Gary Schiller, Mary C. Territo, and Dennis A. Casciato
ACUTE LEUKEMIA
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence. Acute leukemia afflicts 3 to 4/100,000 population annually (11,000 new cases/year) in the United States. Children account for 25% of cases. Acute leukemia is the most common malignant disease of childhood.
1. Cell type. Of cases of acute lymphoblastic leukemia (ALL), 80% occur in children, and 90% of cases of acute myelogenous leukemia (AML) occur in adults.
2. Age. In adults, AML rates begin to rise exponentially after 50 years of age; the age-specific incidence rate is 3.5/100,000 in adults 50 years of age, and increases significantly to 15 at age 70 and 35 at age 90. The mean age for AML in the United States is 63 years. A peak incidence of ALL occurs at 3 to 4 years of age; the incidence steadily decreases after 9 years of age and rises in incidence after 40 years of age. Despite being considered a childhood cancer, the age-related increase in incidence of most cancers also pertains to ALL.
3. Sex. Acute leukemia shows a male predilection only in very young and elderly patients.
B. Etiology
1. Hereditary
a. Hereditary syndromes that are associated with chromosomal abnormalities, a high risk of acute leukemia, and excessive chemosensitivity include the following:
(1) Bloom syndrome is a recessively transmitted disease occurring pre-dominandy in people of Jewish ancestry. Chromosome breaks are readily found in cytogenetic studies. The syndrome is characterized by short and thin stature, delicate features, telangiectatic lesions over the malar eminences of the face, photosensitivity, and a variety of other cutaneous abnormalities (acanthosis nigricans, hypertrichosis, ichthyosis, and café au lait spots). AML is the type of leukemia that develops in these patients.
(2) Fanconi congenital pancytopenia (Fanconi anemia) is an autosomal recessive disease often associated with multiple chromosomal abnormalities. Clinical features include skeletal abnormalities (absence of radii, hypoplasia of the thumbs), squinting, microcephaly, small stature, and hypogonadism. AML, as well as skin carcinoma, often complicates this syndrome.
(3) Down syndrome (mongolism, trisomy 21) is associated with an increased risk for both AML and ALL.
(4) Ataxia telangiectasia is associated with an increased incidence of lymphoid malignancies, including ALL.
b. Siblings of younger patients with acute leukemia have a fivefold increased risk of developing leukemia. There is about a 15% concordance if one member of a pair of monozygotic twins develops AML, although this may be due to placental metastasis.
2. Radiation is a well-documented leukemogenic factor in humans. Increased incidence of leukemia proportional to the cumulative radiation dose has been demonstrated in populations exposed to atomic bombs, in patients irradiated for ankylosing spondylitis, and in radiologists (before current protective precautions). Doses <100 cGy are not believed to be associated with the development of leukemia. The types of leukemia induced by radiation are ALL, AML, and chronic myelogenous leukemia (CML), but not chronic lymphocytic leukemia.
3. Viruses have not been shown to be etiologic for acute leukemias in humans, although an association is seen with Epstein-Barr virus with ALL-L3 (Burkitt leukemia). HTLV-1 is discussed in Chapter 21, in “Non-Hodgkin Lymphoma.”
4. Chemicals. The ability of chemicals to produce acute leukemia and pancytopenia is likely related to their ability to mutate or ablate the bone marrow stem cells.
a. Benzene and toluene were identified as carcinogens associated with acute leukemia a century ago. Acute leukemia develops 1 to 5 years after exposure and is often preceded by bone marrow hypoplasia, dysplasia, and pancytopenia.
b. Drugs. Drug-induced acute leukemia is usually preceded by myelodysplasia. Alkylating agents and topoisomerase II inhibitors given for prolonged periods are associated with a markedly increased risk of AML when compared with the general age-matched population. Exposure to arsenicals has also been implicated as an increased risk factor for leukemia development. Secondary AML currently accounts for 10% to 20% of all AML cases.
5. Hematologic diseases. Transformation into acute leukemia (“blast crisis”) is seen in >80% of cases of CML and is part of its natural history. Patients with myelodysplastic syndromes (MDS) clearly have an increased likelihood of evolution to AML. The incidence of AML in myeloproliferative disorders (MPD), myeloma, and certain solid tumors is increased by the use of chemotherapy.
6. Smoking. Cigarette smoking is associated with approximately 50% increase in leukemia risk. Cigarette smoking has a deleterious effect on survival in AML by shortening complete remission duration and subsequent survival. It has been associated with severe infections during aplasia. Leukemogenic compounds favoring complex karyotypic abnormalities could also be involved.
II. PATHOLOGY, CLASSIFICATION, AND NATURAL HISTORY OF ACUTE LEUKEMIA
A. Classification
1. Morphologic features of acute leukemias
a. The French–American–British (FAB) histopathologic classification of acute leukemia was originally proposed in 1976. This system has been supplanted by the World Health Organization (WHO) classification below. The FAB defined the M1–M7 and L1–L3 subtypes of acute leukemia as follows but is frequently left out in modern interpretations of AML:
b. Auer rods are abnormal condensations of cytoplasmic granules. Their presence in the immature cells distinguishes AML from ALL; their absence is not diagnostically helpful.
c. Cytologic features of the acute leukemia subtypes, particularly the nuclear configurations, cytoplasm granularity, and prevalence of Auer rods, are shown in Appendix C7.
d. Cytochemistry. Identifying the type of early cell may be difficult, but it is facilitated by flow cytometry. Traditionally used histochemical techniques, particularly for myeloperoxidase and nonspecific esterase (see Appendix C7), are seen in AML. Myeloperoxidase activity can be assessed by both cytochemistry and flow cytometry.
e. Immunologic markers assessed by flow cytometry usually distinguish ALL from AML as well as identify their subtypes. These markers are also summarized in Appendix C7. Antibodies against platelet glycoproteins (CD41 or CD61) are useful in distinguishing megakaryocytic (M7) leukemia. Flow cytometry has largely replaced cytochemistry for classification of acute leukemias in most centers. Flow cytometry is most useful when using antibodies against panmyeloid antigens (CD13 and CD33), monocyte antigens (especially CD11b and CD14), and hematopoietic progenitor cell antigens (CD34 and HLA-DR).
2. The WHO classification has replaced the FAB classification. The FAB classification, which provided a consistent morphologic and cytochemical framework, did not reflect the cytogenetic or clinical diversity of the disease. The WHO classification system takes into account the developing knowledge of the biology of AML, its distinct subtypes divided into diseases characterized by proliferative biology and diseases characterized by disorders of maturation. The WHO classification of AML is as follows (with corresponding FAB designations and approximate proportions of AML cases in brackets):
a. AML with recurrent cytogenetic abnormalities (Table 25.1)
AML with abnormal bone marrow eosinophils and inv(16)(p13;q22) or t(16;16)(p13;q22) [M4 Eo, 10% to 12%]
Acute promyelocytic leukemia and variants; t(15;17)(q21;q11) and its variants [M3, M3v; 5% to 8%]
AML with t(8;21)(q22;q22); (AML1/ETO) [M2, 5% to 12%]
AML with 11q23 (MLL) abnormalities [M5 or M1, 5% to 6%]
Table 25.1 Cytogenetic Abnormalities and Prognosis of Acute Myelogenous Leukemia in Adults
aFLT (a tyrosine kinase growth factor receptor) mediates hematopoietic stem cell proliferation and differentiation. FLT3 mutations (internal tandem duplication of exon 11 and 12 termed FLT3-ITD) are common in AML and could be an important prognostic indicator.
b>50% of AML cases in infants.
b. AML with multilineage dysplasia [M2 or M6]
Following MDS or MDS/MPD
Without antecedent MDS
c. AML and MDS, therapy-related (alkylating agents, topoisomerase inhibitors, other types)
d. AML not otherwise categorized
AML minimally differentiated [M0, 5%]
AML without maturation [M1, 10%]
AML with maturation [M2, 30% to 45%]
Acute myelomonocytic leukemia [M4, 15% to 25%]
Acute monoblastic and monocytic leukemia [M5a, M5b; 5% to 8%]
Acute erythroid leukemia [M6, 5% to 6%]
Acute megakaryoblastic leukemia [M7, 3% to 5%]
Acute panmyelosis with myelofibrosis [M7, rare; “acute myelofibrosis”]
Acute basophilic leukemia (very rare)
e. Myeloid sarcoma (“chloroma,” “granulocytic sarcoma”; extramedullary masses of monoblasts or myeloblasts)
f. Acute lymphocytic leukemias are now included in the WHO classification of lymphoid tissues as “precursor B-cell lymphoblastic leukemia/lymphoma” and “precursor T-cell lymphoblastic leukemia/lymphoma” (see Appendix C6). These were designated as L1, L2 or L3 subtypes of ALL in the FAB system.
3. The two most significant differences between the FAB and the WHO classifications are
a. A lower blast threshold for the diagnosis of AML: The WHO defines AML when the blast percentage reaches 20% in the bone marrow (rather than 30% as defined by FAB).
b. Patients with recurring clonal cytogenetic abnormalities should be considered to have AML regardless of the blast percentage: t(8;21)(q22;q22), t(16;16)(p13;q22), inv(16)(p13;q22), or t(15;17) (q22;q12).
4. A more clinically relevant classification of AML can be achieved if two distinct subgroups with different biologic features are recognized.
a. AML that evolves from MDS is associated with multilineage dysplasia, poor-risk cytogenetics, and a poor response to therapy. The incidence of this type increases with age and is consistent with the hypothesis that MDS and MDS-related leukemia results through multiple insults to the molecular constitution of the hematopoietic stem cell.
b. AML that arises de novo usually lacks significant multilineage dysplasia. It is often associated with favorable-risk cytogenetic findings and has a better response to therapy with a higher likelihood of failure-free and overall survival. This type of leukemia has a relatively constant incidence throughout life and is the type most likely to be observed in children and young adults. Some types are clearly related to disorders of differentiation such as AML characterized by core-binding-factor abnormalities, t(8;21) or inv(16) or t(15;17). Others are characterized more by proliferative defects such as AML with normal cytogenetics (often with FLT3 mutations).
B. Pathology. Bone marrow examination in acute leukemia demonstrates hypercellularity with a monotonous infiltration of immature cells. Normal marrow elements are markedly decreased. Erythroblast maturation is commonly megaloblastoid in all types of AML, especially subtype M6. Cytologic features of the AML subtypes are shown in Appendix C7.
C. Natural history. Leukemia cells generally replicate more slowly than their normal counterparts. Hematopoiesis is disturbed even before the proportion of blast cells in the marrow is conspicuously increased. Immature and malfunctioning leukocyte progenitors progressively replace the normal bone marrow and infiltrate other tissues. Relapse is inevitable in most patients unless complete remission after induction and consolidation therapy persists at least 4 years. Relapse is associated with progressively poorer response to therapy and, if second or subsequent remission is achieved, progressively shorter duration of remission. Unsuccessful therapy is usually followed by death within 2 months. Death in acute leukemia is usually caused by either infection or hemorrhage.
D. Biology of acute promyelocytic leukemia (APL)
1. Morphology. Classified as M3 in the FAB classification, APL is characterized morphologically by the presence of blasts cells with heavy azurophilic granules, bundles of Auer rods, and a bilobed or reniform nucleus. Although most APL cases fit the description of hypergranular blasts, a cytologic microgranular variant (M3v) has been identified. The blasts in M3v have a bilobed, multilobed, or reniform nucleus and, under the usual staining, are devoid of granules or contain only a few fine azurophilic granules. The apparent paucity of granules is a result of their submicroscopic size. M3v is commonly associated with hyperleukocytosis and accounts for 15% to 20% of APL cases.
2. Immunophenotyping. APL blasts are positive for CD33 and CD13 but negative for HLA-DR and usually have a low-level expression of CD34. M3v blasts tend to be positive for CD34, CD2, and CD19.
3. Cytogenetics. Both the classic and the M3v forms of APL are associated with a specific cytogenetic abnormality, t(15;17)(q22;q21). This translocation disrupts the PML gene on chromosome 15 and the retinoic acid receptor α(RARα) on chromosome 17, resulting in a fusion gene (PML/RARα). The protein product of PML/RARα retains the retinoic acid (RA) ligand-binding domain and plays a key role in leukemogenesis, as well as in mediating the response to retinoids. Expression profiling by microarray is likely to be used in the future as an adjunct to cytogenetics or as a replacement.
a. Four other alternative translocations associated with APL have been characterized:
t(11;17)(q23;q21) involving the PLZF gene on chromosome 11
t(5;17)(q35;q21) involving the NPM gene on chromosome 5
t(11;17)(q13;q21) involving the NuMA gene on chromosome 11
t(1;17) occurs but is rare.
b. PML/RARα-mediated APL is sensitive to retinoids, as are the variants NPM/RARα- and NuMA/RARα-mediated APL. In contrast, PLZF/RARα-associated APL is considered resistant to retinoids as well as to arsenic trioxide.
III. DIAGNOSIS
A. Symptoms
1. Nonspecific fatigue and weakness are the most common symptoms. Bruising, fever, and weight loss are frequent.
2. Central nervous system (CNS) involvement may be manifested by headaches, nausea, vomiting, blurred vision, or cranial nerve dysfunction.
3. Abdominal fullness usually reflects hepatosplenomegaly, which is more frequent in ALL or the monocytic subtype of AML.
4. Oliguria may result from dehydration, uric acid nephropathy, or disseminated intravascular coagulation (DIC).
5. Obstipation may signify disorders of hypercalcemia or hypokalemia; potassium wasting may occur in monocytic leukemia.
B. Physical findings
1. General examination
a. Pallor, petechiae, and purpura are the most frequent findings in acute leukemia.
b. Sternal tenderness to palpation, lymphadenopathy, and hepatosplenomegaly are much more common in ALL than in AML.
c. Meningismus may indicate CNS involvement. CNS leukemia is most common in ALL. When seen in patients with AML, M4 (particularly with abnormal bone marrow eosinophils) and M5 subtypes are commonly involved. It is far less common in the remaining AML subtypes but can be seen at relapse.
d. Leukemia infiltrates in the optic fundus appear like Roth spots with flame hemorrhages.
2. Extramedullary infiltration or masses of blasts, especially involving the skin, orbits, breasts, gingivae, or testes, are most likely to occur in acute monocytic leukemias (M5) and ALL.
3. Bleeding out of proportion to the degree of thrombocytopenia suggests the presence of DIC, which is particularly common in APL.
4. Signs of infection should be carefully elicited.
C. Laboratory studies. Evaluation of the peripheral blood smear should be done in every case where leukemia is in the differential diagnosis. Finding circulating leukemic blasts establishes the diagnosis, but this should be confirmed by the evaluation of the bone marrow from which successful cytogenetic analysis is more likely. Fluorescent in situ hybridization (FISH) for common, recurring molecular abnormalities may identify distinct clonal abnormalities not easily elicited by conventional cytogenetics.
1. Hemogram
a. Leukocytes. The WBC count is elevated in about 60% of cases, normal in 15%, and decreased in 25%, depending on the referral base of the treatment center. Circulating blasts are demonstrated in virtually every case of acute leukemia; however, some patients present with a very low percentage of circulating blasts.
b. Erythrocytes. 90% of patients have a normocytic, normochromic anemia, which is usually severe. Reticulocytes are nearly always decreased. Macrocytosis usually reflects megaloblastic maturation and suggests a history of prior MDS. Circulating nucleated red blood cells should always prompt further evaluation of the bone marrow.
c. Platelets are decreased in 90% of cases and are <50,000/μL in about 40%.
2. Biochemical tests that should be obtained include the following:
a. Serum uric acid, ionized calcium, phosphorus, magnesium, and lactic dehydrogenase (LDH) levels
b. Serum renal and liver function tests
c. Coagulation tests for DIC
3. Bone marrow findings are discussed earlier, in Section II. Blasts in excess of 20% establish the diagnosis of acute leukemia.
4. Flow cytometry results for AML are shown in Appendix C7. Results for ALL are shown in Appendix C5.
5. Cytogenetic testing is essential in every new patient because of its prognostic significance. Standard banded chromosome evaluation as well as FISH using a panel of the common acute leukemia probes should be obtained. Cytogenetic abnormalities distinguish unique types of AML and are the single most predictive factor for response to treatment, duration of response, and relapse. The abnormalities are categorized as “favorable-,” “standard- or intermediate-,” and “unfavorable- or poor-” risk cytogenetics (Table 25.1).
6. Molecular studies. Advances in defining genomic variations have identified a number of molecular markers that are independent prognostic factors for AML outcome and are particularly important in patients with normal cytogenetics (45% of AML patients). So far, the most clinically relevant abnormalities have been identified in FLT3 (Fms-like tyrosine kinase 3), NPM1 (nucleophosmin 1), and CEBPA (CCAAT enhancer-binding protein-alpha).
FLT3-ITD (internal tandem duplications) and MLL-PTD (MLL gene partial tandem duplications) impart an unfavorable prognosis, whereas NPM1 and CEBPA mutants are more favorable. FTL3 mutations are now considered one of the most common mutations in AML (35% in older adults). Determining these markers at the time of diagnosis is important for determining prognosis of the patient and treatment approaches.
7. Radiographic studies that should be obtained include the following:
a. Chest radiograph to look for leukemic or infectious infiltrates
b. Bone radiographs of painful or tender areas to look for periosteal elevation or bony destruction from extramedullary bone masses
c. CT scans of the chest and abdomen/pelvis should be obtained on patients with ALL to evaluate lymphadenopathy and organomegaly.
8. Cerebrospinal fluid (CSF) examination should be performed at some time in all patients with ALL, where it is usually part of the induction therapy. CSF evaluation should be done in patients with acute monocytic leukemia and in those patients with AML who have meningismus or CNS abnormalities. Cytarabine or methotrexate may be instilled into the CSF at the completion of the examination because of the possibility of leukemic contamination from the blood (see Section IX.B).
The fluid should be cultured for acid-fast bacilli, fungi, and bacteria. Meningeal involvement with leukemia is associated with decreased sugar and increased protein concentrations, pleocytosis, and leukemia cells identified by cytologic examination.
9. Surveillance bacterial cultures of the nose, pharynx, axillae, and perianal regions identify organisms that may have colonized the patient. These cultures, however, are not commonly helpful in determining the etiologic agents responsible for serious infection in the patient with neutropenia. Cultures of the blood, urine, sputum, and any symptomatic areas should be obtained in all febrile leukemia patients.
IV. PROGNOSTIC FACTORS AND SURVIVAL
Complete remission (CR) is the paramount prognostic factor in all forms of acute leukemia. A CR is defined as all of the following:
• Bone marrow contains <2% blasts.
• Granulocyte and platelet counts have recovered.
• Resolution of organomegaly may be required in a clinical-trial setting.
A. AML prognostic factors. The most important factors portending a poor prognosis in AML are
1. Advanced age (typically described as age >60)
2. Antecedent myelodysplasia
3. Therapy-related AML
4. High WBC count at presentation
5. Unfavorable cytogenetics and molecular markers
B. ALL prognostic factors. ALL is not a uniform disease but consists of subtypes with distinct biologic, clinical, and prognostic features. The most important prognostic factors are age, initial WBC count, and immunophenotype, as well as cytogenetic features.
1. Favorable prognostic factors in adult ALL. The Cancer and Leukemia Group B (CALGB) identified the following clinical and biologic features that correlate with favorable long-term outcome:
a. Younger age
b. WBC count (≤30,000/μL)
c. Absence of the Philadelphia chromosome (Ph1)
2. Adverse prognostic factors in ALL
a. Clinical characteristics
(1) Older age
(2) WBC count >30,000/μL
(3) Late achievement of CR (occurring after >3 to 4 weeks)
b. Immunophenotype
(1) Pre–B-cell ALL
(2) Pre–T-cell ALL
(3) Mature T-cell ALL
c. Cytogenetics and molecular genetics
(1) t(9;22)(p34;q11) [Ph1]; BCR/ABL fusion gene: occurs in 25% of adults with ALL
(2) t(1;19)(q23; p13); PBX/E2A: occurs in 25% of children with ALL
(3) Abnormal 11q23; MLL gene rearranged: poor prognosis in infants <1 year of age and adults
(4) t(4:11)/ALL1-AF4; common clinical features of this subtype include
(a) High WBC count (median 180,000/μL)
(b) L1 or L2 morphology with B-cell lineage
(c) Unfavorable immunophenotype (CD10−, CD19+, HLA-DR+) with frequent coexpression of myeloid markers (CD15+, CDw65+)
(5) Expression of multidrug resistance (rarely assayed)
3. Response rates and survival
a. AML. 40% to 70% of patients achieve a CR to standard induction chemotherapy. The median survival is 12 to 24 months for patients who achieve CR; the median duration of first remission is 10 to 12 months. Twenty percent to forty percent of patients who achieve CR (5% to 30% of all patients) survive ≥5 years, and many of these patients may be cured. Most relapses occur within 3 years.
Approximately 50% of patients with “favorable” cytogenetics who achieve CR survive. Only 5% to 15% of patients in CR achieve long-term survival if they are >60 years or develop AML following primary or secondary MDS.
b. ALL (also see Acute Leukemia in Chapter 18, Cancers in Childhood)
(1) “Standard-risk” children (1 to 9 years of age, WBC count <50,000/μL, precursor B-cell subtype, and without adverse prognostic factors). Of cases, <20% relapse if properly treated, and >80% have a 5-year disease-free survival. Relapse or death is unusual in these patients after 4 years of continuous CR.
(2) “High-risk” children (those with adverse prognostic factors) have remission duration and survival similar to those of adults, yet some series report 70% of patients surviving disease-free for 4 years. The survival time for infants is <2 years.
(3) Adolescents and adults have a median first CR duration of 12 to 24 months and a median survival time of 24 to 30 months. Late adolescents (17 to 21 years of age) appear to have a substantially improved survival time if treated with aggressive pediatric protocols. The median survival time is <18 months for patients >60 years of age with an elevated WBC count at presentation.
V. MANAGEMENT OF EVERY PATIENT WITH ACUTE LEUKEMIA WHO MAY UNDERGO ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT)
The following precautions are very important in all patients (generally, <70 years of age) who are eligible for allogeneic HSCT:
• Leukocyte reduction and irradiation of all administered blood products
• Obtain HLA typing of the patient for both class I and class II antigens on admission and before giving any treatment that will suppress blood counts.
• Assess cytomegalovirus (CMV) antibody titers on admission. All blood products should be screened and negative for CMV until titers become available. CMV-seronegative patients should probably receive CMV-negative products if allotransplant is ever contemplated, whereas CMV-positive patients can receive CMV-safe products (positive but leukofiltered).
VI. MANAGEMENT OF AML
A. Remission induction. Intensive chemotherapy, nearly always to the point of severe myelosuppression (which generally occurs about 7 to 12 days after treatment is begun), is presently required to achieve CR in patients with AML. Cytarabine and an anthracycline are usually administered. Cytarabine has been given in doses ranging from 100 mg/m2 to 6,000 mg/m2, but it is not clear that higher dosages in induction give better results. Daunorubicin, idarubicin, and mitoxantrone at equipotent doses also appear to give similar results. Daunorubicin at 45 mg/m2 is definitely considered to be inadequate; higher dosages (60 to 90 mg/m2) are associated with better overall survival and no increase in grade 3 to 5 toxicities or early death. Idarubicin may induce higher remission rate in patients with a high WBC count at presentation. A typical regimen is as follows:
Cytarabine, 200 mg/m2/d by continuous IV infusion for 7 days
Daunorubicin, 60 to 90 mg/m2 (or idarubicin, 12 mg/m2; or mitoxantrone, 12 mg/m2) IV push on days 1, 2, and 3
If the blasts are not cleared from the blood and bone marrow after the first course of treatment, and if the patient can tolerate another such intensive treatment, the combination therapy is repeated again. A CR usually is achieved about 1 month after initiating treatment. More than 95% of CR is achieved with one or two courses of induction chemotherapy.
1. Toxicity of induction therapy
a. Tumor lysis syndrome can occur with its associated hyperuricemia, hyperphosphatemia, hypocalcemia, and hyperkalemia. Patients with acute leukemia should be given allopurinol (300 to 600 mg daily), if possible beginning 12 to 48 hours before starting chemotherapy.
b. Cardiac abnormalities. Anthracyclines may be associated with electrocardiographic changes, arrhythmias, or congestive heart failure. All patients must have a nuclear heart scan or an echocardiogram to assess the left ventricular ejection fraction before starting an anthracycline.
c. Tissue necrosis. Anthracyclines are vesicants and, if infiltrated out of the veins into the tissues, will cause severe tissue necrosis. A safer approach would be to use a well-secured central venous access catheter (i.e., Hickman catheter), which should be checked for position and good blood return before infusing the anthracycline.
d. Pancytopenia secondary to bone marrow suppression is both caused by the disease and a goal of therapy. This results in infectious and hemorrhagic complications. Patients will also become dependent on transfusions until remission is achieved and normal hematopoiesis is restored.
e. Nausea and vomiting tend to be minimal with an effective antiemetic regimen. The emetic potential of cytarabine is low, but patients need effective antiemetics during the anthracycline administration. A typical regimen involves serotonin antagonist (ondansetron, dolasetron, or granisetron) and dexamethasone (10 mg PO daily) for the 3 days of anthracycline administration.
f. Alopecia is the rule and is usually reversible.
g. Toxicity of high-dose cytarabine. When used at high dose (2 to 3 g/m2 over 1 to 3 hours), cytarabine can be associated with cerebellar, ophthalmologic, and GI toxicity, particularly in patients >60 years of age. These toxicities occur in much lower frequency when given in lower dosages (1.5 g/m2) or when a much lower dose of drug is infused over longer periods of time (100 to 400 mg/m2 by continuous IV infusion).
2. Elderly patients. The treatment of patients ≥60 years of age is controversial. Older patients often cannot tolerate the toxic effects of intensive induction therapy as well as can younger patients; the treatment-related mortality during induction is between 10% and 30% with intensive regimens. Furthermore, elderly patients often develop AML with adverse disease features, following antecedent MDS or with high-risk cytogenetics. Remission rates are low. Yet, several studies have shown that aggressive treatment results in improved survival and quality of life when compared to palliative care alone.
a. Unfavorable risk factors that portend a grave prognosis and short survival are
(1) Age ≥75 years
(2) Antecedent hematologic disorder for more than 1 year
(3) Poor-risk cytogenetics
(4) WBC >50,000/μL
(5) LDH >600 IU/L
(6) Poor performance status (>2)
b. Patients who do not have the above unfavorable risk factors can be treated with the following regimen (more intensive daunorubicin dosage has not been shown to be beneficial in this age group):
Cytarabine, 100 mg/m2/d by continuous IV infusion for 7 days, and Daunorubicin, 60 to 90 mg/m2 (or idarubicin, 12 mg/m2) IV push on
days 1, 2, and 3
c. Less intensive regimens, which have been associated with less myelosuppression and fewer early deaths, for elderly patients who are in good general medical condition include
(1) Cytarabine, 100 mg/m2/d for 5 days given by continuous IV infusion and idarubicin, 12 mg/m2 IV for one dose only
(2) Various doses and schedules of drugs approved for myelodysplasia, such as decitabine and azacytidine
(3) “Low-dose cytarabine” (10 mg/m2 SC once or twice daily or 20 mg SC twice daily for 10 days every 4 to 6 weeks)
(4) Investigational agents such as clofarabine (approved for the treatment of ALL) and sapacitabine
d. The use of supportive care alone is a reasonable option for some elderly patients with AML, particularly for those who are not in good general medical condition, although survival is typically measured in weeks.
B. Postremission therapy. After CR is achieved, the goal is to prevent recurrence. Leukemia cells that are not clinically apparent are nearly always present in the bone marrow. Therapy to eradicate residual leukemia is required, or recurrence is inevitable. The best form of postremission therapy, however, remains controversial.
1. Patients <60 years of age are usually presented three potential postremission options.
a. Intensive chemotherapy. Relatively high doses of drugs are given shortly after the patient has achieved CR, has regained normal hematologic function, and has recovered clinically from any complications of prior therapy. Cytarabine alone, or with an anthracycline, is commonly used.
A randomized study treated patients <60 years of age with four cycles of consolidation cytarabine using three different dosages (100 mg/m2, 400 mg/m2, and 3 g/m2). Cytarabine was given over 3 hours every 12 hours on days 1, 3, and 5 for a total of six doses. The higher dose of cytarabine [HDAC] achieved a 45% disease-free survival at 4 years, whereas lower doses were associated with poor survival (25% in the 100 mg/m2 group). Three or four cycles of HDAC are given to patients with favorable-risk AML.
b. Autologous HSCT may offer a lower risk of relapse compared with intensive chemotherapy, but relapse remains higher than that associated with allogeneic transplantation. The major cause of death remains disease recurrence.
Three prospective randomized trials comparing intensive chemotherapy with autologous HSCT demonstrated a lower relapse rate in the transplant arm (40% vs. 57%), but no overall survival advantage (56% vs. 46%). The high transplant-related mortality rate in these cooperative group studies (12%) offset the antileukemic advantage provided with the autograft. With transplant mortality now decreasing to <5%, this may translate into improved overall survival for the autografted patients.
c. Allogeneic HSCT. Most prospective studies have failed to show a survival advantage for allogeneic transplantation in good-risk patients (those with favorable cytogenetics) in first remission. On the other hand, reduced relapse and improved disease-free survival was demonstrated in standard-risk patients. Poor-risk patients with unfavorable cytogenetics seem to derive the maximal benefit from allogeneic HSCT.
2. Patients older than 60 years. Although all large studies have included postremission therapy in these patients, there is no standard postremission strategy. Older patients did not benefit from any dosage of cytosine. A single cycle of HDAC adjusted for the patient’s age and comorbidities is a reasonable choice for these patients. With reduced-intensity conditioning regimens, allogeneic HSCT has become a valid option.
C. Treatment of relapses. Relapses in AML are typically systemic (i.e., in the marrow and elsewhere). Occasionally, extramedullary relapse (e.g., chloromas in skin or lymph nodes) may precede systemic relapse. Up to half of those with recurrent AML achieve a second CR using either the same drugs that induced first remission or investigational drugs. A variety of investigational drugs have been developed to supplant high-dose cytarabine in the relapsed setting. Eligible patients with an available histocompatible stem cell donor should be strongly considered for allogeneic HSCT.
VII. MANAGEMENT OF ACUTE PROMYELOCYTIC LEUKEMIA (APL)
A. Induction. All-trans-retinoic acid (ATRA, 45 mg/m2/d in two divided doses) is given daily throughout the induction period. ATRA should be begun as soon as the diagnosis of APL is suspected (even before proven by flow cytometry). Either idarubicin is given in conventional doses (12 mg/m2) but with increased number of doses (on days 2, 4, 6, and 8 of the induction course) or daunorubicin is given for 3 consecutive days. The role of cytarabine is not established for APL, but it may contribute to lower relapse rates, especially in those with high-risk disease. CR rates were in the range of 70% to 95% in the Italian cooperative group (GIMEMA) and the Spanish cooperative group (PETHEMA) studies. Both ATRA and arsenic trioxide act as differentiation agents in APL.
B. Consolidation. Following CR in APL, it is mandatory to administer consolidation therapy to avoid relapse. Although the optimal regimen is not clearly defined, most protocols utilize an anthracycline with or without cytarabine.
C. Maintenance. The North American Intergroup APL study randomized patients who achieved CR after two courses of consolidation chemotherapy to either a year of daily maintenance ATRA at standard doses or to observation. Patients who received ATRA during both induction and as maintenance had a 5-year disease-free survival of 75%, whereas patients who received no ATRA maintenance had an inferior 5-year disease-free survival of 55%. Other regimens use ATRA maintenance for 2 weeks every 3 months for 2 years with oral chemotherapy (6-mercaptopurine and methotrexate) on a quarterly basis. This regimen may make more sense than the 1-year regimen since ATRA induces its own metabolism.
D. APL differentiation syndrome (APLDS) is a cardiorespiratory syndrome manifested by fever, weight gain, respiratory distress, interstitial pulmonary infiltrates, pleural and pericardial effusion, episodic hypotension, and acute renal failure. The disorder is attributed to rapid differentiation of blasts to (clonal) neutrophils with subsequent vascular complications and can be induced by either ATRA or arsenic trioxide. The incidence is 25% when ATRA is used alone. The concurrent administration of chemotherapy and ATRA may reduce the incidence to below 10%, but this has not been clearly established. Corticosteroids can be effective as prophylaxis and therapy of the differentiation syndrome. The mortality rate with APLDS has declined from 30% to 5%, likely reflecting earlier recognition and earlier institution of dexamethasone therapy. No factors are clearly predictive of APLDS.
E. DIC. Coagulopathy exacerbated by cytotoxic chemotherapy was previously seen in >90% of patients with APL and resulted in severe hemorrhagic manifestations in excess of that expected for the degree of thrombocytopenia. Both the incidence and severity of DIC have substantially decreased with differentiation therapy. Laboratory abnormalities include not only features associated with DIC (decreased fibrinogen and increased fibrin and fibrinogen degradation products) but also evidence of increased fibrinolysis (acquired deficiency of the fibrinolysis inhibitor, α2-antitrypsin).
Patients should be monitored closely for the development of DIC and treated at its first sign. Transfusions with platelets and cryoprecipitate (to sustain fibrinogen levels) are the mainstays of therapy. Heparin is now rarely used. Antifibrinolytic agents, such as epsilon-aminocaproic acid, may be useful in the setting of excess fibrinolysis.
VIII. MANAGEMENT OF ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)
A. Remission induction
1. Children (also see Chapter 18). The combination of vincristine and prednisone (V + P) produces CR in 85% to 90% of cases of childhood ALL. L-asparaginase is typically added. Most children achieve CR within 4 weeks of therapy; if CR is not achieved within 6 weeks, no value is found in continuing the drugs unless under unusual circumstances such as in ataxia telangiectasias. Children often achieved CR without prolonged myelosuppression.
a. Standard-risk patients are treated with V + P plus L-asparaginase for 4 to 6 weeks.
Vincristine, 1.5 mg/m2 (maximum 2 mg) IV push weekly
Prednisone, 40 mg/m2 PO daily
L-asparaginase, 6,000 U/m2 (maximum 10,000 U) IM three times weekly for a total of nine doses
b. High-risk patients are treated with V + P, L-asparaginase, and daunorubicin (25 mg/m2) IV weekly for two doses.
2. Adults. The V + P regimen results in CR in 45% to 65% of adults with ALL. The addition of an anthracycline (with or without L-asparaginase) increases the CR rate to 75%. Regimens with five drugs may further increase the CR rate to 85%; an example regimen is the following (see Larson RA, et al. in Suggested Reading):
Cyclophosphamide, 1,200 mg/m2 IV on day 1
Daunorubicin, 45 mg/m2 IV on days 1, 2, and 3
Vincristine, 2 mg IV on days 1, 8, 15, and 22
Prednisone, 80/m2 IV or PO on days 1 through 21
L-asparaginase, 6,000 U/m2 SC on days 5, 8, 11, 15, 18, and 22
3. Toxicity of induction therapy
a. V + P
(1) Intestinal colic and constipation (bulk laxatives should be used prophylactically)
(2) Peripheral neuropathy (usually reversible)
(3) Bone marrow suppression
(4) Alopecia (uncommon)
b. V + P plus an anthracycline. Same as above, in Section VIII.A.3.a, along with nausea, vomiting, stomatitis, alopecia, myelosuppression, and possibly cardiac toxicity
c. V + P and L-asparaginase. Same as above, in Section VIII.A.3.a, with the addition of coagulation defects with decreased fibrinogen level, allergic reactions, and encephalopathy, hyperbilirubinemia, elevated hepatic transaminases, pancreatitis, phlebitis, or thrombosis
B. CNS prophylaxis after induction chemotherapy prevents early CNS relapse and is mandatory in ALL. The CNS is the initial site of relapse in more than half of children unless prophylaxis is given and it is also a frequent site of relapse in adults.
1. Regimens. The form of CNS prophylaxis is controversial. Many authorities recommend intrathecal methotrexate (6 to 12 mg/m2 of preservative-free methotrexate up to a maximum of 15 mg/dose is given twice weekly for five to eight doses). Intrathecal methotrexate is often combined with craniospinal irradiation (approximately 2,400 cGy in 12 fractions over 2.5 weeks) for patients >1 year of age. Intrathecal methotrexate alone is recommended by some authorities for patients at low risk for relapse (age 2 to 9 years, WBC count <10,000/μL, and CD10+). For adults, prophylactic intrathecal chemotherapy alone is considered sufficient.
2. Toxicity of CNS prophylaxis
a. Transient encephalopathy, which can be fatal, may develop in children for 4 to 8 weeks after completion of cranial irradiation, especially if methotrexate is given in the maintenance program. Symptoms of encephalopathy include somnolence, headache, vomiting, and low-grade fever. Spinal fluid examination shows pleocytosis with neutrophils and mononuclear cells. The differential diagnosis includes CNS infection, cerebrovascular accidents, and leukemic meningitis, which should be distinguishable by MRI scans and by spinal fluid culture and cytology.
b. Alopecia after cranial irradiation
c. Headache after intrathecal drug administration
d. Chemical arachnoiditis with meningismus and back pain related to epidural extravasation of methotrexate
e. Leukoencephalopathy may develop in patients given large doses of IV methotrexate after brain irradiation.
f. Neuropsychologic effects of treatment are common, especially in children <6 years of age. Memory, mathematic, and motor skills may be impaired. CNS prophylaxis and the systemic drugs that have activity in the CNS (methotrexate, prednisone, vincristine, and L-asparaginase) are thought to cause these problems; however, the disease itself may also contribute.
C. Intensive postremission therapy
1. Consolidation treatment with an intensive multidrug regimen has been shown to improve survival in children and is considered standard treatment. A retrospective analysis in adults showed a superior outcome among trials implementing multidrug intensive consolidation, but randomized trials are inconclusive. High-dose cytarabine may be beneficial for T-cell ALL and some high-risk subgroups. High-dose methotrexate may be useful in B-cell lineage ALL.
2. Allogeneic HSCT in first CR has been demonstrated to improve survival for adults with ALL in all age categories. It is not recommended for first CR for children with standard-risk ALL, but HSCT may be important for specific subgroups of ALL (patients with the Philadelphia chromosome) or for those who relapse after initial remission.
D. Maintenance therapy for 2 to 3 years is mandatory in childhood ALL and is typically used in adults as well.
1. Effective drugs. Methotrexate (20 mg/m2 PO to a maximum of 35 mg weekly) plus mercaptopurine (50 to 75 mg/m2 PO daily) are the cornerstones of maintenance therapy in ALL. It is important that the drugs be given in dosages sufficient to produce myelosuppression to produce an impact on disease-free survival. Monthly pulses of V + P are also given. Intrathecal chemotherapy is typically administered every 90 days.
2. Toxicity of maintenance therapy
a. Therapy is interrupted if any of the following occurs:
(1) Significant myelosuppression (which is dose-limiting but a necessary goal)
(2) Abnormal LFT
(3) Stomatitis, diarrhea
(4) Renal tubular necrosis secondary to the methotrexate (renal function is closely monitored)
b. Immunosuppression (increased susceptibility to infection, particularly varicella and Pneumocystis jirovecii)
c. Growth inhibition
d. Skin disorders
e. Osteoporosis with long-term methotrexate treatment
3. When to stop maintenance therapy
a. Children. Prolonged chemotherapy is of greatest consequence in children because adverse, late side effects may develop. Most children in remission are treated for 30 to 36 months; 20% of children taken off treatment relapse, most within the first year. Elective testicular biopsy of boys before stopping maintenance therapy has been shown to be of no clinical value.
b. Adults. Most adults with ALL relapse despite maintenance therapy. The question of how long adults with ALL should continue maintenance is yet to be answered, but it seems that prolonged and more dose-intensive regimens lead to better results. We recommend maintenance therapy for at least 2 years in adults with ALL based on the experience with children.
E. Treatment of relapses. ALL may relapse systemically or in sanctuary sites (testicle or CNS).
1. Extramedullary relapse. Without CNS prophylaxis, relapse only in the CNS is common. Relapse in the testis occurs, but less commonly. Patients who have solitary extramedullary relapse and normal bone marrow may be treated with local therapy alone (i.e., CNS irradiation plus intrathecal chemotherapy for CNS relapse or irradiation of the testicle for testicular relapse). Frequently, relapse in these sites predict for systemic relapse.
2. Systemic relapse may be successfully treated with the agents used to induce the original remission in half of the cases, but any relapse should prompt consideration of allogeneic transplantation.
3. Subsequent remissions. Each subsequent remission becomes progressively shorter, and drugs available for maintenance therapy are progressively limited. Patients who relapse after cessation of maintenance therapy have a better prognosis than those who relapse during therapy.
IX. MANAGEMENT OF ACUTE LEUKEMIAS: OTHER ISSUES
A. Supportive care
1. Indwelling tunneled central venous catheters are used during the induction phase to facilitate the administration of IV therapies and the sampling of blood for laboratory tests.
2. Blood component therapy
a. Platelet transfusions are clearly indicated for patients with severe thrombocytopenia when there is active bleeding, fever, or infection. Without petechiae or bleeding, platelets are transfused prophylactically when counts are ≤10,000/μL unless the patient is febrile, at which point platelets should be kept at a slightly higher level of 20,000/μL owing to enhanced platelet consumption.
b. Packed red blood cell transfusions are used to treat symptomatic anemia and active hemorrhage. The hemoglobin concentration is generally kept ≥8 g/dL because these patients have aregenerative bone marrows. If the patient is actively bleeding or has a medical history, transfusion is given to target a higher hemoglobin level.
c. Granulocyte transfusions are not generally recommended. They can be used, however, in certain settings such as an overwhelming fungal sepsis, when the patient is expected to recover within a short period of time. In the absence of a reasonable chance of recovery, granulocyte transfusions are not typically used.
d. Growth factors (G-CSF and granulocyte–macrophage-CSF [GM-CSF]) may be given on completion of administration of the induction chemotherapy after a repeat bone marrow biopsy on days 10 to 14 is proven to be devoid of leukemic elements. Their use may shorten the duration of neutropenia by 2 to 4 days and appears to decrease morbidity in the elderly. Studies do not indicate that these factors impair the efficacy of chemotherapy.
3. Infections. It is critical to initiate prompt empiric IV antibiotics in the event of fever. The choice of antibiotics is institution-dependent, but should always contain adequate coverage of gram-negative bacteria and also Staphylococcus aureus in patients suspected of having a catheter-related infection. For persistently febrile patients, empiric coverage with antifungal agents has been demonstrated to improve survival.
a. Management of neutropenic fever is thoroughly discussed in Section II of Chapter 35.
b. Prophylaxis against infection (see Chapter 35, Section II.A.2.c)
4. Tumor lysis syndrome (see Chapter 27, Section XIII)
B. Treatment of meningeal leukemia
1. Manifestations. Meningeal leukemia should be considered in the setting of cranial neuropathy, other neurologic signs, or altered mental status. Blast cells identified by cytologic evaluation of the CSF are diagnostic, but evaluation of the CSF is not sensitive.
2. Treatment. Optimal treatment has not been determined. Most patients are given cranial or craniospinal irradiation over a 3-week period plus intrathecal chemotherapy. Intrathecal therapy alone may be insufficient.
a. Drugs. Preservative-free methotrexate (6 to 12 mg/m2 to a maximum of 15 mg) or cytarabine (50 to 100 mg) is used for intrathecal therapy. Methotrexate should be avoided in the setting of renal failure. The concomitant use of methotrexate during CNS irradiation can be associated with increased CNS toxicity. Toxic effects of methotrexate in the periphery may be prevented by giving IV or oral leucovorin.
b. Diluents. Artificial spinal fluid (Elliotts B solution) is available at some institutions to dilute the cytotoxic agents.
c. Technique. Intrathecal chemotherapy is given isovolumetrically and gradually by serial withdrawal and injection of spinal fluid with a syringe containing the chemotherapeutic agents. The drugs can be administered by lumbar or cisternal puncture, or through an inserted intraventricular (Ommaya) reservoir.
d. Duration. Intrathecal chemotherapy is given at 2- to 7-day intervals until abnormal cells and excess protein are cleared from the spinal fluid. Therapy is often continued at 1- to 2-month intervals for a period thereafter.
C. Special clinical problems
1. Leukostasis is more common in AML than in ALL and frequently occurs in patients with WBC count >100,000/μL. Sludging impairs circulation and results in organ dysfunction. The circulating blast count can be rapidly reduced with leukapheresis, thereby reducing the risks of leukostasis, DIC, and metabolic abnormalities associated with tumor lysis. Hydroxyurea (3 g/d) or alternative chemotherapy should be instituted with leukapheresis.
2. Ocular and gingival involvement. Irradiating eyes involved with leukemic infiltrates may prevent blindness. Gingival enlargement in patients with monocytic leukemia does not require special treatment because it should resolve with induction chemotherapy.
3. Patients exposed to varicella zoster infections should be given acyclovir and zoster immune globulin (see Section V.B. in Chapter 35).
4. Acute leukemia during pregnancy (see Chapter 26, Section IV)
MYELODYSPLASTIC SYNDROMES
Patients who have MDS are at a high risk for developing AML. Theoretically, defects in stem cells account for ineffective hematopoiesis and for a wide variety of abnormalities. The diagnosis of a primary MDS may be made only in the absence of conditions that produce secondary myelodysplasia, which include drug and toxin exposure, growth factor therapy, viral infections, immunologic disorders, congenital disorders, vitamin deficiencies, copper deficiency, and excessive zinc supplementation. Notably, folic acid and vitamin B12 deficiencies are reversible disorders that may have bone marrow morphologic changes that can be confused with myelodysplasia.
I. CLINICAL FEATURES
MDS usually affects patients >65 years of age, particularly men. Symptoms are nonspecific and usually reflect the degree of anemia. Physical examination is usually normal. Various cytopenias, usually including macrocytic anemia, may persist for months to years. The bone marrow is usually abnormal.
II. DYSHEMATOPOIESIS
Dyshematopoiesis is manifested by cytopenias in the presence of a normocellular or hypercellular bone marrow. Components and features of dyshematopoiesis, which occur in various combinations for each syndrome, are as follows:
A. Dyserythropoiesis
1. Peripheral blood. Anemia and reticulocytopenia from ineffective erythropoiesis; anisocytosis, poikilocytosis, basophilic stippling; macrocytosis (when megaloblastoid maturation is present); and dimorphic (normocytic, normochromic, and microcytic, hypochromic) red blood cell populations
2. Bone marrow. Erythroid hyperplasia or hypoplasia, ringed sideroblasts, and megaloblastoid maturation (multinucleation, nuclear fragments, karyorrhexis, or cytoplasmic vacuoles)
3. Other assays. Decreased CD55 and CD59 expression on granulocytes or erythrocytes defines paroxysmal nocturnal hemoglobinuria. Periodic acid Schiff (PAS)-positive cytochemistry and increased fetal hemoglobin levels may be detected in some cases of myelodysplasia.
B. Dysgranulocytopoiesis
1. Peripheral blood. Neutropenia, decreased or abnormal neutrophil granules, neutrophil hyposegmentation (pseudo-Pelger-Huët anomaly), hypersegmentation, or bizarre nuclei
2. Bone marrow. Granulocytic hyperplasia, abnormal or decreased granules in neutrophil precursors, increased numbers of blast cells
3. Other assays. Decreased neutrophil alkaline phosphatase score and myeloperoxidase activity
C. Dysmegakaryopoiesis
1. Peripheral blood. Thrombocytopenia, large platelets with abnormal and decreased granularity
2. Bone marrow. Reduced numbers of megakaryocytes, micromegakaryocytes, and megakaryocytes with large, single nuclei or multiple, small separated nuclei
3. Other assays. Abnormal platelet function tests
III. CLASSIFICATION
A. The French–American–British classification of MDS initially categorized patients based entirely on morphology and dysplastic changes in at least two of the three hematopoietic cell lines into six subtypes:
1. Refractory anemia (RA): <5% marrow blasts
2. RA with ringed sideroblasts (RARS): <5% blasts plus ≥15% ringed sideroblasts
3. RA with excess blasts (RAEB): 5% to 20% marrow blasts
4. RAEB in transformation (RAEB-T): 21% to 30% marrow blasts
5. Chronic myelomonocytic leukemia (CMML): ≤20% marrow blasts plus peripheral blood monocytosis >1,000/μL
6. AML: >30% marrow blasts
B. The WHO revised and restructured the traditional FAB classifications of AML, MDS, and MPD. The presence or absence of the Philadelphia (Ph1) chromosome [t(9;22)(q34;q11)] and BCR/ABL fusion gene was taken into account (Table 25.2).
1. WHO classification of MDS lowered the blast percentage threshold for the definition of AML from 30% to 20%. The category of RAEB-T was eliminated. The WHO classification for MDS is shown in Table 25.2.
Table 25.2 World Health Organization (WHO) Classification of Myelodysplastic Syndromes (MDS) and Myeloid Leukemiasa
AR, Auer rods; MCL, marrow cell lineages; Ph1, Philadelphia chromosome or BCR/ABL fusion gene; RA, refractory anemia; RS, ringed sideroblasts (five or more iron granules encircling one-third or more of the nucleus); ww/o, with or without.
aAdapted from Swerdlow SH, et al. World Health Organization classification of tumours of haematopoietic and lymphoid tissues. Lyon, France: IARC Press; 2008.
bSee Section II for definitions of the various dysplasias.
cRA, refractory anemia (RA, by far the most predominant type), refractory neutropenia, or refractory thrombocytopenia. RCUD should not be equated with “idiopathic cytopenias of undetermined significance”.
dCML in the WHO classification is defined as a myeloproliferative disease (MPD), although this contention is debatable.
eMDS/MPD is a category that has both dysplastic and proliferative features. MDS/MPD includes CMML and is presented in Section III.B.3.
2. WHO classification of MPD is as follows:
Polycythemia vera
Chronic idiopathic myelofibrosis (with extramedullary hematopoiesis)
Essential thrombocythemia
Chronic myelogenous leukemia (CML)
Chronic neutrophilic leukemia
Chronic eosinophilic leukemia
Chronic MPD, unclassified
3. WHO classification of myelodysplastic/myeloproliferative disease (MDS/MPD) acknowledges the overlap between MDS and MPD entities. This category includes myeloid disorders that have both myelodysplastic and myeloproliferative features at the time of initial presentation. The MDS/MPD diseases are
Chronic myelomonocytic leukemia (CMML, CMML-1, CMML-2)
Atypical chronic myeloid leukemia
Juvenile myelomonocytic leukemia
MDS/MPD, unclassified
a. Diagnostic criteria for CMML and its subtypes are shown in Table 25.2.
b. Atypical CML is a very aggressive disorder. It is characterized by marked granulocytic and often multilineage dysplasia (which is not seen in chronic-phase CML) and the absence of the Ph1 chromosome and BCR/ABL fusion gene.
c. Juvenile myelomonocytic leukemia affects infants and young children, manifests neutrophilic and monocytic proliferation, and lacks the Ph1 chromosome and BCR/ABL fusion gene.
IV. GENE ABNORMALITIES
A. Cytogenetic abnormalities are nonrandom and occur in 40% to 60% of patients with MDS. Cytogenetic abnormalities traditionally associated with MDS (involving chromosomes 3q, 5q, 7q, 12p, and 20q11 to 20q12, and trisomy 8) are “secondary” genetic events. The unbalanced translocation between chromosomes 1 and 7 [t(1;7)(p11; p11)] results in trisomy for the long arm of chromosome 1 and monosomy for the long arm of chromosome 7 and may be causally related to therapy-related MDS.
B. Molecular mutation and gene methylation. In adults with MDS, disease progression has been associated with mutations in genes such as p53 and FLT3 (see Table 25.1 for the frequency of FLT mutations in AML). FTL3mutations are now considered one of the most common mutations in AML (35% in older adults) and an important predictor of poor outcome.
Disease progression is also associated with progressive methylation and transcriptional inactivation of critical cell cycle regulatory genes, such as p15 INK4b, that normally function to inhibit cyclin-dependent kinase activity at the G1phase of the cell cycle. Patients with MDS have also been shown to have defective activation of signal transduction pathways, particularly involving STAT5, in response to erythropoietin, which may account in part for defective erythropoiesis and persistent anemia.
C. The 5q– syndrome is recognized as a distinct clinical entity that predominantly affects females and has a favorable prognosis with a low risk of transformation to AML. This entity is to be distinguished from AML characterized by a deletion of chromosome 5 or 5q. Patients have macrocytic anemia, modest leukopenia, normal or high platelet counts, bone marrow erythroid hypoplasia, hypolobulated megakaryocytes, and bone marrow blast counts <20%.
The breakpoint most frequently cited is 5q12–14 (proximal breakpoint) and 5q31–33 (distal breakpoint). Many hematopoietic growth factors and growth factor receptor genes, including interleukins (IL) and colony-stimulating factors (CSF), have been localized to chromosome 5q. Those localized to 5q13–33 include IL-3, IL-4, IL-5, IL-9, CSF-1R, RAS p21 activator protein, and interleukin regulatory factor-1 (IRF-1). The deletion of these genes seems to contribute to the clinical development of the 5q– syndrome.
V. PROGNOSIS
Life expectancy in MDS ranges from several months to 10 years, depending on the initial presentation, cytopenia, cytogenetics, and age. Age >50 years is a major unfavorable prognostic factor. The IPSS is a weighted prognostic grouping based on cytopenias, cytogenetics, and blast percentage in the bone marrow. The IPSS classifies patients into low-, intermediate-, or high-risk groups by scoring for initial bone marrow blasts, cytogenetics (favorable vs. unfavorable), and lineage cytopenia. The IPSS and associated median survivals are shown in Table 25.3.
VI. MANAGEMENT OF MDS
Because treatment for MDS is unsuccessful in most patients, patients should be encouraged to enroll into clinical trials. Treatment selection should be based on the patient’s age, performance status, and IPSS subgroup categorization. Following are some of the therapeutic options available to patients, either through standard care or through available clinical trials:
Table 25.3 International Prognostic Scoring System (IPSS) for Myelodysplastic Syndromes
aDefined as acute myelogenous leukemia in the World Health Organization classification
A. Supportive therapies: treatment of anemia. Erythropoietin (EPO) increases hemoglobin levels in approximately 15% of patients; 5% to 10% of patients may have a decrease in red blood cell transfusion requirements. Responses usually occur within 2 to 3 months, if they are to occur. Pretreatment serum EPO concentrations are inversely correlated with probability of response.
1. High doses of EPO (40,000 to 60,000 U weekly) may be helpful. Dosage is adjusted if the drug is effective. Response is more likely if the patient has ringed sideroblasts and serum EPO levels of <500 mU/mL.
2. The combination of EPO and G-CSF (1 μg/kg/d) may increase the response rate of the anemia, producing synergistic erythropoietic activity in patients who fail to respond to erythropoietin alone.
B. Remittive therapies
1. Immunomodulatory agents. Thalidomide, at low doses, has been shown in some trials to improve the degree of anemia and decrease red blood cell transfusion requirements. Lenalidomide (10 mg/d for 21 days monthly) has also been shown to improve hemoglobin and transfusion dependence in some patients with MDS. Lenalidomide is most effective in patients with 5q deletions where 80% of patients achieve an erythroid response; transient cytogenetic responses can also be seen. Responses are less common (approximately 40%) in patients with MDS with normal or other cytogenetic findings.
2. DNA hypomethylating agents. A randomized phase III trial of azacitidine (75 mg/m2/d SC for 7 days every 28 days) compared with supportive care alone identified the value of azacitidine to improve blood cell counts, decrease or eliminate transfusion requirements, and improve both survival and quality of life. Decitabine produced a similar spectrum of improvement in a randomized phase III trial.
3. Immunosuppressive therapy. Low marrow cellularity and absence of blasts increase the likelihood of response of MDS to immunosuppressive agents such as prednisone, antithymocyte globulin (ATG), and cyclosporine.
C. Curative therapies for high-risk MDS. Induction chemotherapy followed by allogeneic HSCT may lead to complete resolution of myelodysplasia. Although commonly believed that HSCT is the only curative option for MDS, the projected 3-year disease-free survival for patients <60 years of age is dependent on the risk category of disease. Allogeneic HSCT should only be offered in intermediate- or advanced-disease settings.
Standard chemotherapy for MDS or MDS-related AML is associated with lower response rates than in de novo AML. This disparity is owing to advanced age in patients with MDS, poor-risk cytogenetics, and increased expression of multidrug resistance.
D. Management of CMML is discussed in Chapter 23, “Chronic Myelomonocytic Leukemia.”
Suggested Reading
Acute Leukemia
Cashen AF, Schiller GJ, O’Donnell MR, et al. Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol 2010;28:556.
Fielding AK, et al.; Medical Research Council of the United Kingdom Adult ALL Working Party; Eastern Cooperative Oncology Group. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood 2007;109:944.
Foran JM. New prognostic markers in acute myeloid leukemia: perspective from the clinic. Hematology Am Soc Hematol Educ Program 2010;2010:47.
Gandhi V, Plunkett W. Clofarabine and nelarabine: two new purine nucleoside analogs. Curr Opin Oncol 2006;18:584.
Grimwade D, Hills RK. Independent prognostic factors for AML outcome. Hematology Am Soc Hematol Educ Program 2009:385.
Juliusson G, et al. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood 2009;113:4179.
Kolitz JE, et al. Dose escalation studies of cytarabine, daunorubicin, and etoposide with and without multidrug resistance modulation in PSC-833 in untreated adults with acute myeloid leukemia younger than 60 years: final induction results of Cancer and Leukemia Group B Study 9621. J Clin Oncol 2004;22:4290.
Larson RA, et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood 1995;85:2025.
Lowenberg B, et al. High dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med 2009;361:1235.
Marks DI, Aversa F, Lazarus HM. Alternative donor transplants for adult acute lymphoblastic leukaemia: a comparison of the three major options. Bone Marrow Transplant 2006;38:467.
Oliansky DM, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute myeloid leukemia in children: an evidence-based review. Biol Blood Marrow Transplant 2007;13:1.
Rowe JM, et al. ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood 2005;106:3760.
Stone RM. Novel therapeutic agents in acute myeloid leukemia [Review]. Exp Hematol 2007;35(4 suppl 1):163.
Myelodysplastic Syndromes
Borthakur G, Estey AE. Therapy-related acute myelogenous leukemia and myelodysplastic syndrome. Curr Oncol Rep 2007;9:373.
Catenacci D V-T, Schiller GJ. Myelodysplastic syndromes: a comprehensive review. Blood Rev 2005;6:301.
Kornblith AB, et al. Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a CALGB study. J Clin Oncol 2002;20:2441.
Melchert M, Kale V, List A. The role of lenalidomide in the treatment of patients with chromosome 5q deletion and other myelodysplastic syndromes. Curr Opinion Hematol 2007;14:123.
Sanz G, Sanz M, Greenberg P. Prognostic factors and scoring systems in myelodysplastic syndromes. Haematologica 1998;83:358.
Swerdlow SH, et al. World Health Organization classification of tumours of haematopoietic and lymphoid tissues. Lyon, France: IARC Press; 2008.
Web Sites
MDS Foundation Web site: www.mds-foundation.org
Aplastic Anemia–vMDS Web site: www.aamds.org