Ronald L. Paquette and Dennis A. Casciato
COMPARABLE ASPECTS
The World Health Organization (WHO) classification of the chronic myeloproliferative disorders (MPDs) includes polycythemia vera (PV), chronic idiopathic myelofibrosis (MF), essential thrombocythemia (ET), chronic eosinophilic leukemia (CEL)/hypereosinophilic syndrome (HES), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia, and unclassifiable chronic MPD. Chronic myelomonocytic leukemia (CMML) has features of both an MPD and a myelodysplastic syndrome (MDS). Details on CML and CMML are presented in Chapter 23. This chapter focuses on PV, ET, MF, CEL/HES, and systemic mastocytosis (SM).
The MPDs each result from a genetic alteration within a pluripotent hematopoietic progenitor cell that induces the excessive production of one or more cell lineages. The individual diseases are distinguished by the predominant lineage that is overproduced. Table 24.1 compares important clinical and distinguishing features of the MPDs. There is considerable overlap between several of the MPDs. Long-term observation may be required to clarify the diagnosis. Unclassifiable MPDs is the best designation for patients who have leukoerythroblastic blood smears, normal red blood cell mass, and a hypercellular marrow that shows only mild fibrosis.
Table 24.1 Clinical Features of the Myeloproliferative Disorders and Chronic Myelogenous Leukemia
PV, polycythemia vera; ET, essential thrombocythemia; MF, myelofibrosis with myeloid metaplasia; U-MPD, unclassifiable myeloproliferative disorder; CML, chronic myelogenous leukemia; N, normal; D, decreased; A, absent.
aThe designations 1 + → 4 + indicate relative degrees of prominence.
Erythrocytosis, granulocytosis, eosinophilia, basophilia, and thrombocytosis may be due to disorders other than MPDs, as discussed in Chapter 34, Sections I to V in “Increased Blood Cell Counts.” Similarly, bone marrow fibrosis may be secondary to a variety of other etiologies, as discussed in Chapter 34, Section I.B in “Cytopenia.”
I. PATHOGENESIS. The MPDs are clonal neoplastic disorders that arise from a single pluripotential hematopoietic stem cell. The molecular abnormalities underlying many of the MPDs are rapidly becoming elucidated.
A. Molecular and cytogenetic abnormalities. A mutation of the Janus kinase 2 (JAK2) gene has been identified in PV, ET, and MF. The JAK2 protein is a tyrosine kinase that is phosphorylated by the receptors for erythropoietin (EPO), thrombopoietin, granulocyte colony-stimulating factor, granulocytemacrophage colony-stimulating factor, and interleukin-3 in response to ligand binding. Activation of JAK2 in this way initiates a signaling cascade that induces cell proliferation in response to these growth factors.
1. The most commonly observed mutation results in the replacement of valine by phenylalanine at position 617 (V617F) in exon 14 of JAK2. The mutated protein enables hematopoietic cells to survive in the absence of growth factors and to have enhanced proliferation when exposed to low growth factor concentrations.
The JAK2 V617F mutation occurs in approximately 95% of PV, 50% of ET or MF, 20% of unclassifiable MPD, and 2% of HES. The mutation is homozygous in approximately 40% of PV due to mitotic recombination. Mutations involving exon 12 of JAK2 have been identified in about 4% PV patients.
In addition, point mutations at position 515 (exon 10) of the thrombopoietin receptor (MPL) have been identified in 5% to 10% of patients with MF or ET. The mutated MPL receptor activates the JAK signaling pathway in the absence of thrombopoietin.
2. Mutations have been identified in additional genes that encode proteins involved in critical cell processes.
a. Kinase signaling. CBL ubiquitinates receptor tyrosine kinases, leading to their inactivation. Loss-of-function CBL mutations have been observed in MF. LNK inhibits JAK2 signaling. Inactivating mutations of LNK have been reported in ET and MF.
b. Epigenetic regulation. TET2 transfers a hydroxyl group to methylcytosine of DNA. Mutations of TET2 have been reported in 5% to 20% of MPDs. ASXL1 participates in histone demethylation and is mutated in <10% of MPD patients. EZH2 plays a role in histone methylation and is mutated in approximately 13% of MF cases.
3. Chromosome analyses have established that a clonal cytogenetic abnormality is present in erythroblasts, neutrophils, basophils, macrophages, megakaryocytes, and subsets of B lymphocytes, but not in fibroblasts. Abnormal karyotypes are found in about 20% of PV cases at the time of diagnosis, with deletions of 20q or 13q or trisomies of 8 or 9 being most common.
4. In MF, abnormal karyotypes are found in 35% of cases; deletions of 20q or 13q and partial trisomy 1q account for 70% of the abnormal karyotypes found. The frequency of chromosomal abnormalities increases over time, particularly if patients are treated with chemotherapeutic agents. In some cases of CEL, a very small interstitial deletion on chromosome 4q12 fuses the FIP1L1 and platelet-derived growth factor receptor (PDGFR)A genes, producing a novel transforming fusion gene. The t(5;12)(q33;p13) occurs in other CEL cases and fuses the PDGFRB gene to the ETV6 gene.
B. Hematopoiesis in the MPDs is generally characterized by autonomous growth of progenitor cells in the absence of growth factors and hypersensitivity to the proliferative effects of growth factors.
1. Erythropoiesis in vitro in semisolid media normally requires exogenous EPO. Bone marrow progenitor cells from patients with PV form colonies in vitro without exogenous EPO and proliferate in response to very low EPO concentrations. Serum EPO levels are usually low in PV and are normal or elevated in most cases of secondary polycythemia.
2. Granulocytopoiesis is frequently increased in all MPDs to varying degrees and is manifested by neutrophilia and myeloid hyperplasia in the marrow.
3. Megakaryocytopoiesis. Megakaryocyte progenitors from ET patients are able to grow autonomously in vitro without added thrombopoietin.
4. Extramedullary hematopoiesis occurs in the liver and spleen in patients with MF and contributes to organ enlargement. However, the degree of organomegaly does not correlate well with the level of extramedullary hematopoiesis.
C. Bone marrows in MPDs demonstrate hypercellularity that is often trilineage but are diagnostic of a specific disorder only in MF. Megakaryocytes are greatly increased in number and size in ET and MF at all stages of disease and to a lesser degree in PV. Reticulin also can be increased in all MPDs, but collagen fibrosis occurs only in MF and in PV that has converted to MF.
1. Fibrosis of the marrow develops in all patients with MF and in many patients with PV or ET over time. The fibrosis is caused by the release of cytokines, including transforming growth factor-β and basic fibroblast growth factor, from clonal megakaryocytes or monocytes. The growth factors act on nonclonal fibroblasts and stromal cells and induce increased deposition of various interstitial and basement membrane glycoproteins, including collagen types I, III, IV, and V. Type III collagen is uniformly and preferentially increased. The fine reticulin fibers that are visible with silver stains are principally type III collagen and do not stain with trichrome dyes.
2. MF. Marrow fibrosis is prominent in MF. Megakaryocytes are increased in number, and they are atypical, enlarged, and immature. Neutrophilic granulopoiesis is hyperplastic. A marked neovascularization is also present, even in the early proliferative phase of the disease.
3. PV. Trilineage hyperplasia in the marrow is the hallmark of PV. Erythroid hyperplasia is prominent. Megakaryocytes are enlarged, clustered, mature, and pleomorphic with multilobulated nuclei. Iron stores are absent or decreased in most untreated patients. In secondary erythrocytosis, erythroid hyperplasia may be present, but megakaryocytes remain small and normal with no tendency to cluster.
4. ET. Increased numbers of enlarged megakaryocytes with mature cytoplasm and multilobulated nuclei and a tendency to cluster in a bone marrow with normal or slightly increased cellularity constitute the hallmarks of ET. In reactive thrombocytosis, increased numbers of megakaryocytes may be present, but they have normal size and morphology and no tendency to cluster.
II. COMPLICATIONS OF THE MPD
A. Thrombotic phenomena, both venous and arterial, can complicate PV, ET, and MF. Myocardial ischemia and cerebrovascular ischemia are the most serious events, but thrombosis can occur anywhere in the venous or arterial system. For example, PV is the most common cause of hepatic vein thrombosis (Budd-Chiari syndrome). In PV, two-thirds of thrombotic events occur either at presentation or before diagnosis, and one-third occur during follow-up.
1. Thrombosis risks and prevention in PV and ET. Risk factors for thrombosis in PV and ET include age ≥60 years and history of a prior thrombotic event. Additional risk factors for thrombosis include elevated WBC (>15,000/μL) at presentation, hypertension, hyperlipidemia, diabetes, and smoking history. In ET and MF, the V617F mutation conveys an increased risk of thrombosis.
In PV, the risk of thrombosis increases with the hematocrit, so phlebotomy is performed to keep the hematocrit <45% in men and <42% in women. Low- and intermediate-risk (0 risk factors) PV and ET patients are given low-dose aspirin. Aspirin appears to be of most benefit in low-risk ET if the JAK2 V617F mutation is present. High-risk (two risk factors) patients also receive hydroxyurea (HU; also known as hydroxycarbamide). In ET, the level of the platelet count does not correlate with the risk of thrombosis. However, reducing the platelet count and WBC is associated with a reduced risk of thrombotic events in retrospective studies.
HU is more effective than anagrelide in preventing arterial thrombotic events in patients at high risk for thrombosis. Aspirin administration to ET patients with very high platelet counts (>1,000,000/μL) can be associated with increased bleeding risk.
B. Microvascular arterial thrombosis is easily and best controlled by low-dose aspirin or by reduction of platelet count to normal levels.
1. Erythromelalgia is the most characteristic vaso-occlusive manifestation in MPDs and is most often associated with PV or ET. It is caused by the toxic effects of platelet arachidonic acid on arterioles. Localized painful erythema and warmth occur in the distal portions of the extremities and may progress to cyanosis or necrosis of toes or fingers.
2. Microvascular arterial thrombosis in PV or ET is usually transient and not progressive. Manifestations can include ocular disturbances, amaurosis fugax, diplopia, headache, vertigo, hypesthesia, paresthesia, dysarthria, aphasia, and syncope. If superimposed on a previously compromised vasculature, these events could result in stroke, myocardial infarction, or digital gangrene.
C. Hemorrhagic phenomena occur in PV, ET, and late MF but are less common than thrombotic events. Easy bruisability and purpura are the usual manifestations. Bleeding can be treated by decreasing the platelet count, platelet transfusion, or administering desmopressin (DDAVP).
1. Bleeding can occur spontaneously without relationship to the platelet count if there is abnormal platelet function, but it occurs especially when the count exceeds 1,000,000/μL. Caution should be exercised in administering aspirin in this setting.
2. Acquired von Willebrand disease develops occasionally in the MPDs. This coagulopathy is characterized by a very high platelet count, a normal or prolonged bleeding time, normal factor VIII, and normal von Willebrand factor (vWF) antigen levels, but with decreased vWF–ristocetin cofactor activity, decreased collagen-binding activity, and a decrease or absence of large vWF multimers. This condition simulates type II vWF deficiency. A ristocetin cofactor activity should be checked, and aspirin should be used cautiously if activity is <50%.
D. Hypercatabolism. Hyperuricemia and hyperuricosuria are present in nearly all patients with active MPD. Treatment with allopurinol can prevent gouty arthritis, uric acid nephropathy, and nephrolithiasis, but its necessity is unproven. Pruritus is a frequent problem, particularly in PV. Fever, heat tolerance, and weight loss ensue when the disease becomes rapidly progressive.
E. Interconversions of the MPDs are uncommon. The only consistent transformation is the conversion of PV or ET into MF.
F. Transformation to acute myelogenous leukemia (AML). The risk of progressing to AML is approximately 2% for ET, 5% for PV, and 10% for MF within 10 years of diagnosis. The risk for AML transformation is higher in patients with MF who have undergone splenectomy. Prior treatment with alkylating agents or radioactive phosphorus (32P) also increases the risk.
G. Misleading laboratory results
1. Normal hematocrits in patients with PV can represent erythrocytosis masked by hemorrhage, iron deficiency, increased plasma volume, or splenomegaly with sequestration.
2. Pseudocoagulopathy. Prolonged clotting times in patients with marked erythrocytosis are usually the result of excessive amounts of anticoagulant relative to the small plasma volume in the test tube. Accurate determinations can be made if the volume of anticoagulant is adjusted for the hematocrit.
3. Pseudohyperkalemia. Marked thrombocytosis may result in elevated serum potassium concentrations because platelets release potassium during the clotting reaction. The true level is determined by measuring the potassium concentration in plasma rather than in serum.
4. Pseudo–hyper-acid-phosphatemia. Platelets are rich in acid phosphatase. Marked thrombocytosis may result in spurious elevations of enzyme levels measured in serum and plasma.
5. Pseudohypoglycemia. Leukocytes metabolize glucose from serum in test tubes. Dramatically low blood glucose concentrations may result from marked granulocytosis. More accurate glucose levels can be measured if the sample is analyzed immediately after the sample is drawn.
6. Pseudohypoxemia. Oxidative respiration is used by monocytes and immature leukocytes to a greater extent than by mature leukocytes and platelets and is not used by mature erythrocytes. Falsely low oxygen tensions may be seen in patients with severe thrombocytosis or granulocytosis because of oxygen consumption within the test tubes. The presence of hypoxemia may be clarified if specimens are collected in test tubes containing fluoride and are immediately placed in ice.
POLYCYTHEMIA VERA
See “Comparable Aspects” at the beginning of this chapter for pathogenesis, bone marrow findings, complications, and misleading laboratory results of the MPDs. Familial cases occur occasionally in PV.
I. DIAGNOSIS. PV is a clonal MPD that harbors a JAK2 mutation (most commonly V617F) in approximately 95% of cases. Therefore, mutation analysis of the JAK2 gene will help to segregate PV from secondary causes of erythrocytosis.
A. WHO criteria (2008). The diagnosis of PV requires both major criteria plus any minor criterion or the A1 criterion plus any two minor criteria.
1. Major criteria
2. Minor criteria
B. Laboratory studies
1. Red blood cell mass (RBCM). Autologous RBCs are 51Cr-labeled and injected intravenously, and then a blood sample is drawn to quantitate the dilution of the labeled cells and calculate the circulating RBCM. RBCM using 51Cr is rarely available today.
2. Clonal genetic abnormality. The presence of the JAK2 V617F or exon 12 mutation in the blood or bone marrow is adequate to demonstrate a clonal etiology for the erythrocytosis. Absence of a JAK2 mutation suggests a secondary cause for the erythrocytosis (see “Comparable Aspects,” Section IA).
3. Erythroid colony-forming assay. PV bone marrow demonstrates EPO independency in culture. However, this assay is cumbersome and not routinely performed by clinical laboratories.
4. Supportive studies
a. CBC. Erythrocytes are usually normocytic and normochromic unless iron deficiency is present. Poikilocytosis and anisocytosis accompany the transition into MF late in the disease course. Granulocytosis in the range of 12,000 to 25,000/μL occurs in two-thirds of patients at presentation. Early forms may be present but are not frequent. Two-thirds of patients have basophilia. Platelet counts usually are in the range of 450,000 to 800,000/μL, occasionally with abnormal morphology.
b. Serum EPO levels can be normal or reduced in PV. Although autonomous expansion of the RBCM would be expected to suppress EPO production, this assay cannot reliably distinguish between PV and EPO-driven erythrocytosis. EPO production is depressed and circulating EPO catabolism is increased as the RBCM expands from any cause. Furthermore, a normal serum EPO level is common in hypoxic erythrocytosis unless the hypoxemia is extreme.
c. Abdominal ultrasonography or CT scanning can rule out renal or hepatic causes of erythrocytosis and quantitate spleen size.
d. Bone marrow examinations can be used to demonstrate panmyelosis and abnormal megakaryocyte morphology consistent with PV, quantitate the extent of reticulin fibrosis if transition to MF is suspected, or evaluate the percentage of blasts if transformation to AML is a concern.
C. Differential diagnosis includes the other MPDs and relative or secondary erythrocytosis (see Chapter 34, Section I in “Increased Blood Cell Counts”). Reduced plasma volume, hypoxemia (e.g., altitude, emphysema, sleep apnea), renal cysts or carcinoma, hepatic neoplasms, or uterine myomata can cause sec ondary erythrocytosis.
II. CLINICAL COURSE. The survival of patients with PV approaches that of a matched otherwise healthy population with modern therapy. The median survival exceeds 12 years.
A. Predominant signs and symptoms early in the disease are secondary to increased red blood cell mass that results in plethora and hyperviscosity. Modest splenomegaly is present in 75% of cases and hepatomegaly in 40%. Splenomegaly is caused by an increased splenic red blood cell pool and not by extramedullary hematopoiesis, which is absent early in the disease. Pruritus develops in 15% to 50% of cases, urticaria in 10%, and gout in 5% to 10%.
1. Hyperviscosity results in decreased blood flow and, consequently, in tissue hypoxia. Manifestations include headache, dizziness, vertigo, tinnitus, visual disturbances, stroke, angina pectoris, claudication, and myocardial infarction.
2. Thrombotic manifestations can result from hyperviscosity associated with the increased RBCM.
a. Types of events. Both arterial and venous thromboses occur in PV, more commonly in women than in men. Approximately two-thirds of the thrombotic events are severe and life-threatening, including cerebrovascular accidents, myocardial infarctions, pulmonary infarctions, and axillary, hepatic, portal, splenic, or mesenteric vein thromboses. The remaining one-third of events are uncomplicated deep vein or other thromboses.
3. Hemorrhagic manifestations (10% to 20% of patients) include epistaxis, ecchymosis, and gastrointestinal (GI) bleeding. Minor mucosal bleeding is most common. Acquired abnormalities of vWF can occur with marked thrombocytosis (see “Comparable Aspects,” Section II.C).
B. Phases of disease
1. Erythrocytic phase. The phase of persistent erythrocytosis that necessitates regular phlebotomies lasts from 5 to 25 years. The manifestations of erythrocytosis and severity of complications depend on comorbid conditions and sufficient use of phlebotomy.
2. Spent phase. Eventually, the patient enters a “spent” or “burned-out” phase; the need for phlebotomies is greatly reduced, or the patient enters a long period of apparent remission. Anemia eventually supervenes, but thrombocytosis and leukocytosis usually persist. The spleen increases in size, but little marrow fibrosis is present.
3. Myelofibrotic phase. Myelofibrosis develops in 5% to 10% of patients with PV, particularly in those who were exposed to chemotherapy or radiotherapy. The development of increased marrow reticulin or osteosclerosis, however, is not synonymous with the “spent phase.” When myelofibrosis does develop, it is not necessarily a progressive or destructive process, does not affect survival, and is potentially reversible. When cytopenias and progressive splenomegaly develop, the clinical manifestations and course become similar to that of MF.
4. Terminal phase. In patients who die from PV, death results from thrombotic or hemorrhagic complications. Death can also result from cytopenias that complicate myelofibrosis. PV patients are at increased risk of developing acute myeloid leukemia. Historically, this risk was significantly increased by treatment with 32P or alkylating agents compared to phlebotomy or HU.
C. Pregnancy and PV. Pregnant patients with PV have an increased incidence of premature births, fetal wastage, pre-eclampsia, and postpartum hemorrhage. Pregnancy does not affect the course of PV.
III. MANAGEMENT. The therapeutic challenge in PV is balancing the control of manifestations with the risks for thrombosis, hemorrhage, and leukemic transformation.
A. Principles of treatment
1. Reduce the hematocrit with phlebotomy
2. Administer low-dose aspirin to reduce thrombotic risk
3. Avoid overtreatment or elective surgery
4. HU can be used in patients with
a. A high risk for thrombotic complications (age >60 or prior thrombosis) or a high requirement for phlebotomy (more frequently than every 2 months)
b. Symptomatic splenomegaly
c. Uncontrolled systemic symptoms (e.g., intractable pruritus, weight loss) or poor venous access
d. Pathologic bleeding in the presence of thrombocytosis
e. Progressive granulocytosis (often a harbinger of extramedullary hematopoiesis or disease acceleration) or progressive thrombocytosis
5. Avoid potentially leukemogenic myelosuppressive agents, especially in young patients
B. Medical management
1. Phlebotomy alone prevents thrombosis and may be adequate treatment for many years. The hematocrit is maintained at <45% in men and 42% in women, and 36% in pregnancy. No additional treatment (other than aspirin) may be needed in stable patients who are at low risk for thrombosis (<60 years of age and no history of thrombosis).
a. Initially, 500 mL of blood may be removed every other day (only 250 mL of blood should be removed in patients with serious vascular disease).
b. About 200 mg of iron is removed with each 500 mL of blood (the normal total body iron content is about 5 g). Iron deficiency is a goal of chronic phlebotomy treatment. Symptomatic iron deficiency (glossitis, cheilosis, dysphagia, asthenia, pruritus) resolves rapidly with iron administration.
2. Myelosuppressive therapy controls the blood counts, minimizes complications from increased circulating elements, reduces symptomatic organomegaly, improves pruritus, and may delay myelofibrosis.
a. HU, 10 to 30 mg/kg daily PO, is arguably the drug of choice for treating panmyelosis. It is effective in most patients within 12 weeks and reduces the incidence of thrombotic events by 50%. The leukemogenic risk of this drug appears to be low. Occasional side effects of HU include fever, rash, stomatitis, leg ulcers, gastric discomfort, and possible renal dysfunction.
b. Interferon-α (IFN-α) suppresses the proliferation of hematopoietic progenitors, inhibits bone marrow fibroblast progenitor cells, and antagonizes the action of platelet-derived growth factor (PDGF). IFN-α, given at a dose of 500,000 to 3 million units SQ three times weekly, can control myeloproliferation, reduce splenomegaly, ameliorate pruritus, and possibly delay myelofibrosis. IFN-α, however, is associated with significant side effects including flu-like symptoms, fatigue, weight loss, altered mental status, depression, peripheral neuropathy, and exacerbation or development of autoimmune disease. IFN-α is not leukemogenic, and it does not damage the bone marrow.
The effect of IFN-α on the natural history of PV is unknown. Pegylated IFN-α is a better tolerated IFN-α preparation that has been shown to induce a high rate of complete hematologic remission (95% at 12 months) and cause a progressive decline of the JAK2 mutant clone down to <10% of baseline after 36 months of treatment. Pegylated IFN-α is started at a dose of 90 μg SQ weekly for 2 weeks, then escalated as tolerated every 2 weeks up to 180 μg/week.
c. Radioactive phosphorus (32P) and alkylating agents (chlorambucil, busulfan, and melphalan) can successfully control panmyelosis and reduce the incidence of thrombosis but unacceptably increase the incidence of AML.
3. Low-dose aspirin (81 to 100 mg/d) reduces the risk of major thrombotic events in PV, including myocardial infarction, stroke, pulmonary embolism, and major venous thrombosis. Aspirin also ameliorates erythromelalgia or other microvasculature problems. Aspirin may be contraindicated in patients with a history of prior GI hemorrhage.
4. Supportive care
a. Hyperuricemia, if associated with complications, is treated with allopurinol, 100 to 600 mg/d PO. Other measures are discussed in Chapter 27, Section IX.
b. Platelet transfusions are given for important bleeding, even if the platelet count is normal or elevated, because platelet function abnormalities may be present.
c. Anticoagulation for acute thrombotic complications is managed as for patients without PV.
d. Pruritus is multifactorial and may be resistant to therapy. The following may be helpful:
(1) Histamine blockers, such as hydroxyzine (25 mg PO q.i.d.), cyproheptadine (4 mg PO t.i.d.), or cimetidine (300 mg PO t.i.d.), should be tried initially.
(2) Selective serotonin reuptake inhibitors, including paroxetine 20 mg/d or fluoxetine 10 mg/d, have been helpful in some patients.
(3) Low-dose ferrous sulfate supplementation to treat pruritus that may be caused by iron deficiency may be considered. If iron is given, the hematocrit must be closely monitored for the expected increase in phlebotomy requirements.
(4) Cholestyramine or psoralen-activated ultraviolet light therapy may be helpful in some cases.
(5) If the above measures fail, HU or IFN-α may be necessary.
e. Symptomatic splenomegaly may be addressed with HU or IFN-α.
C. Surgery
1. Elective surgery should be avoided in patients with PV. More than 75% of patients with uncontrolled PV who undergo surgery develop hemorrhagic or thrombotic complications, and about one-third of patients die as a result. The longer the disease is controlled, the fewer the complications that will occur. The following approaches are recommended:
a. Phlebotomy. The hematocrit should be reduced to ≤45%. The blood obtained by phlebotomy can be saved for autologous transfusion.
b. Prevention of perioperative thromboembolism. Compression stockings or pulsating boots should be used to speed blood flow through the calf. Anticoagulation should be tailored to risks associated with the procedure.
2. Emergency surgery. Aggressive phlebotomy should be performed prior to surgery, if possible. Consider reinfusing the patient’s plasma to prevent depletion of clotting factors.
3. Splenectomy is occasionally performed for massive splenomegaly in the myelofibrotic phase of PV. Unfortunately, progressive hepatomegaly from extramedullary hematopoiesis or transformation to AML can follow this procedure. A high rate of perioperative mortality may be expected for elderly or frail patients.
ESSENTIAL THROMBOCYTHEMIA
See “Comparable Aspects” at the beginning of this chapter for pathogenesis, bone marrow findings, complications, and misleading laboratory results of the MPDs.
I. DIAGNOSIS. The megakaryocyte is the predominant proliferating cell lineage in the panmyelosis of ET.
A. WHO criteria (2008). The diagnosis of ET requires all four major criteria (A1 to A4)
B. Laboratory studies
1. Platelet counts always exceed 450,000/μL and are often present as clumps or megakaryocytic fragments. Counts may reach 15,000,000/μL.
a. Erythrocytes. Hypochromic, microcytic anemia is present in >60% of patients. Howell-Jolly bodies are found in 20% of patients and indicate splenic atrophy from repeated infarctions.
b. Granulocytosis is present in half of cases, usually in the range of 15,000 to 30,000/μL. Myelocytes and earlier forms are rare, and basophilia is mild, if present.
2. Iron studies including iron, TIBC, and ferritin to exclude iron deficiency as the cause for thrombocytosis
3. Markers of inflammation such as Westergren sedimentation rate, ANA, and rheumatoid factor should be ordered if clinically indicated.
4. Bone marrow examination shows hypercellularity, markedly increased numbers of megakaryocytes, often occurring in clumps (see “Comparable Aspects,” Section I.C). Iron stores should be adequate. Cytogenetic studies show no Philadelphia chromosome or BCR/ABL gene rearrangement (observed in CML) and no 5q deletion or 3q26 translocation (observed in MDS).
C. Differential diagnosis of ET includes reactive thrombocytosis (splenectomy, iron deficiency, malignancy, infection, inflammation, or GI bleeding as discussed in Chapter 34, Section III in “Increased Blood Cell Counts”), familial thrombocytosis related to increased levels of thrombopoietin, the other MPDs, CML, and MDS. The MDS subtypes that are most frequently associated with thrombocytosis include refractory anemia with the 5q–chromosomal abnormality or refractory anemia with ringed sideroblasts.
II. CLINICAL COURSE
A. Predominant signs and symptoms. Two-thirds of patients do not have symptoms when ET is discovered. The spleen may be enlarged (one-third of cases), normal, or atrophic. Hepatomegaly is absent. Extramedullary hematopoiesis is not a major feature of ET. Pruritus develops in 10% to 15% of patients.
B. Thrombotic, embolic, or hemorrhagic episodes of varying severity are the most common spontaneous manifestations of ET (see “Comparable Aspects,” Section II). Neither the level of the platelet count nor platelet function tests correlate with thrombotic risk, but platelet counts above 1,000,000/μL are associated with an increased bleeding risk when aspirin is administered.
1. Thrombotic episodes are most frequently venous, with deep vein thrombosis and pulmonary emboli as the most frequent manifestations. Splenic, hepatic, portal, and cerebral veins are also often affected. Arterial thromboses primarily affect small- and medium-sized vessels and most frequently cause digital ischemia or infarction.
2. Hemorrhage episodes occur most frequently in the mucous membranes or skin. Life-threatening hemorrhage rarely occurs except after trauma or surgery or in the presence of antiplatelet drugs.
3. Pregnancy is associated with increased occurrence of spontaneous abortions due to thrombosis of placental vessels, particularly in the presence of the JAK2 mutation. Cardiovascular events are not increased in patients with ET during pregnancy.
C. Survival approaches that of matched, otherwise healthy controls. The median survival exceeds 10 years, and the 5-year survival rate is >80%. Transformation of ET into acute leukemia is rare if leukemogenic agents have not been used.
III. MANAGEMENT
A. Prevention and treatment of thrombosis. (For preventive measures, see section II.A.1.) Patients with either hemorrhagic or vaso-occlusive complications should be treated promptly to lower the platelet count.
1. Low-dose aspirin should be considered for all patients unless there is a contraindication (platelets >1,000,000/μL with reduced ristocetin cofactor activity).
2. Myelosuppressive therapy is administered to high-risk patients (age >60 and history of thrombosis) or patients with platelet counts >1,000,000/mL and contraindication to aspirin due to low ristocetin cofactor activity. An arbitrary goal is to achieve platelet counts <450,000/μL.
a. HU is preferred as it controls both thrombocytosis and leukocytosis. HU is more effective than anagrelide in preventing arterial thromboses in patients with high-risk ET, and it is better tolerated.
b. Anagrelide is a selective inhibitor of platelet production that controls thrombocytosis in >80% of patients, usually within 1 to 2 weeks. The maintenance dosage is usually 2 to 2.5 mg/d in two to four divided doses. The main side effects of anagrelide are headaches, palpitations, fluid retention, and other neurologic, GI, and cardiac manifestations. It should be used with caution in patients with heart disease. Chronic administration causes progressive anemia. It is more likely than HU to be associated with progressive marrow fibrosis.
c. IFN-α is effective in controlling thrombocytosis and pruritus. Its ability to prevent thromboembolic complications is unknown. It causes more frequent and severe side effects than either HU or anagrelide (see “Polycythemia Vera,” Section III.B.2.b) but may be useful if treatment is required during pregnancy.
d. Alkylating agents (melphalan, busulfan, or chlorambucil) and 32P effectively reduce platelet counts but are leukemogenic. Avoid their use in ET, particularly in younger patients.
3. Antiplatelet drugs can eliminate manifestations of microvascular arterial thrombosis (erythromelalgia, transient ischemic attacks, and ocular disturbances) as well as reduce the risk of thromboses.
4. Plateletpheresis is indicated for emergency treatment of life-threatening complications of severe thrombocytosis.
5. Cardiovascular risk factors should be modified when possible.
B. Splenectomy greatly aggravates thrombocytosis, can be life-threatening, and is contraindicated in patients with ET.
C. Pregnancy with ET is successful in 55% of cases and is most frequently complicated by spontaneous abortion during the first trimester (35% of pregnancies). Maternal complications occur in about 5% of pregnancies. Abortion cannot be predicted by history or therapy or platelet counts. Aspirin appears to be safe during pregnancy, but its benefit is unknown. Specific therapies for ET during pregnancy, including plateletpheresis, do not appear to modify the clinical outcome. The ideal management for women with ET during pregnancy is speculative, but IFN-α is recommended for those who require platelet count reduction because it is not teratogenic.
PRIMARY MYELOFIBROSIS
See “Comparable Aspects” at the beginning of this chapter for pathogenesis, bone marrow findings, complications, and misleading laboratory results of the MPDs. Primary myelofibrosis (MF) is also known as myelofibrosis with myeloid metaplasia and agnogenic myeloid metaplasia or idiopathic myelofibrosis. Familial cases occur occasionally in MF. Radiation exposure is associated with an increased incidence of MF but accounts for only a small percentage of cases. No other etiologic factors have been determined.
I. DIAGNOSIS. Monoclonal megakaryocytes and polyclonal fibroblasts are the predominant proliferating cell lines in the panmyelosis of MF.
A. WHO criteria (2008). The diagnosis of MF requires all three major criteria and two minor criteria.
1. Major criteria
2. Minor criteria
B. Laboratory studies
1. JAK2 mutation analysis is positive in approximately 50% of MF patients, and an additional 5% have an MPL mutation. The presence of a mutation excludes secondary causes of fibrosis but does not exclude other MPDs.
2. Erythrocytes. Anemia is moderate in two-thirds of patients at presentation. Dacrocytes (“teardrop” cells), ovalocytes, pronounced anisocytosis, polychromasia, and nucleated red blood cells make up the characteristic and nearly pathognomonic blood picture of MF. The anemia is usually due to ineffective erythropoiesis.
3. Granulocytes usually range from 10,000 to 30,000/μL. Blasts and promyelocytes constitute <10% of the granulocytes. Granulocytopenia occurs in 15% of patients. Basophils are only slightly increased.
4. Platelets are increased in one-third, normal in one-third, and decreased in one-third of patients with MF, depending on the stage of disease. Platelets usually have abnormal morphology.
5. Bone marrow examination shows hypercellularity, granulocytic hyperplasia, and markedly increased numbers of atypical megakaryocytes. Fibrosis is patchy and variable in distribution; reticulin is always increased and is striking in half of the patients. The extent of fibrosis is not correlated with the duration of disease, splenic size, or degree of splenic myeloid metaplasia (see “Comparable Aspects,” Section I.C).
6. Immunologic abnormalities, such as monoclonal antibodies (10%), positive direct Coombs tests (20%), polyclonal hyperglobulinemia, RF, ANAs, antiphospholipid antibodies, or circulating immune complexes are found in more than half of the patients with MF.
C. Differential diagnosis of MF includes the other MPDs, CML, MDS, AML of the megakaryoblastic (M7) subtype, hairy cell leukemia, Hodgkin lymphoma, metastatic carcinoma associated with marrow fibrosis (desmoplastic reaction), autoimmune diseases (especially systemic lupus erythematosus), and disseminated mycobacterial infection. A long list of other disorders associated with secondary myelofibrosis is discussed in Chapter 33, Section I.B in “Cytopenia.”
II. CLINICAL COURSE
A. Symptoms are proportional to the severity of anemia and splenomegaly. Virtually all patients have splenomegaly, which may be massive, and three-fourths of patients have hepatomegaly. One-fourth of patients do not have symptoms at the time of diagnosis. Progression to AML is commonly manifested by fever, weight loss, and debilitating bone pain.
B. Chronic MF. The clinical course of MF is extremely variable. Some patients are symptom-free for long periods without treatment. Hemorrhagic manifestations rarely develop until late in the disease when severe thrombocytopenia develops. Death is due to heart failure, infection, hemorrhage, postsplenectomy mortality, or transformation to AML. Development of AML occurs in approximately 10% of MF patients.
The median survival in patients with MF is 4 to 5 years, but survival can range from <2 years to >10 years (20 years, in some reports) for patients, depending on risk factors. Splenic size and bone marrow findings have not been found to be significant prognostic factors. The expected survival is inversely related to the number of major risk factors that a patient demonstrates.
1. Accepted risk factors in MF
Hemoglobin <10 g/dL
WBC count <4,000/μL or >30,000/μL
Presence of >10% circulating precursors (blasts, promyelocytes, myelocytes)
2. Probable risk factors in MF
Abnormal karyotype
Age >65 years
Presence of constitutional symptoms
C. Associated syndromes
1. Portal hypertension and varices in MF are caused by massive increases in splenoportal blood flow and decreased hepatic vascular compliance. The decreased compliance is due to extramedullary hematopoiesis and its secondary collagen deposition.
2. Extramedullary hematopoietic tumors can develop in any location. Foci of these tumors on serosal surfaces can cause effusions containing immature hematopoietic cells.
3. Neutrophilic dermatoses are skin lesions with intense polymorphonuclear neutrophil infiltration. These raised tender plaques can progress to bullae or pyoderma gangrenosum.
III. MANAGEMENT
A. Medical management
1. Ruxolitinib (Jakafi) is the first JAK2 inhibitor approved by the FDA for the treatment of intermediate or high risk MF that is either primary or secondary to other MPDs. It inhibits the JAK1 and JAK2 kinases, and its activity against JAK2 is not specific for the V617F mutant. Because most, if not all, MF has activation of the JAK2 pathway regardless of mutation status, it is effective in patients with and without the mutation. Ruxolitinib significantly reduces spleen size and constitutional symptoms in MF patients. A survival benefit was with ruxolitinib also observed compared to placebo in one randomized trial.
a. Dosing should be 20 mg b.i.d. for baseline platelet count >200,000/µL and 15 mg b.i.d. for 100,000 to 200,000/µL. Safety and efficacy have not yet been established for patients with lower initial platelet counts. A 6 month trial should be given in the absence of unacceptable toxicity.
b. Side effects. The primary side effect of ruxolitinib is myelosuppression, particularly thrombocytopenia; it may exacerbate anemia. Nonhematologic side effects are typically minor.
2. Packed red blood cells are transfused to alleviate symptoms of anemia.
3. Androgens, such as fluoxymesterone (Halotestin; 10 mg PO b.i.d.) or danazol (200 to 400 mg PO b.i.d.), improve anemia in approximately one-third of MF patients. Several months of treatment are necessary before improvement is evident.
4. Glucocorticoids, such as prednisone (20 to 30 mg/d), can ameliorate systemic symptoms and anemia in approximately 20% of MF patients.
5. Erythropoiesis-stimulating agents in doses of 10,000 to 20,000 units three times per week can improve the anemia in some MF patients.
6. Lenalidomide has myelosuppression as its principal toxicity. In doses of 10 mg PO daily, it can improve anemia, thrombocytopenia, and splenomegaly in approximately 20% of MF patients.
7. Hydroxyurea in low doses can reduce leukocyte and platelet counts, symptomatic splenomegaly, or symptoms of hypercatabolism (fever, sweats, or weight loss). The response to treatment is unpredictable, and careful monitoring is recommended to avoid excessive bone marrow suppression.
8. IFN-α can be cytoreductive in patients with MF. However, its use is often complicated by intolerable side effects and peripheral blood cytopenias (see “Polycythemia Vera,” Section III.B.2.b).
9. Anagrelide can reduce the platelet count, but no other clinical manifestation of MF.
10. Thalidomide and alkylating agents may improve MF manifestations but are associated with unacceptable potential toxicity.
B. Bone marrow or peripheral blood stem cell transplantation is potentially curative for MF, but it is associated with a high rate of morbidity and mortality. Therefore, standard allogeneic transplantation should be considered primarily for younger patients who have high-risk disease. Nonmyeloablative conditioning regimens can reduce the risks of transplantation and extend its use to older patients.
C. Splenectomy should be approached cautiously. The mortality rate is <10% if the procedure is performed by experienced surgeons, but postoperative morbidity exceeds 30%. Peripheral blood cytopenias may persist or worsen if a significant amount of extramedullary hematopoiesis was carried out in the spleen prior to splenectomy. There is no reliable preoperative test to predict the contribution of splenic hematopoiesis. Progressive hepatomegaly and an increased risk for blast transformation after splenectomy are also major concerns.
Splenectomy in medically suitable patients with MF can be considered in the following situations:
1. Persistent discomfort because of a grossly enlarged or infarcted spleen
2. Refractory anemia accompanied by increasingly more frequent transfusions
3. Refractory, severe thrombocytopenia in the absence of disseminated intravascular coagulation
4. Hypercatabolic symptoms that are not responsive to myelosuppression
5. Portal hypertension associated with bleeding varices. Based on circulatory dynamic studies performed at the time of surgery, the following procedures should be performed:
a. Splenectomy alone for portal hypertension secondary to markedly increased blood flow from the liver to the spleen
b. Portosystemic shunt may be considered for portal hypertension secondary to intrahepatic obstruction to blood flow.
D. Radiation therapy (RT)
1. Small doses (20 to 300 cGy per course given in daily fractions of 20 cGy) of RT to the spleen can relieve pain and early satiety secondary to massive splenomegaly in MF, usually for a few months. RT can be considered when splenectomy is contraindicated. Blood counts must be monitored carefully during splenic RT because severe cytopenias can develop rapidly.
2. RT may also palliate focal areas of periostitis, extramedullary hematopoietic tumors, and ascites secondary to myeloid metaplasia of the peritoneum.
CHRONIC EOSINOPHILIC LEUKEMIA (CEL) AND HYPEREOSINOPHILIC SYNDROME (HES)
I. DEFINITION AND MANIFESTATIONS
A. CEL and HES are characterized by blood and bone marrow eosinophilia and by tissue infiltration with relatively mature eosinophils, resulting in multisystem organ dysfunction. CEL is distinguished from HES by the former having evidence of clonality, such as a cytogenetic abnormality or increased bone marrow blasts. In addition, the WHO classification distinguishes CEL from myeloid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1 based on the characteristic chromosomal translocations observed in the latter conditions. HES, on the other hand, is idiopathic and not clonal. Because CEL and HES have overlapping clinical manifestations, they can be difficult to distinguish, and HES is a diagnosis of exclusion. CEL and HES occur predominantly in men, usually between the ages of 20 and 50 years.
B. Etiology and pathogenesis. CEL is associated most commonly with a small interstitial deletion on chromosome 4q12 that fuses the PDGFRA gene to the FIP1L1 gene, producing a novel transforming fusion gene. This deletion is too small to be detected by routine cytogenetics, but it can be identified by fluorescence in situ hybridization (FISH) or reverse transcriptase polymerase chain reaction (PCR) for the FIP1L1–PDGFRA fusion. Rarely, CEL can be associated with a translocation involving the PDGFRB gene on chromosome 5q31–33 and the ETV6 gene on chromosome 12p12–13, resulting in the formation of another novel fusion gene.
The etiology of HES is idiopathic by definition. In some cases, there may be overproduction of cytokines that stimulate eosinophil production, such as granulocyte–macrophage colony-stimulating factor, interleukin-3, or interleukin-5. Other cases may be CEL with occult translocations of PDGFRA or PDGFRB and therefore be misdiagnosed as HES.
C. Organ system involvement
1. Hematopoietic system involvement. The absolute eosinophil count must be >1,500/μL in the absence of other causes of eosinophilia, and usually ranges from 3,000 to 25,000/μL. The eosinophils are usually mature but often contain decreased numbers of granules that are small in size. Half of the patients have a normocytic, normochromic anemia. Bone marrow cytology shows myeloid hyperplasia with 25% to 75% of these cells being eosinophils, which are shifted to the left in maturation. Increased numbers of myeloblasts and cytogenetic abnormalities are absent.
2. Cardiac involvement (55% to 75% of cases). Myocardial necrosis is associated with the presence of increased numbers of eosinophils seen on endomyocardial biopsy. Thrombi develop in the ventricles or atria and can embolize. Mitral or tricuspid valvular regurgitation and restrictive cardiomyopathy due to endomyocardial fibrosis develop after about 2 years of eosinophilia.
3. Neurologic involvement (40% to 70%). Clinical syndromes include cerebral thromboembolism originating in the heart, encephalopathy, and peripheral sensory polyneuropathy. Biopsy findings are inconsistent.
4. Lung involvement (40% to 50%) usually manifests as a chronic nonproductive cough. The chest radiograph is usually clear, but pleural effusions can be present. Pulmonary function test abnormalities are rare in the absence of congestive heart failure or pulmonary emboli arising from the right ventricle. Diffuse or focal infiltrations develop in 20% of patients. Bronchial asthma is a rare occurrence in CEL or HES.
5. Cutaneous involvement. Skin rashes develop in >50% of cases. Urticarial or angioedematous lesions, erythematous papules and nodules, or mucosal ulcers may develop.
6. Involvement of other organs. Splenomegaly develops in 40% of cases. Rheumatologic manifestations include arthralgias, effusions, and Raynaud phenomenon. Eosinophilic gastritis, enterocolitis, chronic active hepatitis, and Budd-Chiari syndrome have been observed in CEL and HES. Visual blurring caused by microemboli or microscopic hematuria may occur.
II. DIFFERENTIAL DIAGNOSIS. See chapter 34, Section IV in “Increased Blood Cell Counts” for eosinophilia.
A. Other chronic MPDs. Patients with CEL or HES rarely have expansions of other cell lines besides eosinophils to the extent seen in the other chronic MPDs and do not develop severe myelofibrosis.
B. Other hematopoietic malignancies, especially acute myelomonocytic leukemia with inv(16) cytogenetics, T-cell lymphoma, and Hodgkin lymphoma
C. Eosinophilic syndromes limited to specific organs lack the multiplicity of organ involvement often found in CEL or HES.
D. Churg-Strauss syndrome is the major vasculitis associated with eosinophilia. It is characterized by asthma, pulmonary infiltrates, eosinophilia, paranasal sinus abnormalities, neuropathy, and blood vessels showing extravascular eosinophils. Asthma is usually absent in HES and may be the only feature that distinguishes it from Churg-Strauss syndrome.
III. DIAGNOSIS
A. Diagnostic criteria for HES
1. Persistently increased absolute eosinophil count >1,500/μL for longer than 6 months
2. Absence of parasites, allergies, or other causes of eosinophilia
3. Evidence of organ system involvement
4. Absence of chromosome abnormalities, which would justify the diagnosis of CEL
B. Helpful studies
1. Complete history and physical examination, CBC, liver and renal function tests, and urinalysis
2. Immunoglobulin E levels and serologic tests for collagen vascular disorders
3. Chest radiograph
4. Electrocardiogram, echocardiogram, and serum troponin T assay to assess cardiac involvement
5. Bone marrow aspirate and biopsy with chromosome analysis
6. FISH and PCR assays for PDGFRA, PDGFRB, and FGFR1 gene rearrangements
7. T-cell receptor gene rearrangement assay to rule out clonal T-cell disorder
8. Biopsy of skin lesions
9. Serum tryptase level and c-KIT mutation analysis to rule out systemic mastocytosis
10. Several stool samples for ova and parasites
11. Duodenal aspirates and blood serology to exclude Strongyloides sp. infection
IV. PROGNOSIS. Historically, >75% of patients survived for at least 5 years and 40% survived at least 10 years, depending on the ability to manage the effects of end-organ damage. Congestive heart failure or a WBC count >90,000/μL at presentation is associated with a poor prognosis. The impact of imatinib therapy on survival has not yet been assessed.
V. MANAGEMENT. All patients with CEL or HES should be given a trial of imatinib 400 mg daily because even patients without identifiable PDGFRA or PDGFRB gene rearrangement have been reported to respond to this therapy. Doses as low as 100 mg/d are effective to treat some patients. When PDGFRA and PDGFRB translocations are present, monitoring of disease status every 3 months while on therapy by quantitative PCR (if available) or FISH should be performed. In patients with baseline cardiac abnormalities, serial monitoring of troponin T levels should be performed after initiating imatinib therapy to monitor for exacerbation of cardiac dysfunction. This potential complication of therapy may be reduced by pretreatment with glucocorticoids of at-risk patients.
Patients not responding to imatinib may benefit from glucocorticoid therapy, although treatment is usually reserved for symptomatic disease. Cytoreductive therapy with HU or IFN-α can sometimes be beneficial for symptomatic patients. These agents are discontinued if organ dysfunction improves and the eosinophil count is reduced to or near the normal range.
MASTOCYTOSIS
I. PATHOGENESIS
Mastocytosis includes a heterogeneous group of diseases characterized by abnormal growth and accumulation of mast cells (MCs) in one or more organ systems. Although not classically listed as a myeloproliferative syndrome, MCs are myeloid cells and are clonally derived from CD34+ progenitors; thus, mastocytosis is included in this chapter.
MCs express stem cell factor receptor (CD117), CD2, and CD25. c-KIT is the proto-oncogene that encodes the tyrosine kinase receptor for stem cell factor. Cutaneous mastocytosis typically presents as urticaria pigmentosa or diffuse cutaneous mastocytosis, accounts for >85% of cases, and usually has a benign course. Malignant mastocytosis is an uncommon disease; it is most frequently reported in Israelis and light-skinned whites. The c-KIT proto-oncogene plays an important role in hematopoiesis in general, in MC growth in particular, and in all categories of MC disease. The mutation seen in MC disorders is located in the tyrosine kinase domain of the c-KIT receptor. Mutations are associated with autonomous phosphorylation and activation of the receptor. More than 80% of patients with systemic mastocytosis (SM) have the point mutation of c-KIT at codon 816 (mostly D816V) detected by PCR or other technologies. The histopathologic diagnosis may be difficult but is facilitated using basic dyes and immunostaining against tryptase.
II. WHO CLASSIFICATION OF MC DISEASE is as follows (note that the D816V mutation has been found in all of these categories):
Cutaneous mastocytosis (CM)
Indolent systemic mastocytosis (ISM)
Aggressive systemic mastocytosis (ASM)
Systemic mastocytosis with associated clonal, hematologic non-MC lineage disease (SM-AHNMD; e.g., AML, CML, MDSs, MPDs, and CEL)
MC leukemia
MC sarcoma and extracutaneous mastocytoma (very rare localized phenomena)
III. CLINICAL FEATURES. CM affecting children accounts for >85% of cases of MC disease. It presents as urticaria pigmentosa or diffuse cutaneous mastocytosis and usually has a benign course that resolves before puberty.
SM is an uncommon disease, affects mostly adults, and is most frequently reported in Israelis and light-skinned whites. MCs infiltrate any organ that contains mesenchymal tissue (particularly the lymph nodes, liver, spleen, and bone marrow) and produce local destructive or fibrotic changes. Organ infiltration often indicates acceleration of the disease.
A. Skin changes. Urticaria pigmentosa is the most common early manifestation of systemic disease. Brownish skin nodules diffusely infiltrated with MCs may be localized or diffuse, flat or raised, bullous, or erythematous. Mild skin trauma may produce urticaria or dermatographia.
B. Organ infiltration may develop years after skin lesions have appeared and is manifested by hepatomegaly, lymphadenopathy, bone pain (osteosclerotic lesions on radiographs are common), bone marrow fibrosis, and, occasionally, MC leukemia. MCs infiltrate any organ that contains mesenchymal tissue (particularly the lymph nodes, liver, spleen, and bone marrow) and can produce local destructive or fibrotic changes. Osteosclerotic lesions on radiographs are common. Extracutaneous organ infiltration often indicates acceleration of the disease. Hyperchlorhydria occasionally occurs and can result in peptic ulcer and malabsorption.
C. Hyperhistaminemia symptoms may be precipitated by exposure to cold, alcohol, narcotics, fever, or hot baths and include the following:
1. Erythematous flushing, urticaria, edema, pruritus
2. Abdominal pain, nausea, vomiting (occasionally diarrhea), flatulence, steatorrhea
3. Sudden hypotension
IV. DIAGNOSIS. The histopathologic diagnosis of SM is made using immunostaining against tryptase, CD117, CD2, and CD25. The source of cells assayed for the c-KIT D816V mutation should be the bone marrow when involved since use of peripheral blood led to falsely negative assays in 80% of cases.
A. CM is confirmed by skin biopsy; bone marrow biopsy is not needed. Serum tryptase levels are normal.
B. SM is diagnosed by biopsies of both skin and bone marrow. Because of its implications regarding treatment, the c-KIT mutation variant should be determined. The diagnosis of SM is established with the major criterion plus one minor criterion or at least three minor criteria.
1. Major criterion for diagnosis: multifocal dense MC infiltrates (≥15 MCs per infiltrate) in the bone marrow or other extracutaneous organ
2. Minor criteria
a. In biopsy specimens of bone marrow or other extracutaneous lesions, >25% of MCs are spindle-shaped or have an atypical morphology.
b. Expression of CD2 and/or CD25 on blood, marrow, or organ MC
c. c-KIT point mutation at codon 816 (mostly D816V) in marrow or extracutaneous organ
d. Serum tryptase level >20 ng/mL (except in cases of SM-AHNMD, where this criterion does not apply)
V. MANAGEMENT. In the vast majority of patients with ISM, the condition is very stable over many years. Results of various treatments have been unsatisfactory.
A. Histamine antagonism by H1- and H2-receptor blockade may help flushing, itching, and gastric distress. Cyclo-oxygenase inhibition may prevent prostaglandin D2–induced hypotension when indicated. Oral cromolyn (200 mg PO q.i.d.) may prevent GI symptoms and bone pain.
B. Cytoreduction is considered when the patient develops evidence of decreased organ function such as anemia (hemoglobin <10 g/dL), neutropenia (<1000/mL), thrombocytopenia (<100,000/mL), abnormal liver function tests, ascites, hypersplenism, malabsorption with weight loss, or large osteolytic lesions and/or severe osteoporosis.
1. Cladribine (2-CdA) is associated with a major response rate of about 50%. The dosing schedule is 0.1 to 0.15 mg/kg/d given IV over 2 to 3 hours for 5 consecutive days every 2 to 6 months for one to six cycles.
2. IFN-α2b is associated with a major response rate of about 20%, as well as significant morbidity from the drug. Doses have ranged from 9 to 42 million units per week, usually given with glucocorticoids. Alkylating agents, cyclosporine, IFN, and corticosteroids occasionally help.
3. Imatinib (Gleevec) inhibits the KIT tyrosine kinase. However, the D816V mutation, which is present in the vast majority of patients, confers resistance to imatinib.
Imatinib is very effective in patients with SM and eosinophilia who harbor the FIP1L1–PDGFRA fusion but not the D816V mutation. The responsive patients tended to have a high serum tryptase level (>150 ng/mL) and to be females with skin lesions. Patients with SM and eosinophilia who do express the D816V mutation, however, are not responsive to imatinib. Dasatinib and nilotinib are also inactive against the D816V KIT mutation.
a. For ASM associated with eosinophilia, the starting dose for imatinib is 100 mg/d.
b. For ASM without the D816V c-KIT mutation or with unknown c-KIT mutational status, the starting dose of imatinib is 400 mg/d.
C. Treatment approach
1. CM and ISM. Patients are treated with drugs targeting only histamine mediators unless they have severe osteopenia or recurrent shock-like episodes. Patients with smoldering SM are observed expectantly; cytoreduction can be considered with progression.
2. ASM with slow progression can be treated with 2-CdA or IFN-α. In the absence of D816V, consider imatinib.
3. ASM with rapid progression or MC leukemia is treated with polychemotherapy, with or without 2-CdA or IFN. In the absence of D816V, consider imatinib. Stem cell transplantation can also be considered.
4. SM-AHNMD components are treated independently.
Suggested Reading
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Swerdlow SH, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer; 2008.
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Polycythemia Vera
Fruchtman SM, et al. A PVSG report on hydroxyurea in patients with polycythemia vera. Semin Hematol 1997;34:17.
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Essential Thrombocythemia
Carobbio A, et al. Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors, and Jak2 mutation status. Blood 2007;109:2310.
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Myelofibrosis
Ballen KK, et al. Outcome of transplantation for myelofibrosis. Biol Blood Marrow Transplant 2010;16:358.
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Hypereosinophilic Syndrome
Cools J, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 2003;348:13.
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Mastocytosis
Garcia-Montero AC, et al. KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on mastocytosis (REMA) in a series of 113 patients. Blood 2006;108:2366.
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