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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.

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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:

  1. American Cancer Society.: Cancer Facts and Figures 2007. Atlanta, Ga: American Cancer Society, 2007. Also available online. Last accessed September 7, 2007.
  2. 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.
  3. Myint H, Lucie NP: The prognostic significance of the CD34 antigen in acute myeloid leukaemia. Leuk Lymphoma 7 (5-6): 425-9, 1992.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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 abnormality have 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]

The 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).[61] Median actuarial disease-free survival for acute monocytic leukemia has been reported to be approximately 21 months.[62]

ACUTE ERYTHROID LEUKEMIAS (FAB CLASSIFICATIONS M6A AND M6B)

The two subtypes of the acute erythroid leukemias, erythroleukemia and pure erythroid leukemia, are characterized by a predominant erythroid population and, in the case of erythroleukemia, the presence of a significant myeloid component. Erythroleukemia (erythroid/myeloid; M6a) is predominantly a disease of adults, comprising approximately 5% to 6% of cases of AML.[59] Pure erythroid leukemia (M6b) is rare and occurs in all age groups. Occasional cases of chronic myeloid leukemia (CML) may evolve to one of the acute erythroid leukemias.[53] Erythroleukemia may present de novo or evolve from an MDS, either RAEB or RCMD-RS and RCMD, respectively. (Refer to the PDQ summary on Myelodysplastic Syndrome Treatment for more information.) The clinical features of these acute leukemias include profound anemia and normoblastemia.

Morphologic and cytochemical features of erythroleukemia include the following:[53]

  • 50% or more erythroid precursors in the entire nucleated cell population of the bone marrow.
  • 20% or more myeloblasts in the nonerythroid population in the bone marrow.
  • Dysplastic erythroid precursors with megaloblastoid nuclei.
  • Multinucleated erythroid cells.
  • Myeloblasts of medium size, occasionally with Auer rods.
  • Ringed sideroblasts.
  • Positive PAS stain in the erythroid precursors.
  • Hypercellular bone marrow.
  • Megakaryocytic dysplasia.

Morphologic and cytochemical features of pure erythroid leukemia include the following:

  • Medium- to large-sized erythroblasts with round nuclei, fine chromatin, one or more nucleoli, deeply basophilic cytoplasm, and occasional coalescent vacuoles.
  • Erythroblasts reactive with alpha-naphthyl acetate esterase.
  • Acid phosphatase.
  • PAS.

Immunophenotyping in erythroleukemia reveals erythroblasts that react with antibodies to glycophorin A and hemoglobin A and myeloblasts that express a variety of myeloid-associated antigens (CD13, CD33, CD117, c-kit, and MPO). Immunophenotyping in acute erythroid leukemia reveals expression of glycophorin A and hemoglobin A in differentiated forms. Markers such as carbonic anhydrase 1, Gero antibody against the Gerbich blood group, or CD36 are usually positive. The differential diagnosis for erythroleukemia includes RAEB and AML with maturation with increased erythroid precursors and AML with multilineage dysplasia (involving =50% of myeloid or megakaryocyte-lineage cells). If erythroid precursors are 50% or more and the nonerythroid component is 20% or more, the diagnosis is erythroleukemia, whereas, if the nonerythroid component is less than 20%, the diagnosis is RAEB. The differential diagnosis for pure erythroid leukemia includes megaloblastic anemia secondary to vitamin B12 or folate deficiency, acute megakaryocytic leukemia, and ALL or lymphoma.[53]

No specific chromosome abnormalities are described for these AMLs. Complex karyotypes with multiple structural abnormalities are common. Chromosomes 5 and 7 appear to be affected frequently.[53,63,64] One study indicates that abnormalities of chromosomes 5 and/or 7 correlate with significantly shorter survival times.[65]

ACUTE MEGAKARYOBLASTIC LEUKEMIA (FAB CLASSIFICATION M7)

Acute megakaryoblastic leukemia, in which 50% or more of blasts are of the megakaryocyte lineage, occurs in all age groups and comprises approximately 3% to 5% of cases of AML.[53] Clinical features include cytopenias; dysplastic changes in neutrophils and platelets; rare organomegaly, except in children with t(1;22); lytic bone lesions in children; and association with mediastinal germ cell tumors in young adult males.[53,66,67]

Morphologic and cytochemical features include the following:[53,66,68]

  • Medium- to large-sized megakaryoblasts with round or indented nucleus and one or more nucleoli.
  • Agranular, basophilic cytoplasm with pseudopod formation.
  • Lymphoblast-like morphology (high nuclear-cytoplasmic ratio) in some cases.
  • Circulating micromegakaryocytes, megakaryoblastic fragments, dysplastic large platelets, and hypogranular neutrophils.
  • Stromal pattern of marrow infiltration mimicking a metastatic tumor in infants.
  • Negative stains for SBB and MPO.
  • Blasts reactive with PAS, acid phosphatase, and nonspecific esterase.

Immunophenotyping reveals megakaryoblast expression of one or more platelet glycoproteins: CD41 (glycoprotein IIb/IIIa) and/or CD61 (glycoprotein IIIa). Myeloid markers CD13 and CD33 may be positive; CD36 is typically positive. Blasts are negative with the anti-MPO antibody and other markers of myeloid differentiation. In bone marrow biopsies, megakaryocytes and megakaryoblasts may react positively to antibodies for Factor VIII.[53] The differential diagnosis includes minimally differentiated AML, acute panmyelosis with myelofibrosis, ALL, pure erythroid leukemia, and blastic transformation of chronic myeloid leukemia or idiopathic myelofibrosis (refer to the PDQ summary on Chronic Myeloproliferative Disorder Treatment for more information), and metastatic tumors in the bone marrow (particularly in children).

No unique chromosomal abnormalities are associated with acute megakaryoblastic leukemia in adults.[53,69] In children, particularly infants, a distinct clinical presentation may be associated with t(1:22)(p13;q13).[66,68] The prognosis for this type of acute leukemia is poor.[70,71]

VARIANT: ACUTE MYELOID LEUKEMIA/TRANSIENT MYELOPROLIFERATIVE DISORDER IN DOWN SYNDROME

Individuals with Down syndrome (trisomy 21) have an increased disposition to acute leukemia, primarily the myeloid type.[72,73] The primary subtype appears to be acute megakaryoblastic leukemia. In cases in which the leukemia remits spontaneously, the process is referred to as transient myeloproliferative disorder or transient leukemia. Clinical features include presentation in the neonatal period (10% of newborn infants with Down syndrome), marked leukocytosis, blast percentage in the blood greater than 30% to 50%, and extramedullary involvement.

Morphologic and cytochemical features include the following:

  • Blasts with round to slightly irregular nuclei and a moderate amount of basophilic cytoplasm.
  • Coarse azurophilic granules in the cytoplasm that resemble basophil granules.
  • Promegakaryocytes and micromegakaryocytes.
  • Dyserythropoiesis.
  • MPO-negative and SBB-negative blasts.

Immunophenotyping reveals markers that are generally similar to those of other cases of childhood acute megakaryoblastic leukemia.

In addition to trisomy 21, some cases may show other clonal abnormalities, particularly trisomy 8.[73,74] Spontaneous remission occurs within 1 to 3 months in transient cases. Recurrence followed by a second spontaneous remission or persistent disease may occur. Treatment outcomes for pediatric patients with Down syndrome and persistent disease may be better than those for pediatric patients with acute leukemia in the absence of trisomy 21.[71]

ACUTE BASOPHILIC LEUKEMIA

Acute basophilic leukemia is an AML that exhibits a primary differentiation to basophils. This acute leukemia is relatively rare, comprising less than 1% of all cases of AML.[53] Clinical features include bone marrow failure, circulating blasts, cutaneous involvement, organomegaly, occasional osseous lytic lesions, and symptoms secondary to hyperhistaminemia.

Morphologic and cytochemical features include the following:

  • Medium-sized blasts with a high nuclear-cytoplasmic ratio and an oval, round, or bilobed nucleus with one or more nucleoli.
  • Moderately basophilic cytoplasm containing a variable number of coarse basophilic granules.
  • Sparse numbers of mature basophils.
  • Dysplastic erythroid features.
  • Blasts with metachromatic positivity, with toluidine blue.
  • Blasts with acid phosphatase positivity.
  • Negative by light microscopy for SBB, MPO, and nonspecific esterase.
  • Hypercellular bone marrow.

Immunophenotypically, the blasts express the myeloid markers CD13 and CD33 and the early hematopoietic markers CD34 and class-II HLA-DR. The differential diagnosis includes: blast crisis of CML, other AML subtypes with basophilia such as AML with maturation (M2) associated with abnormalities of 12p or t(6;9), acute eosinophilic leukemia, and, rarely, a subtype of ALL with prominent coarse granules.[53]

No consistent chromosome abnormality has been identified for acute basophilic leukemia.[53] Due to its rare incidence, little information regarding survival is available.

ACUTE PANMYELOSIS WITH MYELOFIBROSIS

Acute panmyelosis with myelofibrosis (also known as acute myelofibrosis, acute myelosclerosis, and acute myelodysplasia with myelofibrosis) is an acute panmyeloid proliferation associated with fibrosis of the bone marrow. This disorder is very rare and occurs in all age groups.[53] The disorder may occur de novo or after treatment with alkylating-agent chemotherapy and/or radiation (see the section on Acute myeloid leukemias and myelodysplastic syndromes, therapy related). Clinical features include constitutional symptoms such as weakness and fatigue.

Morphologic and cytochemical features include the following:

  • Marked pancytopenia.
  • Anisocytosis.
  • Dysplastic changes in myeloid cells.
  • Hypercellular bone marrow (biopsy).
  • Variable degrees of hyperplasia of erythroid precursors, granulocytes, and megakaryocytes in the bone marrow.
  • Increased number of small- to large-sized megakaryocytes with dysplastic features in the bone marrow.
  • Marked increase in reticulin fibers in the bone marrow.

Immunophenotypically, blasts may express one or more myeloid-associated antigens (CD13, CD33, CD117, and MPO). Some cells may express erythroid or megakaryocytic antigens. The major differential diagnosis includes acute megakaryoblastic leukemia, acute leukemias with associated marrow fibrosis, metastatic tumor with a desmoplasmic reaction, and chronic idiopathic myelofibrosis.[53] (Refer to the PDQ summary on Chronic Myeloproliferative Disorder Treatment for more information.)

No specific chromosomal abnormalities are associated with acute panmyelosis with myelofibrosis. This AML is reported to respond poorly to chemotherapy and to be associated with a short survival.[53]

MYELOID SARCOMA

Myeloid sarcoma (also known as extramedullary myeloid tumor, granulocytic sarcoma, and chloroma) is a tumor mass that consists of myeloblasts or immature myeloid cells, occurring in an extramedullary site;[53] development in 2% to 8% of patients with AML has been reported.[75] Clinical features include occurrence common in subperiosteal bone structures of the skull, paranasal sinuses, sternum, ribs, vertebrae, and pelvis; lymph nodes, skin, mediastinum, small intestine, and the epidural space; and occurrence de novo or concomitant with AML or a myeloproliferative disorder.[53,75]

Morphologic and cytochemical features include the following:

  • Granulocytic sarcoma composed of myeloblasts, neutrophils, and neutrophil precursors with three subtypes based on degree of maturation (i.e., blastic, immature, and differentiated).
  • Monoblastic sarcoma preceding or occurring simultaneously with acute monoblastic leukemia.
  • Tumors with trilineage hematopoiesis occurring with transformation of chronic myeloproliferative disorders.
  • Myeloblasts and neutrophils positive for MPO.
  • Neutrophils positive for naphthol ASD chloroacetate esterase.

Immunophenotyping with antibodies to MPO, lysozyme, and chloroacetate are critical to the diagnosis of these lesions.[53] The myeloblasts in granulocytic sarcomas express myeloid-associated antigens (CD13, CD33, CD117, and MPO). The monoblasts in monoblastic sarcomas express acute monoblastic leukemia antigens (CD14, CD116, and CD11c) and usually react with antibodies to lysozyme and CD68. The main differential diagnosis includes non-Hodgkin lymphoma of the lymphoblastic type, Burkitt lymphoma, large-cell lymphoma, and small round cell tumors, especially in children (e.g., neuroblastoma, rhabdomyosarcoma, Ewing/primitive neuroectodermal tumors, and medulloblastoma).

No unique chromosomal abnormalities are associated with myeloid sarcoma.[53,75] AML with maturation and t(8;21)(q22;q22) and AMML Eo with in (16)(p13q22) or t(16;16)(p13;q22) may be observed and monoblastic sarcoma may be associated with translocations involving 11q23.[53] The presence of myeloid sarcoma in patients with the otherwise good-risk t(8;21) AML may be associated with a lower complete remission rate and decreased remission duration.[76] Myeloid sarcoma occurring in the setting of MDS or MPD is equivalent to blast transformation. In the case of AML, the prognosis is that of the underlying leukemia.[53] Although the initial presentation of myeloid sarcoma may appear to be isolated, several reports indicate that isolated myeloid sarcoma is a partial manifestation of a systemic disease and should be treated with intensive chemotherapy.[75,77,78]

Acute Leukemias of Ambiguous Lineage

Acute leukemias of ambiguous lineage (also known as acute leukemias of undetermined lineage, mixed phenotype acute leukemias, mixed lineage acute leukemias, and hybrid acute leukemias) are types of acute leukemia in which the morphologic, cytochemical, and immunophenotypic features of the blast population do not allow classification in myeloid or lymphoid categories; or the types have morphologic and/or immunophenotypic features of both myeloid and lymphoid cells or both B and T lineages (i.e., acute bilineal leukemia and acute biphenotypic leukemia).[79,80,81,82,83] These rare leukemias account for less than 4% of all cases of acute leukemia and occur in all age groups but are more frequent in adults.[79] Clinical features include symptoms and complications caused by cytopenias, i.e., fatigue, infections, and bleeding disorders.

Morphologic and immunophenotypic features of these acute leukemias include the following:[79,80,82,83]

  • Undifferentiated acute leukemia in which the leukemic cells lack any differentiating characteristics and lack markers for a given lineage.
  • Bilineal acute leukemia in which a dual population of blasts exhibits morphologic features and markers of two distinct lineages, i.e., myeloid and lymphoid or B and T.
  • Biphenotypic acute leukemia in which the blasts exhibit the morphological features of only one lineage but express markers of more than one lineage.

The differential diagnosis includes myeloid antigen-positive ALL or lymphoid-positive AML (from which biphenotypic acute leukemia should be distinguished) and minimally differentiated AML (from which undifferentiated acute leukemia must be distinguished).

Cytogenetic abnormalities are observed in a high percentage of bilineal and biphenotypic leukemias.[80,81,84,85] Approximately 33% of cases have the Philadelphia chromosome, and some cases are associated with t(4;11)(q21;q23) or other 11q23 abnormalities. In general, the prognosis appears to be unfavorable, particularly in adults; the occurrence of the translocation t(4;11) or the Philadelphia chromosome are especially unfavorable prognostic indicators.[79,81,86]

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  55. Roumier C, Eclache V, Imbert M, et al.: M0 AML, clinical and biologic features of the disease, including AML1 gene mutations: a report of 59 cases by the Groupe Français d'Hématologie Cellulaire (GFHC) and the Groupe Français de Cytogénétique Hématologique (GFCH). Blood 101 (4): 1277-83, 2003.
  56. Béné MC, Bernier M, Casasnovas RO, et al.: Acute myeloid leukaemia M0: haematological, immunophenotypic and cytogenetic characteristics and their prognostic significance: an analysis in 241 patients. Br J Haematol 113 (3): 737-45, 2001.
  57. Abu-Duhier FM, Goodeve AC, Wilson GA, et al.: FLT3 internal tandem duplication mutations in adult acute myeloid leukaemia define a high-risk group. Br J Haematol 111 (1): 190-5, 2000.
  58. Alsabeh R, Brynes RK, Slovak ML, et al.: Acute myeloid leukemia with t(6;9) (p23;q34): association with myelodysplasia, basophilia, and initial CD34 negative immunophenotype. Am J Clin Pathol 107 (4): 430-7, 1997.
  59. Stanley M, McKenna RW, Ellinger G, et al.: Classification of 358 cases of acute myeloid leukemia by FAB criteria: analysis of clinical and morphologic features. In: Bloomfield CD, ed.: Chronic and Acute Leukemias in Adults. Boston, Ma: Martinus Nijhoff Publishers, 1985, pp 147-74.
  60. Haferlach T, Schoch C, Schnittger S, et al.: Distinct genetic patterns can be identified in acute monoblastic and acute monocytic leukaemia (FAB AML M5a and M5b): a study of 124 patients. Br J Haematol 118 (2): 426-31, 2002.
  61. Panagopoulos I, Isaksson M, Lindvall C, et al.: Genomic characterization of MOZ/CBP and CBP/MOZ chimeras in acute myeloid leukemia suggests the involvement of a damage-repair mechanism in the origin of the t(8;16)(p11;p13). Genes Chromosomes Cancer 36 (1): 90-8, 2003.
  62. Fenaux P, Vanhaesbroucke C, Estienne MH, et al.: Acute monocytic leukaemia in adults: treatment and prognosis in 99 cases. Br J Haematol 75 (1): 41-8, 1990.
  63. Cigudosa JC, Odero MD, Calasanz MJ, et al.: De novo erythroleukemia chromosome features include multiple rearrangements, with special involvement of chromosomes 11 and 19. Genes Chromosomes Cancer 36 (4): 406-12, 2003.
  64. Domingo-Claros A, Larriba I, Rozman M, et al.: Acute erythroid neoplastic proliferations. A biological study based on 62 patients. Haematologica 87 (2): 148-53, 2002.
  65. Olopade OI, Thangavelu M, Larson RA, et al.: Clinical, morphologic, and cytogenetic characteristics of 26 patients with acute erythroblastic leukemia. Blood 80 (11): 2873-82, 1992.
  66. Bernstein J, Dastugue N, Haas OA, et al.: Nineteen cases of the t(1;22)(p13;q13) acute megakaryblastic leukaemia of infants/children and a review of 39 cases: report from a t(1;22) study group. Leukemia 14 (1): 216-8, 2000.
  67. Nichols CR, Roth BJ, Heerema N, et al.: Hematologic neoplasia associated with primary mediastinal germ-cell tumors. N Engl J Med 322 (20): 1425-9, 1990.
  68. Carroll A, Civin C, Schneider N, et al.: The t(1;22) (p13;q13) is nonrandom and restricted to infants with acute megakaryoblastic leukemia: a Pediatric Oncology Group Study. Blood 78 (3): 748-52, 1991.
  69. Dastugue N, Lafage-Pochitaloff M, Pagès MP, et al.: Cytogenetic profile of childhood and adult megakaryoblastic leukemia (M7): a study of the Groupe Français de Cytogénétique Hématologique (GFCH). Blood 100 (2): 618-26, 2002.
  70. Pagano L, Pulsoni A, Vignetti M, et al.: Acute megakaryoblastic leukemia: experience of GIMEMA trials. Leukemia 16 (9): 1622-6, 2002.
  71. Athale UH, Razzouk BI, Raimondi SC, et al.: Biology and outcome of childhood acute megakaryoblastic leukemia: a single institution's experience. Blood 97 (12): 3727-32, 2001.
  72. Zipursky A, Brown EJ, Christensen H, et al.: Transient myeloproliferative disorder (transient leukemia) and hematologic manifestations of Down syndrome. Clin Lab Med 19 (1): 157-67, vii, 1999.
  73. Zipursky A, Thorner P, De Harven E, et al.: Myelodysplasia and acute megakaryoblastic leukemia in Down's syndrome. Leuk Res 18 (3): 163-71, 1994.
  74. Kounami S, Aoyagi N, Tsuno H, et al.: Additional chromosome abnormalities in transient abnormal myelopoiesis in Down's syndrome patients. Acta Haematol 98 (2): 109-12, 1997.
  75. Yamauchi K, Yasuda M: Comparison in treatments of nonleukemic granulocytic sarcoma: report of two cases and a review of 72 cases in the literature. Cancer 94 (6): 1739-46, 2002.
  76. Byrd JC, Weiss RB, Arthur DC, et al.: Extramedullary leukemia adversely affects hematologic complete remission rate and overall survival in patients with t(8;21)(q22;q22): results from Cancer and Leukemia Group B 8461. J Clin Oncol 15 (2): 466-75, 1997.
  77. Hayashi T, Kimura M, Satoh S, et al.: Early detection of AML1/MTG8 fusion mRNA by RT-PCR in the bone marrow cells from a patient with isolated granulocytic sarcoma. Leukemia 12 (9): 1501-3, 1998.
  78. Imrie KR, Kovacs MJ, Selby D, et al.: Isolated chloroma: the effect of early antileukemic therapy. Ann Intern Med 123 (5): 351-3, 1995.
  79. Brunning RD, Matutes E, Borowitz M: Acute leukaemias of ambiguous lineage. 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 106-7.
  80. Hanson CA, Abaza M, Sheldon S, et al.: Acute biphenotypic leukaemia: immunophenotypic and cytogenetic analysis. Br J Haematol 84 (1): 49-60, 1993.
  81. Legrand O, Perrot JY, Simonin G, et al.: Adult biphenotypic acute leukaemia: an entity with poor prognosis which is related to unfavourable cytogenetics and P-glycoprotein over-expression. Br J Haematol 100 (1): 147-55, 1998.
  82. Matutes E, Morilla R, Farahat N, et al.: Definition of acute biphenotypic leukemia. Haematologica 82 (1): 64-6, 1997 Jan-Feb.
  83. Sulak LE, Clare CN, Morale BA, et al.: Biphenotypic acute leukemia in adults. Am J Clin Pathol 94 (1): 54-8, 1990.
  84. Carbonell F, Swansbury J, Min T, et al.: Cytogenetic findings in acute biphenotypic leukaemia. Leukemia 10 (8): 1283-7, 1996.
  85. Pane F, Frigeri F, Camera A, et al.: Complete phenotypic and genotypic lineage switch in a Philadelphia chromosome-positive acute lymphoblastic leukemia. Leukemia 10 (4): 741-5, 1996.
  86. Killick S, Matutes E, Powles RL, et al.: Outcome of biphenotypic acute leukemia. Haematologica 84 (8): 699-706, 1999.

Treatment Option Overview

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Successful treatment of acute myeloid leukemia (AML) requires the control of bone marrow and systemic disease and specific treatment of central nervous system (CNS) disease, if present. The cornerstone of this strategy includes systemically administered combination chemotherapy. Because only 5% of patients with AML develop CNS disease, prophylactic treatment is not indicated.[1,2,3]

Treatment is divided into two phases: induction (to attain remission) and postremission (to maintain remission). Maintenance therapy for AML was previously administered for several years but is not included in most current treatment clinical trials in the United States (see the Adult AML in remission section of this summary). Other studies have used more intensive consolidation therapy administered for a shorter duration of time after which treatment is discontinued.[4] Consolidation therapy appears to be effective when given either immediately after remission is achieved [4] or when delayed for 9 months.[3]

Since myelosuppression is an anticipated consequence of both the leukemia and its treatment with chemotherapy, patients must be closely monitored during therapy. Facilities must be available for hematologic support with multiple blood fractions including platelet transfusions, as well as for the treatment of related infectious complications.[5] Randomized trials have shown similar outcomes for patients who received prophylactic platelet transfusions at a level of 10,000/mm3 rather than 20,000/mm3.[6] The incidence of platelet alloimmunization was similar among groups randomly assigned to receive pooled platelet concentrates from random donors; filtered, pooled platelet concentrates from random donors; ultraviolet B-irradiated, pooled platelet concentrates from random donors; or filtered platelets obtained by apheresis from single random donors.[7] Colony-stimulating factors, e.g., granulocyte colony–stimulating factor (G-CSF) and granulocyte-macrophage colony–stimulating factor (GM-CSF), have been studied in an effort to shorten the period of granulocytopenia associated with leukemia treatment.[8] If used, these agents are administered after completion of induction therapy. GM-CSF was shown to improve survival in a randomized trial of AML in patients aged 55 to 70 years (median survival was 10.6 months vs. 4.8 months). In this trial, patients were randomized to receive GM-CSF or placebo following demonstration of leukemic clearance of the bone marrow;[9] however, GM-CSF did not show benefit in a separate similar randomized trial in patients aged 60 years and older.[10] In the latter study, clearance of the marrow was not required before initiating cytokine therapy. In a randomized trial of G-CSF given following induction therapy to patients older than 65 years, complete response was higher in patients who received G-CSF, due to a decreased incidence of primary leukemic resistance. Growth factor administration did not impact on mortality or on survival.[11]

The administration of GM-CSF or other myeloid growth factors before and during induction therapy, to augment the effects of cytotoxic therapy through the recruitment of leukemic blasts into cell cycle (growth factor priming), has been an area of active clinical research. Evidence from randomized studies of GM-CSF priming have come to opposite conclusions. A randomized study of GM-CSF priming during conventional induction and consolidation therapy showed no difference in outcomes between patients who received GM-CSF and those who did not receive growth factor priming.[12,13][Level of evidence: 1iiA] In contrast, a similar randomized placebo-controlled study of GM-CSF priming in patients with AML aged 55 to 75 years showed improved disease-free survival in the group receiving GM-CSF (median disease-free survival for patients who achieved complete remission was 23 months vs. 11 months; 2-year disease-free survival was 48% vs. 21%), with a trend towards improvement in overall survival (2-year survival was 39% vs. 27%, P = .082) for patients aged 55 to 64 years.[14][Level of evidence: 1iiDi]

References:

  1. 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.
  2. Wiernik PH: Diagnosis and treatment of acute nonlymphocytic leukemia. In: Wiernik PH, Canellos GP, Dutcher JP, et al., eds.: Neoplastic Diseases of the Blood. 3rd ed. New York, NY: Churchill Livingstone, 1996, pp 283-302.
  3. Morrison FS, Kopecky KJ, Head DR, et al.: Late intensification with POMP chemotherapy prolongs survival in acute myelogenous leukemia--results of a Southwest Oncology Group study of rubidazone versus adriamycin for remission induction, prophylactic intrathecal therapy, late intensification, and levamisole maintenance. Leukemia 6 (7): 708-14, 1992.
  4. Cassileth PA, Lynch E, Hines JD, et al.: Varying intensity of postremission therapy in acute myeloid leukemia. Blood 79 (8): 1924-30, 1992.
  5. Supportive Care. In: Wiernik PH, Canellos GP, Dutcher JP, et al., eds.: Neoplastic Diseases of the Blood. 3rd ed. New York, NY: Churchill Livingstone, 1996, pp 779-967.
  6. Rebulla P, Finazzi G, Marangoni F, et al.: The threshold for prophylactic platelet transfusions in adults with acute myeloid leukemia. Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto. N Engl J Med 337 (26): 1870-5, 1997.
  7. Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. The Trial to Reduce Alloimmunization to Platelets Study Group. N Engl J Med 337 (26): 1861-9, 1997.
  8. Geller RB: Use of cytokines in the treatment of acute myelocytic leukemia: a critical review. J Clin Oncol 14 (4): 1371-82, 1996.
  9. Rowe JM, Andersen JW, Mazza JJ, et al.: A randomized placebo-controlled phase III study of granulocyte-macrophage colony-stimulating factor in adult patients (> 55 to 70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490). Blood 86 (2): 457-62, 1995.
  10. Stone RM, Berg DT, George SL, et al.: Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. Cancer and Leukemia Group B. N Engl J Med 332 (25): 1671-7, 1995.
  11. Dombret H, Chastang C, Fenaux P, et al.: A controlled study of recombinant human granulocyte colony-stimulating factor in elderly patients after treatment for acute myelogenous leukemia. AML Cooperative Study Group. N Engl J Med 332 (25): 1678-83, 1995.
  12. Buchner T, Hiddemann W, Wormann B, et al.: GM-CSF multiple course priming and long-term administration in newly diagnosed AML: hematologic and therapeutic effects. [Abstract] Blood 84 (10 Suppl 1): A-95, 27a, 1994.
  13. Löwenberg B, Boogaerts MA, Daenen SM, et al.: Value of different modalities of granulocyte-macrophage colony-stimulating factor applied during or after induction therapy of acute myeloid leukemia. J Clin Oncol 15 (12): 3496-506, 1997.
  14. Witz F, Sadoun A, Perrin MC, et al.: A placebo-controlled study of recombinant human granulocyte-macrophage colony-stimulating factor administered during and after induction treatment for de novo acute myelogenous leukemia in elderly patients. Groupe Ouest Est Leucémies Aiguës Myéloblastiques (GOELAM). Blood 91 (8): 2722-30, 1998.

Untreated Adult Acute Myeloid Leukemia

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Untreated adult acute myeloid leukemia (AML) is defined as newly diagnosed leukemia with no previous treatment. The patient exhibits the following features: abnormal bone marrow with at least 20% blasts and signs and symptoms of the disease, usually accompanied by an abnormal white blood cell count and differential, hematocrit/hemoglobin, and platelet count.

The 2-drug regimen of daunorubicin given in conjunction with cytarabine will result in a complete response rate of approximately 65%. Some physicians opt to add a third drug, thioguanine, to this regimen, though little evidence is available to conclude that this 3-drug regimen is better therapy. One study suggested that the addition of etoposide during induction therapy may improve response duration.[1] Idarubicin appeared to be more effective than daunorubicin, though the doses of idarubicin and daunorubicin may not have been equivalent.[2,3,4,5] No significant difference between daunorubicin and mitoxantrone has been reported.[6]

The role of high-dose cytarabine in induction therapy is controversial; randomized trials have shown prolongation of disease-free survival [7,8] or no effect [9,10] compared with conventionally dosed cytarabine-based induction chemotherapy. Post hoc analyses of two negative trials suggested potential benefit for the intensified therapy in subsets of patients at high risk for treatment failure;[9,10] however, an analysis of a subset of patients with complex cytogenetic abnormalities treated in a randomized multicenter trial in Germany showed improvement in complete remission (CR) rate with minimal improvement in event-free survival (EFS) (CR = 56% vs. 23%; P = .04; median EFS = 1 month vs. 2 months; P = .04).[11][Level of evidence: 1iiDi]

AML arising from myelodysplasia or secondary to previous cytotoxic chemotherapy has a lower rate of remission than de novo AML. A retrospective analysis of patients undergoing allogeneic bone marrow transplantation in this setting showed that the long-term survival for such patients was identical regardless of whether or not patients had received remission induction therapy (disease-free survival was approximately 20%). These data suggest that patients with these subsets of leukemia may be treated primarily with allogeneic bone marrow transplantation if their overall performance status is adequate, potentially sparing patients the added toxic effect of induction chemotherapy.[12][Level of evidence: 3iiiDi]

Supportive care during remission induction treatment should routinely include red blood cell and platelet transfusions when appropriate.[13,14] Empiric broad spectrum antimicrobial therapy is an absolute necessity for febrile patients who are profoundly neutropenic.[15,16] Careful instruction in personal hygiene, dental care, and recognition of early signs of infection are appropriate in all patients. Elaborate isolation facilities (including filtered air, sterile food, and gut flora sterilization) are not routinely indicated but may benefit transplant patients.[17,18] Rapid marrow ablation with consequent earlier marrow regeneration decreases morbidity and mortality. White blood cell transfusions can be beneficial in selected patients with aplastic marrow and serious infections that do not respond to antibiotics.[19] Prophylactic oral antibiotics may be appropriate in patients with expected prolonged, profound granulocytopenia (<100/mm3 for 2 weeks).[20] Norfloxacin and ciprofloxacin have been shown to decrease the incidence of gram-negative infection and time to first fever in randomized trials. The combination of ofloxacin and rifampin has proven superior to norfloxacin in decreasing the incidence of documented granulocytopenic infection.[21,22,23] Serial surveillance cultures may be helpful in such patients to detect the presence or acquisition of resistant organisms.

Special consideration must be given to induction therapy for acute promyelocytic leukemia (PML). Oral administration of tretinoin (all-trans-retinoic acid (ATRA); 45 mg/mm2/day) can induce remission in 70% to 90% of patients with M3 AML. (ATRA is not effective in patients with AML that resembles M3 morphologically but does not demonstrate the t(15;17) or typical PML-RARa gene rearrangement.)[24,25,26,27,28,29,30] ATRA induces terminal differentiation of the leukemic cells followed by restoration of nonclonal hematopoiesis. Administration of ATRA leads to rapid resolution of coagulopathy in most patients, and heparin administration is not required in patients receiving ATRA. However, randomized trials have not shown a reduction in morbidity and mortality during ATRA induction when compared with chemotherapy. Administration of ATRA can lead to hyperleukocytosis as well as a syndrome of respiratory distress now known as the retinoic acid syndrome. Prompt recognition of the syndrome and aggressive administration of steroids can prevent severe respiratory distress.[31] The optimal management of ATRA-induced hyperleukocytosis has not been established; neither has the optimal postremission management of patients who receive ATRA induction. However, two large cooperative group trials have demonstrated a statistically significant relapse-free and overall survival advantage to patients with M3 AML who receive ATRA at some point during their antileukemic management.[32,33] A randomized study has shown that the relapse rate was reduced in patients treated with concomitant ATRA and chemotherapy compared with ATRA induction followed by chemotherapy given in remission (relative risk [RR] of relapse at 2 years, 0.41; P = .04).[34][Level of evidence: 1iiDi] This trial also showed a disease-free survival benefit to maintenance therapy, which consisted of either 6-mercaptopurine plus methotrexate (RR of relapse = 0.41), intermittent ATRA (RR of relapse = 0.62), or a combination of all three3 drugs. The use of 6-mercaptopurine and methotrexate also produced an improvement in overall survival (RR of relapse = 0.36; P = .0057). Two concurrent clinical trials separately conducted in Italy and Spain included ATRA plus anthracycline induction followed by three cycles of consolidation and maintenance therapy. The two treatment protocols differed only in the addition of nonanthracycline drugs during consolidation cycles in the Italian study; doses of anthracyclines were identical between the two trials. Essentially identical relapse-free survival suggests that the nonanthracycline drugs (i.e., cytarabine, etoposide, and 6-thioguanine) may not contribute significantly to the outcome of patients with acute promyelocytic leukemia induced with ATRA plus anthracycline.[35][Level of evidence: 3iiiDi]

Presence of the unique fusion transcript PML-RARa (measured in bone marrow by polymerase chain reaction) in patients who achieve complete remission may indicate those who are likely to relapse early.[36] In addition, a retrospective review of randomized trials from the Southwest Oncology Group has suggested that the dose-intensity of daunorubicin administered in induction and consolidation chemotherapy may significantly impact on remission rate, disease-free survival, and overall survival in patients with M3 AML.[37] Although most patients currently receive ATRA in their induction therapy, for patients who do not, careful management of coagulopathy is required. Coagulopathy is occasionally a problem in patients undergoing induction with ATRA plus chemotherapy. This coagulopathy can lead to catastrophic intracranial bleeding but can be well-controlled with low-dose heparin infusion or with aggressive replacement of platelets and clotting factors.[38]

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.[39]

TREATMENT OPTIONS FOR REMISSION INDUCTION THERAPY:

  1. One of the following equivalent combination chemotherapy regimens:
    • Dose-intensive cytarabine-based induction therapy.[7,8]
    • Cytarabine + daunorubicin.[40,41]
    • Cytarabine + idarubicin.[2,3,4,5]
    • Cytarabine + daunorubicin + thioguanine.[42]
    • Mitoxantrone + etoposide.[43]
  2. Treatment of central nervous system leukemia, if present:
    • Intrathecal cytarabine or methotrexate.
  3. Clinical trials.

References:

  1. Bishop JF, Lowenthal RM, Joshua D, et al.: Etoposide in acute nonlymphocytic leukemia. Australian Leukemia Study Group. Blood 75 (1): 27-32, 1990.
  2. Wiernik PH, Banks PL, Case DC Jr, et al.: Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood 79 (2): 313-9, 1992.
  3. Vogler WR, Velez-Garcia E, Weiner RS, et al.: A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group Study. J Clin Oncol 10 (7): 1103-11, 1992.
  4. Berman E, Heller G, Santorsa J, et al.: Results of a randomized trial comparing idarubicin and cytosine arabinoside with daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia. Blood 77 (8): 1666-74, 1991.
  5. Mandelli F, Petti MC, Ardia A, et al.: A randomised clinical trial comparing idarubicin and cytarabine to daunorubicin and cytarabine in the treatment of acute non-lymphoid leukaemia. A multicentric study from the Italian Co-operative Group GIMEMA. Eur J Cancer 27 (6): 750-5, 1991.
  6. Arlin Z, Case DC Jr, Moore J, et al.: Randomized multicenter trial of cytosine arabinoside with mitoxantrone or daunorubicin in previously untreated adult patients with acute nonlymphocytic leukemia (ANLL). Lederle Cooperative Group. Leukemia 4 (3): 177-83, 1990.
  7. Bishop JF, Matthews JP, Young GA, et al.: A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood 87 (5): 1710-7, 1996.
  8. Geller RB, Burke PJ, Karp JE, et al.: A two-step timed sequential treatment for acute myelocytic leukemia. Blood 74 (5): 1499-506, 1989.
  9. Weick JK, Kopecky KJ, Appelbaum FR, et al.: A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood 88 (8): 2841-51, 1996.
  10. Büchner T, Hiddemann W, Wörmann B, et al.: Double induction strategy for acute myeloid leukemia: the effect of high-dose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine: a randomized trial by the German AML Cooperative Group. Blood 93 (12): 4116-24, 1999.
  11. Schoch C, Haferlach T, Haase D, et al.: Patients with de novo acute myeloid leukaemia and complex karyotype aberrations show a poor prognosis despite intensive treatment: a study of 90 patients. Br J Haematol 112 (1): 118-26, 2001.
  12. Anderson JE, Gooley TA, Schoch G, et al.: Stem cell transplantation for secondary acute myeloid leukemia: evaluation of transplantation as initial therapy or following induction chemotherapy. Blood 89 (7): 2578-85, 1997.
  13. Slichter SJ: Controversies in platelet transfusion therapy. Annu Rev Med 31: 509-40, 1980.
  14. Murphy MF, Metcalfe P, Thomas H, et al.: Use of leucocyte-poor blood components and HLA-matched-platelet donors to prevent HLA alloimmunization. Br J Haematol 62 (3): 529-34, 1986.
  15. Hughes WT, Armstrong D, Bodey GP, et al.: From the Infectious Diseases Society of America. Guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. J Infect Dis 161 (3): 381-96, 1990.
  16. Rubin M, Hathorn JW, Pizzo PA: Controversies in the management of febrile neutropenic cancer patients. Cancer Invest 6 (2): 167-84, 1988.
  17. Armstrong D: Symposium on infectious complications of neoplastic disease (Part II). Protected environments are discomforting and expensive and do not offer meaningful protection. Am J Med 76 (4): 685-9, 1984.
  18. Sherertz RJ, Belani A, Kramer BS, et al.: Impact of air filtration on nosocomial Aspergillus infections. Unique risk of bone marrow transplant recipients. Am J Med 83 (4): 709-18, 1987.
  19. Schiffer CA: Granulocyte transfusions: an overlooked therapeutic modality. Transfus Med Rev 4 (1): 2-7, 1990.
  20. Wade JC, Schimpff SC, Hargadon MT, et al.: A comparison of trimethoprim-sulfamethoxazole plus nystatin with gentamicin plus nystatin in the prevention of infections in acute leukemia. N Engl J Med 304 (18): 1057-62, 1981.
  21. Karp JE, Merz WG, Hendricksen C, et al.: Oral norfloxacin for prevention of gram-negative bacterial infections in patients with acute leukemia and granulocytopenia. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 106 (1): 1-7, 1987.
  22. Prevention of bacterial infection in neutropenic patients with hematologic malignancies. A randomized, multicenter trial comparing norfloxacin with ciprofloxacin. The GIMEMA Infection Program. Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto. Ann Intern Med 115 (1): 7-12, 1991.
  23. Bow EJ, Mandell LA, Louie TJ, et al.: Quinolone-based antibacterial chemoprophylaxis in neutropenic patients: effect of augmented gram-positive activity on infectious morbidity. National Cancer Institute of Canada Clinical Trials Group. Ann Intern Med 125 (3): 183-90, 1996.
  24. Huang ME, Ye YC, Chen SR, et al.: Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72 (2): 567-72, 1988.
  25. Castaigne S, Chomienne C, Daniel MT, et al.: All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results. Blood 76 (9): 1704-9, 1990.
  26. Warrell RP Jr, Frankel SR, Miller WH Jr, et al.: Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl J Med 324 (20): 1385-93, 1991.
  27. Chen ZX, Xue YQ, Zhang R, et al.: A clinical and experimental study on all-trans retinoic acid-treated acute promyelocytic leukemia patients. Blood 78 (6): 1413-9, 1991.
  28. Muindi J, Frankel SR, Miller WH Jr, et al.: Continuous treatment with all-trans retinoic acid causes a progressive reduction in plasma drug concentrations: implications for relapse and retinoid "resistance" in patients with acute promyelocytic leukemia. Blood 79 (2): 299-303, 1992.
  29. Licht JD, Chomienne C, Goy A, et al.: Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11;17). Blood 85 (4): 1083-94, 1995.
  30. Gallagher RE, Li YP, Rao S, et al.: Characterization of acute promyelocytic leukemia cases with PML-RA