- By Disease
- Complementary & Alternative Medicine
- Clinical Trials
- Screening & Detection
- Supportive Care
Adult Acute Myeloid Leukemia Treatment (PDQ®)
- General Information About Adult Acute Myeloid Leukemia
- Classification of Adult Acute Myeloid Leukemia
- Stage Information for Adult Acute Myeloid Leukemia
- Treatment Option Overview
- Untreated Adult Acute Myeloid Leukemia
- Adult Acute Myeloid Leukemia in Remission
- Recurrent Adult Acute Myeloid Leukemia
- Changes to This Summary (02/12/2013)
- About This PDQ Summary
- Get More Information From NCI
General Information About Adult Acute Myeloid Leukemia
Incidence and Mortality
Note: Estimated new cases and deaths from acute myeloid leukemia (AML) in the United States in 2013:
- New cases: 14,590.
- Deaths: 10,370.
Advances in the treatment of AML (also called acute myelogenous leukemia, acute nonlymphocytic leukemia, or ANLL) have resulted in substantially improved complete remission rates. 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 25% of adults with AML (about 45% 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 syndromes or another antecedent hematological disorder. Patients with leukemias that express the progenitor cell antigen CD34 and/or the P-glycoprotein (MDR1 gene product) have an inferior outcome. 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.
Cytogenetic analysis provides some of the strongest prognostic information available, predicting outcome of both remission induction and postremission therapy, as seen in a trial from the Southwest Oncology Group (SWOG) and the Eastern Cooperative Oncology Group (ECOG) (E-3489). Cytogenetic abnormalities that indicate a good prognosis include t(8; 21), inv(16) or t(16;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, as seen in the trial from the Medical Research Council (MRC-LEUK-AML11), predict clinical outcome in older patients with AML as well as in younger patients. The fusion genes formed in t(8; 21) and inv(16) can be detected by reverse transcriptase–polymerase chain reaction (RT–PCR) or fluorescence in situ hybridization (FISH), 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.
The classification of AML has been revised by a group of pathologists and clinicians under the auspices of the World Health Organization (WHO). 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. 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.
The differentiation of AML from acute lymphocytic leukemia has important therapeutic implications. Histochemical stains and cell surface antigen determinations aid in discrimination.1American Cancer Society.: Cancer Facts and Figures 2013. Atlanta, Ga: American Cancer Society, 2013. Available online. Last accessed May 2, 2013.2Myint H, Lucie NP: The prognostic significance of the CD34 antigen in acute myeloid leukaemia. Leuk Lymphoma 7 (5-6): 425-9, 1992.3Geller 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, 1990.4Campos 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, 1992.5Kottaridis 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, 2001.6Yanada 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, 2005.7Slovak 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, 2000.8Grimwade 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, 2001.9Mrózek 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, 2001.10Brunning 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 77-80.11Bennett 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, 1976.12Cheson 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, 1990.13Micallef 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 of Adult Acute Myeloid Leukemia
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. 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.
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. 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.”
Although this lowering of the blast threshold has been met with some criticism, several studies indicate that survival patterns for cases with 20% to 29% blasts are similar to survival patterns for cases with 30% or more blasts in the bone marrow. 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, disease progression, in addition to the blast percentage, and most importantly, patient preference.
Several groups have begun to investigate the use of gene expression profiling (GEP) using microarrays to augment current diagnostic and prognostic studies for AML. Distinct subsets can be identified using GEP that correspond to known cytogenetic and molecular abnormalities. The positive predictive value appears to be sufficiently powerful to be clinically useful only for patients with the t(8;21) and inv(16) (now referred to as core-binding factor leukemias) and acute promyelocytic leukemia with the t(15;17). GEP identified several cases of core-binding factor leukemias that were not diagnosed using conventional cytogenetics. 
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); (CBFβ/MYH11).Acute promyelocytic leukemia (AML with t(15;17)(q22; q12); (PML/RARα) and variants). AML with 11q23 (MLL) abnormalities.
- AML with an FLT3 mutation (not in the WHO classification scheme).
- 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 (AML) With Characteristic Genetic Abnormalities
This category is characterized by characteristic genetic abnormalities and frequently high rates of remission and favorable prognoses with the notable exception of those with 11q23 abnormalities. 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) or fluorescence in situ hybridization (FISH), 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) (occurring most commonly in 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. 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%.
The translocation t(8; 21)(q22; q22) involves the AML1 gene, also known as RUNX1, which encodes core binding factor-alpha (CBF-alpha), and the ETO (eight-twenty-one) gene. 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 postremission phase as in the Cancer and Leukemia Group B (CLB-9022 and CLB-8525) trials. Additional chromosome abnormalities are common, e.g., loss of a sex chromosome and del(9)(q22). Expression of the neural cell adhesion molecule CD56 appears to be an adverse prognostic indicator.
Acute myeloid leukemia with inv(16)(p13; q22) or t(16; 16)(p13; q22); (CBFβ/MYH11)
AML with inv(16)(p13; q22) or t(16; 16)(p13; q22) is found in approximately 10% to 12% of all cases of AML, predominantly in younger patients. Morphologically, this type of AML is associated with 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)(p13; q22) and t(16; 16)(p13; q22) result in the fusion of the core-binding factor–beta (CBFβ) gene at 16q22 to the smooth muscle myosin heavy chain (MYH11) gene at 16p13, thereby forming the fusion gene CBFβ/MYH11. The use of 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. Patients with this type of AML may achieve higher complete remission rates when treated with high-dose cytarabine in the postremission phase.
Acute promyelocytic leukemia [AML with t(15; 17)(q22; q12); (PML/RARα) 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. Both typical and microgranular APL are commonly associated with disseminated intravascular coagulation (DIC). In microgranular APL, unlike typical APL, the leukocyte count is very high with a rapid doubling time.
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 (RARα) gene on 17q12 fuses with a nuclear regulatory factor on 15q22 (promyelocytic leukemia or PML gene) resulting in a PML/RARα gene fusion transcript. Rare cases of cryptic or masked t(15;17) lack typical cytogenetic findings and involve complex variant translocations or submicroscopic insertion of the RARα gene into PML gene leading to the expression of the PML/RARα fusion transcript. FISH and/or RT–PCR methods may be required to unmask these cryptic genetic rearrangements.
APL has a specific sensitivity to treatment with all-trans retinoic acid (ATRA, tretinoin), which acts as a differentiating agent. High complete remission rates in APL may be obtained by combining ATRA treatment with chemotherapy. In approximately 1% of the cases of APL, variant chromosomal aberrations may be found in which the RARα gene is fused with other genes. Variant translocations involving the RARα gene include: t(11;17)(q23; q21), t(5;17)(q32; q12) and t(11; 17)(q13; q21).
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).
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).
The MLL gene on 11q23, a developmental regulator, is involved in translocations with approximately 22 different partner chromosomes. Genes other than MLL may be involved in 11q23 abnormalities. FISH may be required to detect genetic abnormalities involving MLL. 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.
Acute Myeloid Leukemia With Mutations of FLT3, NPM1, or CMBPA
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. 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.
- 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. 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.[Level of evidence: 3iiiDiv]
One study from the German-Austrian Acute Myeloid Leukemia Study Group examined data on 872 patients with cytogenetically normal AML treated with intensive induction and postremission regimens over an 11-year period.[Level of evidence: 3iiiA] The study group found that patients with a mutant CCAAT/enhancer binding-protein alpha (CEBPA) or a nucleophosmin mutation (NPM1) without fms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) had higher complete response rates, disease-free survival rates, and overall survival (OS) rates (with a 4-year OS rate of 62% and 60%, respectively) than other cytogenetically normal AML patients (who had a 4-year OS rate of between 25% and 30%). As yet, no clear strategy exists for improving patient outcome in FLT3 mutant AML, or in patients with abnormalities other than CEBPA or the NPM1 without the FLT3-ITD, 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. 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. AML with multilineage dysplasia may occur de novo or following MDS or a myelodysplastic and myeloproliferative disorder (MDS and MPD). (Refer to the PDQ summaries on Myelodysplastic Syndromes Treatment and Myelodysplastic/ Myeloproliferative Neoplasms for more information.) The diagnostic terminology “AML with multilineage dysplasia evolving from a myelodysplastic syndrome” should be used when an MDS precedes AML.
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.
As evidenced in several Southwest Oncology Group studies, such as SWOG-8600 and NCT00023777, the numerous chromosome abnormalities observed in AML with multilineage dysplasia were similar to those found in MDS and frequently involved gain or loss of major segments of certain chromosomes, predominately chromosomes 5 and/or 7. The probability of achieving a complete remission has been reported to be affected adversely by a diagnosis of AML with multilineage dysplasia.
Acute Myeloid Leukemias and Myelodysplastic Syndromes, Therapy Related
This category includes AML and MDS that arise secondary to cytotoxic chemotherapy and/or radiation therapy. 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.
Alkylating agent-related acute myeloid leukemia and myelodysplastic syndromes
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. 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 cytopenia with multilineage dysplasia (RCMD), with approximately 33% of these cases exhibiting ringed sideroblasts in excess of 15% (RCMD-RS). (Refer to the PDQ summary on Myelodysplastic Syndromes 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.
Common morphologic features include the following:
- Ringed sideroblasts (60% of cases; >15% in 33% of cases).
- Hypercellular bone marrow (50% of cases).
Cases may correspond morphologically to AML 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. Complex chromosomal abnormalities (≥3 distinct abnormalities) are the most common finding. Therapy-related AML is usually refractory to antileukemia therapy. Median survival after diagnosis of these disorders is approximately 7 to 8 months.
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. The mean latency period from the time of institution of the causative therapy to the development of AML is approximately 2 years. 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.
As with alkylating agent/radiation-related acute leukemias and myelodysplastic syndromes, the cytogenetic abnormalities are often complex. The predominant cytogenetic finding involves chromosome 11q23 and the MLL gene. 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.
Acute myeloblastic leukemia, minimally differentiated (FAB Classification M0)
This AML shows no evidence of myeloid differentiation by morphology and light microscopy cytochemistry. The myeloid nature of the blasts is demonstrated by immunophenotyping and/or ultrastructural studies. Immunophenotyping studies must be performed to distinguish this acute leukemia from acute lymphoblastic leukemia (ALL). 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.
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.
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. Mutation of FLT3, a receptor tyrosine kinase gene, occurs in approximately 25% of cases and has been associated with short survival. The median OS is approximately 10 months.
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. Most patients are adults. Patients usually present with anemia, thrombocytopenia, and neutropenia. (Refer to the PDQ summary on Fatigue for more information on anemia.)
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.
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. 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. Patients frequently present with anemia, thrombocytopenia, and neutropenia. (Refer to the PDQ summary on Fatigue for more information on anemia.)
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). (Refer to the Acute myeloid leukemia with characteristic genetic abnormalities section of the Classification section of this summary for more information). Such cases have a favorable prognosis. Rare cases with t(6; 9)(q23; q34) are reported to have a poor prognosis.
Acute promyelocytic leukemia [AML with t(15; 17)(q22; q12); (PML/RARα) and variants] (FAB Classification M3)
(Refer to the Acute promyelocytic leukemia (FAB Classification M3) section of the Acute Myeloid Leukemia With Characteristic Genetic Abnormalities section of this summary for more information.)
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. (Refer to the PDQ summary on Fatigue for more information on anemia.) 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 Neoplasms for more information.) This type of AML occurs more commonly in older individuals.
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. Some cases may have a 11q23 genetic abnormality. Cases with increased abnormal eosinophils in the bone marrow associated with a chromosome 16 abnormality have a favorable prognosis. (Refer to the Acute myeloid leukemia with characteristic genetic abnormalities section of the Classification section of this summary for more information.)
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. 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. 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. 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. (Refer to the Acute myeloid leukemia with characteristic genetic abnormalities section of the Classification section of this summary for more information.) 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). 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). Median actuarial disease-free survival for acute monocytic leukemia has been reported to be approximately 21 months.
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. 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. Erythroleukemia may present de novo or evolve from an MDS, either RAEB or RCMD-RS or RCMD. (Refer to the PDQ summary on Myelodysplastic Syndromes Treatment for more information.) The clinical features of these acute leukemias include profound anemia and normoblastemia. (Refer to the PDQ summary on Fatigue for more information.)
Morphologic and cytochemical features of erythroleukemia include the following:
- 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.
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.
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. One study indicates that abnormalities of chromosomes 5 and/or 7 correlate with significantly shorter survival times.
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. 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.
- 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. 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 and metastatic tumors in the bone marrow (particularly in children). (Refer to the PDQ summary on Chronic Myeloproliferative Disorders Treatment for more information on chronic myeloid leukemia or idiopathic myelofibrosis).
No unique chromosomal abnormalities are associated with acute megakaryoblastic leukemia in adults. In children, particularly infants, a distinct clinical presentation may be associated with t(1:22)(p13; q13). The prognosis for this type of acute leukemia is poor.
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. 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.
- 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. 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.
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. 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.
No consistent chromosome abnormality has been identified for acute basophilic leukemia. 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. The disorder may occur de novo or after treatment with alkylating-agent chemotherapy and/or radiation (Refer to the section on Acute myeloid leukemias and myelodysplastic syndromes, therapy related of this summary for more information). Clinical features include constitutional symptoms such as weakness and fatigue. (Refer to the PDQ summary on Fatigue for more information.)
Morphologic and cytochemical features include the following:
- Marked pancytopenia.
- 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. (Refer to the PDQ summary on Chronic Myeloproliferative Disorders 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.
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; development in 2% to 8% of patients with AML has been reported. 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.
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. 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. AML with maturation and t(8; 21)(q22; q22) and AMML Eo with in (16)(p13; q22) or t(16;16)(p13; q22) may be observed and monoblastic sarcoma may be associated with translocations involving 11q23. 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. 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. 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.
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). 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. Clinical features include symptoms and complications caused by cytopenias, i.e., fatigue, infections, and bleeding disorders. (Refer to the PDQ summary on Fatigue for more information.)
- 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. 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.1Brunning 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 77-80.2Bennett JM, Catovsky D, Daniel MT, et al.: Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann Intern Med 103 (4): 620-5, 1985.3Cheson 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, 1990.4Brunning RD, Matute E, Harris NL, et al.: Acute myeloid leukemia with multilineage dysplasia. 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 88-9.5Steensma DP, Tefferi A: The myelodysplastic syndrome(s): a perspective and review highlighting current controversies. Leuk Res 27 (2): 95-120, 2003.6Huh YO, Jilani I, Estey E, et al.: More cell death in refractory anemia with excess blasts in transformation than in acute myeloid leukemia. Leukemia 16 (11): 2249-52, 2002.7Greenberg P, Anderson J, de Witte T, et al.: Problematic WHO reclassification of myelodysplastic syndromes. Members of the International MDS Study Group. J Clin Oncol 18 (19): 3447-52, 2000.8Estey E, Thall P, Beran M, et al.: Effect of diagnosis (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or acute myeloid leukemia [AML]) on outcome of AML-type chemotherapy. Blood 90 (8): 2969-77, 1997.9Strupp C, Gattermann N, Giagounidis A, et al.: Refractory anemia with excess of blasts in transformation: analysis of reclassification according to the WHO proposals. Leuk Res 27 (5): 397-404, 2003.10Valk PJ, Verhaak RG, Beijen MA, et al.: Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med 350 (16): 1617-28, 2004.11Haferlach T, Kohlmann A, Schnittger S, et al.: Global approach to the diagnosis of leukemia using gene expression profiling. Blood 106 (4): 1189-98, 2005.12Verhaak RG, Wouters BJ, Erpelinck CA, et al.: Prediction of molecular subtypes in acute myeloid leukemia based on gene expression profiling. Haematologica 94 (1): 131-4, 2009.13Brunning RD, Matutes E, Flandrin G, et al.: Acute myeloid leukaemia with recurrent genetic abnormalities. 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 81-7.14Caligiuri MA, Strout MP, Gilliland DG: Molecular biology of acute myeloid leukemia. Semin Oncol 24 (1): 32-44, 1997.15Downing JR: The AML1-ETO chimaeric transcription factor in acute myeloid leukaemia: biology and clinical significance. Br J Haematol 106 (2): 296-308, 1999.16Bloomfield CD, Lawrence D, Byrd JC, et al.: Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype. Cancer Res 58 (18): 4173-9, 1998.17Byrd JC, Mrózek K, Dodge RK, et al.: Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 100 (13): 4325-36, 2002.18Palmieri S, Sebastio L, Mele G, et al.: High-dose cytarabine as consolidation treatment for patients with acute myeloid leukemia with t(8;21). Leuk Res 26 (6): 539-43, 2002.19Grimwade D, Walker H, Oliver F, et al.: The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood 92 (7): 2322-33, 1998.20Baer MR, Stewart CC, Lawrence D, et al.: Expression of the neural cell adhesion molecule CD56 is associated with short remission duration and survival in acute myeloid leukemia with t(8;21)(q22;q22). Blood 90 (4): 1643-8, 1997.21Raspadori D, Damiani D, Lenoci M, et al.: CD56 antigenic expression in acute myeloid leukemia identifies patients with poor clinical prognosis. Leukemia 15 (8): 1161-4, 2001.22Marlton P, Keating M, Kantarjian H, et al.: Cytogenetic and clinical correlates in AML patients with abnormalities of chromosome 16. Leukemia 9 (6): 965-71, 1995.23Poirel H, Radford-Weiss I, Rack K, et al.: Detection of the chromosome 16 CBF beta-MYH11 fusion transcript in myelomonocytic leukemias. Blood 85 (5): 1313-22, 1995.24Kwaan HC, Wang J, Boggio LN: Abnormalities in hemostasis in acute promyelocytic leukemia. Hematol Oncol 20 (1): 33-41, 2002.25Barbui T, Falanga A: Disseminated intravascular coagulation in acute leukemia. Semin Thromb Hemost 27 (6): 593-604, 2001.26de Thé H, Chomienne C, Lanotte M, et al.: The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus. Nature 347 (6293): 558-61, 1990.27Melnick A, Licht JD: Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 93 (10): 3167-215, 1999.28Lo Coco F, Diverio D, Falini B, et al.: Genetic diagnosis and molecular monitoring in the management of acute promyelocytic leukemia. Blood 94 (1): 12-22, 1999.29Zaccaria A, Valenti A, Toschi M, et al.: Cryptic translocation of PML/RARA on 17q. A rare event in acute promyelocytic leukemia. Cancer Genet Cytogenet 138 (2): 169-73, 2002.30Castaigne 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, 1990.31Tallman MS, Andersen JW, Schiffer CA, et al.: All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med 337 (15): 1021-8, 1997.32Tallman MS, Andersen JW, Schiffer CA, et al.: All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood 100 (13): 4298-302, 2002.33Fenaux P, Chastang C, Chevret S, et al.: A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood 94 (4): 1192-200, 1999.34Jansen JH, Löwenberg B: Acute promyelocytic leukemia with a PLZF-RARalpha fusion protein. Semin Hematol 38 (1): 37-41, 2001.35Giugliano E, Rege-Cambrin G, Scaravaglio P, et al.: Two new translocations involving the 11q23 region map outside the MLL locus in myeloid leukemias. Haematologica 87 (10): 1014-20, 2002.36König M, Reichel M, Marschalek R, et al.: A highly specific and sensitive fluorescence in situ hybridization assay for the detection of t(4;11)(q21;q23) and concurrent submicroscopic deletions in acute leukaemias. Br J Haematol 116 (4): 758-64, 2002.37Kim HJ, Cho HI, Kim EC, et al.: A study on 289 consecutive Korean patients with acute leukaemias revealed fluorescence in situ hybridization detects the MLL translocation without cytogenetic evidence both initially and during follow-up. Br J Haematol 119 (4): 930-9, 2002.38Gilliland DG, Griffin JD: The roles of FLT3 in hematopoiesis and leukemia. Blood 100 (5): 1532-42, 2002.39Levis M, Small D: FLT3: ITDoes matter in leukemia. Leukemia 17 (9): 1738-52, 2003.40Kottaridis 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, 2001.41Yanada 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, 2005.42Wang L, Lin D, Zhang X, et al.: Analysis of FLT3 internal tandem duplication and D835 mutations in Chinese acute leukemia patients. Leuk Res 29 (12): 1393-8, 2005.43Schlenk RF, Döhner K, Krauter J, et al.: Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 358 (18): 1909-18, 2008.44Gahn B, Haase D, Unterhalt M, et al.: De novo AML with dysplastic hematopoiesis: cytogenetic and prognostic significance. Leukemia 10 (6): 946-51, 1996.45Head DR: Revised classification of acute myeloid leukemia. Leukemia 10 (11): 1826-31, 1996.46Leith CP, Kopecky KJ, Chen IM, et al.: Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/P-glycoprotein, MRP1, and LRP in acute myeloid leukemia: a Southwest Oncology Group Study. Blood 94 (3): 1086-99, 1999.47Leith CP, Kopecky KJ, Godwin J, et al.: Acute myeloid leukemia in the elderly: assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group study. Blood 89 (9): 3323-9, 1997.48Mrózek K, Heinonen K, de la Chapelle A, et al.: Clinical significance of cytogenetics in acute myeloid leukemia. Semin Oncol 24 (1): 17-31, 1997.49Brunning RD, Matutes E, Flandrin G, et al.: Acute myeloid leukaemias and myelodysplastic syndromes, therapy related. 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 89-91.50Smith SM, Le Beau MM, Huo D, et al.: Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series. Blood 102 (1): 43-52, 2003.51Ellis M, Ravid M, Lishner M: A comparative analysis of alkylating agent and epipodophyllotoxin-related leukemias. Leuk Lymphoma 11 (1-2): 9-13, 1993.52Olney HJ, Mitelman F, Johansson B, et al.: Unique balanced chromosome abnormalities in treatment-related myelodysplastic syndromes and acute myeloid leukemia: report from an international workshop. Genes Chromosomes Cancer 33 (4): 413-23, 2002.53Mauritzson N, Albin M, Rylander L, et al.: Pooled analysis of clinical and cytogenetic features in treatment-related and de novo adult acute myeloid leukemia and myelodysplastic syndromes based on a consecutive series of 761 patients analyzed 1976-1993 and on 5098 unselected cases reported in the literature 1974-2001. Leukemia 16 (12): 2366-78, 2002.54Pedersen-Bjergaard J, Andersen MK, Christiansen DH, et al.: Genetic pathways in therapy-related myelodysplasia and acute myeloid leukemia. Blood 99 (6): 1909-12, 2002.55Leone G, Voso MT, Sica S, et al.: Therapy related leukemias: susceptibility, prevention and treatment. Leuk Lymphoma 41 (3-4): 255-76, 2001.56Bloomfield CD, Archer KJ, Mrózek K, et al.: 11q23 balanced chromosome aberrations in treatment-related myelodysplastic syndromes and acute leukemia: report from an international workshop. Genes Chromosomes Cancer 33 (4): 362-78, 2002.57Brunning RD, Matutes E, Flandrin G, et al.: Acute myeloid leukaemia not otherwise categorised. 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 91-105.58Venditti A, Del Poeta G, Stasi R, et al.: Minimally differentiated acute myeloid leukaemia (AML-M0): cytochemical, immunophenotypic and cytogenetic analysis of 19 cases. Br J Haematol 88 (4): 784-93, 1994.59Roumier 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, 2003.60Béné 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, 2001.61Abu-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, 2000.62Alsabeh 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, 1997.63Stanley 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 147-74.64Haferlach 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, 2002.65Panagopoulos 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, 2003.66Fenaux 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, 1990.67Cigudosa 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, 2003.68Domingo-Claros A, Larriba I, Rozman M, et al.: Acute erythroid neoplastic proliferations. A biological study based on 62 patients. Haematologica 87 (2): 148-53, 2002.69Olopade OI, Thangavelu M, Larson RA, et al.: Clinical, morphologic, and cytogenetic characteristics of 26 patients with acute erythroblastic leukemia. Blood 80 (11): 2873-82, 1992.70Bernstein 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, 2000.71Nichols CR, Roth BJ, Heerema N, et al.: Hematologic neoplasia associated with primary mediastinal germ-cell tumors. N Engl J Med 322 (20): 1425-9, 1990.72Carroll 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, 1991.73Dastugue 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, 2002.74Pagano L, Pulsoni A, Vignetti M, et al.: Acute megakaryoblastic leukemia: experience of GIMEMA trials. Leukemia 16 (9): 1622-6, 2002.75Athale 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, 2001.76Zipursky 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, 1999.77Zipursky A, Thorner P, De Harven E, et al.: Myelodysplasia and acute megakaryoblastic leukemia in Down's syndrome. Leuk Res 18 (3): 163-71, 1994.78Kounami 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, 1997.79Yamauchi 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, 2002.80Byrd 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, 1997.81Hayashi 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, 1998.82Imrie KR, Kovacs MJ, Selby D, et al.: Isolated chloroma: the effect of early antileukemic therapy. Ann Intern Med 123 (5): 351-3, 1995.83Brunning 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 106-7.84Hanson CA, Abaza M, Sheldon S, et al.: Acute biphenotypic leukaemia: immunophenotypic and cytogenetic analysis. Br J Haematol 84 (1): 49-60, 1993.85Legrand 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, 1998.86Matutes E, Morilla R, Farahat N, et al.: Definition of acute biphenotypic leukemia. Haematologica 82 (1): 64-6, 1997 Jan-Feb.87Sulak LE, Clare CN, Morale BA, et al.: Biphenotypic acute leukemia in adults. Am J Clin Pathol 94 (1): 54-8, 1990.88Carbonell F, Swansbury J, Min T, et al.: Cytogenetic findings in acute biphenotypic leukaemia. Leukemia 10 (8): 1283-7, 1996.89Pane 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, 1996.90Killick S, Matutes E, Powles RL, et al.: Outcome of biphenotypic acute leukemia. Haematologica 84 (8): 699-706, 1999.
Stage Information for Adult Acute Myeloid Leukemia
There is no clear-cut staging system for this disease.
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, an abnormal hematocrit/hemoglobin count, and an abnormal platelet count.
Adult acute myeloid leukemia (AML) in remission is defined as a normal peripheral blood cell count (absolute neutrophil count >1,000/mm3 and platelet count >100,000/mm3)  and normocellular marrow with less than 5% blasts in the marrow and no signs or symptoms of the disease. In addition, no signs or symptoms are evident of central nervous system leukemia or other extramedullary infiltration. Because the vast majority of AML patients meeting these criteria for remission have residual leukemia, modifications to the definition of complete remission have been suggested, including cytogenetic remission, in which a previously abnormal karyotype reverts to normal, and molecular remission, in which interphase fluorescence in situ hybridization (FISH) or multiparameter flow cytometry are used to detect minimal residual disease. Immunophenotyping and interphase FISH have greater prognostic significance than the conventional criteria for remission.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with adult acute myeloid leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.1Cheson 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, 1990.2Cheson BD, Bennett JM, Kopecky KJ, et al.: Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 21 (24): 4642-9, 2003.3Bacher U, Kern W, Schoch C, et al.: Evaluation of complete disease remission in acute myeloid leukemia: a prospective study based on cytomorphology, interphase fluorescence in situ hybridization, and immunophenotyping during follow-up in patients with acute myeloid leukemia. Cancer 106 (4): 839-47, 2006.
Treatment Option Overview
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.
Treatment is divided into two phases: remission 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, other than for acute promyelocytic leukemia. (Refer to the Adult Acute Myeloid Leukemia in Remission section of this summary for more information.) Other studies have used more intensive postremission therapy administered for a shorter duration of time after which treatment is discontinued. postremission therapy appears to be effective when given immediately after remission is achieved. 
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. 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. 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. 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. 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 Eastern Cooperative Oncology Group (ECOG) (EST-1490) trial, patients were randomized to receive GM-CSF or placebo following demonstration of leukemic clearance of the bone marrow; however, GM-CSF did not show benefit in a separate similar randomized trial in patients aged 60 years and older. In the latter study, clearance of the marrow was not required before initiating cytokine therapy. In a Southwest Oncology Group (NCT00023777) 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. Because the majority of randomized clinical trials have not shown an impact of growth factors on survival, their use is not routinely recommended in the remission induction setting.
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 postremission therapy showed no difference in outcomes between patients who received GM-CSF and those who did not receive growth factor priming.[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.[Level of evidence: 1iiDii]1Kebriaei P, Champlin R, deLima M, et al.: Management of acute leukemias. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1928-54.2Wiernik 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 283-302.3Morrison 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, 1992.4Cassileth PA, Lynch E, Hines JD, et al.: Varying intensity of postremission therapy in acute myeloid leukemia. Blood 79 (8): 1924-30, 1992.5Supportive 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 779-967.6Rebulla 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, 1997.7Leukocyte 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, 1997.8Geller RB: Use of cytokines in the treatment of acute myelocytic leukemia: a critical review. J Clin Oncol 14 (4): 1371-82, 1996.9Rowe 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, 1995.10Stone 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, 1995.11Dombret 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, 1995.12Godwin JE, Kopecky KJ, Head DR, et al.: A double-blind placebo-controlled trial of granulocyte colony-stimulating factor in elderly patients with previously untreated acute myeloid leukemia: a Southwest oncology group study (9031). Blood 91 (10): 3607-15, 1998.13Buchner 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, 1994.14Löwenberg 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, 1997.15Witz 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
The two-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 three-drug regimen is better therapy. One study suggested that the addition of etoposide during induction therapy may improve response duration. Idarubicin appeared to be more effective than daunorubicin, particularly in younger adults, though the doses of idarubicin and daunorubicin may not have been equivalent. No significant survival difference between daunorubicin and mitoxantrone has been reported.
The role of high-dose cytarabine in induction therapy is controversial; randomized trials have shown prolongation of disease-free survival  or no effect  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; 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).[Level of evidence: 1iiDii]
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 BMT 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 BMT if their overall performance status is adequate, potentially sparing patients the added toxic effect of induction chemotherapy.[Level of evidence: 3iiiDii]
Older adults who decline intensive remission induction therapy or are considered unfit for intensive remission induction therapy may derive benefit from low-dose cytarabine, administered twice daily for 10 days in cycles repeated every 4 to 6 weeks. The complete remission rate using this regimen was 18% compared to 1% for patients treated with hydroxyurea (P = .006). Survival with low-dose cytarabine was better than survival was with hydroxyurea (OR = 0.60; 95% confidence interval, 0.44–0.81; P = .009).[Level of evidence: 1iiA]
Supportive care during remission induction treatment should routinely include red blood cell and platelet transfusions when appropriate. Empiric broad spectrum antimicrobial therapy is an absolute necessity for febrile patients who are profoundly neutropenic. 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. Rapid marrow ablation with consequent earlier marrow regeneration decreases morbidity and mortality. Prophylactic oral antibiotics may be appropriate in patients with expected prolonged, profound granulocytopenia (<100/mm3 for 2 weeks). 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. Serial surveillance cultures may be helpful in such patients to detect the presence or acquisition of resistant organisms.
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.
Acute Promyelocytic Leukemia
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-RARα gene rearrangement.) 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 differentiation syndrome. Prompt recognition of the syndrome and aggressive administration of steroids can prevent severe respiratory distress. 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 (OS) advantage to patients with M3 AML who receive ATRA at some point during their antileukemic management.
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).[Level of evidence: 1iiDii] 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 three drugs. The use of 6-mercaptopurine and methotrexate also produced an improvement in OS (RR of relapse, 0.36; P = .005). Two concurrent clinical trials separately conducted in Italy and Spain included ATRA plus anthracycline induction followed by three cycles of postremission and maintenance therapy. The two treatment protocols differed only in the addition of nonanthracycline drugs during postremission therapy 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.[Level of evidence: 3iiiDii]
In contrast, a trial randomly assigned low-risk patients (age < 60, white blood cell count [WBC] < 10,000/mm3) to receive all-trans-retinoic acid (ATRA) and daunorubicin as induction therapy, followed by daunorubicin consolidation and ATRA plus mercaptopurine plus methotrexate as maintenance therapy. Patients were randomly assigned to receive cytarabine in the induction and consolidation modules, or not. The trial was stopped at an early interim analysis following randomization of 172 patients. The cytarabine group demonstrated a superior 2-year relapse rate (4.7% vs. 15.9%, P = .011), 2-year EFS (93.3% vs. 77.2%, P = .002), and 2-year OS (97.9% vs. 89.6%, P = .007).[Level of evidence: 3iiiA] The latter study used a different chemotherapy platform than the one used by the Italian and Spanish groups, which reported no benefit to cytarabine.
Studies are beginning to examine the inclusion of arsenic trioxide (ATO) in the management of previously untreated patients. In one trial, 85 newly diagnosed patients were treated with ATRA plus ATO until remission; hydroxyurea or idarubicin and cytarabine were added if the WBC was greater than 10,000/mm3. This was followed by three cycles of consolidation (ara-C plus daunorubicin, plus cytarabine, and ara-C plus homoharringtonine) and maintenance with five cycles of sequential ATRA (1 month), ATO (1 month) and 6-mercaptopurine plus methotrexate (1 month). Eighty patients achieved remission with five induction deaths. Four relapses developed between 8 months and 39 months following remission attainment, all of which were in the central nervous system. Five-year event-free survival (EFS) was 89%.
In another trial, investigators used an ATO-based regimen, which included gemtuzumab ozogamycin (GO) as the only cytotoxic drug. Patients received ATRA plus ATO induction; patients also received a dose of GO if the WBC was greater than 10,000/mm3 on presentation or rose to over 30,000/mm3 during induction. Patients in remission received alternating months of ATO and ATRA for a total of seven cycles; GO was substituted if either ATO or ATRA were discontinued as a result of toxicity. Eighty-two patients were treated; seven patients died during induction, the remainder achieved remission. Three patients relapsed and four patients died during remission; thus EFS was approximately 76%.
Presence of the unique fusion transcript PML-RARα (measured in bone marrow by polymerase chain reaction) in patients who achieve complete remission may indicate those who are likely to relapse early. In addition, a retrospective review of randomized trials from the Southwest Oncology Group suggested that the dose-intensity of daunorubicin administered in induction and postremission chemotherapy may significantly impact on remission rate, disease-free survival, and OS in patients with M3 AML. 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 (in the setting of clotting) or with aggressive replacement of platelets and clotting factors.
Treatment options for remission induction therapy:
- One of the following equivalent combination chemotherapy regimens: Cytarabine plus daunorubicin. Cytarabine plus idarubicin. Cytarabine plus mitoxantrone.Dose-intensive cytarabine-based induction therapy.Cytarabine plus daunorubicin plus thioguanine.
- Treatment of central nervous system leukemia, if present: Intrathecal cytarabine or methotrexate.
- Clinical trials.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with untreated adult acute myeloid leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.1Bishop JF, Lowenthal RM, Joshua D, et al.: Etoposide in acute nonlymphocytic leukemia. Australian Leukemia Study Group. Blood 75 (1): 27-32, 1990.2Wiernik 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, 1992.3Vogler 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, 1992.4Berman 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, 1991.5Mandelli 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, 1991.6Arlin 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, 1990.7Bishop 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, 1996.8Geller RB, Burke PJ, Karp JE, et al.: A two-step timed sequential treatment for acute myelocytic leukemia. Blood 74 (5): 1499-506, 1989.9Weick 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, 1996.10Büchner 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, 1999.11Schoch 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, 2001.12Anderson 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, 1997.13Burnett AK, Milligan D, Prentice AG, et al.: A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer 109 (6): 1114-24, 2007.14Slichter SJ: Controversies in platelet transfusion therapy. Annu Rev Med 31: 509-40, 1980.15Murphy 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, 1986.16Hughes 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, 1990.17Rubin M, Hathorn JW, Pizzo PA: Controversies in the management of febrile neutropenic cancer patients. Cancer Invest 6 (2): 167-84, 1988.18Armstrong 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, 1984.19Sherertz 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, 1987.20Wade 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, 1981.21Karp 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, 1987.22Prevention 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, 1991.23Bow 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, 1996.24Micallef 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, 2001.25Huang 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, 1988.26Castaigne 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, 1990.27Warrell 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, 1991.28Chen 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, 1991.29Muindi 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, 1992.30Licht 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, 1995.31Gallagher RE, Li YP, Rao S, et al.: Characterization of acute promyelocytic leukemia cases with PML-RAR alpha break/fusion sites in PML exon 6: identification of a subgroup with decreased in vitro responsiveness to all-trans retinoic acid. Blood 86 (4): 1540-7, 1995.32Frankel SR, Eardley A, Lauwers G, et al.: The "retinoic acid syndrome" in acute promyelocytic leukemia. Ann Intern Med 117 (4): 292-6, 1992.33Fenaux P, Le Deley MC, Castaigne S, et al.: Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial. European APL 91 Group. Blood 82 (11): 3241-9, 1993.34Tallman MS, Andersen J, Schiffer CA, et al.: Phase III randomized study of all-trans retinoic acid (ATRA) vs daunorubicin (D) and cytosine arabinoside (A) as induction therapy and ATRA vs observation as maintenance therapy for patients with previously untreated acute promyelocytic leukemia (APL). [Abstract] Blood 86 (10 Suppl 1): A-488, 125a, 1995.35Fenaux P, Chastang C, Chevret S, et al.: A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood 94 (4): 1192-200, 1999.36Sanz MA, Lo Coco F, Martín G, et al.: Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood 96 (4): 1247-53, 2000.37Adès L, Chevret S, Raffoux E, et al.: Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol 24 (36): 5703-10, 2006.38Hu J, Liu YF, Wu CF, et al.: Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A 106 (9): 3342-7, 2009.39Ravandi F, Estey E, Jones D, et al.: Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol 27 (4): 504-10, 2009.40Lo Coco F, Diverio D, Pandolfi PP, et al.: Molecular evaluation of residual disease as a predictor of relapse in acute promyelocytic leukaemia. Lancet 340 (8833): 1437-8, 1992.41Head D, Kopecky KJ, Weick J, et al.: Effect of aggressive daunomycin therapy on survival in acute promyelocytic leukemia. Blood 86 (5): 1717-28, 1995.42Stone RM, Mayer RJ: The unique aspects of acute promyelocytic leukemia. J Clin Oncol 8 (11): 1913-21, 1990.43Yates J, Glidewell O, Wiernik P, et al.: Cytosine arabinoside with daunorubicin or adriamycin for therapy of acute myelocytic leukemia: a CALGB study. Blood 60 (2): 454-62, 1982.44Dillman RO, Davis RB, Green MR, et al.: A comparative study of two different doses of cytarabine for acute myeloid leukemia: a phase III trial of Cancer and Leukemia Group B. Blood 78 (10): 2520-6, 1991.45Löwenberg B, Suciu S, Archimbaud E, et al.: Mitoxantrone versus daunorubicin in induction-consolidation chemotherapy--the value of low-dose cytarabine for maintenance of remission, and an assessment of prognostic factors in acute myeloid leukemia in the elderly: final report. European Organization for the Research and Treatment of Cancer and the Dutch-Belgian Hemato-Oncology Cooperative Hovon Group. J Clin Oncol 16 (3): 872-81, 1998.46Gale RP, Foon KA, Cline MJ, et al.: Intensive chemotherapy for acute myelogenous leukemia. Ann Intern Med 94 (6): 753-7, 1981.
Adult Acute Myeloid Leukemia in Remission
Although individual patients have been reported to have long disease-free survival (DFS) or cure with a single cycle of chemotherapy, postremission therapy is always indicated in therapy that is planned with curative intent. In a small randomized study conducted by the Eastern Cooperative Oncology Group (ECOG), all patients who did not receive postremission therapy experienced a relapse after a short median complete remission duration. Current approaches to postremission therapy include short-term, relatively intensive chemotherapy with cytarabine-based regimens similar to standard induction clinical trials (postremission chemotherapy), postremission chemotherapy with more dose-intensive cytarabine-based treatment, high-dose chemotherapy or chemoradiation therapy with autologous bone marrow rescue, and high-dose marrow-ablative therapy with allogeneic bone marrow rescue. While older studies have included longer-term therapy at lower doses (maintenance), no convincing evidence is available with acute myeloid leukemia (AML) that maintenance therapy provides prolonged disease-free survival (DFS) beyond shorter-term, more dose-intensive approaches, and few current treatment clinical trials include maintenance therapy.
Nontransplant postremission therapy using cytarabine-containing regimens has treatment-related death rates that are usually less than 10% to 20% and have yielded reported long-term DFS rates from 20% to 50%. A large randomized trial that compared three different cytarabine-containing postremission therapy regimens showed a clear benefit in survival to patients younger than 60 years who received high-dose cytarabine. Intensification of cytarabine dose or duration of postremission chemotherapy with conventionally dosed cytarabine did not improve disease-free or OS in patients aged 60 years or older, as evidenced in the Medical Research Council (MRC-LEUK-AML11) trial. The duration of postremission therapy has ranged from one cycle  to four or more cycles. The optimal doses, schedules, and duration of postremission chemotherapy have not been determined. Therefore, to address these issues, patients with AML should be included in clinical trials at institutions that treat large numbers of such patients.
Dose-intensive cytarabine-based chemotherapy can be complicated by severe neurologic  and/or pulmonary toxic effects  and should be administered by physicians experienced in these regimens at centers that are equipped to deal with potential complications. In a retrospective analysis of 256 patients who received high-dose bolus cytarabine at a single institution, the most powerful predictor of cytarabine neurotoxicity was renal insufficiency. The incidence of neurotoxicity was significantly greater in patients treated with twice daily doses of 3 g/m2/dose when compared with 2 g/m2/dose.
Allogeneic bone marrow transplantation (BMT) results in the lowest incidence of leukemic relapse, even when compared with BMT from an identical twin (syngeneic BMT). This has led to the concept of an immunologic graft-versus-leukemia effect, similar to (and related to) graft-versus-host disease. The improvement in freedom from relapse using allogeneic BMT as the primary postremission therapy is offset, at least in part, by the increased morbidity and mortality caused by graft-versus-host disease, veno-occlusive disease of the liver, and interstitial pneumonitis. The DFS rates using allogeneic transplantation in first complete remission have ranged from 45% to 60%. The use of allogeneic BMT as primary postremission therapy is limited by the need for a human leukocyte antigen (HLA)-matched sibling donor and the increased mortality from allogeneic BMT of patients who are older than 50 years. The mortality from allogeneic BMT that uses an HLA-matched sibling donor ranges from 20% to 40%, depending on the series. The use of matched, unrelated donors for allogeneic BMT is being evaluated at many centers but has a very substantial rate of treatment-related mortality, with DFS rates less than 35%. Retrospective analysis of data from the International Bone Marrow Transplant Registry suggests that postremission chemotherapy does not lead to an improvement in DFS or OS for patients in first remission undergoing allogeneic BMT from an HLA-identical sibling.[Level of evidence: 3iiiA]
A common clinical trial design used to evaluate the benefit of allogeneic transplant as consolidation therapy for AML in first remission is the so-called donor-no donor comparison. In this design, newly diagnosed AML patients who achieve a complete remission (CR1), have one or more siblings, and are deemed medically eligible for allogeneic transplant undergo HLA typing. If a sibling donor is identified, the patient is allocated to the transplantation arm. Analysis of outcome is by intention to treat; that is, patients assigned to the donor arm who do not receive a transplant are grouped in the analysis with the patients who did actually receive a transplant. Relapse-free survival (RFS) is the usual endpoint for this type of trial. Overall survival (OS) from the time of diagnosis is less frequently reported in these trials. Results of these trials have been mixed, with some trials showing a clear benefit across all cytogenetic subgroups, and others showing no benefit.
Investigators attempted to address this issue with a meta-analysis using data from 18 separate prospective trials of AML patients using the donor-no donor design, with data from an additional six trials included for sensitivity analysis. The trials included in this meta-analysis enrolled adult patients aged 60 and younger during the years 1982 to 2006. Median follow-up ranged from 42 months to 142 months. Preparative regimens were similar among the different trials. Allogeneic transplant was compared to autologous transplant (6 trials) or to a variety of consolidation chemotherapy regimens with high-dose cytarabine being the most common.
Treatment-related mortality ranged from 5% to 42% in the donor groups compared with 3% to 27% in the no-donor group. Of 18 trials reporting RFS across all cytogenetic risk groups, the combined hazard ratio (HR) for overall RFS benefit with allogeneic transplant was 0.80, indicating a statistically significant reduction in death or relapse in CR1. Of the 15 trials reporting OS across all cytogenetic risk groups, the combined HR for OS was 0.90, again indicating a statistically significant reduction in death or relapse in CR1.
In subgroup analysis according to cytogenetic risk category, there was no RFS or OS benefit of allogeneic transplant for patients with good-risk AML (RFS: HR, 1.07; 95% confidence interval [CI], 0.83–1.38; P = .59; OS: HR, 1.06; 95% CI, 0.64–1.76; P = .81). However, a transplant benefit was seen for patients with intermediate (RFS: HR, 0.83; 95% CI, 0.74–0.93; P < .01; OS: HR, 0.84; 95% CI, 0.71–0.99; P = .03) or poor-risk cytogenetics (RFS: HR, 0.73; 95% CI, 0.59–0.90; P < .01; OS: HR, 0.60; 95% CI, 0.40–0.90; P = .01). The conclusion from this meta-analysis was that allogeneic transplant from a sibling donor in CR1 is justified on the basis of improved RFS and OS for patients with intermediate- or poor-risk, but not good-risk, cytogenetics.[Level of evidence: 2A]
An important caveat to this analysis is that induction and postremission strategies for AML among studies included in the meta-analysis were not uniform; nor were definitions of cytogenetic risk groups uniform. This may have resulted in inferior survival rates among chemotherapy-only treated patients. Most U.S. leukemia physicians agree that transplantation should be offered to AML patients in CR1 in the setting of poor-risk cytogenetics and should not be offered to patients in CR1 with good-risk cytogenetics.
The use of matched, unrelated donors for allogeneic BMT is being evaluated at many centers but has a very substantial rate of treatment-related mortality, with DFS rates less than 35%. Retrospective analysis of data from the International Bone Marrow Transplant Registry suggests that postremission chemotherapy does not lead to an improvement in DFS or OS for patients in first remission undergoing allogeneic BMT from an HLA-identical sibling.[Level of evidence: 3iiiA]
Autologous BMT yielded DFS rates between 35% and 50% in patients with AML in first remission. Autologous BMT has also cured a smaller proportion of patients in second remission. Treatment-related mortality rates of patients who have had autologous peripheral blood or marrow transplantation range from 10% to 20%. Ongoing controversies include the optimum timing of autologous stem cell transplantation, whether it should be preceded by postremission chemotherapy, and the role of ex vivo treatment of the graft with chemotherapy, such as 4-hydroperoxycyclophosphamide (4-HC)  or mafosphamide, or monoclonal antibodies, such as anti-CD33. Purged marrows have demonstrated delayed hematopoietic recovery; however, most studies that use unpurged marrow grafts have included several cycles of postremission chemotherapy and may have included patients who were already cured of their leukemia.
In a prospective trial of patients with AML in first remission, City of Hope investigators treated patients with one course of high-dose cytarabine postremission therapy, followed by unpurged autologous BMT following preparative therapy of total-body radiation therapy, etoposide, and cyclophosphamide. In an intent-to-treat analysis, actuarial DFS was approximately 50%, which is comparable to other reports of high-dose postremission therapy or purged autologous transplantation.[Level of evidence: 3iiDii]
A randomized trial by ECOG and the Southwest Oncology Group (SWOG) compared autologous BMT using 4-HC-purged bone marrow with high-dose cytarabine postremission therapy. No difference in DFS was found between patients treated with high-dose cytarabine, autologous BMT, or allogeneic BMT; however, OS was superior for patients treated with cytarabine compared with those who received BMT.[Level of evidence: 1iiA]
A randomized trial has compared the use of autologous BMT in first complete remission to postremission chemotherapy, with the latter group eligible for autologous BMT in second complete remission. The two arms of the study had equivalent survival. Two randomized trials in pediatric AML have shown no advantage of autologous transplantation following busulfan/cyclophosphamide preparative therapy and 4HC-purged graft when compared with postremission chemotherapy including high-dose cytarabine. An additional randomized Groupe Ouest Est d'etude des Leucemies et Autres Maladies du Sang trial (NCT01074086) of autologous BMT versus intensive postremission chemotherapy in adult AML, using unpurged bone marrow, showed no advantage to receiving autologous BMT in first remission. Certain subsets of AML may specifically benefit from autologous BMT in first remission. In a retrospective analysis of 999 patients with de novo AML treated with allogeneic or autologous BMT in first remission in whom cytogenetic analysis at diagnosis was available, patients with poor-risk cytogenetics (abnormalities of chromosomes 5, 7, 11q, or hypodiploidy) had less favorable outcomes following allogeneic BMT than patients with normal karyotypes or other cytogenetic abnormalities. Leukemia-free survival for the patients in the poor-risk groups was approximately 20%.[Level of evidence: 3iiiDii]
An analysis of the SWOG/ECOG (E-3489) randomized trial of postremission therapy according to cytogenetic subgroups suggested that in patients with unfavorable cytogenetics, allogeneic BMT was associated with an improved relative risk of death, whereas in the favorable cytogenetics group, autologous transplantation was superior. These data were based on analysis of small subsets of patients and were not statistically significant. While secondary myelodysplastic syndromes have been reported following autologous BMT, the development of new clonal cytogenetic abnormalities following autologous BMT does not necessarily portend the development of secondary myelodysplastic syndromes or AML.[Level of evidence: 3iiiDiv] Whenever possible, patients should be entered on clinical trials of postremission management.
Because BMT can cure about 30% of patients who experience relapse following chemotherapy, some investigators suggested that allogeneic BMT can be reserved for early first relapse or second complete remission without compromising the number of patients who are ultimately cured; however, clinical and cytogenetic information can define certain subsets of patients with predictable better or worse prognoses using postremission chemotherapy. Good-risk factors include t(8; 21), inv(16) associated with M4 AML with eosinophilia, and t(15; 17) associated with M3 AML. Poor-risk factors include deletion of 5q and 7q, trisomy 8, t(6; 9), t(9; 22), and a history of myelodysplasia or antecedent hematologic disorder. Patients in the good-risk group have a reasonable chance of cure with intensive postremission therapy, and it may be reasonable to defer transplantation in that group until early first relapse. The poor-risk group is unlikely to be cured with postremission chemotherapy, and allogeneic BMT in CR1 is a reasonable option for patients with an HLA-identical sibling donor. However, even with allogeneic stem cell transplantation, the outcome for patients with high-risk AML is poor (5-year DFS of 8% to 30% for patients with treatment-related leukemia or myelodysplasia). The efficacy of autologous stem cell transplantation in the poor-risk group has not been reported to date but is the subject of active clinical trials. Patients with normal cytogenetics are in an intermediate-risk group, and postremission management should be individualized or, ideally, managed according to a clinical trial.
The rapid engraftment kinetics of peripheral blood progenitor cells demonstrated in trials of high-dose therapy for epithelial neoplasms has led to interest in the alternative use of autologous and allogeneic peripheral blood progenitor cells as rescue for myeloablative therapy for the treatment of AML. One pilot trial of the use of autologous transplantation with unpurged peripheral blood progenitor cells in first remission had a 3-year DFS rate of 35%; detailed prognostic factors for these patients were not provided. This result appears inferior to the best results of chemotherapy or autologous BMT and suggests that the use of peripheral blood progenitor cells be limited to clinical trials.
Allogeneic stem cell transplantation can be performed using stem cells obtained from a bone marrow harvest or a peripheral blood progenitor cell harvest. In a randomized trial of 175 patients undergoing allogeneic stem cell transplantation, with either bone marrow or peripheral blood stem cells, for a variety of hematologic malignancies using methotrexate and cyclosporine to prevent graft-versus-host disease, the use of peripheral blood progenitor cells led to earlier engraftment (median neutrophil engraftment = 16 vs. 21 days, median platelet engraftment = 13 vs. 19 days). The use of peripheral blood progenitor cells was associated with a trend toward increased graft-versus-host disease but comparable transplant-related death. The relapse rate at 2 years appeared lower in patients receiving peripheral blood progenitor cells (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.24–1.00); however, OS was not significantly increased (HR for death within 2 years, 0.62; 95% confidence interval, 0.38–1.02).
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with adult acute myeloid leukemia in remission. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.1Vaughan WP, Karp JE, Burke PJ: Long chemotherapy-free remissions after single-cycle timed-sequential chemotherapy for acute myelocytic leukemia. Cancer 45 (5): 859-65, 1980.2Cassileth PA, Harrington DP, Hines JD, et al.: Maintenance chemotherapy prolongs remission duration in adult acute nonlymphocytic leukemia. J Clin Oncol 6 (4): 583-7, 1988.3Mayer RJ, Davis RB, Schiffer CA, et al.: Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med 331 (14): 896-903, 1994.4Champlin R, Gajewski J, Nimer S, et al.: Postremission chemotherapy for adults with acute myelogenous leukemia: improved survival with high-dose cytarabine and daunorubicin consolidation treatment. J Clin Oncol 8 (7): 1199-206, 1990.5Rohatiner AZ, Gregory WM, Bassan R, et al.: Short-term therapy for acute myelogenous leukemia. J Clin Oncol 6 (2): 218-26, 1988.6Geller RB, Burke PJ, Karp JE, et al.: A two-step timed sequential treatment for acute myelocytic leukemia. Blood 74 (5): 1499-506, 1989.7Stone RM, Berg DT, George SL, et al.: Postremission therapy in older patients with de novo acute myeloid leukemia: a randomized trial comparing mitoxantrone and intermediate-dose cytarabine with standard-dose cytarabine. Blood 98 (3): 548-53, 2001.8Goldstone AH, Burnett AK, Wheatley K, et al.: Attempts to improve treatment outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom Medical Research Council AML11 trial. Blood 98 (5): 1302-11, 2001.9Baker WJ, Royer GL Jr, Weiss RB: Cytarabine and neurologic toxicity. J Clin Oncol 9 (4): 679-93, 1991.10Haupt HM, Hutchins GM, Moore GW: Ara-C lung: noncardiogenic pulmonary edema complicating cytosine arabinoside therapy of leukemia. Am J Med 70 (2): 256-61, 1981.11Clift RA, Buckner CD, Thomas ED, et al.: The treatment of acute non-lymphoblastic leukemia by allogeneic marrow transplantation. Bone Marrow Transplant 2 (3): 243-58, 1987.12Reiffers J, Gaspard MH, Maraninchi D, et al.: Comparison of allogeneic or autologous bone marrow transplantation and chemotherapy in patients with acute myeloid leukaemia in first remission: a prospective controlled trial. Br J Haematol 72 (1): 57-63, 1989.13Bostrom B, Brunning RD, McGlave P, et al.: Bone marrow transplantation for acute nonlymphocytic leukemia in first remission: analysis of prognostic factors. Blood 65 (5): 1191-6, 1985.14Busca A, Anasetti C, Anderson G, et al.: Unrelated donor or autologous marrow transplantation for treatment of acute leukemia. Blood 83 (10): 3077-84, 1994.15Tallman MS, Rowlings PA, Milone G, et al.: Effect of postremission chemotherapy before human leukocyte antigen-identical sibling transplantation for acute myelogenous leukemia in first complete remission. Blood 96 (4): 1254-8, 2000.16Koreth J, Schlenk R, Kopecky KJ, et al.: Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA 301 (22): 2349-61, 2009.17Chao NJ, Stein AS, Long GD, et al.: Busulfan/etoposide--initial experience with a new preparatory regimen for autologous bone marrow transplantation in patients with acute nonlymphoblastic leukemia. Blood 81 (2): 319-23, 1993.18Linker CA, Ries CA, Damon LE, et al.: Autologous bone marrow transplantation for acute myeloid leukemia using busulfan plus etoposide as a preparative regimen. Blood 81 (2): 311-8, 1993.19Sanz MA, de la Rubia J, Sanz GF, et al.: Busulfan plus cyclophosphamide followed by autologous blood stem-cell transplantation for patients with acute myeloblastic leukemia in first complete remission: a report from a single institution. J Clin Oncol 11 (9): 1661-7, 1993.20Cassileth PA, Andersen J, Lazarus HM, et al.: Autologous bone marrow transplant in acute myeloid leukemia in first remission. J Clin Oncol 11 (2): 314-9, 1993.21Jones RJ, Santos GW: Autologous bone marrow transplantation with 4-hydroperoxycyclophosphamide purging. In: Gale RP, ed.: Acute Myelogenous Leukemia: Progress and Controversies: Proceedings of a Wyeth-Ayerst-UCLA Symposia Western Workshop Held at Lake Lanier, Georgia, November 28-December 1, 1989. New York: Wiley-Liss, 1990, pp 411-419.22Gorin NC, Aegerter P, Auvert B, et al.: Autologous bone marrow transplantation for acute myelocytic leukemia in first remission: a European survey of the role of marrow purging. Blood 75 (8): 1606-14, 1990.23Robertson MJ, Soiffer RJ, Freedman AS, et al.: Human bone marrow depleted of CD33-positive cells mediates delayed but durable reconstitution of hematopoiesis: clinical trial of MY9 monoclonal antibody-purged autografts for the treatment of acute myeloid leukemia. Blood 79 (9): 2229-36, 1992.24Stein AS, O'Donnell MR, Chai A, et al.: In vivo purging with high-dose cytarabine followed by high-dose chemoradiotherapy and reinfusion of unpurged bone marrow for adult acute myelogenous leukemia in first complete remission. J Clin Oncol 14 (8): 2206-16, 1996.25Cassileth PA, Harrington DP, Appelbaum FR, et al.: Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med 339 (23): 1649-56, 1998.26Zittoun RA, Mandelli F, Willemze R, et al.: Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Leukemia Cooperative Groups. N Engl J Med 332 (4): 217-23, 1995.27Ravindranath Y, Yeager AM, Chang MN, et al.: Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood. Pediatric Oncology Group. N Engl J Med 334 (22): 1428-34, 1996.28Woods WG, Neudorf S, Gold S, et al.: Aggressive post-remission (REM) chemotherapy is better than autologous bone marrow transplantation (BMT) and allogeneic BMT is superior to both in children with acute myeloid leukemia (AML). [Abstract] Proceedings of the American Society of Clinical Oncology 15: A-1091, 368, 1996.29Harousseau JL, Cahn JY, Pignon B, et al.: Comparison of autologous bone marrow transplantation and intensive chemotherapy as postremission therapy in adult acute myeloid leukemia. The Groupe Ouest Est Leucémies Aiguës Myéloblastiques (GOELAM). Blood 90 (8): 2978-86, 1997.30Ferrant A, Labopin M, Frassoni F, et al.: Karyotype in acute myeloblastic leukemia: prognostic significance for bone marrow transplantation in first remission: a European Group for Blood and Marrow Transplantation study. Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Blood 90 (8): 2931-8, 1997.31Slovak 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, 2000.32Imrie KR, Dubé I, Prince HM, et al.: New clonal karyotypic abnormalities acquired following autologous bone marrow transplantation for acute myeloid leukemia do not appear to confer an adverse prognosis. Bone Marrow Transplant 21 (4): 395-9, 1998.33Schiller GJ, Nimer SD, Territo MC, et al.: Bone marrow transplantation versus high-dose cytarabine-based consolidation chemotherapy for acute myelogenous leukemia in first remission. J Clin Oncol 10 (1): 41-6, 1992.34Edenfield WJ, Gore SD: Stage-specific application of allogeneic and autologous marrow transplantation in the management of acute myeloid leukemia. Semin Oncol 26 (1): 21-34, 1999.35Witherspoon RP, Deeg HJ, Storer B, et al.: Hematopoietic stem-cell transplantation for treatment-related leukemia or myelodysplasia. J Clin Oncol 19 (8): 2134-41, 2001.36Bensinger WI, Martin PJ, Storer B, et al.: Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med 344 (3): 175-81, 2001.
Recurrent Adult Acute Myeloid Leukemia
No standard regimen exists for the treatment of patients with relapsed acute myeloid leukemia (AML), particularly in patients with a first remission duration of less than 1 year.
A number of agents have activity in recurrent AML. A combination of mitoxantrone and cytarabine was successful in 50% to 60% of patients who experienced relapse after initially obtaining a complete remission. Other studies using idarubicin and cytarabine or high-dose etoposide and cyclophosphamide reported similar results. Mitoxantrone, etoposide, and cytarabine (MEC) demonstrated a complete remission induction rate of 55% in a population including 30 patients with relapsed AML, 28 patients with primary refractory AML, and 16 patients with secondary AML.[Level of evidence: 3iiiDiv] However, in a phase III Eastern Cooperative Oncology Group (ECOG) (E-2995) trial of MEC with or without PSC388, a multidrug resistance modulator, complete response (CR) was only 17% to 25% in a population including relapse at less than 6 months after first complete remission, relapse after allogeneic or autologous bone marrow transplantation (BMT), second or greater relapse, primary induction failures, secondary AML, and high-risk myelodysplastic syndromes.[Level of evidence: 1iiDiv] Thus, treatments with new agents under clinical evaluation remain appropriate in eligible patients with recurrent AML.
The immunotoxin gemtuzumab ozogamicin has been reported to have a 30% response rate in patients with relapsed AML expressing CD33. This included 16% of patients who achieved CRs and 13% of patients who achieved a CRp, a new response criteria defined for this trial. CRp refers to clearance of leukemic blasts from the marrow, with adequate myeloid and erythroid recovery but with incomplete platelet recovery (though platelet transfusion independence for at least 1 week was required). Unclear is whether the inadequate platelet recovery is due to megakaryocyte toxic effects of gemtuzumab or to subclinical residual leukemia. The long-term outcomes of patients who achieve CRp following gemtuzumab are not yet known. Gemtuzumab induces profound bone marrow aplasia similar to leukemia induction chemotherapy and also has substantial hepatic toxic effects, including hepatic venoocclusive disease. The farnesyltransferase inhibitor tipifarnib (R115777) demonstrated a 32% response rate in a phase I study in patients with relapsed and refractory acute leukemia (two CRs and six partial responses in 24 patients treated) and has entered phase II trials. Clofarabine, a novel purine nucleoside analogue, induced complete remissions in 8 out of 19 patients in first relapse as a single agent  and in 7 out of 29 patients when administered in combination with intermediate-dose cytarabine.[Level of evidence: 3iiiDiv]
A subset of relapsed patients treated aggressively may have extended disease-free survival (DFS); however, cures in patients following a relapse are thought to be more commonly achieved using BMT.[Level of evidence: 3iDii] A retrospective study from the International Bone Marrow Transplant Registry compared adults younger than 50 years with AML in second complete remission who received HLA-matched sibling transplantation versus a variety of postremission approaches. The chemotherapy approaches were heterogeneous; some patients received no postremission therapy. The transplantation regimens were similarly diverse. Leukemia-free survival appeared to be superior for patients receiving BMTs for two groups: patients older than 30 years whose first remission was less than 1 year; and patients younger than 30 years whose first remission was longer than 1 year.[Level of evidence: 3iDii]
Allogeneic BMT from an HLA-matched donor in early first relapse or in second complete remission provides a DFS rate of approximately 30%.[Level of evidence: 3iiiA] Transplantation in early first relapse potentially avoids the toxic effects of reinduction chemotherapy. Allogeneic BMT can salvage some patients whose disease fails to go into remission with intensive chemotherapy (primary refractory leukemia). Nine of 21 patients with primary refractory AML were alive and disease free at 10 years following allogeneic BMT.[Level of evidence: 3iiiA] Randomized trials testing the efficacy of this approach are not available. Autologous BMT is an option for patients in second complete remission, offering a DFS that may be comparable to autografting in first complete remission.
Patients who relapse following an allogeneic BMT may undergo an infusion of lymphocytes from the donor (Donor Lymphocyte Infusion or DLI), similar to the therapy patients with relapsing chronic myelogenous leukemia (CML) undergo. (Refer to the Relapsing Chronic Myelogenous Leukemia section of the PDQ summary on Chronic Myelogenous Leukemia Treatment for more information.) There are no published studies of any prospective trials examining the role of DLI for patients with AML who relapsed following allogeneic BMT. A retrospective study of European patients found that, out of 399 patients who relapsed after an allogeneic BMT, 171 patients received DLI as part of their salvage therapy. A multivariate analysis of survival showed a significant advantage for the 171 DLI recipients, who achieved a 2-year overall survival from the time of relapse of 21%, compared to 9% for the 228 patients who did not receive DLI (P < .04; RR, 0.8; 95% confidence interval, 0.64–0.99).[Level of evidence: 3iiiA] The strength of this finding is limited by the retrospective nature of the study, and the possibility that much of the survival advantage could have been the result of selection bias. Furthermore, the remission rate of 34% reported in this study was considerably less than the 67% to 91% reported for CML. Therefore, even if the survival advantage conferred by DLI is real, the fraction of relapsed AML patients who might benefit from this therapy appears to be quite limited.
Arsenic trioxide, an agent with both differentiation-inducing and apoptosis-inducing properties against acute promyelocytic leukemia (APL) cells, has a high rate of successful remission induction in patients with relapsed APL. Clinical complete remissions have been reported in 85% of patients induced with arsenic trioxide, with a median time to clinical complete remission of 59 days. Eighty-six percent of evaluable patients tested negative for the presence of PML-RARα transcript after induction or postremission therapy with arsenic trioxide. Actuarial 18-month relapse-free survival was 56%. Induction with arsenic trioxide may be complicated by APL differentiation syndrome (identical to ATRA syndrome), prolongation of QT interval, and neuropathy. Arsenic trioxide is now being incorporated into the postremission treatment strategy of de novo APL patients in clinical trials.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent adult acute myeloid leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.1Ferrara F, Palmieri S, Mele G: Prognostic factors and therapeutic options for relapsed or refractory acute myeloid leukemia. Haematologica 89 (8): 998-1008, 2004.2Hiddemann W, Kreutzmann H, Straif K, et al.: High-dose cytosine arabinoside and mitoxantrone: a highly effective regimen in refractory acute myeloid leukemia. Blood 69 (3): 744-9, 1987.3Brown RA, Herzig RH, Wolff SN, et al.: High-dose etoposide and cyclophosphamide without bone marrow transplantation for resistant hematologic malignancy. Blood 76 (3): 473-9, 1990.4Paciucci PA, Dutcher JP, Cuttner J, et al.: Mitoxantrone and ara-C in previously treated patients with acute myelogenous leukemia. Leukemia 1 (7): 565-7, 1987.5Lambertenghi-Deliliers G, Maiolo AT, Annaloro C, et al.: Idarubicin in sequential combination with cytosine arabinoside in the treatment of relapsed and refractory patients with acute non-lymphoblastic leukemia. Eur J Cancer Clin Oncol 23 (7): 1041-5, 1987.6Harousseau JL, Reiffers J, Hurteloup P, et al.: Treatment of relapsed acute myeloid leukemia with idarubicin and intermediate-dose cytarabine. J Clin Oncol 7 (1): 45-9, 1989.7Forman SJ, Schmidt GM, Nademanee AP, et al.: Allogeneic bone marrow transplantation as therapy for primary induction failure for patients with acute leukemia. J Clin Oncol 9 (9): 1570-4, 1991.8Spadea A, Petti MC, Fazi P, et al.: Mitoxantrone, etoposide and intermediate-dose Ara-C (MEC): an effective regimen for poor risk acute myeloid leukemia. Leukemia 7 (4): 549-52, 1993.9Greenberg PL, Lee SJ, Advani R, et al.: Mitoxantrone, etoposide, and cytarabine with or without valspodar in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome: a phase III trial (E2995). J Clin Oncol 22 (6): 1078-86, 2004.10Estey E, Plunkett W, Gandhi V, et al.: Fludarabine and arabinosylcytosine therapy of refractory and relapsed acute myelogenous leukemia. Leuk Lymphoma 9 (4-5): 343-50, 1993.11Sievers EL, Larson RA, Stadtmauer EA, et al.: Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol 19 (13): 3244-54, 2001.12Giles FJ, Kantarjian HM, Kornblau SM, et al.: Mylotarg (gemtuzumab ozogamicin) therapy is associated with hepatic venoocclusive disease in patients who have not received stem cell transplantation. Cancer 92 (2): 406-13, 2001.13Karp JE, Lancet JE, Kaufmann SH, et al.: Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial. Blood 97 (11): 3361-9, 2001.14Kantarjian H, Gandhi V, Cortes J, et al.: Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood 102 (7): 2379-86, 2003.15Faderl S, Gandhi V, O'Brien S, et al.: Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias. Blood 105 (3): 940-7, 2005.16Gale RP, Horowitz MM, Rees JK, et al.: Chemotherapy versus transplants for acute myelogenous leukemia in second remission. Leukemia 10 (1): 13-9, 1996.17Clift RA, Buckner CD, Thomas ED, et al.: The treatment of acute non-lymphoblastic leukemia by allogeneic marrow transplantation. Bone Marrow Transplant 2 (3): 243-58, 1987.18Clift RA, Buckner CD, Appelbaum FR, et al.: Allogeneic marrow transplantation during untreated first relapse of acute myeloid leukemia. J Clin Oncol 10 (11): 1723-9, 1992.19Meloni G, De Fabritiis P, Petti MC, et al.: BAVC regimen and autologous bone marrow transplantation in patients with acute myelogenous leukemia in second remission. Blood 75 (12): 2282-5, 1990.20Chopra R, Goldstone AH, McMillan AK, et al.: Successful treatment of acute myeloid leukemia beyond first remission with autologous bone marrow transplantation using busulfan/cyclophosphamide and unpurged marrow: the British autograft group experience. J Clin Oncol 9 (10): 1840-7, 1991.21Gorin NC, Labopin M, Meloni G, et al.: Autologous bone marrow transplantation for acute myeloblastic leukemia in Europe: further evidence of the role of marrow purging by mafosfamide. European Co-operative Group for Bone Marrow Transplantation (EBMT). Leukemia 5 (10): 896-904, 1991.22Schmid C, Labopin M, Nagler A, et al.: Donor lymphocyte infusion in the treatment of first hematological relapse after allogeneic stem-cell transplantation in adults with acute myeloid leukemia: a retrospective risk factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party. J Clin Oncol 25 (31): 4938-45, 2007.23Dazzi F, Szydlo RM, Craddock C, et al.: Comparison of single-dose and escalating-dose regimens of donor lymphocyte infusion for relapse after allografting for chronic myeloid leukemia. Blood 95 (1): 67-71, 2000.24Soignet SL, Frankel SR, Douer D, et al.: United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 19 (18): 3852-60, 2001.25Shen ZX, Chen GQ, Ni JH, et al.: Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 89 (9): 3354-60, 1997.
Changes to This Summary (02/12/2013)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Adult Acute Myeloid Leukemia
Updated statistics with estimated new cases and deaths for 2013 (cited American Cancer Society as reference 1).
Adult Acute Myeloid Leukemia in Remission
An editorial change was made to this section.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of acute myeloid leukemia. It 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.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
- be discussed at a meeting,
- be cited with text, or
- replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Adult Acute Myeloid Leukemia Treatment are:
- Steven D. Gore, MD (Johns Hopkins University)
- Mark J. Levis, MD, PhD (Johns Hopkins University)
- Mikkael A. Sekeres, MD, MS (Cleveland Clinic Taussig Cancer Institute)
Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this 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.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
National Cancer Institute: PDQ® Adult Acute Myeloid Leukemia Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/adultAML/healthprofessional. Accessed <MM/DD/YYYY>.
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Coping with Cancer: Financial, Insurance, and Legal Information page.
More information about contacting us or receiving help with the Cancer.gov Web site can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the Web site’s Contact Form.
Get More Information From NCI
For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 8:00 a.m. to 8:00 p.m., Eastern Time. A trained Cancer Information Specialist is available to answer your questions.
The NCI's LiveHelp® online chat service provides Internet users with the ability to chat online with an Information Specialist. The service is available from 8:00 a.m. to 11:00 p.m. Eastern time, Monday through Friday. Information Specialists can help Internet users find information on NCI Web sites and answer questions about cancer.
Write to us
For more information from the NCI, please write to this address:
- NCI Public Inquiries Office
- 9609 Medical Center Dr.
- Room 2E532 MSC 9760
- Bethesda, MD 20892-9760
Search the NCI Web site
The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use the search box in the upper right corner of each Web page. The results for a wide range of search terms will include a list of "Best Bets," editorially chosen Web pages that are most closely related to the search term entered.
There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.
The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237).
This information was last updated on 2013-02-12