Instituto Nacional del Cáncer


Acute myeloid (myelogenous) leukemia (AML) treatment options include chemotherapy, radiation therapy, stem cell transplant, and other medications. Cytogenetic analysis helps predict treatment outcomes. Get detailed information about AML in this summary for clinicians.

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.

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).

Adult AML Treatment

Adult Acute Myeloid Leukemia Treatment

adult acute myeloid leukemia

General Information About Adult Acute Myeloid Leukemia (AML)

AML is also called acute myelogenous leukemia and acute nonlymphocytic leukemia.

Incidence and Mortality

Estimated new cases and deaths from AML in the United States in 2020:

  • New cases: 19,940.
  • Deaths: 11,180.

Based on Surveillance, Epidemiology, and End Results (SEER) Program 18 data from 2009 to 2015, 28.3% of patients with AML were alive 5 years after diagnosis.

Anatomy

Blood cell development; drawing shows the steps a blood stem cell goes through to become a red blood cell, platelet, or white blood cell. A myeloid stem cell becomes a red blood cell, a platelet, or a myeloblast, which then becomes a granulocyte (the types of granulocytes are eosinophils, basophils, and neutrophils). A lymphoid stem cell becomes a lymphoblast and then becomes a B-lymphocyte, T-lymphocyte, or natural killer cell.Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell.

AML is a heterogenous group of blood cancers that arise as a result of clonal expansion of myeloid hematopoietic precursors in the bone marrow. Not only are circulating leukemia cells (also called blasts) seen in the peripheral blood, but granulocytopenia, anemia, and thrombocytopenia are also common as proliferating leukemia cells interfere with normal hematopoiesis.

Clinical Presentation

The diagnosis of AML is uncommon before age 45 years; the median age at diagnosis is 68 years. Patients may present with symptoms that include the following:

  • Weakness.
  • Fever.
  • Infection.
  • Pallor.
  • Bleeding.

The hampered production of normal blood cells due to leukemic infiltration of the bone marrow can also cause other symptoms and complications. Less commonly, patients have signs or symptoms related to the collection of leukemia cells in certain anatomic locations, such as central nervous system (CNS) or testicular involvement, or the presence of a myeloid sarcoma (also called chloroma). The symptoms of acute leukemia often arise over a 4- to 6-week period before diagnosis.

Diagnostic Evaluation

The differentiation of AML from other forms of leukemia, in particular chronic myelogenous leukemia and acute lymphocytic leukemia, has vital therapeutic implications. The primary diagnostic tool in this determination is the use of flow cytometry to evaluate surface antigens on the leukemia cells. Simple morphology is not adequate in determining lineage, and at a minimum, special histochemical stains are needed. While a diagnosis can be made by the evaluation of peripheral blood, a bone marrow biopsy is used to evaluate morphology and cell surface markers as well as provide material for cytogenetic and molecular analysis. A peripheral blood or bone marrow blast count of 20% or greater is required to make the diagnosis, except for cases with certain chromosomal abnormalities (i.e., t(15;17), t(8;21), inv(16), or t(16;16)).

Prognosis and Prognostic Factors

Advances in the treatment of AML have resulted in substantially improved complete remission (CR) rates. Treatment should be sufficiently aggressive to achieve CR because partial remission offers no substantial survival benefit. Approximately 60% to 70% of adults with AML can be expected to attain CR status after appropriate induction therapy. More than 25% of adults with AML (about 45% of those who attain CR) can be expected to survive 3 or more years and may be cured.

Approximately half of the patients with AML will harbor chromosomal abnormalities; therefore, conventional cytogenetic analysis remains mandatory in the evaluation of suspected AML. With the routine use of molecular diagnostics, the identification of recurrent somatic mutations in NPM1, FLT3, CEPBA, and RUNX1, among other genes, has become a routine part of determining prognosis. Cytogenetic and molecular analyses provide the strongest prognostic information available, predicting outcome of both remission induction and postremission therapy. Cytogenic and molecular information has been combined to form distinct prognostic groups.

Additional adverse prognostic factors for AML include the following:

  • Age at diagnosis. 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.
  • CNS involvement with leukemia.
  • Systemic infection at diagnosis.
  • Elevated white blood cell count (>100,000/mm3) at diagnosis.
  • Therapy-related myeloid neoplasms, resulting from alkylating agents and radiation therapy.
  • History of myelodysplastic syndrome or another antecedent hematological disorder.

Long-term Effects of Cancer Treatment

The risk of developing any long-term effects depends on the type and dose of treatment that was used and the age at which the patient underwent treatment.

A study of 30 patients who had AML that was in remission for at least 10 years demonstrated a 13% incidence of secondary malignancies. Of 31 female long-term survivors of AML or acute lymphoblastic leukemia (ALL) (diagnosed before age 40 years), 26 resumed normal menstruation after completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.

Most patients with AML who undergo intensive therapy are treated with an anthracycline. Anthracyclines have been associated with increased risk of congestive heart failure (CHF). Anthracycline cardiotoxicity is dose-dependent. In one study, doxorubicin-related CHF was 5% at a lifetime cumulative dose of 400 mg/m2, rising to 26% at a cumulative dose of 550 mg/m2. In many cases, heart failure can manifest as a late effect. In an analysis of children who underwent treatment for acute leukemia, the cumulative incidence of CHF at 10 years was 1.7% in ALL and 7.5% in AML.

Patients who undergo allogeneic hematopoietic stem cell transplantation (HSCT) can experience a large number of long-term or late side effects of treatment, including chronic fatigue, thyroid and gonadal dysfunction, infertility, chronic infection, accelerated coronary heart disease, osteopenia, cataracts, iron overload, adverse psychological outcomes, and second cancers as a result of high-dose chemotherapy and/or radiation, and as an effect of chronic graft-versus-host disease and immunosuppression.

In the Bone Marrow Transplant Survivor Study, hematopoietic cell transplantation (HCT) survivors had accelerated aging and were 8.4 times more likely to be frail than their siblings (95% confidence interval [CI], 2.0−34.5; P = .003). In a multivariable analysis, frailty was associated with a 2.76-fold increase in the risk of death as compared with a non-frail state (95% CI, 1.7−4.4; P < .001).

Related Summaries

Other PDQ summaries containing information related to AML include the following:

  • Chronic Myelogenous Leukemia Treatment
  • Myelodysplastic Syndromes Treatment
  • Childhood Acute Myeloid Leukemia /Other Myeloid Malignancies Treatment

References

  1. American Cancer Society: Cancer Facts and Figures 2020. Atlanta, Ga: American Cancer Society, 2020. Available online. Last accessed May 12, 2020.
  2. Surveillance, Epidemiology, and End Results Program: Cancer Stat Facts: Leukemia — Acute Myeloid Leukemia (AML). Bethesda, Md: National Cancer Institute, DCCPS, Surveillance Research Program, 2020. Available online. Last accessed June 24, 2020.
  3. Sekeres MA, Gerds AT: Mitigating Fear and Loathing in Managing Acute Myeloid Leukemia. Semin Hematol 52 (3): 249-55, 2015.
  4. Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th rev. ed. Lyon, France: International Agency for Research on Cancer, 2017.
  5. Slovak ML, Kopecky KJ, Cassileth PA, et al.: Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 96 (13): 4075-83, 2000.
  6. Grimwade D, Walker H, Harrison G, et al.: The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood 98 (5): 1312-20, 2001.
  7. Döhner H, Estey E, Grimwade D, et al.: Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129 (4): 424-447, 2017.
  8. Micallef IN, Rohatiner AZ, Carter M, et al.: Long-term outcome of patients surviving for more than ten years following treatment for acute leukaemia. Br J Haematol 113 (2): 443-5, 2001.
  9. Steinherz LJ, Steinherz PG, Tan CT, et al.: Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA 266 (12): 1672-7, 1991.
  10. Swain SM, Whaley FS, Ewer MS: Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 97 (11): 2869-79, 2003.
  11. Hequet O, Le QH, Moullet I, et al.: Subclinical late cardiomyopathy after doxorubicin therapy for lymphoma in adults. J Clin Oncol 22 (10): 1864-71, 2004.
  12. Chellapandian D, Pole JD, Nathan PC, et al.: Congestive heart failure among children with acute leukemia: a population-based matched cohort study. Leuk Lymphoma 60 (2): 385-394, 2019.
  13. Inamoto Y, Lee SJ: Late effects of blood and marrow transplantation. Haematologica 102 (4): 614-625, 2017.
  14. Sun CL, Francisco L, Baker KS, et al.: Adverse psychological outcomes in long-term survivors of hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study (BMTSS). Blood 118 (17): 4723-31, 2011.
  15. Armenian SH, Sun CL, Kawashima T, et al.: Long-term health-related outcomes in survivors of childhood cancer treated with HSCT versus conventional therapy: a report from the Bone Marrow Transplant Survivor Study (BMTSS) and Childhood Cancer Survivor Study (CCSS). Blood 118 (5): 1413-20, 2011.
  16. Arora M, Sun CL, Ness KK, et al.: Physiologic Frailty in Nonelderly Hematopoietic Cell Transplantation Patients: Results From the Bone Marrow Transplant Survivor Study. JAMA Oncol 2 (10): 1277-1286, 2016.
adult acute myeloid leukemia

Classification of Adult AML

World Health Organization (WHO) Classification

The classification of adult acute myeloid leukemia (AML) has been revised by a group of pathologists and clinicians under the auspices of the WHO. While elements of the French-American-British (FAB) classification have been retained (i.e., morphology, immunophenotype, cytogenetics, and clinical features), the WHO classification incorporates and interrelates morphology, cytogenetics, molecular genetics, and immunologic markers, which construct a classification that is universally applicable and has prognostic and therapeutic relevance. Each criterion has prognostic and treatment implications but, for practical purposes, initial antileukemic therapy is similar for all subtypes.

In 2001, the WHO proposed a new classification system that incorporated diagnostic cytogenetic information and that more reliably correlated with outcome. This classification system also decreased the bone marrow percentage of leukemic blast requirement for the diagnosis of AML from 30% to 20%. An additional clarification was made so patients with recurrent cytogenetic abnormalities did not need to meet the minimum blast requirement to be considered as having an AML diagnosis.

In 2008, the WHO expanded the number of cytogenetic abnormalities linked to AML classification and, for the first time, included specific gene mutations (CEBPA and NPM) in its classification system. With the addition of these gene mutations, FAB subclassification no longer provided prognostic information for patients with a diagnosis of AML, not otherwise specified (NOS).

In 2016, the WHO classification underwent revisions to incorporate the expanding knowledge of leukemia biomarkers that are significantly important to the diagnosis, prognosis, and treatment of leukemia. With emerging technologies aimed at genetic, epigenetic, proteomic, and immunophenotypic classification, AML classification will continue to evolve and provide informative prognostic and biologic guidelines to clinicians and researchers.

2016 WHO classification of AML and related neoplasms

  • AML with recurrent genetic abnormalities:
    • AML with t(8;21)(q22;q22), RUNX1-RUNX1T1.
    • AML with inv(16)(p13.1;q22) or t(16;16)(p13.1;q22), CBFB-MYH11.
    • Acute promyelocytic leukemia (APL) with PML-RARA.
    • AML with t(9;11)(p21.3;q23.3), MLLT3-KMT2A.
    • AML with t(6;9)(p23;q34.1), DEK-NUP214.
    • AML with inv(3)(q21.3;q26.2) or t(3;3)(q21.3;q26.2), GATA2, MECOM.
    • AML (megakaryoblastic) with t(1;22)(p13.3;q13.3), RBM15-MKL1.
    • AML with BCR-ABL1 (provisional entity).
    • AML with mutated NPM1.
    • AML with biallelic mutations of CEBPA.
    • AML with mutated RUNX1 (provisional entity).
  • AML with myelodysplasia-related features.
  • Therapy-related myeloid neoplasms.
  • AML, NOS:
    • AML with minimal differentiation (FAB classification M0).
    • AML without maturation (FAB classification M1).
    • AML with maturation (FAB classification M2).
    • Acute myelomonocytic leukemia (FAB classification M4).
    • Acute monoblastic/monocytic leukemia (FAB classification M5a and M5b).
    • Pure erythroid leukemia (FAB classification M6a and M6b).
    • Acute megakaryoblastic leukemia (FAB classification M7).
    • Acute basophilic leukemia.
    • Acute panmyelosis with myelofibrosis.
  • Myeloid sarcoma.
  • Myeloid proliferations related to Down syndrome:
    • Transient abnormal myelopoiesis (TAM).
    • Myeloid leukemia associated with Down syndrome.

AML With Recurrent Genetic Abnormalities

AML with well-defined genetic abnormalities is characterized by recurrent genetic 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 chromosomal 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 either reverse transcriptase–polymerase chain reaction (RT–PCR) or fluorescence in situ hybridization (FISH), which has a higher sensitivity than metaphase cytogenetics. Other recurring cytogenetic abnormalities are less common.

Molecular diagnostic platforms such as next-generation sequencing along with RT-PCR are used to identify recurrent molecular abnormalities in AML, helping to further refine diagnostic categories in the 2016 WHO classification system.

AML with t(8;21)(q22;q22), RUNX1-RUNX1T1

The translocation t(8;21)(q22;q22) is one of the most common chromosomal aberrations in AML and accounts for 5% to 12% of cases. 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-Huët nuclei) and/or cytoplasmic staining abnormalities.
  • Increased eosinophil precursors.
  • Reduced or absent monocytes.
  • Normal erythroblasts and megakaryocytes.

Rarely, AML with this translocation presents with a bone marrow blast percentage of less than 20%. Along with inv(16)(p13;q22) or t(16;16)(p13;q22), AML with t(8;21) makes up a category known as core binding factor AML. This category of AML is associated with long-term survival when treated with high-dose cytarabine.

The translocation t(8;21)(q22;q22) involves the RUNX1 gene, which encodes CBF-alpha, and the RUNX1T1 (8;21) gene. The RUNX1/RUNX1T1 fusion transcript is consistently detected in patients with t(8;21) AML. This translocation is usually associated with a good response to chemotherapy and a high complete remission (CR) rate with long-term survival when treated with high-dose cytarabine in the postremission phase, as demonstrated in the Cancer and Leukemia Group B (CLB-9022 and CLB-8525) trials. Additional chromosome abnormalities are common, for example, loss of a sex chromosome and del(9)(q22). Leukocytosis (i.e., white blood count >25 x 109/L) is associated with an inferior outcome, as is the presence of a KIT mutation.

AML with inv(16)(p13.1;q22) or t(16;16)(p13.1;q22), CBFB-MYH11

The inv(16)(p13;q22) abnormality or t(16;16)(p13;q22) translocation is found in approximately 10% to 12% of all cases of AML, predominantly in younger patients. 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.

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 CBFB gene at 16q22 to the smooth muscle MYH11 gene at 16p13, thereby forming the fusion gene CBFB/MYH11. The use of FISH and RT–PCR methods is sometimes necessary to document this fusion gene because its presence is not always documented by traditional cytogenetics banding techniques. Similar to AML with t(8;21), patients with the CBFB/MYH11 fusion gene achieve higher CR rates and long-term survival when treated with high-dose cytarabine in the postremission setting. Unlike AML with t(8;21), the prognostic relevance of KIT mutations is unclear.

APL with PML-RARA

APL is defined by the presence of the PML-RARA fusion protein, typically a result of t(15;17)(q22;q12), but can be cryptic or result from complex cytogenetic rearrangements other than t(15;17)(q22;q12). It is also an AML in which promyelocytes are the dominant leukemic cell type. APL exists as two subtypes, hypergranular or typical APL and microgranular or 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 can be 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 RARA gene on 17q12 fuses with a nuclear regulatory factor on 15q22 (PML gene) resulting in a PML/RARA 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 RARA gene into the PML gene, leading to the expression of the PML/RARA fusion transcript. FISH and/or RT–PCR methods may be required to unmask these cryptic genetic rearrangements. In approximately 1% of the patients with APL, variant chromosomal aberrations may be found in which the RARA gene is fused with other genes. Variant translocations involving the RARA gene include t(11;17)(q23;q21), t(5;17)(q32;q12), and t(11;17)(q13;q21).

APL has a specific sensitivity to treatment with all-trans retinoic acid (ATRA, tretinoin), which acts as a differentiating agent. High CR rates and long-term disease-free survival in APL may be obtained by combining ATRA treatment with chemotherapy, or in a chemotherapy-free regimen with arsenic trioxide.

AML with t(9;11)(p21.3;q23.3), MLLT3-KMT2A

AML with 11q23 abnormalities comprises 5% to 6% of cases of AML and is typically associated with monocytic features. This type of AML is more common in children. Two clinical subgroups who have a high frequency of AML with 11q23 abnormalities are infants with AML and patients with 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 include the following:

  • Monoblasts and promonocytes predominate in the bone marrow.
  • Monoblasts and promonocytes with strong, positive nonspecific-esterase reactions.

The MLLT3 gene on 11q23, an epigenetic regulator, is involved in translocations with approximately 135 different rearrangements having been identified so far. Genes other than MLLT3 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) have been reported to have poor outcomes.

AML with t(6;9)(p23;q34.1), DEK-NUP214

The t(6;9) translocation leads to the formation of a leukemia-associated fusion protein DEK-NUP214 and accounts for approximately 1% of AML cases. NUP214 is a component of the nuclear pore complex. This subgroup of AML has been associated with a poor prognosis.

AML with inv(3)(q21.3;q26.2) or t(3;3)(q21.3;q26.2), GATA2, MECOM

The inv(3) abnormality or t(3;3) translocation occur infrequently and account for approximately 1% of all AML cases. MECOM at chromosome 3q26 codes for two proteins, EVI1 and MDS1-EVI1, both of which are transcription regulators. The inv(3) and t(3;3) abnormalities do not lead to a fusion gene, rather they reposition the distal GATA2 enhancer, resulting in overexpression of EVI1, and simultaneously confer GATA2 haploinsufficiency. These abnormalities are associated with poor prognosis. Abnormalities involving MECOM can be detected in some AML cases with other 3q abnormalities and are also associated with poor prognosis.

AML (megakaryoblastic) with t(1;22)(p13.3;q13.3), RBM15-MKL1

The t(1;22)(p13;q13) translocation that produces RBM15-MKL1 is an uncommon driver of pediatric AML (<1% of pediatric AML) and is restricted to acute megakaryocytic leukemia. (Refer to the PDQ summary on Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment for more information.)

AML with BCR-ABL1 (provisional entity)

This provisional entity was added by the WHO in 2016 in an effort to recognize that patients with the BCR-ABL1 fusion protein should be treated with a tyrosine kinase inhibitor. However, this entity is very difficult to distinguish from chronic myelogenous leukemia (CML) in blast phase (BP-CML). Loss of IKZF1 and/or CDKN2A may help distinguish true cases of AML with BCR-ABL1 from BP-CML. (Refer to the PDQ summary on Chronic Myelogenous Leukemia Treatment for more information.)

AML with mutated NPM1

NPM1 is a protein that has been linked to ribosomal protein assembly and transport and is also a molecular chaperone involved in preventing protein aggregation in the nucleolus. Immunohistochemical methods can be used to accurately identify patients with NPM1 mutations by the demonstration of cytoplasmic localization of NPM. Mutations in the NPM1 protein diminish its nuclear localization and lead to impaired hematopoietic differentiation. They are primarily associated with a normal karyotype (50%), and less commonly seen in conjunction with an abnormal karyotype (<10%), or complex karyotype (<3%). The presence of an NPM1 mutation confers improved prognosis in the absence of FLT3–internal tandem duplication (ITD) mutations.

AML with biallelic mutations of CEBPA

In adults younger than 60 years, 10% to 15% of cytogenetically normal AML cases have mutations in CEBPA. The CEBPA gene is located on chromosome 19 and encodes a transcription factor that coordinates myeloid differentiation and cellular growth arrest.

Outcomes for patients with AML with CEBPA mutations are relatively favorable and similar to that of patients with core-binding factor leukemias. Studies have demonstrated that CEBPA double-mutant, but not single-mutant, AML is independently associated with a favorable prognosis, leading to the WHO 2016 revision that requires biallelic mutations for the disease definition.

AML with mutated RUNX1 (provisional entity)

AML with mutated RUNX1, which is a provisional entity in the 2016 WHO classification of AML and related neoplasms, denotes a distinct population of de novo AML without myelodysplastic syndrome (MDS)-related features. Mutations in RUNX1 are associated with a high risk of treatment failure.

AML With Myelodysplasia-related Features

AML with myelodysplasia-related features 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 or must have the presence of an MDS-related cytogenetic abnormality. AML with myelodysplasia-related features may occur de novo or following MDS or a myelodysplastic/myeloproliferative neoplasm overlap. (Refer to the PDQ summaries on Myelodysplastic Syndromes Treatment and Myelodysplastic/ Myeloproliferative Neoplasms Treatment for more information.) The diagnostic terminology AML with myelodysplasia-related features evolving from a myelodysplastic syndrome should be used when an MDS precedes AML. In the presence of a mutation in NPM1 or biallelic mutations of CEBPA, the presence of multilineage dysplasia alone will not classify a case as AML with myelodysplasia-related changes.

AML with myelodysplasia-related features occurs primarily in older patients. Patients with AML with myelodysplasia-related features frequently present with severe pancytopenia.

Common morphologic features include the following:

  • Multilineage dysplasia in the blood or bone marrow.
  • Dysplasia in 50% or more of the cells of two or more cell lines.
  • Dysgranulopoiesis (neutrophils with hypogranular cytoplasm, hyposegmented nuclei or bizarrely segmented nuclei).
  • Dyserythropoiesis (megaloblastic nuclei, karyorrhexis, or multinucleation of erythroid precursors and ringed sideroblasts).
  • Dysmegakaryopoiesis (micromegakaryocytes and normal size or large megakaryocytes with monolobed or multiple separated nuclei).

Chromosome abnormalities observed in AML with myelodysplasia-related features are similar to those found in MDS and frequently involve gain or loss of major segments of certain chromosomes, predominately chromosomes 5 and/or 7. The probability of achieving a CR has been reported to be affected adversely by a diagnosis of AML with myelodysplasia-related features.

Therapy-related Myeloid Neoplasms

Therapy-related myeloid neoplasms (t-MN) include AML (t-AML) and MDS (t-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 can be distinguished by the specific mutagenic agents involved, this distinction may be difficult to make because of the frequent overlapping use of multiple potentially mutagenic agents in treating cancer. Because the associated cytogenetic abnormality, not the mutagenetic agent, determines prognosis and treatment it should be noted in the diagnosis.

Given that t-MN has been associated with germline mutations in cancer susceptibility genes, consideration for germline testing or genetic counseling is warranted in those with strong family histories.

Alkylating agent-related t-MN

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 of occurrence is related to both the total cumulative dose of the alkylating agent and the age of the patient.

Cytogenetic abnormalities have been observed in more than 90% of cases of t-MN and commonly include chromosomes 5 and/or 7. Complex chromosomal abnormalities (≥3 distinct abnormalities) are the most common finding.

Topoisomerase II inhibitor-related t-MN

Topoisomerase II inhibitor-related t-MN 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 t-MN is approximately 2 years.

As with alkylating agent/radiation-related t-MN, the cytogenetic abnormalities are often complex. The predominant cytogenetic finding involves chromosome 11q23 and the MLL gene.

AML, Not Otherwise Specified (NOS)

Cases of AML that do not fulfill the criteria for AML with recurrent genetic abnormalities, AML with myelodysplasia-related features, or t-MN fall within the category of AML, NOS. As mentioned before, the subcategories of AML, NOS lack prognostic significance when the mutation status of NPM1 and CEBPA are known. Classification in this subset of AML is based on leukemic cell features of morphology, cytochemistry, and maturation (i.e., the FAB classification system) and include the following:

  • AML with minimal differentiation.
  • AML without maturation.
  • AML with maturation.
  • Acute myelomonocytic leukemia.
  • Acute monoblastic/monocytic leukemia.
  • Pure erythroid leukemia.
  • Acute megakaryoblastic leukemia.
  • Acute basophilic leukemia.
  • Acute panmyelosis with myelofibrosis.

Myeloid Sarcoma

Myeloid sarcoma (also known as extramedullary myeloid tumor, granulocytic sarcoma, and chloroma) is a tumor mass that consists of myeloblasts or immature myeloid cells, occurring in an extramedullary site. Development of myeloid sarcoma has been reported in 2% to 8% of patients with AML. 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 that are positive for MPO.
  • Neutrophils that are positive for naphthol ASD chloroacetate esterase.

Immunophenotyping with antibodies to MPO, lysozyme, and chloroacetate is 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). When able, FISH for common chromosomal abnormalities should be completed, as well as molecular studies to refine diagnosis and aid in prognosis.

No unique chromosomal abnormalities are associated with myeloid sarcoma. The presence of myeloid sarcoma in patients with the otherwise good-risk t(8;21) AML may be associated with a lower CR rate and decreased remission duration. Myeloid sarcoma occurring in the setting of MDS or myeloproliferative disorder is equivalent to blast transformation (progression to AML). 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, it is a partial manifestation of a systemic disease and should be treated with intensive chemotherapy.

Myeloid Proliferations Related to Down Syndrome

Refer to the Transient Abnormal Myelopoiesis (TAM) or Children With Down Syndrome and AML section of the PDQ summary on Childhood Acute Myeloid Leukemia/Other Myeloid Disorders for information on TAM and myeloid leukemia associated with Down syndrome.

Acute Leukemias of Ambiguous Lineage

Acute leukemias of ambiguous lineage are rare 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).

They include the following subcategories:

  • Acute undifferentiated leukemia.
  • Mixed phenotype acute leukemia (MPAL) with t(9;22)(q34.1;q11.2); BCR-ABL1.
  • MPAL with t(v;11q23.3); KMT2A rearranged.
  • MPAL, B/myeloid, NOS.
  • MPAL, T/myeloid, NOS.

The diagnosis of MPAL is made in leukemias with expression of antigens of more than one lineage:

Table 1. Mixed Phenotype Acute Leukemia Diagnostic Criteria

DiagnosisCriteriaMPO = myeloperoxidase.Myeloid LineageMPO (flow cytometry, immunohistochemistry, or cytochemistry) or monocytic differentiation (≥ 2 of the following: nonspecific esterase cytochemistry, CD11c, CD14, CD64, lysozyme).T-cell LineageStrong cytoplasmic CD3 (with antibodies to CD3 epsilon chain) or surface CD3.B-cell LineageStrong CD19 with ≥1 of the following strongly expressed: cytoplasmic CD79a, cCD22, or CD10; or weak CD19 with at least two of the following strongly expressed: CD79a, cCD22, or CD10.

Cytogenetic abnormalities are observed in a high percentage of acute leukemias of ambiguous lineage. 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. The occurrence of 11q23 abnormalities or BCR-ABL1 are especially unfavorable prognostic indicators; however, preliminary results indicate that tyrosine kinase inhibitors can be used successfully.

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adult acute myeloid leukemia

Treatment Option Overview for Adult AML

Phases of Therapy

The treatment of patients with adult acute myeloid leukemia (AML) is based on whether the disease is newly diagnosed (previously untreated), in remission, or recurrent. Also, the intensity of the treatment and the patient's overall health status is considered when choosing a treatment approach. Successful treatment of 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% or less of patients with AML develop CNS disease, prophylactic treatment is not indicated.

  • Newly diagnosed (untreated): Untreated adult AML is defined as newly diagnosed leukemia that has not been previously treated. The initial treatment for patients with newly diagnosed AML is often induction therapy that aims to induce a remission. In patients with AML, a complete remission (CR) 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 CNS leukemia or other extramedullary infiltration.

    Some responses are deeper than a CR, and others may not meet all the criteria for a complete response, and because the vast majority of AML patients meeting the criteria for CR have residual leukemia, modifications to the definition of CR have been proposed.

Table 2. Treatment Response Categories for Newly Diagnosed Adult Acute Myeloid Leukemia

Response CategoryDefinitionANC = absolute neutrophil count; CR = complete remission; MLFS = morphologic leukemia-free state; PR = partial remission; RT–qPCR = reverse transcription–quantitative polymerase chain reaction.CR without measurable residual disease (CRMRD−)If studied pretreatment, CR with negativity for a genetic marker by RT–qPCR, or CR with negativity by multicolor flow cytometry.CRBone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC ≥1.0 × 109/L (1,000/microL); platelet count ≥100 × 109/L (100,000/microL).CR with incomplete hematologic recovery (CRi)All CR criteria except for residual neutropenia (<1.0 × 109/L [1,000/microL]) or thrombocytopenia (<100 × 109/L [100,000/microL]).MLFSBone marrow blasts <5%; absence of blasts with Auer rods; absence of extramedullary disease; no hematologic recovery required.PRAll hematologic criteria of CR; decrease of bone marrow blast percentage to 5 to 25%; and decrease of pretreatment bone marrow blast percentage by at least 50%.
  • In remission: When patients are in a remission following induction chemotherapy, consolidation chemotherapy is given, with the aim of deepening the response and consolidating the remission. This phase of treatment is also called postremission (to maintain remission). Maintenance therapy is not included in most current treatment protocols and clinical trials. Postremission therapy appears to be effective when administered immediately after remission is achieved.
  • Persistent/recurrent disease: Despite intensive chemotherapy, some patients with newly diagnosed AML will not go into remission and have primary refractory disease. Also, some patients who are in a remission after induction and consolidation chemotherapy may have a return of their disease. The rates of primary refractory disease and relapse vary with the age of the patient, genomic variants seen in the leukemia cells, and initial treatment given.

Table 3. Treatment Response Categories for Persistent/Recurrent Adult Acute Myeloid Leukemia

Response CategoryDefinitionCR = complete remission; CRi = complete remission with incomplete hematologic recovery; MRD- = absence of minimal residual disease; MLFS = morphological leukemia-free state; PR = partial response; RT–qPCR = reverse transcription–quantitative polymerase chain reaction. Primary refractory diseaseNo CR or CRi after two courses of intensive induction treatment; excluding patients with death in aplasia or death due to an indeterminate cause.Hematologic relapse (after CRMRD-, CR, CRi)Bone marrow blasts ≥5%; or reappearance of blasts in the blood; or development of extramedullary disease.Molecular relapse (after CRMRD-)If studied pretreatment, reoccurrence of MRD as assessed by RT–qPCR or by multicolor flow cytometry.Stable diseaseAbsence of CRMRD-, CR, CRi, PR, MLFS; and criteria for progressive disease not met.Progressive diseaseEvidence for an increase in bone marrow blast percentage and/or increase of absolute blast counts in the blood: >50% increase in marrow blasts; or >50% increase in peripheral blasts in the absence of differentiation syndrome; or New extramedullary disease.

Supportive Care During Therapy

Because 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 and for the treatment of related infectious complications.

Transfusion therapy

Supportive care during remission induction treatment should routinely include red blood cell and platelet transfusions when appropriate. Rapid marrow ablation with consequent earlier marrow regeneration decreases morbidity and mortality. 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.

No good evidence exists to support granulocyte transfusions in the treatment of AML. A multicenter randomized trial (RING [NCT00627393]) to address the utility of granulocyte transfusions in the setting of infections was conducted. There was no difference between the granulocyte and control arms for the composite primary endpoint of survival plus microbial response at 42 days after randomization. However, the power to detect a true beneficial effect was low because enrollment was half that of the planned study size.

Growth factors

The following growth factors have been studied in the treatment of AML:

  • Colony–stimulating factors: Granulocyte colony–stimulating factor and granulocyte-macrophage colony–stimulating factor have been studied in an effort to shorten the period of granulocytopenia associated with leukemia treatment. If used, these agents are administered after administration of chemotherapy. Although the use of growth factors decreases the time to neutrophil recovery by 2 to 5 days, and decreases rates of febrile neutropenia and duration of hospitalization, randomized clinical trials have not shown an impact of growth factors on overall survival and their cost-effectiveness has been inconsistently reported. Use of growth factors is not routinely recommended in the remission induction setting.
  • Erythropoiesis-stimulating agents: Anemia associated with the diagnosis of AML and induction chemotherapy is managed primarily with red blood transfusions. Unlike myelodysplastic syndromes, there is no role for the use of erythropoiesis stimulating agents (e.g., epoetin alfa and darbepoetin) during the treatment of AML.
  • Thrombopoietin mimetics: Clinical trials have assessed the use of thrombopoietin mimetics in the treatment of AML. Eltrombopag as a single agent was tested in a multicenter, randomized, placebo-controlled, double-blind, phase I/II trial of 98 patients with platelet counts less than 30x109/L as a result of AML or MDS. No significant improvements in platelet counts were recorded. Significant hemorrhage was reported in ten (16%) patients given eltrombopag and nine (26%) patients given placebo. No difference in disease progression or overall survival was observed.

    Eltrombopag appeared to hasten platelet recovery and reduce the number of platelet transfusions needed when added in an unblinded fashion to induction chemotherapy in older FLT3-negative AML patients. However, in a separate, randomized double-blind study of 148 patients, eltrombopag or placebo was added to high-dose induction chemotherapy. The results of this study did not indicate any clinical benefit of eltrombopag over placebo. Given the minimal efficacy signal at this point, eltrombopag is not routinely recommended in the supportive care or remission induction setting.

Antimicrobial therapy

Empiric broad spectrum antimicrobial therapy is an absolute necessity for febrile patients who are profoundly neutropenic. Careful instruction in personal hand 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 indicated. Likewise, there are no advantages to eating a cooked neutropenic diet, as demonstrated in randomized trials.

Antibiotic prophylaxis with a fluoroquinolone and antifungal prophylaxis with an oral triazole or parenteral echinocandin is appropriate for patients with expected prolonged, profound neutropenia (<100/mm3 for 2 weeks for profound neutropenia lasting >7 days). Unlike patients undergoing treatment for acute lymphoblastic lymphoma, Pneumocystis jirovecii prophylaxis is not routinely employed.

Nucleoside analog-based antiviral prophylaxis, such as acyclovir, is appropriate for patients who are seropositive for herpes simplex virus undergoing induction chemotherapy.

References

  1. Kebriaei 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.
  2. Morrison FS, Kopecky KJ, Head DR, et al.: Late intensification with POMP chemotherapy prolongs survival in acute myelogenous leukemia--results of a Southwest Oncology Group study of rubidazone versus adriamycin for remission induction, prophylactic intrathecal therapy, late intensification, and levamisole maintenance. Leukemia 6 (7): 708-14, 1992.
  3. Döhner H, Estey EH, Amadori S, et al.: Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 115 (3): 453-74, 2010.
  4. Cassileth PA, Lynch E, Hines JD, et al.: Varying intensity of postremission therapy in acute myeloid leukemia. Blood 79 (8): 1924-30, 1992.
  5. Supportive Care. In: Wiernik PH, Canellos GP, Dutcher JP, et al., eds.: Neoplastic Diseases of the Blood. 3rd ed. New York, NY: Churchill Livingstone, 1996, pp 779-967.
  6. Slichter SJ: Controversies in platelet transfusion therapy. Annu Rev Med 31: 509-40, 1980.
  7. Murphy MF, Metcalfe P, Thomas H, et al.: Use of leucocyte-poor blood components and HLA-matched-platelet donors to prevent HLA alloimmunization. Br J Haematol 62 (3): 529-34, 1986.
  8. Rebulla P, Finazzi G, Marangoni F, et al.: The threshold for prophylactic platelet transfusions in adults with acute myeloid leukemia. Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto. N Engl J Med 337 (26): 1870-5, 1997.
  9. Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. The Trial to Reduce Alloimmunization to Platelets Study Group. N Engl J Med 337 (26): 1861-9, 1997.
  10. Price TH, Boeckh M, Harrison RW, et al.: Efficacy of transfusion with granulocytes from G-CSF/dexamethasone-treated donors in neutropenic patients with infection. Blood 126 (18): 2153-61, 2015.
  11. Geller RB: Use of cytokines in the treatment of acute myelocytic leukemia: a critical review. J Clin Oncol 14 (4): 1371-82, 1996.
  12. Rowe JM, Andersen JW, Mazza JJ, et al.: A randomized placebo-controlled phase III study of granulocyte-macrophage colony-stimulating factor in adult patients (> 55 to 70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490). Blood 86 (2): 457-62, 1995.
  13. Stone RM, Berg DT, George SL, et al.: Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. Cancer and Leukemia Group B. N Engl J Med 332 (25): 1671-7, 1995.
  14. Platzbecker U, Wong RS, Verma A, et al.: Safety and tolerability of eltrombopag versus placebo for treatment of thrombocytopenia in patients with advanced myelodysplastic syndromes or acute myeloid leukaemia: a multicentre, randomised, placebo-controlled, double-blind, phase 1/2 trial. Lancet Haematol 2 (10): e417-26, 2015.
  15. Mukherjee S, Li H, Hobbs BP: A single arm, phase II study of eltrombopag to enhance platelet count recovery in older patients with acute myeloid leukemia (AML) undergoing remission induction therapy. [Abstract] Blood 134 (Suppl 1): 2595, 2019.
  16. Frey N, Jang JH, Szer J, et al.: Eltrombopag treatment during induction chemotherapy for acute myeloid leukaemia: a randomised, double-blind, phase 2 study. Lancet Haematol 6 (3): e122-e131, 2019.
  17. Hughes WT, Armstrong D, Bodey GP, et al.: From the Infectious Diseases Society of America. Guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. J Infect Dis 161 (3): 381-96, 1990.
  18. Rubin M, Hathorn JW, Pizzo PA: Controversies in the management of febrile neutropenic cancer patients. Cancer Invest 6 (2): 167-84, 1988.
  19. Armstrong D: Symposium on infectious complications of neoplastic disease (Part II). Protected environments are discomforting and expensive and do not offer meaningful protection. Am J Med 76 (4): 685-9, 1984.
  20. Sherertz RJ, Belani A, Kramer BS, et al.: Impact of air filtration on nosocomial Aspergillus infections. Unique risk of bone marrow transplant recipients. Am J Med 83 (4): 709-18, 1987.
  21. Gardner A, Mattiuzzi G, Faderl S, et al.: Randomized comparison of cooked and noncooked diets in patients undergoing remission induction therapy for acute myeloid leukemia. J Clin Oncol 26 (35): 5684-8, 2008.
  22. Taplitz RA, Kennedy EB, Bow EJ, et al.: Antimicrobial Prophylaxis for Adult Patients With Cancer-Related Immunosuppression: ASCO and IDSA Clinical Practice Guideline Update. J Clin Oncol 36 (30): 3043-3054, 2018.
untreated adult acute myeloid leukemia

Treatment of Newly Diagnosed Adult AML

Standard Treatment Options for Newly Diagnosed (Untreated; Remission Induction) AML

Standard treatment options for newly diagnosed (untreated; remission induction) acute myeloid leukemia (AML) include the following:

  1. Chemotherapy.

Chemotherapy

Chemotherapy for adult AML is divided into the following two general categories:

  1. Intensive remission-induction chemotherapy.
  2. Nonintensive chemotherapy.

One of the following combination chemotherapy regimens may be used as intensive remission induction therapy:

  • Cytarabine plus daunorubicin.
  • Cytarabine plus idarubicin.
  • Cytarabine plus mitoxantrone.
  • Cytarabine plus anthracycline plus midostaurin.
  • Cytarabine plus anthracycline plus gemtuzumab ozogamicin.
  • Liposomal daunorubicin-cytarabine (CPX-351).
  • Intrathecal cytarabine or methotrexate may be used to treat central nervous system (CNS) leukemia, if present.

The two-drug regimen of cytarabine given as a continuous infusion for seven days and a three-day course of anthracycline (the so-called 7+3 induction therapy) results in a complete response rate of approximately 65%. In most instances, there is no further clinical benefit when adding potentially non-cross−resistant drugs (such as fludarabine, topoisomerase inhibitors, thioguanine, mitoxantrone, histone deacetylases inhibitors, or clofarabine) to a 7+3 regimen. Cladribine, when added to 7+3 induction chemotherapy, showed improved remission rates and survival rates across two randomized controlled trials, but this regimen has not been widely adopted in the absence of confirmatory trials. The addition of midostaurin and gemtuzumab ozogamicin to intensive induction chemotherapy is discussed below.

The choice of anthracycline and the dose-intensity of anthracycline may influence the survival of patients with AML. Idarubicin appeared to be more effective than daunorubicin, particularly in younger adults, although the doses of idarubicin and daunorubicin may not have been equivalent. No significant survival difference between daunorubicin and mitoxantrone has been reported.

Selection of an anthracycline/dose

At present, there is no conclusive evidence to recommend one anthracycline over another.

Evidence (anthracycline):

  1. In a systematic review and meta-analysis, 18 randomized controlled trials that included 6,755 patients assessed the use of idarubicin versus daunorubicin as part of induction chemotherapy.
    • The use of idarubicin lead to improved outcomes, including overall survival (OS) when compared with daunorubicin (12 studies, 5,976 patients; hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.84−0.96; P = .0008). However, there was an increased risk of death during induction (14 studies, 6,349 patients; relative risk [RR], 1.18; 95% CI, 1.01−1.36; P = .03) and mucositis (five studies, 2,000 patients; RR, 1.22; 95% CI, 1.04−1.44; P = .02) with idarubicin as compared with daunorubicin. Moreover, the survival benefit for idarubicin was no longer present if a daunorubicin dose of at least 180 mg/m2 was used (four studies, 2,867 patients; HR, 0.91; 95% CI, 0.82−1.00; P = .06).
    • In patients aged 60 years and younger, outcomes for those who received daunorubicin (90 mg/m2/dose, total induction dosing at 270 mg/m2) were superior to those who received more traditional dosing (45 mg/m2/dose; total dose = 135 mg/m2). The complete remission (CR) rate was 71% versus 57% (P< .001), and the median survival was 24 months versus 16 months (P = .003).
    • No randomized comparison data between daunorubicin at 270 mg/m2 and daunorubicin at 180 mg/m2, nor between daunorubicin at 270 mg/m2 and idarubicin, are available.

Addition of midostaurin

Both mutations in the kinase domain and internal transmembrane duplications of the FLT3 gene are frequent in AML and are often associated with an inferior outcome.

Evidence (midostaurin):

  1. In a multicenter, randomized phase III trial (NCT00651261), the addition of the FLT3/multikinase inhibitor midostaurin, versus placebo, to cytarabine and daunorubicin induction chemotherapy in patients with FLT3-mutated AML led to improved survival (median, 75 vs. 26 months; HR for death, 0.78; one-sided P = .009).
    • OS and event-free survival were better for patients on the midostaurin arm (HR for event or death, 0.78; one-sided P = .002) and the survival benefit was consistent across all FLT3 mutation subtypes. The rates of CR (59% vs. 54%) and time to neutrophil count recovery were similar between the two arms.[Level of evidence: 1iA]

Addition of gemtuzumab ozogamicin

Evidence (gemtuzumab ozogamicin):

  1. In a meta-analysis of more than 3,000 patients, the addition of the CD33-directed immunotoxin gemtuzumab ozogamicin to cytarabine plus anthracycline or clofarabine plus anthracycline led to a small increase in the OS rate at 5 years (30.7% vs. 34.6%; HR, 0.90; 95% CI, 0.82−0.98; P = .01).
    • The improvement in the 5-year OS rate was seen across all ages, but this effect was greatest in patients with favorable-risk cytogenetics (55.2% vs. 76.3%; HR, 0.47 [range, 0.31−0.73]; P = .0005), and to a lesser extent with intermediate-risk cytogenetics (34.1% vs. 39.4%; HR, 0.84 [range, 0.75−0.95]; P = .007). It was not seen in patients with an adverse-risk karyotype.[Level of evidence: 1iiA]
    • In contrast, gemtuzumab ozogamicin did not improve the 1-year survival rate of elderly patients who received low-dose cytarabine, although the CR rate increased from 17% to 30% (odds ratio [OR], 0.48 (0.32–0.73); P = .006).

    The U.S. Food and Drug Administration (FDA) label for gemtuzumab ozogamicin includes a boxed warning about the risk of hepatotoxicity, including severe or fatal hepatic sinusoidal obstruction syndrome.

Liposomal daunorubicin-cytarabine (CPX-351)

CPX-351 is a two-drug liposomal encapsulation that delivers cytarabine and daunorubicin at a fixed 5:1 synergistic molar ratio.

Evidence (CPX-351):

  1. A multicenter trial investigated CPX-351 in patients aged 60 to 75 years with therapy-related AML, AML with a history of myelodysplastic syndrome (MDS), or AML with myelodysplasia-related changes.
    • Compared with 7+3 induction chemotherapy, CPX-351 resulted in a better overall remission rate (47.7% vs. 33.3%; P = .016), and improved median OS (9.56 vs. 5.95 months; HR, 0.69; 95% CI, 0.52−0.90; P = .003).[Level of evidence: 1iiA]
    • The rates of early mortality and toxicities were similar between the two arms. However, the median time to recovery of neutrophils and platelets was longer for CPX-351 (35.0 and 36.5 days, respectively) as compared with 7+3 induction chemotherapy (29 and 29 days, respectively).

Older adults or adults with significant comorbid conditions

Some patients may decline or be too frail for intensive induction chemotherapy. Low-dose cytarabine, decitabine, azacitidine, or best supportive care can be considered equivalently effective treatment approaches for older patients with AML who decline traditional 7+3 induction chemotherapy. Unlike a succinct course of 7+3 induction, these less-intensive therapies are continued indefinitely, as long as the patient is deriving benefit (i.e., until disease progression or significant toxicity occurs).

One of the following chemotherapy regimens may be used as less-intensive therapy:

  • Hypomethylating agents (azacitidine and decitabine).
  • Low-dose cytarabine.
  • Venetoclax plus azacitidine/decitabine or low-dose cytarabine.
  • Glasdegib plus low-dose cytarabine.
  • Ivosidenib.
  • Enasidenib.
  • Intrathecal cytarabine or methotrexate may be used to treat CNS leukemia, if present.

Evidence (chemotherapy for adults who decline intensive remission induction therapy):

  1. Hypomethylating agents: The hypomethylating agents azacitidine and decitabine are used commonly in this population of older adults, particularly in the United States. Although approval of the drugs by the U.S. FDA is for a myelodysplastic syndrome indication, the registration studies leading to approval included patients with 20% to 30% myeloblasts, or what would now be considered oligoblastic AML.
    1. Azacitidine: An international phase III trial (NCT01074047) randomly assigned patients with AML who were 65 years or older to receive either azacitidine or conventional regimens (7+3 induction, low-dose cytarabine, or best supportive care alone).
      • Azacitidine led to a median OS of 10.4 months (95% CI, 8.0−12.7 months) as compared with 6.5 months (95% CI, 5.0−8.6 months) with conventional regimens (HR, 0.85; 95% CI, 0.69−1.03; P = .1009).[Level of evidence: 1iiA]
    2. Decitabine: One phase III trial randomly assigned 485 patients with AML who were older than 65 years to receive either decitabine (n = 242) or their preferred choice (n = 243) of either supportive care (n = 28) or low-dose cytarabine (n = 215).
      • Although rates of CR + CRp (CR with incomplete platelet recovery) were more than double in the decitabine arm (17.8%) compared with the treatment-choice arm (7.8%) (P = .001), median OS was not significantly improved for patients receiving decitabine (7.7 months) compared with the treatment of choice (5.0 months) (HR for death for decitabine, 0.85; 95% CI, .69–1.04; P = .11).

      Compared with treatment for five consecutive days, treatment for ten consecutive days may lead to higher response rates, particularly in those with TP53 mutations and/or unfavorable cytogenetic features.[Level of evidence: 3iiiDiv]

  2. Low-dose cytarabine: 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 CR rate using this regimen was 18% compared with 1% for patients treated with hydroxyurea (P = .006).
    • Survival with low-dose cytarabine was better than was survival with hydroxyurea (OR, 0.60; 95% CI, 0.44–0.81; P = .009).[Level of evidence: 1iiA]
  3. Venetoclax plus azacitidine/decitabine or low-dose cytarabine: Venetoclax, an inhibitor of the anti-apoptotic protein BCL2 is approved by the U.S. FDA in combination with low-dose cytarabine or a hypomethylating agent for the treatment of AML in patients aged 75 years or older, and those who cannot undergo 7+3 induction chemotherapy because of comorbidities. Approval was granted on the basis of the results of two studies.
    1. The first study (NCT02203773) was a nonrandomized open-label clinical trial (phase Ib) of venetoclax in combination with azacitidine or decitabine.
      • In this study, 35 (61%; 95% CI, 47.6%−74.0%) of 57 patients had CR or CR with incomplete marrow recovery (CRi). The median duration of response for all patients with a response (CR + CRi + partial remission [PR]) was 8.4 months (4.7−11.7; n = 36).
    2. The second study (NCT02287233) was a phase I/IIb study of venetoclax in combination with low-dose cytarabine in 82 patients with newly diagnosed AML, including patients with previous exposure to a hypomethylating agent for an antecedent hematologic disorder such as MDS.
      • In the 82 patients enrolled in the study, the CR/CRi rate was 54% (95% CI, 42%−65%), with a median duration of remission of 8.1 months (95% CI, 5.3−14.9 months). The median OS for all patients, irrespective of response, was 10.1 months (95% CI, 5.7−14.2 months).
      • The most common adverse events with venetoclax combinations are gastrointestinal symptoms and myelosuppression, which may require delays between cycles, growth factor support, or decreased duration of venetoclax administration per cycle. Additionally, appropriate prophylactic measures are typically taken to prevent tumor lysis syndrome.[Level of evidence: 3iiDiv]
  4. Glasdegib plus low-dose cytarabine: Glasdegib, an oral inhibitor of the hedgehog pathway, combined with low-dose cytarabine was compared with low-dose cytarabine alone in a randomized, phase II open-label study that included 116 patients with AML who were aged 75 years or older or who had severe comorbid conditions (cardiac disease, renal impairment, or Eastern Cooperative Oncology Group [ECOG] performance status 2).
    • Of the 78 patients with AML who received glasdegib plus low-dose cytarabine, 24% (n = 19) of patients had a CR or CRi compared with 5% (2 of 38) of patients who received low-dose cytarabine alone. The median OS was 8.3 months (80%; CI, 6.6–9.5) for patients who received glasdegib/low-dose cytarabine and 4.3 months (80%; CI, 2.9–4.9) for patients who received low-dose cytarabine alone in patients with AML (HR, 0.46; 80% CI, 0.35–0.62; P = .0002).[Level of evidence:1iiA]

    Similar to venetoclax, glasdegib was approved by the U.S. FDA in combination with low-dose cytarabine for the treatment of AML in patents aged 75 years or older or who are unable to receive intensive induction chemotherapy.

  5. Ivosidenib: For patients with an AML that harbors a mutation in IDH1, the IDH1 inhibitor ivosidenib is an option for older or frail patients. The U.S. FDA has approved ivosidenib for the treatment of AML that has a susceptible IDH1 mutation (detected by an FDA-approved diagnostic test) in adults aged 75 years or older with newly diagnosed AML or who have comorbidities that preclude use of intensive induction chemotherapy. Within the context of a phase I study, 34 patients with newly diagnosed IDH1-mutated AML who were not candidates for intensive induction chemotherapy were treated with single-agent ivosidenib.
    • Differentiation syndrome was reported in 6 patients (18%), but did not require treatment discontinuation.
    • The rate of CR plus CRi was 42.4% (95% CI, 25.5%−60.8%), with a median duration of response that was not reached (lower bound of the 95% CI was 4.6 months).
    • For all 34 patients on the study, the median overall survival was 12.6 months (95% CI, 4.5−25.7).[Level of evidence: 3iiDiv]
  6. Enasidenib: For patients with an AML that harbors a mutation in IDH2, the IDH2 inhibitor enasidenib is an option for older or frail patients. Although it does not have approval in this setting, enasidenib monotherapy was evaluated in a phase I/II trial in patients with newly diagnosed AML who were not fit for standard chemotherapy.
    • Of the 39 patients enrolled, seven (18%) had CR, one (3%) had CRi, and two (5%) had a partial remission.
    • Median OS for all patients was 11.3 months (95% CI, 5.7−15.1), and was not reached for patients who had a response.[Level of evidence: 3iiDiv]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

  1. Yates 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.
  2. Dillman 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.
  3. Wiernik PH, Banks PL, Case DC, 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.
  4. Vogler WR, Velez-Garcia E, Weiner RS, et al.: A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group Study. J Clin Oncol 10 (7): 1103-11, 1992.
  5. Berman E, Heller G, Santorsa J, et al.: Results of a randomized trial comparing idarubicin and cytosine arabinoside with daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia. Blood 77 (8): 1666-74, 1991.
  6. Mandelli F, Petti MC, Ardia A, et al.: A randomised clinical trial comparing idarubicin and cytarabine to daunorubicin and cytarabine in the treatment of acute non-lymphoid leukaemia. A multicentric study from the Italian Co-operative Group GIMEMA. Eur J Cancer 27 (6): 750-5, 1991.
  7. Löwenberg 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.
  8. Stone RM, Mandrekar SJ, Sanford BL, et al.: Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med 377 (5): 454-464, 2017.
  9. Hills RK, Castaigne S, Appelbaum FR, et al.: Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol 15 (9): 986-96, 2014.
  10. Lancet JE, Uy GL, Cortes JE, et al.: CPX-351 (cytarabine and daunorubicin) Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia. J Clin Oncol 36 (26): 2684-2692, 2018.
  11. Holowiecki J, Grosicki S, Robak T, et al.: Addition of cladribine to daunorubicin and cytarabine increases complete remission rate after a single course of induction treatment in acute myeloid leukemia. Multicenter, phase III study. Leukemia 18 (5): 989-97, 2004.
  12. Holowiecki J, Grosicki S, Giebel S, et al.: Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study. J Clin Oncol 30 (20): 2441-8, 2012.
  13. Arlin Z, Case DC, 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.
  14. Li X, Xu S, Tan Y, et al.: The effects of idarubicin versus other anthracyclines for induction therapy of patients with newly diagnosed leukaemia. Cochrane Database Syst Rev (6): CD010432, 2015.
  15. Fernandez HF, Sun Z, Yao X, et al.: Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med 361 (13): 1249-59, 2009.
  16. Burnett AK, Hills RK, Hunter AE, et al.: The addition of gemtuzumab ozogamicin to low-dose Ara-C improves remission rate but does not significantly prolong survival in older patients with acute myeloid leukaemia: results from the LRF AML14 and NCRI AML16 pick-a-winner comparison. Leukemia 27 (1): 75-81, 2013.
  17. Silverman LR, Demakos EP, Peterson BL, et al.: Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 20 (10): 2429-40, 2002.
  18. Kantarjian H, O'brien S, Cortes J, et al.: Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer 106 (5): 1090-8, 2006.
  19. Dombret H, Seymour JF, Butrym A, et al.: International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 126 (3): 291-9, 2015.
  20. Kantarjian HM, Thomas XG, Dmoszynska A, et al.: Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol 30 (21): 2670-7, 2012.
  21. Welch JS, Petti AA, Miller CA, et al.: TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. N Engl J Med 375 (21): 2023-2036, 2016.
  22. Burnett 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.
  23. DiNardo CD, Pratz KW, Letai A, et al.: Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol 19 (2): 216-228, 2018.
  24. Wei AH, Strickland SA, Hou JZ, et al.: Venetoclax Combined With Low-Dose Cytarabine for Previously Untreated Patients With Acute Myeloid Leukemia: Results From a Phase Ib/II Study. J Clin Oncol 37 (15): 1277-1284, 2019.
  25. Cortes JE, Heidel FH, Hellmann A, et al.: Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia 33 (2): 379-389, 2019.
  26. Roboz GJ, DiNardo CD, Stein EM, et al.: Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood 135 (7): 463-471, 2020.
  27. Pollyea DA, Tallman MS, de Botton S, et al.: Enasidenib, an inhibitor of mutant IDH2 proteins, induces durable remissions in older patients with newly diagnosed acute myeloid leukemia. Leukemia 33 (11): 2575-2584, 2019.
adult acute myeloid leukemia in remission

Adult AML 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 (CR) 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 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 DFS 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 standard postremission therapy for AML patients in remission is high-dose cytarabine; however, there exists some controversy about whether it benefits all younger AML patients in first complete response versus selected subgroups, such as those with core-binding factor abnormalities. 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 (CR) 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 CR 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 with autologous transplant (6 trials) or with 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 a first CR. 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 a first CR.

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 a first CR 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 first CR in the setting of poor-risk cytogenetics and should not be offered to patients in first CR 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 CR with postremission chemotherapy, with the latter group eligible for autologous BMT in second CR. 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 CR 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 in those using postremission chemotherapy. Good-risk factors include t(8;21), inv(16) associated with M4 AML with eosinophilia, normal karyotype with NPM1 mutation (in absence of FLT-3 mutation), and normal karyotype with double cytosine-cytosine-adenosine-adenosine-thymidine (CCAAT)-enhancer binding protein (C/EBP)-alpha mutations. Poor-risk factors include deletion of 5q and 7q, trisomy 8, t(6;9), t(9;22), most translocations involving chromosome 11q23, and mutations of the MLL gene, a history of myelodysplasia or antecedent hematologic disorder, and normal karyotype with FLT-3 mutation. 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 first CR 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% CI, 0.24–1.00); however, OS was not significantly increased (HR for death within 2 years, 0.62; 95% CI, 0.38–1.02).

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

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recurrent adult acute myeloid leukemia

Recurrent Adult AML

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 (CR). Other studies using idarubicin and cytarabine or high-dose etoposide and cyclophosphamide reported similar results. Mitoxantrone, etoposide, and cytarabine (MEC) demonstrated a CR 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 (CR), 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 criterion 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 (although platelet transfusion independence for at least 1 week was required). Unclear is whether the inadequate platelet recovery is the result of megakaryocyte toxic effects of gemtuzumab or 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 CR in 8 out of 19 patients in first relapse as a single agent and in seven 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 CR 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 CR 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 CR, offering a DFS that may be comparable to autografting in first CR.

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 CRs have been reported in 85% of patients induced with arsenic trioxide, with a median time to clinical CR of 59 days. Eighty-six percent of evaluable patients tested negative for the presence of PML-RARA 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.

Some patients induced into second remissions with ATO have experienced long-term DFS following autologous stem cell transplantation.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

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  13. Karp 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.
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Changes to This Summary (08/11/2020)

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.

The General Information About Adult Acute Myeloid Leukemia (AML), Classification of Adult AML, Treatment Option Overview for Adult AML, and Treatment of Newly Diagnosed Adult AML sections were comprehensively reviewed, extensively revised, and reformatted.

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:

  • Aaron Gerds, MD
  • 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 NCI website's Email Us. 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:

PDQ® Adult Treatment Editorial Board. PDQ Adult Acute Myeloid Leukemia Treatment. Bethesda, MD: National Cancer Institute. Updated . Available at: https://www.cancer.gov/types/leukemia/hp/adult-aml-treatment-pdq. Accessed . [PMID: 26389432]

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.

Disclaimer

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 Managing Cancer Care page.

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More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

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