Approach

Dose-intense chemotherapy is recommended for patients with AML who are considered fit and healthy enough to tolerate intensive therapy.[23][38]​​[60][65]​​​ Patients unsuitable for intensive therapy should be considered for low-intensity therapy.

Enrollment in a clinical trial should be considered for all patients, where possible. Clinical trials frequently offer the best management option for patients with AML, particularly those who are older, are unable to tolerate chemotherapy, or have unfavorable disease (e.g., those with TP53 mutations or 17p deletion).[38][60][65]

Treatment goals

The early goals of treatment are to achieve complete remission and reduce the risk of relapse. See Criteria for treatment response criteria.

The long-term goal is to improve disease-free survival and overall survival, with minimal long-term adverse effects. For fit younger patients (<60 years of age) who are treated with intensive chemotherapy, the overall goal is disease cure. In older patients, the goal is usually to achieve complete remission that extends survival and quality of life; cure may be possible for a subset of fit older patients.

The goals of treatment should be discussed with the patient in the context of their disease and fitness, and this should inform decision-making and treatment planning throughout the course of treatment.

Treatment phases

Treatment for AML involves using multiagent, dose-intense chemotherapy regimens in two main phases: induction and consolidation. Some patients may undergo allogeneic stem cell transplantation (SCT) or maintenance therapy if complete remission is achieved.

Treatment is guided by the patient’s ability to tolerate intensive treatment regimens (e.g., based on age, fitness/performance status, comorbidities), risk stratification (e.g., based on genetic abnormalities), disease biology/subtype, measurable (minimal) residual disease (MRD) assessment, and patient preference/goals.

See Criteria for risk stratification.

Induction therapy for AML

Induction therapy is the first phase of treatment. The aim of induction is to achieve complete remission with low or undetectable MRD.

Patients who are fit and able to tolerate intensive therapy should undergo induction therapy with dose-intense chemotherapy regimens.[23][38][60][65]

The standard intensive induction regimen is:[23][38][60]​​ [ Cochrane Clinical Answers logo ]

  • Cytarabine for 7 days plus an anthracycline (e.g., daunorubicin, idarubicin) for 3 days (i.e., standard 7+3 regimen)

Alternative intensive induction regimens include:[23][38][60]

  • Cytarabine for 7 days plus mitoxantrone for 3 days

  • Fludarabine plus cytarabine plus granulocyte colony-stimulating factor (G-CSF) plus idarubicin (FLAG-IDA; use with caution in patients ages >60 years)

  • Liposomal daunorubicin/cytarabine (also known as CPX-351; a liposome-encapsulated fixed-dose combination of daunorubicin plus cytarabine) for patients with therapy-related AML (tAML) or AML with myelodysplasia-related changes (AML-MRC), particularly those ages >60 years

One or two courses of induction therapy is recommended.​[60]

Complete remission rate with standard induction chemotherapy is 70% to 80% in patients <60 years of age.[66][67][68][69]​​​ In patients ≥60 years of age, the complete remission rate is lower (60% to 70%).[70][71]​​​ However, complete remission rate varies significantly depending on disease biology.

Patients who do not achieve complete remission following induction therapy are considered to have refractory disease.

Consolidation therapy for AML

The aim of consolidation therapy is to maintain complete remission and reduce the risk of relapse following induction therapy.

Consolidation therapy is guided by risk factors for relapse (e.g., genetic abnormalities, white blood cell [WBC] count at presentation, MRD).

Consolidation regimens usually consist of up to 4 cycles of intermediate-dose or high-dose cytarabine (IDAC or HiDAC) alone or in combination with other chemotherapy drugs (e.g., idarubicin, daunorubicin, mitoxantrone).​[38]

Patients with tAML or AML-MRC who received liposomal daunorubicin/cytarabine for induction therapy can also receive this regimen for consolidation therapy (up to 2 cycles).[72][73][74]

Measurable (minimal) residual disease (MRD) assessment in AML

MRD assessment (e.g., using molecular genetic testing or flow cytometry) should be performed during and after treatment to assess treatment response (i.e., the presence of leukemic cells in the peripheral blood and/or bone marrow).[23][75]​ MRD should also be assessed before allogeneic SCT.[51]

MRD assessment can inform prognosis and treatment planning when combined with standard morphology-based assessment of treatment response. Leukemic cells may persist in patients who achieve morphologic complete remission following treatment; therefore, MRD assessment can determine deeper remission status and improve prognostication and risk stratification.

The European LeukemiaNet has published recommendations for assessing MRD (including frequency and timing) in AML patients.​​​​​​​[23][75]

Stem cell transplantation (SCT) for AML

Patients with intermediate-risk disease and particularly those with adverse-risk disease may be considered for allogeneic SCT (with reduced-intensity conditioning for older patients) following one or more cycles of consolidation chemotherapy, if they are fit and able to tolerate SCT.[51][76][77]​​​​​ These patients may also proceed directly to transplant if a suitable donor is available at first complete remission (i.e., in lieu of consolidation chemotherapy).

Allogeneic SCT may be considered in patients with favorable-risk disease with persistent MRD if a suitable donor is available.[23][51]

Autologous SCT is an alternative to allogeneic SCT in select patients (e.g., those with intermediate-risk disease who are MRD negative) if a donor is not available, but is not commonly performed.[23][60]​​[78][79]​​​

Targeted therapies for AML

Targeted therapies can be considered for patients with certain biologic markers and genetic abnormalities.

CD33-positive AML

Patients with CD33-positive AML and favorable- or intermediate-risk disease can be treated with gemtuzumab ozogamicin (an anti-CD33 monoclonal antibody conjugated with the cytotoxic agent calicheamicin) in combination with induction and consolidation chemotherapy.​[80][81]​​​[82][83]​​ Important adverse effects associated with gemtuzumab ozogamicin include hypersensitivity reactions, hepatotoxicity (veno-occlusive disease), and myelotoxicity.

FLT3-mutated AML

Patients with FLT3-mutated AML can be treated with the oral tyrosine kinase inhibitors midostaurin (for FLT3-ITD-mutated or FLT3-TKD-mutated) or quizartinib (for FLT3-ITD-mutated only) in combination with standard intensive induction and consolidation chemotherapy.[84][85][86]​​ Quizartinib is available only through a restricted Risk Evaluation and Mitigation Strategy (REMS) program.

Maintenance therapy for AML

Maintenance therapy with oral azacitidine (single agent) may be considered for patients with complete remission after intensive induction chemotherapy (with or without complete blood count recovery), but who are not candidates for intensive consolidation therapy (including SCT).[87]

Maintenance therapy with oral azacitidine should not replace consolidation therapy.

FLT3-mutated AML: maintenance therapy post-consolidation chemotherapy

Patients with FLT3-mutated AML who achieve complete remission with midostaurin or quizartinib (in combination with standard induction and consolidation chemotherapy) may continue these agents as monotherapy for maintenance therapy post-consolidation chemotherapy.[84]​​​[85]​​[86]​​

FLT3-mutated AML: maintenance therapy posttransplant

Several oral tyrosine kinase inhibitors can be considered for post-allogeneic SCT maintenance therapy in patients with FLT3-mutated AML. These include:[38][85][86]​​​[88][89][90]​​​

  • Sorafenib (for FLT3-ITD-mutated only)

  • Gilteritinib (for FLT3-ITD-mutated or FLT3-TKD-mutated, particularly if patients are MRD-positive before or after SCT)

  • Midostaurin (for FLT3-ITD-mutated or FLT3-TKD-mutated)

  • Quizartinib (for FLT3-ITD-mutated only)

The role of maintenance therapy in the posttransplant setting is still evolving.

Treatment for patients with AML who are not suitable for standard intensive chemotherapy

Low-intensity therapy should be considered for newly diagnosed patients who are not suitable for standard intensive chemotherapy (e.g., due to age, frailty, comorbidities). Options include:

  • Venetoclax (a BCL-2 inhibitor) is approved for use in combination with a hypomethylating agent (decitabine or azacitidine) or low-dose subcutaneous cytarabine (LDAraC) for patients with newly diagnosed AML ages 75 years or older, or who are unsuitable for intensive induction chemotherapy due to comorbidities.[91][92][93][94][95]​​​​ Tumor lysis syndrome (TLS) has been uncommonly reported in patients with AML treated with venetoclax.[96] See Management approach (Supportive care for AML and APL).

  • Glasdegib (a Hedgehog pathway inhibitor) is approved for use in combination with LDAraC for patients ages ≥75 years who are unsuitable for standard induction chemotherapy.[97][98][99]

  • Ivosidenib (an IDH1 inhibitor) is approved in the US for use as monotherapy or in combination with azacitidine for patients with newly diagnosed IDH1-mutated AML who are ages 75 years or older, or who are unsuitable for intensive induction chemotherapy due to comorbidities.[100][101]​​​​​ Life-threatening differentiation syndrome has been reported in patients receiving ivosidenib. See Management approach (Supportive care for AML and APL).

  • Enasidenib (an IDH2 inhibitor) may be used as monotherapy or in combination with azacitidine for patients with newly diagnosed IDH2-mutated AML who are unsuitable for intensive induction chemotherapy.[102][103][104]​​​​​​ The US Food and Drug Administration (FDA) has issued a warning regarding differentiation syndrome associated with enasidenib.[105] Differentiation syndrome has reportedly occurred as early as 10 days and up to 5 months after starting treatment. See Management approach (Supportive care for AML and APL).

  • Gemtuzumab ozogamicin (single agent) may be used for patients with CD33-positive AML who are not suitable for standard induction chemotherapy.[106]

Patients should continue low-intensity therapy until disease progression or intolerance. SCT may be an option in select patients who respond to low-intensity therapy. If eligible and a suitable donor is available, patients should undergo allogeneic SCT (with reduced-intensity conditioning) at first remission.[38][60]

AML with TP53 mutations or 17p deletion

Patients with TP53 mutations or 17p deletion are typically unresponsive to standard intensive chemotherapy and the prognosis is poor.[107]​ A clinical trial is recommended for these patients.[38]​ If a clinical trial is not available, low-intensity therapy (e.g., venetoclax plus decitabine) and allogeneic SCT (if eligible and a suitable donor is available) can be considered.[95]

Relapsed or refractory AML

Patients with relapsed or refractory disease have a poor prognosis.[108]

There is no standard salvage regimen for relapsed or refractory disease. Where possible, patients should be offered enrollment in a clinical trial.

At relapse, all patients should undergo molecular re-evaluation to identify targets (actionable genes) for salvage therapy, which may have emerged since diagnosis (due to clonal evolution) or were not detected at diagnosis.[23] 

Relapse after first complete remission occurs in approximately 50% of patients who have received standard induction therapy, usually in the first year following treatment. Approximately 40% to 60% of relapsed patients achieve a second complete remission with intensive salvage chemotherapy (e.g., IDAC or HiDAC with or without an anthracycline or mitoxantrone), although duration of remission is usually limited.[109]

Patients unsuitable for intensive salvage chemotherapy can be considered for low-intensity salvage therapy, which should be continued until disease progression or intolerance. Options include:

  • Venetoclax combined with a hypomethylating agent (azacitidine or decitabine) or LDAraC.[110][111]​​​

  • Gilteritinib (an oral kinase inhibitor) for patients with FLT3-mutated AML.[112] Gilteritinib has been associated with differentiation syndrome.

  • Ivosidenib for patients with IDH1-mutated AML.[113]

  • Olutasidenib for patients with IDH1-mutated AML.[114][115]​​ Olutasidenib has been associated with differentiation syndrome.​

  • Enasidenib for patients with IDH2-mutated AML.[102]

  • Gemtuzumab ozogamicin (single agent) for patients with CD33-positive AML.​[116]

Important predictors of response to salvage therapy are age, genetic abnormalities, duration of first remission, and history of previous SCT.[117][118][119]

Patients who achieve a second complete remission with intensive salvage therapy should undergo allogeneic SCT to reduce the risk of relapse, if they are eligible and a suitable donor is available.[38][60][108]

Patients who are unable to tolerate salvage therapy or who decline further treatment should be offered best supportive care and/or palliative care.

Reinduction therapy (with chemotherapy) may be considered for all patients with relapse following long remission (i.e., ≥12 months following induction therapy).[38][60]

Management of acute promyelocytic leukemia (APL)

APL is a subtype of AML (characterized by the presence of the PML::RARA fusion gene) that requires urgent treatment to prevent very early death caused by coagulopathy.[38][60][61]​​​ Treatment should commence as soon as APL is suspected (i.e., before confirmation by genetic testing).

Patients with APL are managed in three treatment phases: induction, consolidation, and maintenance.

Treatment is based on whether patients are non-high risk (defined as WBC count ≤10,000/microliter [≤10 × 10⁹/L] at presentation) or high risk (defined as WBC count >10,000/microliter [>10 × 10⁹/L] at presentation).[38][60][61]

Once a treatment regimen and protocol have been decided, it should be adhered to in its entirety from induction to consolidation and maintenance (barring major complication or inadequate response).[38]

Induction therapy for APL

Induction regimens for non-high-risk APL include:[38][61]

  • All-trans-retinoic acid (ATRA; also known as tretinoin) plus arsenic trioxide (standard of care)

  • ATRA plus idarubicin or gemtuzumab ozogamicin; considered only if arsenic trioxide is not available or contraindicated

Induction regimens for high-risk APL include:[38][61]

  • ATRA plus arsenic trioxide plus an anthracycline (idarubicin or daunorubicin)

  • ATRA plus arsenic trioxide plus gemtuzumab ozogamicin (single dose)

  • ATRA plus anthracycline-based chemotherapy (e.g., idarubicin; or daunorubicin plus cytarabine)

ATRA and arsenic trioxide can cause differentiation syndrome, which can be life-threatening if not treated promptly. Arsenic trioxide can also prolong QT interval and cause electrolyte abnormalities. See Management approach (Supportive care for AML and APL).

Induction therapy should continue until complete remission is achieved, after which consolidation therapy should be given.[61] Complete remission following ATRA-based induction therapy is achieved in most (>90%) patients.[120]

Consolidation therapy for APL

Consolidation regimens for APL are usually similar to induction regimens (e.g., ATRA plus arsenic trioxide [for non-high-risk APL]; ATRA plus arsenic trioxide plus chemotherapy [for high-risk APL]).[38][61]

Maintenance therapy for APL

Maintenance therapy may be considered for patients with high-risk APL, but it is not required for non-high-risk patients.[60]​​[61]

Maintenance regimens for APL usually consist of ATRA plus mercaptopurine and methotrexate for 1 to 2 years.[121][122][123] With close MRD monitoring post-consolidation, the role of maintenance therapy is now being challenged.[124][125]​​ In some countries, such as the UK, maintenance therapy for APL is no longer used.

Measurable (minimal) residual disease (MRD) assessment in APL

MRD assessment (to detect the PML::RARA fusion transcript) should be carried out following consolidation therapy to evaluate treatment response (i.e., molecular remission) and guide subsequent treatment.[60][61]

Patients with high-risk APL should undergo long-term MRD monitoring (e.g., every 3 months for 2 years following treatment) due to the increased risk of relapse.[38][60][61]​​ Long-term MRD monitoring is not required for non-high-risk patients in molecular remission following consolidation therapy.

Relapsed or refractory APL

Patients with relapsed or refractory APL should be considered for salvage therapy to achieve molecular remission (i.e., MRD negativity).

Salvage therapy should be based on previous treatment and whether relapse occurs early or late (definitions vary, but most relapses occur <2 years).[38][60][61]​ Patients who relapse early following treatment comprising ATRA plus arsenic trioxide can be treated with ATRA plus chemotherapy, or single-agent gemtuzumab ozogamicin.[38][61] Patients who relapse early following treatment with ATRA plus chemotherapy (without arsenic trioxide) can be treated with arsenic trioxide-containing regimens (e.g., ATRA plus arsenic trioxide).[38][61]​ Retreatment with the previous regimen may be considered if relapse occurs late.

Patients with relapsed or refractory disease should be referred to a transplant center. An autologous SCT (if MRD negative) or allogeneic SCT (if MRD positive or refractory disease) should be arranged.[38][61] Patients not eligible for SCT may be continued on salvage therapy or enrolled in a clinical trial (if available).

Central nervous system (CNS) involvement in AML and APL

CNS imaging and lumbar puncture should be carried out in patients with neurologic signs and symptoms suggesting CNS involvement.[23][38]

A screening lumbar puncture (in patients without neurologic signs and symptoms) should be considered at first remission before consolidation therapy in patients at high-risk for CNS disease; for example, those with any of the following:[38]

  • WBC count >40,000/microliter (>40 × 10⁹/L)

  • Monocytic lineage

  • Mixed-phenotype acute leukemia

  • Extramedullary disease

  • FLT3 mutations

  • High-risk APL

If CNS disease is confirmed, intrathecal cytarabine or methotrexate should be given two times per week until the cerebrospinal fluid is clear and weekly thereafter for a further 4 to 6 weeks.[38]

Supportive care for AML and APL

Consider supportive care measures for all patients, at all stages of treatment, to prevent or manage complications.

Patients with AML who are unsuitable for or decline standard- or low-intensive chemotherapy should be offered best supportive care.[38][126]

Electrolyte abnormalities

  • Correction of electrolyte abnormalities is important before and during treatment (particularly for patients with APL who are treated with arsenic trioxide).

  • Patients should be commenced on hydration (e.g., intravenous fluids).

Tumor lysis syndrome (TLS)

  • An oncologic emergency. TLS is characterized by hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, and/or elevated serum lactate dehydrogenase, which can occur following treatment (including chemotherapy and targeted agents e.g., venetoclax) or spontaneously (rare), particularly if WBC count (tumor burden) is high.

  • TLS can lead to cardiac arrhythmias, seizures, acute renal failure, and death, if untreated.​ Vigorous hydration (with intravenous fluids), phosphate-binding agents, and hypouricemic agents (e.g., allopurinol or rasburicase) should be used to prevent or treat TLS. See Tumor lysis syndrome.

  • TLS associated with venetoclax may occur as early as 6 to 8 hours following the first dose in patients with AML.[96] TLS risk assessment should be carried out before administering venetoclax, and​ guidance on TLS prophylaxis, laboratory monitoring, dose titration, and drug interactions should be strictly adhered to during treatment with venetoclax.[38][96]

Differentiation syndrome

  • Treatments for AML (e.g., ivosidenib, enasidenib, olutasidenib, gilteritinib) and APL (e.g., ATRA, arsenic trioxide) can cause differentiation syndrome, which can be life-threatening if not treated promptly.[105][115][127][128] 

  • Differentiation syndrome is characterized by fever, fluid retention, respiratory distress, pulmonary infiltrates, pulmonary or pericardial effusion, and an elevated WBC count (>10,000/microliter [>10 × 10⁹/L]). Patients should be monitored for hypoxia, pulmonary infiltrates, and pleural effusion. Patients with differentiation syndrome should be promptly treated with dexamethasone.[61]​ In severe cases, the treatment causing differentiation syndrome may be temporarily discontinued until symptoms resolve.[61]

Hyperleukocytosis

  • Generally defined as a WBC count >100,000/microliter (>100 × 10⁹/L) and is considered a poor prognostic factor.

  • In AML patients with hyperleukocytosis, hydroxyurea is recommended for leukoreduction.[23][38]​ It is recommended that WBC count is lowered to <25,000/microliter (<25 × 10⁹/L), particularly before initiating treatment with hypomethylating agents and venetoclax.[23][38]​​​​

  • In APL patients, hydroxyurea should be considered to manage high WBC count during treatment with ATRA and arsenic trioxide (particularly if differentiation syndrome occurs).​[38][61]

  • Urgent leukapheresis may be considered in patients with AML who are symptomatic and have a very high WBC count; however, this is not recommended in patients with APL because leukapheresis may worsen coagulopathy.​[38][61]

Anemia and thrombocytopenia

  • Red blood cell and platelet transfusions may be required depending on symptoms and blood counts.[126] During the acute phase of APL, patients are at particular risk of significant coagulopathy.

  • Packed red blood cell transfusion is recommended to keep hematocrit >25%.

  • Platelets should be prophylactically transfused once platelet count is <10,000/microliter (<10 × 10⁹/L).[23][38]​ Platelet count needs to be maintained at >50,000/microliter (>50 × 10⁹/L) in patients with APL or those with significant bleeding.[38][61]​ 

  • Activated partial thromboplastin time (aPTT) and fibrinogen levels should be normalized by infusions of fresh frozen plasma and cryoprecipitate in patients with APL or those with significant bleeding.

Infections and febrile neutropenia

  • During acute illness and chemotherapy, all patients should receive antibiotic prophylaxis (e.g., a fluoroquinolone) to reduce the risk of infection and febrile neutropenia.[129] Patients should also receive antifungal prophylaxis with a mold-active antifungal agent (e.g., posaconazole).[129]

  • Patients presenting with febrile illness need to be investigated and treated appropriately and promptly with antibiotics or anti-infective agents. See Febrile neutropenia.

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