Incidence and Mortality

Estimated new cases and deaths from AML in the United States in 2024:[1]

• New cases: 20,800.
• Deaths: 11,220.

Based on Surveillance, Epidemiology, and End Results (SEER) Program data from 2013 to 2019, 31.7% of patients with AML were alive 5 years after diagnosis.[2]

Anatomy

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 result from 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.[3]

Clinical Presentation

The diagnosis of AML is uncommon before age 45 years; the median age at diagnosis is 69 years.[2] 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 anatomical 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.[3]

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 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 evaluating 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)).[4]

Prognosis and Prognostic Factors

Advances in the treatment of AML have resulted in substantially improved complete remission (CR) rates.[2] 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 patients with AML will harbor chromosomal abnormalities; therefore, conventional cytogenetic analysis remains mandatory in the evaluation of suspected AML.[5,6] 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.[7] 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 hematologic 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.[8] 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.[8]

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).[9] 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.[10] In many cases, heart failure can manifest as a late effect.[11] 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.[12]

Patients who undergo allogeneic hematopoietic stem cell transplant can experience a large number of long-term or late side effects of treatment as a result of high-dose chemotherapy and/or radiation, and as an effect of chronic graft-versus-host disease and immunosuppression. These side effects may include chronic fatigue, thyroid and gonadal dysfunction, infertility, chronic infection, accelerated coronary heart disease, osteopenia, cataracts, iron overload, adverse psychological outcomes, and second cancers.[13-15]

In the Bone Marrow Transplant Survivor Study, hematopoietic cell transplant 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, compared with a nonfrail state (95% CI, 1.7−4.4; P < .001).[16]

References

1. American Cancer Society: Cancer Facts and Figures 2024. American Cancer Society, 2024. Available online. Last accessed June 21, 2024.
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 October 5, 2023.
3. Sekeres MA, Gerds AT: Mitigating Fear and Loathing in Managing Acute Myeloid Leukemia. Semin Hematol 52 (3): 249-55, 2015. [PubMed: 26111473]
4. Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th rev. ed. 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. [PubMed: 11110676]
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. [PubMed: 11520776]
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. [PMC free article: PMC5291965] [PubMed: 27895058]
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. [PubMed: 11380414]
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. [PubMed: 1886191]
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. [PubMed: 12767102]
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. [PubMed: 15143078]
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. [PubMed: 29966479]
13. Inamoto Y, Lee SJ: Late effects of blood and marrow transplantation. Haematologica 102 (4): 614-625, 2017. [PMC free article: PMC5395102] [PubMed: 28232372]
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. [PMC free article: PMC3208286] [PubMed: 21821714]
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. [PMC free article: PMC3152502] [PubMed: 21652685]
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. [PMC free article: PMC5078990] [PubMed: 27254472]

World Health Organization (WHO) Classification

The classification of acute myeloid leukemia (AML) has been revised by a group of pathologists and clinicians under the auspices of the WHO.[1] While elements of the French-American-British (FAB) classification have been retained (i.e., morphology, immunophenotype, cytogenetics, and clinical features),[2,3] 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.[1,3,4] 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.[5-7]

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.[5,8] 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).[9]

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.[10] With emerging technologies aimed at genetic, epigenetic, proteomic, and immunophenotypic classification, AML classification will continue to evolve and provide informative prognostic and biological guidelines to clinicians and researchers.

AML With Recurrent Genetic Abnormalities

AML with well-defined genetic abnormalities is characterized by recurrent genetic abnormalities.[10] The reciprocal translocations t(8;21), inv(16) or t(16;16), t(15;17), and translocations involving the 11q23 breakpoint are the most commonly identified 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.[10]

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.[11] Myeloid sarcomas (chloromas) may be present and may be associated with a bone marrow blast percentage of less than 20%.

Common morphological 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%.[5] 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.[12-15]

The translocation t(8;21)(q22;q22) involves the RUNX1 gene, which encodes CBF-alpha, and the RUNX1T1 (8;21) gene.[5,16] 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.[12-15] Additional chromosome abnormalities are common, for example, loss of a sex chromosome and del(9)(q22). Leukocytosis (i.e., white blood count >25 × 10⁹/L) is associated with an inferior outcome,[17] as is the presence of a KIT mutation.[18]

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.[5,19] Myeloid sarcomas may be present at initial diagnosis or at relapse.

Common morphological 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 CBFB::MYH11 fusion gene .[11] 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.[20] 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.[12,13,15] Unlike AML with t(8;21), the prognostic relevance of KIT mutations is unclear.[21]

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.[5] Both typical and microgranular APL are commonly associated with disseminated intravascular coagulation (DIC).[22,23] In microgranular APL, unlike typical APL, the leukocyte count can be very high with a rapid doubling time.[5]

Common morphological 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 morphological 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.[24-26] 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.[5] FISH and/or RT–PCR methods may be required to unmask these cryptic genetic rearrangements.[27,28] In approximately 1% of the patients with APL, variant chromosomal aberrations may be found in which the RARA gene is fused with other genes.[29] Variant translocations involving the RARA gene include t(11;17)(q23;q21), t(5;17)(q32;q12), and t(11;17)(q13;q21).[5]

APL has a specific sensitivity to treatment with all-trans retinoic acid (ATRA, tretinoin), which acts as a differentiating agent.[30-32] High CR rates and long-term disease-free survival in APL may be obtained by combining ATRA treatment with chemotherapy,[33] or in a chemotherapy-free regimen with arsenic trioxide.[34]

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).[5]

Common morphological 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.[35] Genes other than MLLT3 may be involved in 11q23 abnormalities.[36] FISH may be required to detect genetic abnormalities involving MLL.[36-38] 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.[13]

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.[5] 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.[5] AML with myelodysplasia-related features may occur de novo or after MDS or a myelodysplastic/myeloproliferative neoplasm overlap. The diagnostic terminology AML with myelodysplasia-related features evolving from a myelodysplastic syndrome should be used when an MDS precedes AML.[5] 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.[5] For more information, see Myelodysplastic Syndromes Treatment and Myelodysplastic/Myeloproliferative Neoplasms Treatment.

AML with myelodysplasia-related features occurs primarily in older patients.[5] Patients with AML with myelodysplasia-related features frequently present with severe pancytopenia.

Common morphological 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.[65-67]

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.[5] The therapy-related (or secondary) MDS are included because of their close clinicopathological 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.[68] Because the associated cytogenetic abnormality, not the mutagenetic agent, determines prognosis and treatment it should be noted in the diagnosis.[10]

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.[69]

Alkylating agent-related t-MN

The alkylating agent/radiation-related acute leukemias and myelodysplastic syndromes typically occur 5 to 6 years after exposure to the mutagenic agent, with a reported range of approximately 10 to 192 months.[70,71] 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.[70,72,73] Complex chromosomal abnormalities (≥3 distinct abnormalities) are the most common finding.[68,72-74]

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.[70] The mean latency period from the time of institution of the causative therapy to the development of t-MN is approximately 2 years.[75]

As with alkylating agent/radiation-related t-MN, the cytogenetic abnormalities are often complex.[68,72-74] The predominant cytogenetic finding involves chromosome 11q23 and the MLL gene.[68,76]

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.[10] As mentioned before, the subcategories of AML, NOS lack prognostic significance when the mutation status of NPM1 and CEBPA are known.[9] 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:[5]

• 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.[5] Development of myeloid sarcoma has been reported in 2% to 8% of patients with AML.[77] 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.[10,77,78]

Morphological 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.[5] 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.[77,79] 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.[80] 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.[10] 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.[77,78,81,82]

Myeloid Proliferations Related to Down Syndrome

For more information about TAM and myeloid leukemia associated with Down syndrome, see Childhood Myeloid Proliferations Associated With Down Syndrome Treatment.

Acute Leukemias of Ambiguous Lineage

Acute leukemias of ambiguous lineage are rare types of acute leukemia in which the morphological, cytochemical, and immunophenotypic features of the blast population do not allow classification in myeloid or lymphoid categories; or the types have morphological 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).[10,83,84]

They include the following subcategories:[5]

• 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:[5]

Cytogenetic abnormalities are observed in a high percentage of acute leukemias of ambiguous lineage.[85-88] 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;[86,89,90] however, preliminary results indicate that tyrosine kinase inhibitors can be used successfully.[91,92]

References

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8. Arber DA, Vardiman JW, Brunning RD: Acute myeloid leukaemia with recurrent genetic abnormalities. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. International Agency for Research on Cancer, 2008, pp 110-23.
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48. Nacheva EP, Grace CD, Brazma D, et al.: Does BCR/ABL1 positive acute myeloid leukaemia exist? Br J Haematol 161 (4): 541-50, 2013. [PubMed: 23521501]
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Phases of Therapy

The treatment of patients with 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 are 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 fewer of patients with AML develop CNS disease, prophylactic treatment is not indicated.[1,2]

• Newly diagnosed (untreated): Untreated 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.[3]
  Modifications to the definition of CR have been proposed because some responses are deeper than a CR, and others may not meet all the criteria for a complete response. In addition, most AML patients meeting the criteria for CR have residual leukemia.[3]

• In remission: When patients are in a remission after 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.[4]
• 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.[3] 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.

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.[5]

References

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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. [PubMed: 30704923]
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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. [PMC free article: PMC4879706] [PubMed: 18955453]
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. [PubMed: 30179565]

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

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

1. Chemotherapy.

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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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. [PubMed: 9508168]
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. [PMC free article: PMC5754190] [PubMed: 28644114]
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. [PMC free article: PMC4137593] [PubMed: 25008258]
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. [PMC free article: PMC6127025] [PubMed: 30024784]
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. [PubMed: 14999298]
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. [PubMed: 22508825]
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. [PubMed: 2179638]
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. [PubMed: 26037486]
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. [PMC free article: PMC4480917] [PubMed: 19776406]
16. Erba HP, Montesinos P, Kim HJ, et al.: Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 401 (10388): 1571-1583, 2023. [PubMed: 37116523]
17. 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. [PubMed: 22964882]
18. 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. [PubMed: 12011120]
19. 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. [PubMed: 16435386]
20. 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. [PMC free article: PMC4504945] [PubMed: 25987659]
21. 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. [PMC free article: PMC4874148] [PubMed: 22689805]
22. 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. [PMC free article: PMC5217532] [PubMed: 27959731]
23. 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. [PubMed: 17315155]
24. 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. [PubMed: 29339097]
25. 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. [PMC free article: PMC6524989] [PubMed: 30892988]
26. 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. [PMC free article: PMC6365492] [PubMed: 30555165]
27. 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. [PMC free article: PMC7019193] [PubMed: 31841594]
28. Montesinos P, Recher C, Vives S, et al.: Ivosidenib and Azacitidine in IDH1-Mutated Acute Myeloid Leukemia. N Engl J Med 386 (16): 1519-1531, 2022. [PubMed: 35443108]
29. 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. [PMC free article: PMC9724489] [PubMed: 30967620]

Chemotherapy

Nontransplant postremission therapy using cytarabine-containing regimens has treatment-related death rates that are usually less than 10% to 20% and has reported long-term DFS rates from 20% to 50%.[3-6] The optimal doses, schedules, and duration of postremission chemotherapy have not been determined.

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.[7-11] The duration of postremission therapy has ranged from one cycle [4,6] to four or more cycles.[3,5]

Evidence (chemotherapy):

1. 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.[3]
2. Intensification of cytarabine dose or duration of postremission chemotherapy with conventionally dosed cytarabine did not improve DFS or overall survival (OS) in patients aged 60 years or older, as evidenced in the Medical Research Council (MRC-LEUK-AML11) trial.[12,13]

Dose-intensive cytarabine-based chemotherapy can be complicated by severe neurological [14] and/or pulmonary toxic effects [15] and should be administered by physicians experienced in these regimens at centers that are equipped to treat 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.

Maintenance Therapy

While a number of older studies have included longer-term therapy at lower doses (maintenance), there has been no convincing evidence that maintenance therapy provides prolonged DFS or OS. However, maintenance therapy with midostaurin or oral azacitidine may improve outcomes.

Hematopoietic Cell (Bone Marrow or Stem Cell) Transplant

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. Vaughan WP, Karp JE, Burke PJ: Long chemotherapy-free remissions after single-cycle timed-sequential chemotherapy for acute myelocytic leukemia. Cancer 45 (5): 859-65, 1980. [PubMed: 6942904]
2. Cassileth PA, Harrington DP, Hines JD, et al.: Maintenance chemotherapy prolongs remission duration in adult acute nonlymphocytic leukemia. J Clin Oncol 6 (4): 583-7, 1988. [PubMed: 3282032]
3. Mayer RJ, Davis RB, Schiffer CA, et al.: Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med 331 (14): 896-903, 1994. [PubMed: 8078551]
4. Champlin R, Gajewski J, Nimer S, et al.: Postremission chemotherapy for adults with acute myelogenous leukemia: improved survival with high-dose cytarabine and daunorubicin consolidation treatment. J Clin Oncol 8 (7): 1199-206, 1990. [PubMed: 1694236]
5. Rohatiner AZ, Gregory WM, Bassan R, et al.: Short-term therapy for acute myelogenous leukemia. J Clin Oncol 6 (2): 218-26, 1988. [PubMed: 3422261]
6. Geller RB, Burke PJ, Karp JE, et al.: A two-step timed sequential treatment for acute myelocytic leukemia. Blood 74 (5): 1499-506, 1989. [PubMed: 2676014]
7. Löwenberg B: Sense and nonsense of high-dose cytarabine for acute myeloid leukemia. Blood 121 (1): 26-8, 2013. [PubMed: 23287624]
8. Weick JK, Kopecky KJ, Appelbaum FR, et al.: A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood 88 (8): 2841-51, 1996. [PubMed: 8874180]
9. Löwenberg B, Pabst T, Vellenga E, et al.: Cytarabine dose for acute myeloid leukemia. N Engl J Med 364 (11): 1027-36, 2011. [PubMed: 21410371]
10. Schaich M, Röllig C, Soucek S, et al.: Cytarabine dose of 36 g/m² compared with 12 g/m² within first consolidation in acute myeloid leukemia: results of patients enrolled onto the prospective randomized AML96 study. J Clin Oncol 29 (19): 2696-702, 2011. [PubMed: 21606413]
11. Miyawaki S, Ohtake S, Fujisawa S, et al.: A randomized comparison of 4 courses of standard-dose multiagent chemotherapy versus 3 courses of high-dose cytarabine alone in postremission therapy for acute myeloid leukemia in adults: the JALSG AML201 Study. Blood 117 (8): 2366-72, 2011. [PubMed: 21190996]
12. Stone RM, Berg DT, George SL, et al.: Postremission therapy in older patients with de novo acute myeloid leukemia: a randomized trial comparing mitoxantrone and intermediate-dose cytarabine with standard-dose cytarabine. Blood 98 (3): 548-53, 2001. [PubMed: 11468148]
13. Goldstone AH, Burnett AK, Wheatley K, et al.: Attempts to improve treatment outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom Medical Research Council AML11 trial. Blood 98 (5): 1302-11, 2001. [PubMed: 11520775]
14. Baker WJ, Royer GL, Weiss RB: Cytarabine and neurologic toxicity. J Clin Oncol 9 (4): 679-93, 1991. [PubMed: 1648599]
15. Haupt HM, Hutchins GM, Moore GW: Ara-C lung: noncardiogenic pulmonary edema complicating cytosine arabinoside therapy of leukemia. Am J Med 70 (2): 256-61, 1981. [PubMed: 7468613]
16. 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. [PMC free article: PMC5754190] [PubMed: 28644114]
17. Larson RA, Mandrekar SJ, Sanford BL: An Analysis of Maintenance Therapy and Post-Midostaurin Outcomes in the International Prospective Randomized, Placebo-Controlled, Double-Blind Trial (CALGB 10603/RATIFY [Alliance]) for Newly Diagnosed Acute Myeloid Leukemia (AML) Patients with FLT3 Mutations. [Abstract] Blood 130 (Suppl 1):145, 2017.
18. Schlenk RF, Weber D, Fiedler W, et al.: Midostaurin added to chemotherapy and continued single-agent maintenance therapy in acute myeloid leukemia with FLT3-ITD. Blood 133 (8): 840-851, 2019. [PubMed: 30563875]
19. Maziarz RT, Levis M, Patnaik MM, et al.: Midostaurin after allogeneic stem cell transplant in patients with FLT3-internal tandem duplication-positive acute myeloid leukemia. Bone Marrow Transplant 56 (5): 1180-1189, 2021. [PMC free article: PMC8113057] [PubMed: 33288862]
20. Wei AH, Döhner H, Pocock C, et al.: Oral Azacitidine Maintenance Therapy for Acute Myeloid Leukemia in First Remission. N Engl J Med 383 (26): 2526-2537, 2020. [PubMed: 33369355]
21. Clift RA, Buckner CD, Thomas ED, et al.: The treatment of acute non-lymphoblastic leukemia by allogeneic marrow transplantation. Bone Marrow Transplant 2 (3): 243-58, 1987. [PubMed: 3332174]
22. Reiffers J, Gaspard MH, Maraninchi D, et al.: Comparison of allogeneic or autologous bone marrow transplantation and chemotherapy in patients with acute myeloid leukaemia in first remission: a prospective controlled trial. Br J Haematol 72 (1): 57-63, 1989. [PubMed: 2660902]
23. Bostrom B, Brunning RD, McGlave P, et al.: Bone marrow transplantation for acute nonlymphocytic leukemia in first remission: analysis of prognostic factors. Blood 65 (5): 1191-6, 1985. [PubMed: 3888309]
24. D'Souza A, Fretham C, Lee SJ, et al.: Current Use of and Trends in Hematopoietic Cell Transplantation in the United States. Biol Blood Marrow Transplant 26 (8): e177-e182, 2020. [PMC free article: PMC7404814] [PubMed: 32438042]
25. Schiller GJ, Nimer SD, Territo MC, et al.: Bone marrow transplantation versus high-dose cytarabine-based consolidation chemotherapy for acute myelogenous leukemia in first remission. J Clin Oncol 10 (1): 41-6, 1992. [PubMed: 1727924]
26. 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. [PMC free article: PMC5291965] [PubMed: 27895058]
27. Witherspoon RP, Deeg HJ, Storer B, et al.: Hematopoietic stem-cell transplantation for treatment-related leukemia or myelodysplasia. J Clin Oncol 19 (8): 2134-41, 2001. [PubMed: 11304765]
28. Koreth J, Schlenk R, Kopecky KJ, et al.: Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA 301 (22): 2349-61, 2009. [PMC free article: PMC3163846] [PubMed: 19509382]
29. Tallman MS, Wang ES, Altman JK, et al.: Acute Myeloid Leukemia, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 17 (6): 721-749, 2019. [PubMed: 31200351]
30. Gerds AT, Appelbaum FR: To transplant or not to transplant for adult acute myeloid leukemia: an ever-evolving decision. Clin Adv Hematol Oncol 10 (10): 655-62, 2012. [PMC free article: PMC3895910] [PubMed: 23187771]
31. Gooley TA, Chien JW, Pergam SA, et al.: Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 363 (22): 2091-101, 2010. [PMC free article: PMC3017343] [PubMed: 21105791]
32. Ciurea SO, Zhang MJ, Bacigalupo AA, et al.: Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia. Blood 126 (8): 1033-40, 2015. [PMC free article: PMC4543223] [PubMed: 26130705]
33. Ballen KK, Lazarus H: Cord blood transplant for acute myeloid leukaemia. Br J Haematol 173 (1): 25-36, 2016. [PubMed: 26766286]
34. Chao NJ, Stein AS, Long GD, et al.: Busulfan/etoposide--initial experience with a new preparatory regimen for autologous bone marrow transplantation in patients with acute nonlymphoblastic leukemia. Blood 81 (2): 319-23, 1993. [PubMed: 8422458]
35. Linker CA, Ries CA, Damon LE, et al.: Autologous bone marrow transplantation for acute myeloid leukemia using busulfan plus etoposide as a preparative regimen. Blood 81 (2): 311-8, 1993. [PubMed: 8422457]
36. Sanz MA, de la Rubia J, Sanz GF, et al.: Busulfan plus cyclophosphamide followed by autologous blood stem-cell transplantation for patients with acute myeloblastic leukemia in first complete remission: a report from a single institution. J Clin Oncol 11 (9): 1661-7, 1993. [PubMed: 8102640]
37. Cassileth PA, Andersen J, Lazarus HM, et al.: Autologous bone marrow transplant in acute myeloid leukemia in first remission. J Clin Oncol 11 (2): 314-9, 1993. [PubMed: 8426209]
38. Jones RJ, Santos GW: Autologous bone marrow transplantation with 4-hydroperoxycyclophosphamide purging. In: Gale RP, ed.: Acute Myelogenous Leukemia: Progress and Controversies: Proceedings of a Wyeth-Ayerst-UCLA Symposia Western Workshop Held at Lake Lanier, Georgia, November 28-December 1, 1989. Wiley-Liss, 1990, pp 411-419.
39. Gorin NC, Aegerter P, Auvert B, et al.: Autologous bone marrow transplantation for acute myelocytic leukemia in first remission: a European survey of the role of marrow purging. Blood 75 (8): 1606-14, 1990. [PubMed: 2328313]
40. Robertson MJ, Soiffer RJ, Freedman AS, et al.: Human bone marrow depleted of CD33-positive cells mediates delayed but durable reconstitution of hematopoiesis: clinical trial of MY9 monoclonal antibody-purged autografts for the treatment of acute myeloid leukemia. Blood 79 (9): 2229-36, 1992. [PubMed: 1571539]

Chemotherapy

Allogeneic Hematopoietic Cell Transplant

When patients with relapsed disease are treated aggressively, they may have extended disease-free survival (DFS); however, patients with relapsed disease can only be cured with HCT.[24][Level of evidence C2] Allogeneic HCT for patients in their second CR provides better DFS rates than transplant for patients in relapse.[25][Level of evidence C1]

Evidence (allogeneic HCT):

1. Current transplant outcomes are reported by the Center for International Blood and Marrow Transplantation Registry. The group reported the following outcomes for transplants done in the United States between 2008 and 2018:[26][Level of evidence C2]

   • The 3-year survival rate was 53% for patients with AML in second or subsequent CR versus 31% for patients with relapsed disease (or never in a CR) who underwent a matched sibling donor transplant.
   • The 3-year survival rate was 50% for patients with AML in second or subsequent CR versus 30% for patients with relapsed disease (or who never achieved CR) who underwent a matched unrelated donor transplant.

Allogeneic HCT can be effective salvage therapy in some patients whose disease fails to go into remission with intensive chemotherapy (primary refractory leukemia). A number of retrospective studies have demonstrated the ability of allogeneic HCT to induce remission in primary refractory disease.[27]

Evidence (allogeneic HCT to induce remission):

1. In one retrospective analysis of 168 patients with AML and primary refractory disease who underwent allogeneic HCT, the 5-year OS rate was 22%.[28]
2. Another analysis was conducted among patients enrolled in a prospective cooperative group trial, SWOG S0106 (NCT00085709).[29]

   • Of the 589 patients treated in the cooperative group trial, 150 (25%) had primary refractory disease.
   • Among the 64 patients with primary refractory disease who received an allogeneic HCT, the 4-year survival rate was 48% compared with 4% among the 86 patients who did not undergo transplant.[29][Level of evidence C3]

Randomized trials testing the efficacy of this approach are not available.

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. 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. [PMC free article: PMC5291965] [PubMed: 27895058]
2. Sekeres MA, Guyatt G, Abel G, et al.: American Society of Hematology 2020 guidelines for treating newly diagnosed acute myeloid leukemia in older adults. Blood Adv 4 (15): 3528-3549, 2020. [PMC free article: PMC7422124] [PubMed: 32761235]
3. Jackson G, Taylor P, Smith GM, et al.: A multicentre, open, non-comparative phase II study of a combination of fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor in relapsed and refractory acute myeloid leukaemia and de novo refractory anaemia with excess of blasts in transformation. Br J Haematol 112 (1): 127-37, 2001. [PubMed: 11167793]
4. Pastore D, Specchia G, Carluccio P, et al.: FLAG-IDA in the treatment of refractory/relapsed acute myeloid leukemia: single-center experience. Ann Hematol 82 (4): 231-5, 2003. [PubMed: 12707726]
5. Spadea A, Petti MC, Fazi P, et al.: Mitoxantrone, etoposide and intermediate-dose Ara-C (MEC): an effective regimen for poor risk acute myeloid leukemia. Leukemia 7 (4): 549-52, 1993. [PubMed: 8464233]
6. Greenberg PL, Lee SJ, Advani R, et al.: Mitoxantrone, etoposide, and cytarabine with or without valspodar in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome: a phase III trial (E2995). J Clin Oncol 22 (6): 1078-86, 2004. [PMC free article: PMC5457168] [PubMed: 15020609]
7. Paciucci PA, Dutcher JP, Cuttner J, et al.: Mitoxantrone and ara-C in previously treated patients with acute myelogenous leukemia. Leukemia 1 (7): 565-7, 1987. [PubMed: 3478540]
8. Hiddemann W, Kreutzmann H, Straif K, et al.: High-dose cytosine arabinoside and mitoxantrone: a highly effective regimen in refractory acute myeloid leukemia. Blood 69 (3): 744-9, 1987. [PubMed: 3469002]
9. Brown RA, Herzig RH, Wolff SN, et al.: High-dose etoposide and cyclophosphamide without bone marrow transplantation for resistant hematologic malignancy. Blood 76 (3): 473-9, 1990. [PubMed: 2378980]
10. Lambertenghi-Deliliers G, Maiolo AT, Annaloro C, et al.: Idarubicin in sequential combination with cytosine arabinoside in the treatment of relapsed and refractory patients with acute non-lymphoblastic leukemia. Eur J Cancer Clin Oncol 23 (7): 1041-5, 1987. [PubMed: 3478198]
11. Harousseau JL, Reiffers J, Hurteloup P, et al.: Treatment of relapsed acute myeloid leukemia with idarubicin and intermediate-dose cytarabine. J Clin Oncol 7 (1): 45-9, 1989. [PubMed: 2642539]
12. Herzig RH, Lazarus HM, Wolff SN, et al.: High-dose cytosine arabinoside therapy with and without anthracycline antibiotics for remission reinduction of acute nonlymphoblastic leukemia. J Clin Oncol 3 (7): 992-7, 1985. [PubMed: 3894588]
13. Liu Yin JA, Wheatley K, Rees JK, et al.: Comparison of 'sequential' versus 'standard' chemotherapy as re-induction treatment, with or without cyclosporine, in refractory/relapsed acute myeloid leukaemia (AML): results of the UK Medical Research Council AML-R trial. Br J Haematol 113 (3): 713-26, 2001. [PubMed: 11380463]
14. Becker PS, Kantarjian HM, Appelbaum FR, et al.: Clofarabine with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming for relapsed and refractory acute myeloid leukaemia. Br J Haematol 155 (2): 182-9, 2011. [PMC free article: PMC4834701] [PubMed: 21848522]
15. Scappini B, Gianfaldoni G, Caracciolo F, et al.: Cytarabine and clofarabine after high-dose cytarabine in relapsed or refractory AML patients. Am J Hematol 87 (12): 1047-51, 2012. [PubMed: 23151979]
16. Perl AE, Martinelli G, Cortes JE, et al.: Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med 381 (18): 1728-1740, 2019. [PubMed: 31665578]
17. Perl AE, Larson RA, Podoltsev NA, et al.: Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood 139 (23): 3366-3375, 2022. [PMC free article: PMC9197557] [PubMed: 35081255]
18. Stein EM, DiNardo CD, Pollyea DA, et al.: Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 130 (6): 722-731, 2017. [PMC free article: PMC5572791] [PubMed: 28588020]
19. DiNardo CD, Stein EM, de Botton S, et al.: Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML. N Engl J Med 378 (25): 2386-2398, 2018. [PubMed: 29860938]
20. Stahl M, DeVeaux M, Montesinos P, et al.: Hypomethylating agents in relapsed and refractory AML: outcomes and their predictors in a large international patient cohort. Blood Adv 2 (8): 923-932, 2018. [PMC free article: PMC5916007] [PubMed: 29685952]
21. Larson RA, Sievers EL, Stadtmauer EA, et al.: Final report of the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients with CD33-positive acute myeloid leukemia in first recurrence. Cancer 104 (7): 1442-52, 2005. [PubMed: 16116598]
22. Kantarjian H, Gandhi V, Cortes J, et al.: Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood 102 (7): 2379-86, 2003. [PubMed: 12791647]
23. Faderl S, Gandhi V, O'Brien S, et al.: Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias. Blood 105 (3): 940-7, 2005. [PubMed: 15486072]
24. Forman SJ, Schmidt GM, Nademanee AP, et al.: Allogeneic bone marrow transplantation as therapy for primary induction failure for patients with acute leukemia. J Clin Oncol 9 (9): 1570-4, 1991. [PubMed: 1875218]
25. Clift RA, Buckner CD, Thomas ED, et al.: The treatment of acute non-lymphoblastic leukemia by allogeneic marrow transplantation. Bone Marrow Transplant 2 (3): 243-58, 1987. [PubMed: 3332174]
26. Phelan R, Arora M, Chen M: The US Summary Slides - HCT Trends and Survival Data. Center for International Blood and Marrow Transplant Research, 2020. Available online. Last accessed October 5, 2023.
27. Gyurkocza B, Lazarus HM, Giralt S: Allogeneic hematopoietic cell transplantation in patients with AML not achieving remission: potentially curative therapy. Bone Marrow Transplant 52 (8): 1083-1090, 2017. [PubMed: 28244979]
28. Craddock C, Labopin M, Pillai S, et al.: Factors predicting outcome after unrelated donor stem cell transplantation in primary refractory acute myeloid leukaemia. Leukemia 25 (5): 808-13, 2011. [PubMed: 21339758]
29. Othus M, Appelbaum FR, Petersdorf SH, et al.: Fate of patients with newly diagnosed acute myeloid leukemia who fail primary induction therapy. Biol Blood Marrow Transplant 21 (3): 559-64, 2015. [PMC free article: PMC4386840] [PubMed: 25536215]

Treatment of Newly Diagnosed APL

Treatment options for newly diagnosed APL include the following:

1. All-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) for low- to intermediate-risk disease.
2. ATRA plus chemotherapy, followed by ATO-based consolidation therapy for high-risk disease.

ATRA induces terminal differentiation of the leukemic cells followed by restoration of nonclonal hematopoiesis. Administration of ATRA leads to rapid resolution of coagulopathy in most patients, and heparin administration is not required in patients receiving ATRA. However, randomized trials have not shown a reduction in morbidity and mortality during ATRA induction when compared with chemotherapy. ATRA administration may result in the following conditions:

• Differentiation syndrome: Administration of ATRA can lead to a syndrome of respiratory distress, known as differentiation syndrome. Prompt recognition of the syndrome and aggressive administration of steroids can prevent severe respiratory distress.[1]
• Hyperleukocytosis: The optimal management of ATRA-induced hyperleukocytosis has not been established. Hyperleukocytosis in APL is typically treated with the addition of cytotoxic chemotherapy. Leukopheresis is not recommended because of an increased risk of complications such as bleeding events and disseminated intravascular coagulation.

Studies performed in the 1990s demonstrated that overall survival (OS) rates improved in patients receiving ATRA in addition to chemotherapy.[2,3] ATO, an agent with both differentiation-inducing and apoptosis-inducing properties against APL cells, is also used in the treatment of APL. Induction remission therapy for APL is determined by disease risk. Low- to intermediate-risk APL (white blood cell [WBC] count ≤10 × 10⁹/L) is treated without chemotherapy (ATRA and ATO), and high-risk is treated with a combination of ATRA and ATO plus chemotherapy.

Treatment of Recurrent APL

Treatment options for recurrent APL include the following:

1. ATO with or without chemotherapy.
2. Hematopoietic cell transplant (HCT).

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. Frankel SR, Eardley A, Lauwers G, et al.: The "retinoic acid syndrome" in acute promyelocytic leukemia. Ann Intern Med 117 (4): 292-6, 1992. [PubMed: 1637024]
2. Adès L, Guerci A, Raffoux E, et al.: Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience. Blood 115 (9): 1690-6, 2010. [PubMed: 20018913]
3. Sanz MA, Montesinos P, Vellenga E, et al.: Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy: long-term outcome of the LPA 99 multicenter study by the PETHEMA Group. Blood 112 (8): 3130-4, 2008. [PubMed: 18664623]
4. Lo-Coco F, Avvisati G, Vignetti M, et al.: Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 369 (2): 111-21, 2013. [PubMed: 23841729]
5. Burnett AK, Russell NH, Hills RK, et al.: Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol 16 (13): 1295-305, 2015. [PubMed: 26384238]
6. Lo-Coco F, Avvisati G, Vignetti M, et al.: Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood 116 (17): 3171-9, 2010. [PubMed: 20644121]
7. Iland HJ, Bradstock K, Supple SG, et al.: All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood 120 (8): 1570-80; quiz 1752, 2012. [PubMed: 22715121]
8. Ravandi F, Estey E, Jones D, et al.: Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol 27 (4): 504-10, 2009. [PMC free article: PMC4881307] [PubMed: 19075265]
9. Abaza Y, Kantarjian H, Garcia-Manero G, et al.: Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab. Blood 129 (10): 1275-1283, 2017. [PMC free article: PMC5413297] [PubMed: 28003274]
10. Lengfelder E, Lo-Coco F, Ades L, et al.: Arsenic trioxide-based therapy of relapsed acute promyelocytic leukemia: registry results from the European LeukemiaNet. Leukemia 29 (5): 1084-91, 2015. [PubMed: 25627637]
11. Leoni F, Gianfaldoni G, Annunziata M, et al.: Arsenic trioxide therapy for relapsed acute promyelocytic leukemia: a bridge to transplantation. Haematologica 87 (5): 485-9, 2002. [PubMed: 12010661]
12. Soignet SL, Frankel SR, Douer D, et al.: United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 19 (18): 3852-60, 2001. [PubMed: 11559723]
13. Thirugnanam R, George B, Chendamarai E, et al.: Comparison of clinical outcomes of patients with relapsed acute promyelocytic leukemia induced with arsenic trioxide and consolidated with either an autologous stem cell transplant or an arsenic trioxide-based regimen. Biol Blood Marrow Transplant 15 (11): 1479-84, 2009. [PubMed: 19822309]
14. Raffoux E, Rousselot P, Poupon J, et al.: Combined treatment with arsenic trioxide and all-trans-retinoic acid in patients with relapsed acute promyelocytic leukemia. J Clin Oncol 21 (12): 2326-34, 2003. [PubMed: 12805334]
15. Yanada M, Tsuzuki M, Fujita H, et al.: Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia. Blood 121 (16): 3095-102, 2013. [PubMed: 23412094]
16. Holter Chakrabarty JL, Rubinger M, Le-Rademacher J, et al.: Autologous is superior to allogeneic hematopoietic cell transplantation for acute promyelocytic leukemia in second complete remission. Biol Blood Marrow Transplant 20 (7): 1021-5, 2014. [PMC free article: PMC4097890] [PubMed: 24691221]
17. de Botton S, Fawaz A, Chevret S, et al.: Autologous and allogeneic stem-cell transplantation as salvage treatment of acute promyelocytic leukemia initially treated with all-trans-retinoic acid: a retrospective analysis of the European acute promyelocytic leukemia group. J Clin Oncol 23 (1): 120-6, 2005. [PubMed: 15534358]

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 in the care of their 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).

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The lead reviewer for Acute Myeloid Leukemia Treatment is:

• Aaron Gerds, MD (Cleveland Clinic Taussig Cancer Institute)

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

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