Leukemia, acute myeloid, adult: Treatment - Health Professional Information [NCI PDQ]

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Adult Acute Myeloid Leukemia Treatment (PDQ®)
Purpose of This PDQ Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult acute myeloid leukemia. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.
Information about the following is included in this summary:
Prognostic factors.
Cellular classification.
Staging.
Treatment options by cancer stage.
This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.
This summary is available in a patient version, written in less technical language, and in Spanish.
General Information
Note: Estimated new cases and deaths from acute myeloid leukemia (AML) in the United States in 2007:[1]
New cases: 13,410.
Deaths: 8,990.
Advances in the treatment of AML (also called acute nonlymphocytic leukemia or ANLL) have resulted in substantially improved complete remission rates.[2] Treatment should be sufficiently aggressive to achieve complete remission because partial remission offers no substantial survival benefit. Approximately 60% to 70% of adults with AML can be expected to attain complete remission status following appropriate induction therapy. More than 15% of adults with AML (about 25% of those who attain complete remission) can be expected to survive 3 or more years and may be cured. Remission rates in adult AML are inversely related to age, with an expected remission rate of more than 65% for those younger than 60 years. Data suggest that once attained, duration of remission may be shorter in older patients. Increased morbidity and mortality during induction appear to be directly related to age. Other adverse prognostic factors include central nervous system involvement with leukemia, systemic infection at diagnosis, elevated white blood cell count (>100,000/mm³), treatment-induced AML, and history of myelodysplastic syndrome. Leukemias that express the progenitor cell antigen CD34 and/or the P-glycoprotein (MDR1 gene product) have an inferior outcome.[3,4,5] AML associated with an internal tandem duplication of the FLT3 gene (FLT3/ITD mutation) has an inferior outcome that is attributed to a higher relapse rate.[6,7]
Cytogenetic analysis provides some of the strongest prognostic information available, predicting outcome of both remission induction and postremission therapy.[8] Cytogenetic abnormalities that indicate a good prognosis include t(8;21), inv(16), and t(15;17). Normal cytogenetics portend average-risk AML. Patients with AML that is characterized by deletions of the long arms or monosomies of chromosomes 5 or 7; by translocations or inversions of chromosome 3, t(6;9), t(9;22); or by abnormalities of chromosome 11q23 have particularly poor prognoses with chemotherapy. These cytogenetic subgroups predict clinical outcome in elderly patients with AML as well as in younger patients.[9] The fusion genes formed in t(8;21) and inv(16) can be detected by reverse transcriptase–polymerase chain reaction (RT–PCR), which will indicate the presence of these genetic alterations in some patients in whom standard cytogenetics was technically inadequate. RT–PCR does not appear to identify significant numbers of patients with good risk fusion genes who have normal cytogenetics.[10]
The classification of AML has been revised by a group of pathologists and clinicians under the auspices of the World Health Organization (WHO).[11] While elements of the French-American-British classification have been retained (i.e., morphology, immunophenotype, cytogenetics and clinical features), the WHO classification incorporates more recent discoveries regarding the genetics and clinical features of AML in an attempt to define entities that are biologically homogeneous and that have prognostic and therapeutic relevance.[11,12,13] Each criterion has prognostic and treatment implications but, for practical purposes, antileukemic therapy is similar for all subtypes.
A long-term follow-up of 30 patients who had AML that was in remission for at least 10 years has demonstrated a 13% incidence of secondary malignancies. Of 31 long-term female survivors of AML or acute lymphoblastic leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, 2 congenital problems occurred.[14]
The differentiation of AML from acute lymphocytic leukemia has important therapeutic implications. Histochemical stains and cell surface antigen determinations aid in discrimination.
References:
American Cancer Society.: Cancer Facts and Figures 2007. Atlanta, Ga: American Cancer Society, 2007. Also available online. Last accessed December 20, 2007.
Sheinberg DA, Maslak PG, Weiss MA: Acute leukemias. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 2088-116.
Myint H, Lucie NP: The prognostic significance of the CD34 antigen in acute myeloid leukaemia. Leuk Lymphoma 7 (5-6): 425-9, 1992.
Geller RB, Zahurak M, Hurwitz CA, et al.: Prognostic importance of immunophenotyping in adults with acute myelocytic leukaemia: the significance of the stem-cell glycoprotein CD34 (My10) Br J Haematol 76 (3): 340-7, 1990.
Campos L, Guyotat D, Archimbaud E, et al.: Clinical significance of multidrug resistance P-glycoprotein expression on acute nonlymphoblastic leukemia cells at diagnosis. Blood 79 (2): 473-6, 1992.
Kottaridis PD, Gale RE, Frew ME, et al.: The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 98 (6): 1752-9, 2001.
Yanada M, Matsuo K, Suzuki T, et al.: Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia 19 (8): 1345-9, 2005.
Slovak ML, Kopecky KJ, Cassileth PA, et al.: Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 96 (13): 4075-83, 2000.
Grimwade D, Walker H, Harrison G, et al.: The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood 98 (5): 1312-20, 2001.
Mrózek K, Prior TW, Edwards C, et al.: Comparison of cytogenetic and molecular genetic detection of t(8;21) and inv(16) in a prospective series of adults with de novo acute myeloid leukemia: a Cancer and Leukemia Group B Study. J Clin Oncol 19 (9): 2482-92, 2001.
Brunning RD, Matutes E, Harris NL, et al.: Acute myeloid leukaemia: introduction. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 77-80.
Bennett JM, Catovsky D, Daniel MT, et al.: Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol 33 (4): 451-8, 1976.
Cheson BD, Cassileth PA, Head DR, et al.: Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol 8 (5): 813-9, 1990.
Micallef IN, Rohatiner AZ, Carter M, et al.: Long-term outcome of patients surviving for more than ten years following treatment for acute leukaemia. Br J Haematol 113 (2): 443-5, 2001.
Classification
The World Health Organization (WHO) classification of acute myeloid leukemia (AML) incorporates and interrelates morphology, cytogenetics, molecular genetics, and immunologic markers in an attempt to construct a classification that is universally applicable and prognostically valid.[1] In the older French-American-British (FAB) criteria, the classification of AML is solely based upon morphology as determined by the degree of differentiation along different cell lines and the extent of cell maturation.[2,3]
Under the WHO classification, the category “acute myeloid leukemia not otherwise categorized” is morphology-based and reflects the FAB classification with a few significant modifications.[2,3] The most significant difference between the WHO and FAB classifications is the WHO recommendation that the requisite blast percentage for the diagnosis of AML be at least 20% blasts in the blood or bone marrow. The FAB scheme required the blast percentage in the blood or bone marrow to be at least 30%. This threshold value for blast percentage eliminated the category “refractory anemia with excess blasts in transformation” (RAEB-t) found in the FAB classification of myelodysplastic syndromes (MDS), where RAEB-t is defined by a marrow blast percentage between 20% and 29%. In the WHO classification, RAEB-t is no longer considered a distinct clinical entity, and is instead included within the broader category “AML with multilineage dysplasia” as “AML with multilineage dysplasia following a myelodysplastic syndrome.”[4]
Although this lowering of the blast threshold has been met with some criticism, several studies indicate that survival pattern for cases with 20% to 29% blasts is similar to cases with 30% or more blasts in the bone marrow.[5,6,7,8,9] The diagnosis of AML in itself does not represent a therapeutic mandate. The decision to treat should be based on other factors including patient age, previous history of MDS, clinical findings and disease progression, in addition to the blast percentage.
In the following outline and discussion, the older FAB classifications are noted where appropriate.
AML with characteristic genetic abnormalities.
AML with t(8;21)(q22;q22); (AML/ETO).
AML with inv(16)(p13q22) or t(16;16)(p13;q22); (CBFß/MYH11).
Acute promyelocytic leukemia (AML with t(15;17)(q22;q12); (PML/RARa) and variants).
AML with 11q23 (MLL) abnormalities.
AML with an FLT3 mutation .
AML with multilineage dysplasia.
AML and MDS, therapy related.
Alkylating agent-related AML and MDS.
Topoisomerase II inhibitor-related AML.
AML not otherwise categorized.
Acute myeloblastic leukemia, minimally differentiated (FAB Classification M0).
Acute myeloblastic leukemia without maturation (FAB Classification M1).
Acute myeloblastic leukemia with maturation (FAB Classification M2).
Acute myelomonocytic leukemia (AMML) (FAB Classification M4).
Acute monoblastic leukemia and acute monocytic leukemia (FAB classifications M5a and M5b).
Acute erythroid leukemias (FAB classifications M6a and M6b).
Acute megakaryoblastic leukemia (FAB Classification M7).
AML/transient myeloproliferative disorder in Down syndrome.
Acute basophilic leukemia.
Acute panmyelosis with myelofibrosis.
Myeloid sarcoma.
Acute leukemias of ambiguous lineage.
Acute Myeloid Leukemia With Characteristic Genetic Abnormalities
This category is characterized by characteristic genetic abnormalities and frequently high rates of remission and favorable prognoses.[10] The reciprocal translocations t(8;21), inv(16) or t(16:16), t(15;17), and translocations involving the 11q23 breakpoint are the most commonly identified genetic abnormalities. These structural chromosome rearrangements result in the formation of fusion genes that encode chimeric proteins that may contribute to the initiation or progression of leukemogenesis. Many of these translocations are detected by reverse transcriptase–polymerase chain reaction (RT–PCR), which has a higher sensitivity than cytogenetics. Other recurring cytogenetic abnormalities are less common and described below in AML not otherwise categorized.
ACUTE MYELOID LEUKEMIA WITH T(8;21)(Q22;Q22); (AML/ETO)
AML with the translocation t(8;21)(q22;q22) (FAB classification M2) is one of the most common genetic aberrations in AML and accounts for 5% to 12% of cases of AML and 33% of karyotypically abnormal cases of acute myeloblastic leukemia with maturation.[11] Myeloid sarcomas (chloromas) may be present and may be associated with a bone marrow blast percentage of less than 20%.
Common morphologic features include the following:
Large blasts with abundant basophilic cytoplasm, often containing numerous azurophilic granules.
A few blasts in some cases show very large granules (pseudo Chediak-Higashi granules).
Auer rods, which may be detected in mature neutrophils.
Smaller blasts, predominantly in the peripheral blood.
Promyelocytes, myelocytes, and mature neutrophils with variable dysplasia in the bone marrow.
Abnormal nuclear segmentation (pseudo Pelger-Huet nuclei) and/or cytoplasmic staining abnormalities.
Increased eosinophil precursors.
Reduced or absent monocytes.
Normal erythroblasts and megakaryocytes.
AML with maturation (FAB classification M2) is the most common morphologic type correlating with t(8;21). Rarely, AML with this translocation presents with a bone marrow blast percentage less than 20%.[10]
The translocation t(8;21)(q22;q22) involves the AML1 gene, also known as RUNX1, which encodes core binding factor-a (CBFa), and the ETO (eight-twenty-one) gene.[10,12] The AML1/ETO fusion transcript is consistently detected in patients with t(8;21) AML. This type of AML is usually associated with a good response to chemotherapy and a high complete remission rate with long-term survival when treated with high-dose cytarabine in the consolidation phase.[13,14,15,16] Additional chromosome abnormalities are common, e.g., loss of a sex chromosome and del(9)(q22). Expression of the neural cell adhesion molecule (NCAM) CD56 appears to be adverse prognostic indicator.[17,18]
ACUTE MYELOID LEUKEMIA WITH INV(16)(P13Q22) OR T(16;16)(P13;Q22); (CBFß/MYH11)
AML with inv(16)(p13q22) or t(16;16)(p13;q22) is found in approximately 10% to 12% of all cases of AML, predominantly in younger patients.[10,19] Morphologically, this type of AML is referred to as acute myelomonocytic leukemia (FAB classification M4) with abnormal eosinophils (AMML Eo). Myeloid sarcomas may be present at initial diagnosis or at relapse.
Common morphologic features include the following:
Monocytic and granulocytic differentiation.
A characteristically abnormal eosinophil component with immature purple-violet eosinophil granules that may obscure cell morphology if present in great numbers.
Auer rods in myeloblasts.
Decreased neutrophils in bone marrow.
Most cases with this genetic abnormalityhave been identified as AMML Eo, but occasional cases have been reported to lack eosinophilia. As is found in rare cases of AML with t(8;21), the bone marrow blast percentage in this AML is occasionally less than 20%.
Both inv(16)(p13q22) and t(16;16)(p13;q22) result in the fusion of the core binding factor-ß (CBFß) gene at 16q22 to the smooth muscle myosin heavy chain (MYH11) gene at 16p13, thereby forming the fusion gene CBFß/MYH11.[11] The use of fluorescence in situ hybridization (FISH) and RT–PCR methods may be necessary to document this fusion gene because its presence cannot be reliably documented by traditional cytogenetics banding techniques.[20] Patients with this type of AML may achieve higher complete remission rates when treated with high-dose cytarabine in the consolidation phase.[13,14,16]
ACUTE PROMYELOCYTIC LEUKEMIA (AML WITH T(15;17)(Q22;Q12); (PML/RARa) AND VARIANTS) (FAB CLASSIFICATION M3)
Acute promyelocytic leukemia (APL) AML with t(15;17)(q22;q12) is an AML in which promyelocytes predominate. APL exists as two types, hypergranular or typical APL and microgranular (hypogranular) APL. APL comprises 5% to 8% of cases of AML and occurs predominately in adults in midlife.[10] Both typical and microgranular APL are commonly associated with disseminated intravascular coagulation (DIC).[21,22] In microgranular APL, unlike typical APL, the leukocyte count is very high with a rapid doubling time.[10]
Common morphologic features of typical APL include the following:
Kidney-shaped or bilobed nuclei.
Cytoplasm densely packed with large granules (bright pink, red, or purple in Romanowsky stains).
Bundles of Auer rods within the cytoplasm (faggot cells).
Larger Auer rods than in other types of AML.
Strongly positive myeloperoxidase (MPO) reaction in all leukemic promyelocytes.
Only occasional leukemic promyelocytes in the blood.
Common morphologic features of microgranular APL include the following:
Bilobed nuclear shape.
Apparent scarce or absent granules (submicroscopic azurophilic granules).
Small number of abnormal promyelocytes with visible granules and/or bundles of Auer rods (faggot cells).
High leukocyte count in the peripheral blood.
Strongly positive MPO reaction in all leukemic promyelocytes.
In APL, the retinoic acid receptor alpha (RARa) gene on 17q12 fuses with a nuclear regulatory factor on 15q22 (promyelocytic leukemia or PML gene) resulting in a PML/RARa gene fusion transcript.[11,23,24] Rare cases of cryptic or masked t(15;17) lack typical cytogenetic findings and involve complex variant translocations or submicroscopic insertion of the RARa gene into PML gene leading to the expression of the PML/RARa fusion transcript.[10] FISH and/or RT–PCR methods may be required to unmask these cryptic genetic rearrangements.[25,26]
APL has a specific sensitivity to treatment with all-trans retinoic acid (ATRA, tretinoin), which acts as a differentiating agent.[27,28,29] High complete remission rates in APL may be obtained by combining ATRA treatment with chemotherapy.[30] In approximately 1% of the cases of APL, variant chromosomal aberrations may be found in which the RARa gene is fused with other genes.[31] Variant translocations involving the RARa gene include: t(11;17)(q23;q21), t(5;17)(q32;q12) and t(11;17)(q13;q21).[10]
ACUTE MYELOID LEUKEMIA WITH 11Q23 (MLL) ABNORMALITIES
AML with 11q23 abnormalities comprises 5% to 6% of cases of AML and is typically associated with monocytic features. This AML is more common in children. Two clinical subgroups of patients have a high frequency of AML with 11q23 abnormalities: AML in infants and therapy-related AML, usually occurring after treatment with DNA topoisomerase inhibitors. Patients may present with DIC and extramedullary monocytic sarcomas and/or tissue infiltration (gingiva, skin).[10]
Common morphologic features of this AML include the following:
Monoblasts and promonocytes predominate in the bone marrow.
Monoblasts and promonocytes with strong positive nonspecific esterase reactions.
11q23 abnormalities are associated frequently with acute myelomonocytic, monoblastic, and monocytic leukemias (FAB classifications M4, M5a and M5b, respectively) and occasionally with AML with and without maturation (FAB classifications M2 and M1, respectively).[10]
The MLL gene on 11q23, a developmental regulator, is involved in translocations with approximately 22 different partner chromosomes.[10,11] Genes other than MLL may be involved in 11q23 abnormalities.[32] FISH may be required to detect genetic abnormalities involving MLL.[32,33,34] In general, risk categories and prognoses for individual 11q23 translocations are difficult to determine because of the lack of studies involving significant numbers of patients; however, patients with t(11;19)(q23;p13.1) are reported to have poor outcomes.[14]
Acute Myeloid Leukemia With an FLT3 Mutation
Activating mutations of FLT3 (FMS-like tyrosine kinase-3), present at diagnosis in 20% to 30% of de novo AML, represent the most frequent molecular abnormality in this disease.[35,36] The most common type of mutation (23%) is an internal tandem duplication mutation (FLT3/ITD) localized to the juxtamembrane region of the receptor, while point mutations in the kinase domain are less common (7%). Common clinical features of patients with FLT3/ITD AML are:
Normal cytogenetics.
Leukocytosis.
Monocytic differentiation.
Patients with FLT3/ITD mutations, and possibly those with FLT3 point mutations, are consistently reported to have an increased relapse rate and reduced overall survival.[37,38] The complete remission rate for patients with FLT3 mutant AML is generally reported to be no different than that for patients with AML with nonmutant FLT3, but most studies examining this clinical parameter used results from patients treated with intensive chemotherapy regimens, and some data are available to suggest that the conventional 7+3 regimen leads to a reduced remission rate in this group of patients.[39][Level of evidence: 3iiiDiii] As yet, no clear strategy exists for improving patient outcome in FLT3 mutant AML, but small molecule FLT3 inhibitors are in development, and the role of allogeneic transplant is being considered.
Acute Myeloid Leukemia With Multilineage Dysplasia
Note: In the WHO classification, refractory anemia with excess blasts in transformation (RAEB-t) is no longer considered a distinct clinical entity and is instead included within the broader category “AML with multilineage dysplasia” as one of the following:
AML evolving from an MDS.
AML following an MDS.
AML with multilineage dysplasia is characterized by 20% or more blasts in the blood or bone marrow and dysplasia in two or more myeloid cell lines, generally including megakaryocytes.[4] To make the diagnosis, dysplasia must be present in 50% or more of the cells of at least two lineages and must be present in a pretreatment bone marrow specimen.[4,40] AML with multilineage dysplasia may occur de novo or following MDS (refer to the PDQ summary on Myelodysplastic Syndrome Treatment for more information) or a myelodysplastic/myeloproliferative disorder (MDS/MPD). (Refer to the PDQ summary on Myelodysplastic/ and Myeloproliferative Diseases Treatment for more information). The diagnostic terminology “AML with multilineage dysplasia evolving from a myelodysplastic syndrome” should be used when an MDS precedes AML.[4]
This category of AML occurs primarily in elderly patients.[4,41] Patients with this type of AML frequently present with severe pancytopenia.
Common morphologic features include the following:
Multilineage dysplasia in the blood or bone marrow.
Dysplasia in 50% or more of the cells of two or more cell lines.
Dysgranulopoiesis (neutrophils with hypogranular cytoplasm, hyposegmented nuclei or bizarrely segmented nuclei).
Dyserythropoiesis (megaloblastic nuclei, karyorrhexis, or multinucleation of erythroid precursors and ringed sideroblasts).
Dysmegakaryopoiesis (micromegakaryocytes and normal size or large megakaryocytes with monolobed or multiple separated nuclei).
The differential diagnosis of AML with multilineage dysplasia includes acute erythroid-myeloid leukemia and acute myeloblastic leukemia with maturation (FAB classifications M6a and M2). Some cases may overlap two morphologic types.[4]
As evidenced in several Southwest Oncology Group studies, tThe numerous chromosome abnormalities observed in AML with multilineage dysplasia are similar to those found in MDS and frequently involve gain or loss of major segments of certain chromosomes, predominately chromosomes 5 and/or 7.[41,42,43,44] The probability of achieving a complete remission has been reported to be affected adversely by a diagnosis of AML with multilineage dysplasia.[41,42,43]
Acute Myeloid Leukemias and Myelodysplastic Syndromes, Therapy-Related
This category includes AML and MDS that arise secondary to cytotoxic chemotherapy and/or radiation therapy.[45] The therapy-related (or secondary) MDS are included because of their close clinicopathologic relationships to therapy-related AML. Although these therapy-related disorders are distinguished by the specific mutagenic agents involved, a recent study suggests this distinction may be difficult to make because of the frequent overlapping use of multiple potentially mutagenic agents in treating cancer.[46]
ALKYLATING AGENT-RELATED ACUTE MYELOID LEUKEMIA AND MYELODYSPLASTIC SYNDROME
The alkylating agent/radiation-related acute leukemias and myelodysplastic syndromes typically occur 5 to 6 years following exposure to the mutagenic agent, with a reported range of approximately 10 to 192 months.[45,47] The risk for occurrence is related to both the total cumulative dose of the alkylating agent and the age of the patient. Clinically, the disorder commonly presents initially as an MDS with evidence of bone marrow failure. This stage is followed by dysplastic features in multiple cell lineages with a blast percentage that is usually less than 5%. In the MDS phase, approximately 66% of cases satisfy the criteria for refractory anemia with multilineage dysplasia (RCMD), with approximately 33% of these cases exhibiting ringed sideroblasts in excess of 15% (RCMD-RS).[45] (Refer to the PDQ summary on Myelodysplastic Syndrome Treatment for more information.) Another 25% of cases satisfy the criteria for refractory anemia with excess blasts 1 or 2 (RAEB-1; RAEB-2). The MDS phase may evolve to a higher grade MDS or AML. Although a minority of patients may present with acute leukemia, a substantial number of patients succumb to the disorder in the MDS phase.[45]
Common morphologic features include the following:
Panmyelosis.
Dysgranulopoiesis.
Dyserythropoiesis.
Ringed sideroblasts (60% of cases; >15% in 33% of cases).
Hypercellular bone marrow (50% of cases).
Cases may correspond morphologically to acute myeloid leukemia with maturation, acute monocytic leukemia, AMML, erythroleukemia, or acute megakaryoblastic leukemia (FAB classifications M2, M5b, M4, M6a, and M7, respectively).
Cytogenetic abnormalities have been observed in more than 90% of cases of therapy-related AML or MDS and commonly include chromosomes 5 and/or 7.[45,48,49] Complex chromosomal abnormalities are the most common finding.[46,48,49,50] Therapy-related AML is usually refractory to antileukemia therapy. Median survival after diagnosis of these disorders is approximately 7 to 8 months.[46,48]
TOPOISOMERASE II INHIBITOR-RELATED ACUTE MYELOID LEUKEMIA
This type of AML occurs in patients treated with topoisomerase II inhibitors. The agents implicated are the epipodophyllotoxins etoposide and teniposide and the anthracyclines doxorubicin and 4-epi-doxorubicin.[45] The mean latency period from the time of institution of the causative therapy to the development of AML is approximately 2 years.[51] Morphologically, there is a significant monocytic component. Most cases are categorized as acute monoblastic or myelomonocytic leukemia. Other morphologies reported include acute promyelocytic leukemia, myelodysplastic syndromes, and acute megakaryoblastic leukemia.[45]
As with alkylating agent/radiation-related acute leukemias and myelodysplastic syndromes, the cytogenetic abnormalities are often complex.[46,48,49,50] The predominant cytogenetic finding involves chromosome 11q23 and the MLL gene.[46,52] Current data are insufficient to predict survival times.
Acute Myeloid Leukemia Not Otherwise Categorized
Cases of AML that do not fulfill the criteria for AML with recurrent genetic abnormalities, AML with multilineage dysplasia, or AML and MDS, therapy-related, fall within this category. Classification within this category is based on leukemic cell features of morphology, cytochemistry, and maturation.[53]
ACUTE MYELOBLASTIC LEUKEMIA, MINIMALLY DIFFERENTIATED (FAB CLASSIFICATION M0)
This AML shows no evidence of myeloid differentiation by morphology and light microscopy cytochemistry.[54] The myeloid nature of the blasts is demonstrated by immunophenotyping and/or ultrastructural studies.[53] Immunophenotyping studies must be performed to distinguish this acute leukemia from acute lymphoblastic leukemia (ALL).[53] Cases of AML, minimally differentiated, comprise approximately 5% of cases of AML. Patients with this AML typically present with evidence of marrow failure, thrombocytopenia, and neutropenia.[54]
Morphologic and cytochemical features include the following:
Medium-sized blasts with dispersed nuclear chromatin.
Agranular cytoplasm.
Occasionally small blasts that resemble lymphoblasts.
Cytochemistry negative for myeloperoxidase (MPO), Sudan Black B (SBB), and naphthol ASD chloroacetate esterase (<3% positive blasts).
Cytochemistry negative for alpha naphthyl acetate and butyrate esterases.
Markedly hypercellular marrow.
Immunophenotyping reveals blast cells that express one or more panmyeloid antigens (CD13, CD33, and CD117) and are negative for B and T lymphoid-restricted antigens. Most cases express primitive hematopoietic-associated antigens (CD34, CD38, and HLA-DR). The differential diagnosis includes ALL, acute megakaryoblastic leukemia, biphenotypic/mixed lineage acute leukemia, and, rarely, the leukemic phase of large cell lymphoma. Immunophenotyping studies are required to distinguish these disorders.[53]
Although no specific chromosomal abnormalities have been found in AML, minimally differentiated point mutations of the AML1 gene have been observed in approximately 25% of cases. This mutation appears to correlate clinically with a higher white blood cell count and greater marrow blast involvement.[53,55] Mutation of FLT3, a receptor tyrosine kinase gene, occurs in approximately 25% of cases and has been associated with short survival.[37,55] The median overall survival is approximately 10 months.[56]
ACUTE MYELOBLASTIC LEUKEMIA WITHOUT MATURATION (FAB CLASSIFICATION M1)
AML without maturation is characterized by a high percentage of bone marrow blasts with little evidence of maturation to mature neutrophils and comprises approximately 10% of cases of AML.[53] Most patients are adults. Patients usually present with anemia, thrombocytopenia, and neutropenia.
Common morphologic and cytochemical features include the following:
Myeloblasts of 90% or more of the nonerythroid cells in the bone marrow.
Myeloblasts that may have azurophilic granules and/or Auer rods.
Myeloblasts that resemble lymphoblasts.
MPO and SBB positivity in blasts of 3% or more .
Typically markedly hypercellular marrow.
Immunophenotyping reveals blasts that express at least two myelomonocytic antigens (CD13, CD33, CD117) and/or MPO. CD34 is often positive. The differential diagnosis includes ALL in cases of AML without maturation with no granules and a low percentage of MPO positive blasts, and AML with maturation in cases of AML with maturation with a high percentage of blasts.
Although no specific chromosomal abnormality has been identified for AML without maturation, mutation of the FLT3 gene has been associated with leukocytosis, a high percentage of bone marrow blast cells, and a worse prognosis.[37,53,57]
ACUTE MYELOBLASTIC LEUKEMIA WITH MATURATION (FAB CLASSIFICATION M2)
AML with maturation is characterized by 20% or more myeloblasts in the blood or bone marrow and 10% or more neutrophils at different stages of maturation. Monocytes constitute less than 20% of bone marrow cells.[53] This AML comprises approximately 30% to 45% of cases of AML. While it occurs in all age groups, 20% of patients are less than 25 years and 40% of patients are 60 years or older .[53] Patients frequently present with anemia, thrombocytopenia, and neutropenia.
Morphologic features include the following:
Myeloblasts with and without azurophilic granules.
Auer rods.
Promyelocytes, myelocytes, and neutrophils 10% or more of the bone marrow cells.
Abnormal nuclear segmentation in neutrophils.
Increased eosinophil precursors (frequently).
Hypercellular marrow (usually).
Blasts and maturing neutrophils reactive with antibodies to MPO and lysozyme.
With immunophenotyping, the blasts typically express one or more myeloid-associated antigens (CD13, CD33, and CD15). The differential diagnosis includes: RAEB in cases with a low blast percentage, AML without maturation when the blast percentage is high, and AMML in cases with increased monocytes.
Approximately 33% of karyotypically abnormal cases of AML with maturation are associated with t(8;21)(q22:q22) (see Acute myeloid leukemia with characteristic genetic abnormalities).[11] Such cases have a favorable prognosis. Rare cases with t(6;9)(q23:q34) are reported to have a poor prognosis.[53,58]
ACUTE PROMYELOCYTIC LEUKEMIA (AML WITH T(15;17)(Q22;Q12); (PML/RARa) AND VARIANTS) (FAB CLASSIFICATION M3)
See the preceding section on Acute promyelocytic leukemia (FAB Classification M3).
ACUTE MYELOMONOCYTIC LEUKEMIA (FAB CLASSIFICATION M4)
Acute myelomonocytic leukemia (AMML) is characterized by the proliferation of neutrophil and monocyte precursors. Patients usually present with anemia and thrombocytopenia. This classification of AML comprises approximately 15% to 25% of cases of AML, and some patients have a previous history of chronic myelomonocytic leukemia (CMML). (Refer to the PDQ summary on Myelodysplastic/Myeloproliferative Disease Treatment for more information.) This type of AML occurs more commonly in older individuals.[53]
Morphologic and cytochemical features include the following:
20% or more blasts in the bone marrow.
20% or more neutrophils, monocytes, and their precursors in the bone marrow (to distinguish AMML from AML with or without maturation and to increase monocytes).
5 x 10⁹/L or more monocytes in the blood.
Large monoblasts with round nuclei, abundant cytoplasm, and prominent nucleoli.
MPO positivity in at least 3% of blasts.
Monoblasts, promonocytes, and monocytes typically nonspecific esterase- (NSE) positive.
Immunophenotyping generally reveals monocytic differentiation markers (CD14, CD4, CD11b, CD11c, CD64, and CD36) and lysozyme. The differential diagnosis includes AML with maturation and acute monocytic leukemia.
Most cases of AMML exhibit nonspecific cytogenetic abnormalities.[53] Some cases may have a 11q23 genetic abnormality (see Acute myeloid leukemia with characteristic genetic abnormalities). Cases with increased abnormal eosinophils in the bone marrow associated with a chromosome 16 abnormality have a favorable prognosis (see Acute myeloid leukemia with characteristic genetic abnormalities).
ACUTE MONOBLASTIC LEUKEMIA AND ACUTE MONOCYTIC LEUKEMIA (FAB CLASSIFICATIONS M5A AND M5B)
Acute monoblastic and acute monocytic leukemia are AMLs in which 80% or more of the leukemic cells are of a monocytic lineage. These cells include monoblasts, promonocytes, and monocytes. These two leukemias are distinguished by the relative proportions of monoblasts and promonocytes. In acute monoblastic leukemia, most monocytic cells are monoblasts (usually =80%). In acute monocytic leukemia, most of the monocytic cells are promonocytes.[53] Acute monoblastic leukemia comprises 5% to 8% of cases of AML and occurs most commonly in young individuals. Acute monocytic leukemia comprises 3% to 6% of cases and is more common in adults.[59] Common clinical features for both acute leukemias include bleeding disorders, extramedullary masses, cutaneous and gingival infiltration, and central nervous system involvement.
Morphologic and cytochemical features of acute monoblastic leukemia include the following:
Large basophilic monoblasts with abundant cytoplasm, pseudopod formation, round nuclei, and one or more prominent nucleoli.
Rare Auer rods.
Typically intensely NSE positive and MPO negative.
Hypercellular marrow with large numbers of monoblasts.
Lysozyme positive.
Morphologic and cytochemical features of acute monocytic leukemia include the following:
Promonocytes with an irregular nuclear configuration with a moderately basophilic cytoplasm and cytoplasmic azurophilic granules.
Typically intensely NSE positive.
Occasional MPO positivity.
Lysozyme positive.
Hemophagocytosis (erythrophagocytosis).
The extramedullary lesions of these leukemias may be predominantly monoblastic or monocytic or an admixture of the two cell types. Immunophenotyping of these leukemias may reveal expression of the myeloid antigens CD13, CD33, CD117, CD14 ( + ), CD4, CD36, CD 11b, CD11c, CD64, and CD68.[53] The differential diagnosis of acute monoblastic leukemia includes AML without maturation, minimally differentiated AML, and acute megakaryoblastic leukemia. The differential diagnosis of acute monocytic leukemia includes AMML and microgranular APL.
An abnormal karyotype has been observed in approximately 75% of cases of acute monoblastic leukemia while approximately 30% of cases of acute monocytic leukemia are associated with an abnormal karyotype. Almost 30% of cases of acute monoblastic leukemia and 12% of cases of acute monocytic leukemia are associated with 11q23 genetic abnormalities involving the MLL gene (see Acute myeloid leukemia with characteristic genetic abnormalities). Mutation of FLT3, a receptor tyrosine kinase gene, has been observed in about 30% of cases of acute monocytic leukemia (approximately 7% in acute monoblastic leukemia).[60] The translocation t(8;16)(p11;p13) (strongly associated with acute monocytic leukemia, hemophagocytosis by leukemic cells, and a poor response to chemotherapy) fuses the MOZ gene (8p11) with the CBP gene (16p13).[