amyloidosis is suspected, a blind aspiration of the abdominal fat pad will reveal amyloid two-thirds of the time. If the fat pad aspiration is unrevealing, then the affected organ needs biopsy. In 90% of patients with primary amyloidosis, analysis of the serum and urine will reveal a kappa or lambda light chain paraprotein by PEP, IFE, or free light chain assay; in the remainder, mass spectroscopy demonstrates light chain in the tissue biopsy. Lambda amyloid is more common than kappa amyloid, a relative proportion opposite from normal B-cell stoichiometry. Most patients with primary amyloidosis have a small excess of kappa or lambda restricted plasma cells in the bone marrow that may show interstitial amyloid deposition or amyloid in the blood vessels of the marrow.

Patients with primary cardiac amyloidosis have an infiltrative cardiomyopathy with thick ventricular walls on echocardiogram that sometimes shows a unique speckling pattern. Paradoxically, QRS voltages are low on ECG. With renal amyloid, albuminuria is present, which can be in the nephrotic range. Late in renal involvement, kidney function decreases.

 Differential Diagnosis

Primary amyloidosis must be distinguished from MGUS and multiple myeloma or other malignant lymphoproliferative disorders. Of note, 12% of patients with MGUS will convert to primary amyloidosis in a median of 9 years. One-fifth of patients who have primary amyloidosis will meet the diagnostic criteria for multiple myeloma; conversely, 5% of patients with multiple myeloma will have amyloid deposition of the paraprotein.

 Treatment

The treatment approach to primary amyloidosis closely resembles that of multiple myeloma. Prospective, randomized trials of multiple myeloma chemotherapy versus colchicine have demonstrated a survival benefit to chemotherapy. The concept is reduction of light chain production and a reduction of light chain deposition as a means to arrest progressive end-organ dysfunction. Active agents in primary amyloidosis include melphalan, dexamethasone, lenalidomide, and bortezomib (see Table 39–12). As in multiple myeloma, autologous hematopoietic stem cell transplantation after high-dose melphalan is used in patients with reasonable organ function and a good performance status. The treatment-related mortality, however, is higher in patients with primary amyloidosis than in myeloma (8% vs 1%). Some patients will demonstrate end-organ improvement after therapy. Agents are being developed that facilitate amyloid dissolution or correct protein folding abnormalities in the amyloid protein.

 Prognosis

Untreated primary amyloidosis is associated with progressive end-organ failure and premature death. There is no known cure for primary amyloidosis. Although virtually every tissue examined at autopsy will contain amyloid, patients with primary amyloidosis will have one or two primary organs failing that clinically drive the presentation and prognosis. The cardiac biomarkers, B-type natriuretic peptide (BNP) and n-terminal pro-BNP, and troponins T and I are prognostic in this disease regardless of overt clinical cardiac involvement. Historically, patients with predominantly cardiac or autonomic nerve presentations had survivals of 3–9 months, and those with carpal tunnel syndrome or nephrosis, 1.5–3 years, and those with peripheral neuropathy, 5 years. These survivals are roughly doubled with multiple myeloma-like treatment. In those patients able to undergo autologous hematopoietic stem cell transplantation, the median survival now approaches 5 years.

 When to Refer

  • All patients who have primary amyloidosis or in whom it is suspected should be referred to a hematologist or oncologist.
  • All patients with hereditary amyloidosis should be referred to a hepatologist for consideration of liver transplantation.

 When to Admit

  • Patients with systemic amyloidosis require hospitalization to treat exacerbations of end-organ failure, such as heart failure or liver failure.
  • Patients with primary amyloidosis require hospitalization to undergo autologous hematopoietic stem cell transplantation.

Gertz MA. Immunoglobulin light chain amyloidosis: 2013 update on diagnosis, prognosis, and treatment. Am J Hematol. 2013 May;88(5):416–25. [PMID: 23605846]

Kapoor P et al. Cardiac amyloidosis: a practical approach to diagnosis and management. Am J Med. 2011 Nov;124(11):1006–15. [PMID: 22017778]

Sanchorawala V. Role of high-dose melphalan and autologous peripheral blood stem cell transplantation in AL amyloidosis. Am J Blood Res. 2012;2(1):9–17. [PMID: 22432083]

STEM CELL TRANSPLANTATION

Stem cell transplantation using hematopoietic stem cells is an extremely valuable treatment for a variety of hematologic malignancies and is also used in a few non-hematologic cancers and some nonmalignant conditions. In many cases, stem cell transplantation offers the only curative option for some types of cancer and can be a life-saving procedure.

The basis of treatment with stem cell transplantation is the ability of the hematopoietic stem cell to completely restore bone marrow function and formation of all blood components, as well as the ability to re-form the immune system. These hematopoietic stem cells were formerly collected from the bone marrow but are now more commonly collected from the peripheral blood after maneuvers, usually involving the administration of filgrastim (G-CSF) to mobilize them from the bone marrow into the blood.

In the field of cancer chemotherapy, the dose-limiting toxicity of almost all chemotherapy has been myelosuppression from damage to the bone marrow. It is typical during the administration of chemotherapy for blood counts to be transiently suppressed and to have to wait for recovery of the blood in order to safely give the next treatment. However, if too high a dose of chemotherapy is given, it is possible to damage the bone marrow beyond recovery, and for the blood counts to never return to within normal ranges. For cancers for which there is a dose-response relationship, that is, a relationship between the dose of chemotherapy administered and the number of cancer cells killed, the limits placed on the allowable dose of chemotherapy can make the difference between cure and failure to cure. In stem cell transplantation, the limit placed on the allowable dose of chemotherapy by the risks of permanent bone marrow damage is eliminated and much higher doses of chemotherapy can be given, since reinfusion of hematopoietic stem cells can completely restore the bone marrow.

AUTOLOGOUS STEM CELL TRANSPLANTATION

Autologous stem cell transplantation is a treatment in which hematopoietic stem cells are collected from the patient and then re-infused after chemotherapy. Therefore, autologous stem cell transplantation relies solely for its effectiveness on the ability to give much higher doses of chemotherapy than would otherwise be possible. In this procedure, the hematopoietic stem cells are usually collected from the patient’s peripheral blood. First, the hematopoietic stem cells are mobilized from the bone marrow into the blood. This can be accomplished by a variety of techniques, most commonly the use of myeloid growth factors such as filgrastim either alone or in combination with chemotherapy. The CXCR4 antagonist plerixafor can help mobilize these cells into the blood. During the process of leukapheresis the patient’s blood is centrifuged into layers of different densities; the hematopoietic stem cells are collected from the appropriate layer while the remainder of the blood elements are returned unchanged to the patient. After collection, these autologous hematopoietic stem cells are frozen and cryopreserved for later use. Treatment with autologous stem cell transplantation involves administration of high-dose chemotherapy (referred to as the “preparative regimen”) followed, after clearance of the chemotherapy out of the patient’s system, by intravenous re-infusion of the thawed autologous hematopoietic stem cells. The hematopoietic stem cells home to the bone marrow and grow into new bone marrow cells.

With the autologous stem cell transplantation treatment, there is a period of severe pancytopenia during the gap between myelosuppression caused by the chemotherapy and the recovery produced from the new bone marrow derived from the infused hematopoietic stem cells. This period of pancytopenia typically lasts 7–10 days and requires support with transfusions of red blood cells and platelets as well as antibiotics. Hospitalization to receive such treatment usually lasts 2–3 weeks. The morbidity of such a treatment varies according to the type of chemotherapy used, and the chance of fatal treatment-related complications is between 1% and 4%.

Autologous stem cell transplantation has the potential to cure cancers that would otherwise be fatal and is the treatment of choice for lymphomas such as diffuse large B-cell lymphomas that have recurred after initial chemotherapy but are still responsive to chemotherapy. It is similarly also the treatment of choice for relapsed Hodgkin lymphoma that still responds to chemotherapy, and for testicular germ cell cancers that have recurred. Based on the aggressive clinical course of peripheral T-cell lymphomas, autologous stem cell transplantation is often used following chemotherapy as front-line therapy. Autologous stem cell transplantation also plays an important role in the treatment of AML in both first and second remission and is potentially curative in these settings. Autologous stem cell transplantation is currently part of the standard of care for the treatment of mantle cell lymphoma and multiple myeloma, based not on curative potential, but the prolongation of remission and overall survival.

ALLOGENEIC STEM CELL TRANSPLANTATION

Allogeneic stem cell transplantation is a treatment in which the source of hematopoietic stem cells to restore bone marrow and immune function are derived, not from the patient, but from a different donor. Initially allogeneic stem cell transplantation was thought to derive its effectiveness from the high-dose chemotherapy (or radiation plus chemotherapy) that forms the “preparative regimen” in a manner similar to autologous stem cell transplantation. However, it is now known that there is a second type of effector mechanism in allogeneic stem cell transplantation, the alloimmune graft-versus-malignancy (GVM) effect derived from the donor immune system. In some cases, this GVM effect can be more important than the chemotherapy in producing a cure of disease. This understanding has led to the development of less myelotoxic preparative regimens, referred to as reduced-intensity or non-myeloablative.

In order to perform an allogeneic stem cell transplantation, an appropriate donor of hematopoietic stem cells must be located. At the present time, it is important that the donor be matched with the patient (recipient) at the HLA loci (HLA A, B, C, DR) that specify major histocompatibility antigens. These donors may be full siblings or unrelated donors recruited from a large panel of anonymous volunteer donors through the National Marrow Donor Program (NMDP). Approaches utilizing haploidentical donors, ie, other children of the parents of the prospective recipient, are increasingly being used, with promising results. Finally, cells derived from umbilical cord blood units may also be used. The hematopoietic stem cells are collected from the donor either from the bone marrow, or, more commonly through leukopheresis of the blood after mobilizing hematopoietic stem cells from the bone marrow with filgrastim (G-CSF). They are infused intravenously into the recipient and may be given either fresh or after cryopreservation and thawing. The hematopoietic stem cells home to the bone marrow and start to grow.

In the allogeneic stem cell transplantation procedure, the patient is treated with the “preparative regimen” with two purposes: to treat the underlying cancer and to sufficiently suppress the patient’s immune system so that the hematopoietic stem cells from the donor will not be rejected. As with autologous stem cell transplantation, the hematopoietic stem cells are infused after the preparative chemotherapy has been given and has had a chance to clear from the body. There is a period of pancytopenia in the gap between the effect of the chemotherapy given to the patient and the time it takes the infused hematopoietic stem cells to grow into bone marrow, usually 10–14 days.

A major difference between autologous and allogeneic stem cell transplantation is that in the allogeneic setting, the patient becomes a “chimera,” that is, a mixture of self and non-self. In allogeneic stem cell transplantation, the infused cells contain mature cells of the donor immune system, and the infused hematopoietic stem cells will grow into bone marrow and blood cells as well as cells of the new immune system. Unless the donor is an identical twin (called a “syngeneic transplant”), the donor’s immune system will recognize the patient’s tissues as foreign and initiate the “graft-versus-host” (GVH) reaction, the graft from the donor reacting against the patient (host). This GVH is the major cause of morbidity and mortality during an allogeneic stem cell transplantation. Immunosuppression must be given during allogeneic stem cell transplantation to reduce the incidence and severity of GVH reaction. The most common regimen used for GVH prophylaxis is a combination of cyclosporine or tacrolimus plus methotrexate. In contrast to the experience with solid organ transplant in which life-long immunosuppression is required to prevent rejection of the transplanted organ, in most cases of allogeneic stem cell transplantation, the immunosuppression can be tapered and discontinued 6 or more months after transplantation.

However, there is an important and positive side to the alloimmune reaction of the donor against the host. If there are residual cancer cells present in the patient that have survived the high-dose chemoradiotherapy of the preparative regimen, these residual cancer cells can be recognized as foreign by the donor immune system and killed in the GVM effect. Even cells that are resistant to chemotherapy may not be resistant to killing through the immune system. Depending on the type of cancer cell, this can be a highly effective mechanism of long-term cancer control. Based on the understanding of how important GVM can be, the allogeneic stem cell transplantation procedure can be modified by reducing the intensity of the preparative regimen, relying for cure more on the GVM effect and less on the high-dose chemotherapy. In these “reduced-intensity” allogeneic stem cell transplantation procedures, the preparative regimen still has to suppress the patient’s immune system enough to avoid rejection of the donor hematopoietic stem cells, but these types of transplants can be far less toxic than full-dose transplants. Based on this greatly reduced short-term toxicity, the potential benefits of allogeneic stem cell transplantation have been extended to older adults (age 60–75) and to those with comorbid conditions that would have been a contraindication to standard full-dose stem cell transplantation.

Allogeneic stem cell transplantation is the treatment of choice for high-risk acute leukemias, and in many cases will be the only potentially curative treatment. Allogeneic stem cell transplantation is the only curative treatment for myelodysplasia and for CML, although its use in CML has been greatly curtailed based on the effectiveness of imatinib and related tyrosine kinase inhibitors. Allogeneic stem cell transplantation is also the only definitive treatment for most cases of severe aplastic anemia. The use of reduced-intensity allogeneic stem cell transplantation has led to its exploration in the management of difficult cases of CLL and follicular lymphoma, and it will likely play a major role in these diseases. Given the age of many patients with AML and myelodysplasia, this procedure will likely play an important role in these diseases as well.

Deeg HJ et al. Who is fit for allogeneic transplantation? Blood. 2010 Dec 2;116(23):4762–70. [PMID: 20702782]

Jenq RR et al. Allogeneic haematopoietic stem cell transplantation: individualized stem cell and immune therapy of cancer. Nat Rev Cancer. 2010 Mar;10(3):213–21. [PMID: 20168320]

Majhail NS et al; Center for International Blood and Marrow Transplant Research (CIBMTR); American Society for Blood and Marrow Transplantation (ASBMT); European Group for Blood and Marrow Transplantation (EBMT); Asia-Pacific Blood and Marrow Transplantation Group (APBMT); Bone Marrow Transplant Society of Australia and New Zealand (BMTSANZ); East Mediterranean Blood and Marrow Transplantation Group (EMBMT); Sociedade Brasileira de Transplante de Medula Ossea (SBTMO). Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation. Hematol Oncol Stem Cell Ther. 2012;5(1):1–30. [PMID: 22446607]

Sorror ML. Comorbidities and hematopoietic cell transplantation outcomes. Hematology Am Soc Hematol Educ Program. 2010;2010:237–47. [PMID: 21239800]

Spellman SR et al; National Marrow Donor Program; Center for International Blood and Marrow Transplant Research. A perspective on the selection of unrelated donors and cord blood units for transplantation. Blood. 2012 Jul 12;120(2):259–65. [PMID: 22596257]

BLOOD TRANSFUSIONS

RED BLOOD CELL TRANSFUSIONS

Red blood cell transfusions are given to raise the hemoglobin and hematocrit levels in patients with anemia or to replace losses after acute bleeding episodes.

 Preparations of Red Cells for Transfusion

Several types of preparations containing red blood cells are available.

  1. Fresh Whole Blood

The advantage of whole blood for transfusion is the simultaneous presence of red blood cells, plasma, and fresh platelets. Fresh whole blood is never absolutely necessary, since all the above components are available separately. The major indications for use of whole blood are cardiac surgery or massive hemorrhage when more than 10 units of blood is required in a 24-hour period.

  1. Packed Red Blood Cells

Packed red cells are the component most commonly used to raise the hematocrit. Each unit has a volume of about 300 mL, of which approximately 200 mL consists of red blood cells. One unit of packed red cells will usually raise the hematocrit by approximately 3–4%. The expected rise in hematocrit can be calculated using an estimated red blood cell volume of 200 mL/unit and a total blood volume of about 70 mL/kg. For example, a 70-kg man will have a total blood volume of 4900 mL, and each unit of packed red blood cells (PRBC) will raise the hematocrit by 200 ÷ 4900, or 4%. Current guidelines recommend a transfusion “trigger” threshold of 7–8 g/dL (70–80 g/L) for hospitalized critically ill patients, those undergoing cardiothoracic surgery or repair of a hip fracture, those with upper gastrointestinal bleeding, and those with hematologic malignancy undergoing chemotherapy.

  1. Leukocyte-Poor Blood

Most blood products are leukoreduced in-line during acquisition and are thus prospectively leukocyte-poor. Leukoreduced blood products reduce the incidence of leukoagglutination reactions, platelet alloimmunization, transfusion-related acute lung injury (see below), and CMV exposure.

  1. Frozen Packed Red Blood Cells

Packed red blood cells can be frozen and stored for up to 10 years, but the technique is cumbersome and expensive, and should be used sparingly. The major application is for the purpose of maintaining a supply of rare blood types. Patients with such types may donate units for autologous transfusion should the need arise. Frozen red cells are also occasionally needed for patients with severe leukoagglutinin reactions or anaphylactic reactions to plasma proteins, since frozen blood has essentially all white blood cells and plasma components removed.

  1. Autologous Packed Red Blood Cells

Patients scheduled for elective surgery may donate blood for autologous transfusion. These units may be stored for up to 35 days before freezing is necessary.

 Compatibility Testing

Before transfusion, the recipient’s and the donor’s blood are typed and cross-matched to avoid hemolytic transfusion reactions. Although many antigen systems are present on red blood cells, only the ABO and Rh systems are specifically tested prior to all transfusions. The A and B antigens are the most important, because everyone who lacks one or both red cell antigens has IgM isoantibodies (called isoagglutinins) in his or her plasma against the missing antigen(s). The isoagglutinins activate complement and can cause rapid intravascular lysis of the incompatible red blood cells. In emergencies, type O/Rh-negative blood can be given to any recipient, but only packed cells should be given to avoid transfusion of donor plasma containing anti-A and anti-B antibodies.

The other important antigen routinely tested for is the D antigen of the Rh system. Approximately 15% of the population lacks this antigen. In patients lacking the antigen, anti-D antibodies are not naturally present, but the antigen is highly immunogenic. A recipient whose red cells lack D and who receives D-positive blood may develop anti-D antibodies that can cause severe lysis of subsequent transfusions of D-positive red cells.

Blood typing includes a crossmatch assay of recipient serum for unusual alloantibodies directed against donor red blood cells by mixing recipient serum with panels of red blood cells representing commonly occurring minor red cell antigens. The screening is particularly important if the recipient has had previous transfusions or pregnancy.

 Hemolytic Transfusion Reactions

The most severe hemolytic transfusion reactions are acute (temporally related to the transfusion), involving incompatible mismatches in the ABO system and are isoagglutinin-mediated. Most of these cases are due to clerical errors and mislabeled specimens. With current compatibility testing and double check clerical systems, the risk of an acute hemolytic reaction is 1 in 76,000 transfused units of red blood cells. Death from acute hemolytic reaction occurs in 1 in 1.8 million transfused units. Hemolysis is rapid and intravascular, releasing free hemoglobin into the plasma. The severity of these reactions depends on the dose of red blood cells given. The most severe reactions are those seen in surgical patients under anesthesia.

Delayed hemolytic transfusion reactions are caused by minor red blood cell antigen discrepancies and are typically less severe. The hemolysis usually takes place at a slower rate and is mediated by IgG alloantibodies causing extravascular red blood cell destruction. These transfusion reactions may be delayed for 5–10 days after transfusion. In such cases, the recipient has received red blood cells containing an immunogenic antigen, and in the time since transfusion, a new alloantibody has formed. The most common antigens involved in such reactions are Duffy, Kidd, Kell, and C and E loci of the Rh system. The current risk of a delayed hemolytic transfusion reaction is 1 in 6000 transfused units of red blood cells.

  1. Symptoms and Signs

Major acute hemolytic transfusion reactions cause fever and chills, with backache and headache. In severe cases, there may be apprehension, dyspnea, hypotension, and cardiovascular collapse. Patients under general anesthesia will not manifest such symptoms, and the first indication may be tachycardia, generalized bleeding, or oliguria. The transfusion must be stopped immediately. In severe cases, acute DIC, acute kidney injury from tubular necrosis, or both can occur. Death occurs in 4% of acute hemolytic reactions due to ABO incompatibility.

Delayed hemolytic transfusion reactions are usually without symptoms or signs.

  1. Laboratory Findings

When an acute hemolytic transfusion episode is suspected, the identification of the recipient and of the transfusion product bag label should be rechecked. The transfusion product bag with its pilot tube must be returned to the blood bank, and a fresh sample of the recipient’s blood must accompany the bag for retyping and re–cross-matching of donor and recipient blood samples.

The hematocrit will fail to rise by the expected amount. Coagulation studies may reveal evidence of acute kidney injury or acute DIC. The plasma free hemoglobin in the recipient will be elevated resulting in hemoglobinuria.

In cases of delayed hemolytic reactions, the hematocrit will fall and the indirect bilirubin will rise. In these cases, the new offending alloantibody is easily detected in the patient’s serum.

  1. Treatment

If an acute hemolytic transfusion reaction is suspected, the transfusion should be stopped at once. The patient should be vigorously hydrated to prevent acute tubular necrosis. Forced diuresis with mannitol may help prevent or minimize acute kidney injury.

 Leukoagglutinin Reactions

Most transfusion reactions are not hemolytic but represent reactions to antigens present on transfused passenger leukocytes in patients who have been sensitized to leukocyte antigens through previous transfusions or pregnancy. Transfusion products relatively rich in leukocyte-rich plasma, especially platelets, are most likely to cause this. Moderate to severe leukoagglutinin reactions occur in 1% of red blood cell transfusions and 2% of platelet transfusions. Most commonly, fever and chills develop in patients within 12 hours after transfusion. In severe cases, cough and dyspnea may occur and the chest radiograph may show transient pulmonary infiltrates. Because no hemolysis is involved, the hematocrit rises by the expected amount despite the reaction.

Leukoagglutinin reactions may respond to acetaminophen (500–650 mg) and diphenhydramine (25 mg); corticosteroids, such as hydrocortisone (1 mg/kg), are also of value. Overall, leukoagglutination reactions are diminishing through the routine use of in-line leukotrapping during blood donation (ie, leukoreduced blood). Patients experiencing severe leukoagglutination episodes despite receiving leukoreduced blood transfusions should receive leukopoor or washed blood products.

 Hypersensitivity Reactions

Urticaria or bronchospasm may develop during or soon after a transfusion. These reactions are almost always due to exposure to allogeneic plasma proteins rather than to leukocytes. The risk is low enough that the routine use of antihistamine premedications has been eliminated before PRBC transfusions. A hypersensitivity reaction, including anaphylactic shock, may develop in patients who are IgA deficient because of antibodies to IgA in the patient’s plasma directed against the IgA in the transfused blood product. Patients with such reactions may require transfusion of washed or even frozen red blood cells to avoid future severe reactions.

 Contaminated Blood

Blood products can be contaminated with bacteria. Platelets are especially prone to bacterial contamination because they cannot be refrigerated. Bacterial contamination occurs in 1 of every 30,000 red blood cell donations and 1 of every 5000 platelet donations. Receipt of a blood product contaminated with gram-positive bacteria will cause fever and bacteremia but rarely causes a sepsis syndrome. Receipt of a blood product contaminated with gram-negative bacteria often causes septic shock, acute DIC, and acute kidney injury due to the transfused endotoxin and is usually fatal. Strategies to reduce bacterial contamination include enhanced venipuncture site skin cleansing, diverting of the first few milliliters of donated blood, use of single donor blood products (as opposed to pooled donor products), and point of care rapid bacterial screening in order to discard questionable units. The current risk of a septic transfusion reaction from a culture-negative unit of single-donor platelets is 1 in 60,000. In any patient who may have received contaminated blood, the recipient and the donor blood bag should both be cultured, and antibiotics should be given immediately to the recipient.

 Infectious Diseases Transmitted Through Transfusion

Despite the use of only volunteer blood donors and the routine screening of blood, transfusion-associated viral diseases remain a problem. All blood products (red blood cells, platelets, plasma, cryoprecipitate) can transmit viral diseases. All blood donors are screened with questionnaires designed to detect (and therefore reject) donors at high risk for transmitting infectious diseases. All blood is screened for hepatitis B surface antigen, antibody to hepatitis B core antigen, syphilis, p24 antigen and antibody to HIV, antibody to hepatitis C virus (HCV), antibody to human T cell lymphotropic/leukemia virus (HTLV), and nucleic acid testing for West Nile virus. Clinical trials are examining the value of screening blood donors for Trypanosoma cruzi, the infectious agent that causes Chagas disease.

With improved screening, the risk of posttransfusion hepatitis has steadily decreased after the receipt of screened ‘negative’ blood products. The risk of acquiring hepatitis B is about 1 in 290,000 transfused units in the United States (versus about 1 in 21,000 to 1 in 600 transfused units in Asia). The risk of hepatitis C acquisition is 1 in 1.5 to 2 million transfused units in the United States. The risk of HIV acquisition is 1 in 2 million transfused units. Unscreened leukoreduced blood products appear to be equivalent to CMV screened-negative blood products in terms of the risk of CMV transmission to a CMV-seronegative recipient.

 Transfusion Graft-Versus-Host Disease

Allogeneic passenger lymphocytes within transfused blood products will engraft in some recipients and mount an alloimmune attack against tissues expressing discrepant HLA-antigens causing graft-versus-host disease (GVHD). The symptoms and signs of transfusion-associated GVHD include fever, rash, diarrhea, hepatitis, lymphadenopathy, and severe pancytopenia. The outcome is usually fatal. Transfusion-associated GVHD occurs most often in recipients with immune defects, malignant lymphoproliferative disorders, solid tumors being treated with chemotherapy or immunotherapy, treatment with immunosuppressive medications (especially purine analogs such as fludarabine), or older patients undergoing cardiac surgery. HIV infection alone does not seem to increase the risk. The use of leukoreduced blood products is inadequate to prevent transfusion-associated GVHD. This complication can be avoided by irradiating blood products (25 Gy or more) to prevent lymphocyte proliferation in recipients at high risk for transfusion-associated GVHD.

 Transfusion-Related Acute Lung Injury

Transfusion-related acute lung injury (TRALI) occurs in 1 in every 5000 transfused units of blood products. It has been associated with allogeneic antibodies in the donor plasma component that bind to recipient leukocyte antigens, including HLA antigens and other granulocyte- and monocyte-specific antigens. In 20% of cases, no antileukocyte antibodies are identified raising the concern that bioactive lipids or other substances that accumulate while the blood product is in storage can also mediate TRALI in susceptible recipients. TRALI is clinically defined as noncardiogenic pulmonary edema after a blood product transfusion without other explanation, and transfused surgical and critically ill patients seem most susceptible. Ten to 20% of female blood donors and 1–5% of male blood donors have antileukocyte antibodies in their serum. The risk of TRALI is reduced through the use of male only plasma donors, when possible. There is no specific treatment for TRALI, only supportive care.

PLATELET TRANSFUSIONS

Platelet transfusions are indicated in cases of thrombocytopenia due to decreased platelet production. They are of some use in immune thrombocytopenia when active bleeding is evident, but the clearance of transfused platelets is rapid as they are exposed to the same pathophysiologic forces as the recipient’s endogenous platelets. The risk of spontaneous bleeding rises when the platelet count falls to < 80,000/mcL (< 80 × 10 9/L), and the risk of life-threatening spontaneous bleeding increases when the platelet count is < 5000/mcL (< 5 × 10 9/L). Because of this, prophylactic platelet transfusions are often given at these very low levels, usually when < 10,000/mcL (< 10 × 10 9/L). Platelet transfusions are also given prior to invasive procedures or surgery in thrombocytopenic patients, and the goal is often to raise the platelet count to 50,000/mcL (50 × 10 9/L) or more.

Platelets for transfusion are most commonly derived from single donor apheresis collections (roughly the equivalent to the platelets recovered from six donations of whole blood). A single donor unit of platelets should raise the platelet count by 50,000 to 60,000 platelets per mcL (50–60 × 10 9/L) in a transfusion-naïve recipient without hypersplenism or ongoing platelet consumptive disorder. Transfused platelets typically last for 2 or 3 days. Platelet transfusion responses may be suboptimal with poor platelet increments and short platelet survival times. This may be due to one of several causes, including fever, sepsis, splenomegaly, DIC, large body habitus, low platelet dose in the transfusion, or platelet alloimmunization (from prior transfusions, prior pregnancy or prior organ transplantation). Many, but not all, alloantibodies causing platelet destruction are directed at HLA antigens. Patients requiring long periods of platelet transfusion support should be monitored to document adequate responses to transfusions so that the most appropriate product can be used. Patients requiring ongoing platelet transfusions who become alloimmunized may benefit from HLA-matched platelets derived from either volunteer donors or family members. Techniques of cross-matching platelets have been developed and appear to identify suitable volunteer platelet donors (nonreactive with the patient’s serum) without the need for HLA typing. Leukocyte reduction of platelets has been shown to delay or prevent the onset of alloimmunization in multiply transfused recipients.

TRANSFUSION OF PLASMA COMPONENTS

Fresh-frozen plasma (FFP) is available in units of approximately 200 mL. FFP contains normal levels of all coagulation factors (about 1 unit/mL of each factor). FFP is used to correct coagulation factor deficiencies and to treat thrombotic thrombocytopenia purpura or hemolytic-uremic syndrome. FFP is also used to correct or prevent coagulopathy in trauma patients receiving massive transfusion of PRBC. A FFP:PRBC ratio of ≥ 1:2 is associated with improved survival in trauma patients receiving massive transfusions, regardless of the presence of a coagulopathy.

Cryoprecipitate is made from fresh plasma by cooling the plasma to 4°C and collecting the precipitate. One unit of cryoprecipitate has a volume of approximately 15–20 mL and contains approximately 250 mg of fibrinogen and between 80 and 100 units of factor VIII and von Willebrand factor. Cryoprecipitate is used to supplement fibrinogen in cases of acquired hypofibrinogenemia (eg, DIC) or in rare instances of congenital hypofibrinogenemia. One unit of cryoprecipitate will raise the fibrinogen level by about 8 mg/dL (0.24 mcmol/L). Cryoprecipitate is sometimes used to temporarily correct the acquired platelet dysfunction associated with kidney disease.

Allain JP et al; ISBT HBV Safety Collaborative Group. Hepatitis B virus in transfusion medicine: still a problem? Biologicals. 2012 May;40(3):180–6. [PMID: 22305086]

Brown LM et al. A high fresh frozen plasma: packed red blood cell transfusion ratio decreases mortality in all massively transfused trauma patients regardless of admission international normalized ratio. J Trauma. 2011 Aug;71(2 Suppl 3):S358–63. [PMID: 21814104]

Carson JL et al; Clinical Transfusion Medicine Committee of the AABB. Red blood cell transfusion: a clinical practice guideline from the AABB. Ann Intern Med. 2012 Jul 3;157(1):49–58. [PMID: 22751760]

Goodnough LT et al. Concepts of blood transfusion in adults. Lancet. 2013 May 25;381(9880):1845–54. [PMID: 23706801]

Sharma S et al. Transfusion of blood and blood products: indications and complications. Am Fam Physician. 2011 Mar 15;83(6):719–24. [PMID: 21404983]

Slichter SJ et al. Dose of prophylactic platelet transfusions and prevention of hemorrhage. N Engl J Med. 2010 Feb 18;362(7):600–13. [PMID: 20164484]

Stanworth SJ et al; TOPPS Investigators. A no-prophylaxis platelet-transfusion strategy for hematologic cancers. N Engl J Med. 2013 May 9;368(19):1771–80. [PMID: 23656642]

Strauss RG. Role of granulocyte/neutrophil transfusions for haematology/oncology patients in the modern era. Br J Haematol. 2012 Aug;158(3):299–306. [PMID: 22712550]

Thiagarajan P et al. Platelet transfusion therapy. Hematol Oncol Clin North Am. 2013 Jun;27(3):629–43. [PMID: 23714315]