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Home > Living Well > Health Library > Acute Myeloid Leukemia Treatment (PDQ®): Treatment - Health Professional Information [NCI]
This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
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 2021:
Based on Surveillance, Epidemiology, and End Results (SEER) Program data from 2011 to 2017, 29.5% of patients with AML were alive 5 years after diagnosis.
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.
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:
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.
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.[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. Cytogenic and molecular information has been combined to form distinct prognostic groups.
Additional adverse prognostic factors for AML include the following:
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.[13,14,15]
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).
Other PDQ summaries containing information related to AML include the following:
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. 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.[5,6,7]
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).
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 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:
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.[12,13,14,15]
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.[12,13,14,15] 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.[5,19] Myeloid sarcomas may be present at initial diagnosis or at relapse.
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.[12,13,15] 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).[22,23] 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:
Common morphologic features of microgranular APL include the following:
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.[24,25,26] 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. 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. 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.[30,31,32] 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).
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.[36,37,38] 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.
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.[39,40,41] NUP214 is a component of the nuclear pore complex. This subgroup of AML has been associated with a poor prognosis.[39,42,43]
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.[44,45] These abnormalities are associated with poor prognosis.[15,46,47] 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 withBCR-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 mutatedNPM1
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%).[50,51,52] The presence of an NPM1 mutation confers improved prognosis in the absence of FLT3–internal tandem duplication (ITD) mutations.[50,53,54]
AML with biallelic mutations ofCEBPA
In adults younger than 60 years, 10% to 15% of cytogenetically normal AML cases have mutations in CEBPA.[53,55] 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.[53,57] Studies have demonstrated that CEBPA double-mutant, but not single-mutant, AML is independently associated with a favorable prognosis,[55,58,59,60] leading to the WHO 2016 revision that requires biallelic mutations for the disease definition.
AML with mutatedRUNX1(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.[62,63,64]
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 after 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.
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.[65,66,67]
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. 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 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.[68,72,73,74]
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. 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.[68,72,73,74] 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. 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:
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.[10,77,78]
Morphologic and cytochemical features include the following:
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.[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. 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.[77,78,81,82]
Myeloid Proliferations Related to Down Syndrome
Refer to the Transient Abnormal Myelopoiesis (TAM) Associated With Down Syndrome section of the PDQ summary on Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment 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).[10,83,84]
They include the following subcategories:
The diagnosis of MPAL is made in leukemias with expression of antigens of more than one lineage:
Cytogenetic abnormalities are observed in a high percentage of acute leukemias of ambiguous lineage.[85,86,87,88] 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]
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 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.[1,2]
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.
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.
Supportive care during remission induction treatment should routinely include red blood cell and platelet transfusions when appropriate.[6,7] 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.
The following growth factors have been studied in the treatment of AML:
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.
Empiric broad spectrum antimicrobial therapy is an absolute necessity for febrile patients who are profoundly neutropenic.[17,18] 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.[19,20] 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.
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:
Chemotherapy for AML is divided into the following two general categories:
One of the following combination chemotherapy regimens may be used as intensive remission induction therapy:
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.[3,4,5,6] 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.
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.
Addition of gemtuzumab ozogamicin
Evidence (gemtuzumab ozogamicin):
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.
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:
Evidence (chemotherapy for patients who decline intensive remission induction therapy):
Compared with treatment for 5 consecutive days, treatment for 10 consecutive days may lead to higher response rates, particularly in those with TP53 mutations and/or unfavorable cytogenetic features.[Level of evidence: 3iiiDiv]
Similar to venetoclax, glasdegib was approved by the FDA in combination with low-dose cytarabine for the treatment of AML in patients aged 75 years or older or who are unable to receive intensive induction 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.
Although individual patients with acute myeloid leukemia (AML) 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, all patients who did not receive postremission therapy experienced a relapse after a short median complete remission (CR) duration.
Treatment options for AML in remission (postremission phase) include the following:
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%.[3,4,5,6] 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.[7,8,9,10,11] The duration of postremission therapy has ranged from one cycle [4,6] to four or more cycles.[3,5]
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 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.
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.
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.
While maintenance was well tolerated in the RATIFY study, only a small subset of patients tolerated midostaurin as maintenance therapy after chemotherapy or transplantation in a separate phase II study.
Evidence (oral azacitidine):
Hematopoietic Cell (Bone Marrow or Stem Cell) Transplantation
Allogeneic HCT, even with minimal conditioning chemotherapy, results in the lowest incidence of leukemic relapse, even when compared with HCT from an identical twin (syngeneic HCT). This finding 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 HCT 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 infection. The DFS rates using allogeneic transplantation in first complete remission have ranged from 45% to 60%.[21,22,23,24]
The use of allogeneic HCT in adults requires either a human leukocyte antigen (HLA)-matched sibling donor, an HLA-matched unrelated donor, a haploidentical donor ("half HLA-matched"), or two well-matched umbilical cord blood units. Including patients who underwent HCT from 2007 to 2017, the 3-year probabilities of survival after HLA-matched sibling transplant were 59% (±1%) for patients with early disease, 53% (±1%) for patients with intermediate disease, and 29% (±1%) for patients with advanced disease, according to the Center for International Blood and Marrow Transplant Research registry. The probabilities of survival after an unrelated donor transplant were 53% (±1%) for patients with early disease, 50% (±1%) for intermediate disease, and 27% (±1%) for patients with advanced disease. [Level of evidence: 3iiiA]
Because HCT can cure more than 30% of patients who experience relapse after chemotherapy, some investigators suggested that allogeneic bone marrow transplant (BMT) can be reserved for early first relapse or second CR without compromising the number of patients who are ultimately cured. Clinical and cytogenetic information can define certain subsets of patients with predictable better or worse prognoses according to favorable- and adverse-risk factors in those using postremission chemotherapy.
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 are deemed medically eligible for allogeneic transplant and undergo HLA typing. If a matched sibling or matched unrelated 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. RFS is the usual endpoint for this type of trial. OS from the time of diagnosis is less frequently reported in these trials.
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 years and younger from 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 (six trials) or with a variety of consolidation chemotherapy regimens, with high-dose cytarabine being the most common.
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 physicians who treat patients with leukemia agree that transplantation should be offered to AML patients in first CR in the setting of adverse-risk cytogenetics and should not be offered to patients in first CR with favorable-risk cytogenetics. However, older patients with favorable-risk AML who are unlikely to tolerate intensive cytarabine-based consolidation therapy can be considered for allogeneic HCT as postremission therapy.
Autologous hematopoietic stem cell transplantation
The role of autologous transplantation for AML patients has diminished over time because of the improvements in the nonrelapse mortality associated with allogeneic HCT, as well as the advent of haploidentical and umbilical cord transplantation expanding the potential donor pool so that nearly every patient has a donor.[30,31,32,33] Autologous HCT can yield DFS rates between 35% and 50% in patients with AML in first remission. Autologous HCT has also cured a smaller proportion of patients in second remission.[34,35,36,37,38,39,40] Treatment-related mortality rates of patients who have had autologous peripheral blood or marrow transplantation range from 10% to 20%.
No standard treatment regimen exists for patients with refractory or recurrent acute myeloid leukemia (AML).[1,2]
Treatment options for refractory or recurrent AML include the following:
Intensive salvage chemotherapy
A number of intensive salvage chemotherapy regimens have demonstrated efficacy in recurrent AML, including the following:
Fludarabine, cytarabine, and filgrastim (FLAG)
FLAG has shown antileukemic activity in patients with relapsed and refractory AML.
Idarubicin has been added to this regimen as well (FLAG-Ida).
Mitoxantrone, etoposide, and cytarabine (MEC)
Standard or high-dose cytarabine and mitoxantrone
Evidence (standard or high-dose cytarabine and mitoxantrone):
High-dose etoposide and cyclophosphamide
Evidence (high-dose etoposide and cyclophosphamide):
Idarubicin and cytarabine
Evidence (idarubicin and cytarabine):
Other intensive regimens
Reduced-intensity therapy, including targeted therapy
Patients who are unable or unwilling to undergo intensive therapy can be treated with reduced-intensity therapies, including the following:
Gilteritinib is an oral FLT3 inhibitor with activity in both internal tandem duplication (ITD) and tyrosine kinase domain (TKD) subtypes.
Enasidenib is an oral small molecule inhibitor with activity against the mutant IDH2 enzyme.
Ivosidenib is an oral small molecule inhibitor with activity against the mutant IDH1 enzyme.
Evidence (hypomethylating agents):
The antibody-targeted chemotherapy agent gemtuzumab ozogamicin has been evaluated in patients who had relapsed AML and expressed CD33.
The long-term outcomes of patients who receive gemtuzumab and achieve CR without platelet recovery are unclear. Gemtuzumab induces profound bone marrow aplasia similar to leukemia induction chemotherapy and also has substantial hepatic toxic effects, including hepatic veno-occlusive disease.[Level of evidence: 3iiiDiv]
Clofarabine with or without cytarabine
Evidence (clofarabine with or without cytarabine):
Allogeneic Hematopoietic Cell Transplantation
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.[Level of evidence: 3iDii] Allogeneic HCT for patients in their second CR provides better DFS rates than transplantation for patients in relapse.[Level of evidence: 3iiiA]
Evidence (allogeneic HCT):
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.
Evidence (allogeneic HCT to induce remission):
Randomized trials testing the efficacy of this approach are not available.
Special consideration must be given to induction therapy for APL. Treatment is centered around the use of differentiating agents to clear the leukemic cells. Early mortality is related to bleeding, differentiation syndrome, or infection. High complete remission (CR) rates are very common across treatment regimens, and persistent disease or relapse is rare.
Treatment of Newly Diagnosed APL
Treatment options for newly diagnosed APL include the following:
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:
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 x109 /L) is treated without chemotherapy (ATRA and ATO), and high-risk is treated with a combination of ATRA and ATO plus chemotherapy.
ATRA plus ATO for low- to intermediate-risk disease
Evidence (ATRA plus ATO for low- to intermediate-risk disease):
ATRA plus chemotherapy, followed by ATO-based consolidation therapy for high-risk disease
Remission induction with a combination of anthracycline and ATRA is used for remission induction in patients with high-risk disease (WBC count, >10x109 /L).
Evidence (ATRA plus chemotherapy, followed by ATO-based consolidation therapy for high-risk disease):
An ATO-based regimen, which includes gemtuzumab ozogamicin as the only cytotoxic drug, has been developed.
Long-term follow up from this study has been published.
It is important to note that most current regimens for the treatment of APL include some form of maintenance therapy. A meta-analysis of randomized trials has indicated that maintenance clearly improves DFS but not OS; however, these trials did not include ATO-containing regimens.
Treatment of Recurrent APL
Treatment options for recurrent APL include the following:
ATO with or without chemotherapy
ATO has high rates of second remission in patients with relapsed APL. As a single agent, ATO can lead to complete response rates of 80% to 90% in patients with hematologic relapse, and 70% to 80% in patients with molecular remission.[11,12,13,14] The choice of salvage therapy is based on the previous therapy and interval of time between first remission and relapse.
For patients receiving ATO as salvage therapy, a small randomized trial suggested that the addition of ATRA does not confer any benefit over ATO alone in patients who previously received ATRA. In this 20-patient study, the complete response rate after one cycle of ATO with or without ATRA was 80%.
Some patients in second remission with ATO have experienced long-term DFS after autologous stem cell transplantation,[15,16] and it can be considered in patients who are in molecular remission (negative quantitative polymerase chain reaction [PCR] on a marrow sample). Patients who do not go into remission or have evidence of minimal residual disease by quantitative PCR on a marrow sample after salvage therapy are considered for an allogeneic HCT. A registry study reported a 3-year OS rate after transplant in second CR of 80% compared with 59% in patients without transplant (P = .03).
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.
This summary was renamed from Adult Acute Myeloid Leukemia Treatment.
General Information About Acute Myeloid Leukemia (AML)
Revised text to state that based on Surveillance, Epidemiology, and End Results (SEER) Program data from 2011 to 2017, 29.5% of patients with AML were alive 5 years after diagnosis.
Treatment of Refractory or Recurrent AML
This section was 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.
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:
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 reviewer for Acute Myeloid Leukemia Treatment is:
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
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The preferred citation for this PDQ summary is:
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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Last Revised: 2021-06-22
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