Acute myeloid leukemia: Induction therapy in medically fit adults

INTRODUCTION — Acute myeloid leukemia (AML) describes a heterogeneous group of aggressive blood cancers that arise from malignant transformation and clonal expansion of hematopoietic precursor cells in the bone marrow. AML interferes with production of normal blood cells, which can cause fatigue, weakness, infection, bleeding, and other potentially life-threatening complications. Up to 40 percent of patients with de novo AML can achieve long-term remission/cure, but this generally requires intensive remission induction therapy that is suitable only for patients with adequate medical fitness. Because of age-related comorbidities, caution should be used when considering intensive chemotherapy for patients who are ≥75 years.

This topic discusses remission induction therapy for medically fit adults with de novo AML.

Other topics related to initial management of AML are provided separately:

●(See "Acute myeloid leukemia in adults: Overview".)

●(See "Acute myeloid leukemia: Management of medically unfit adults".)

●(See "Therapy-related myeloid neoplasms: Management and prognosis".)

OVERVIEW — Induction therapy for AML in medically fit patients involves intensive treatment with a significant risk of complications from the underlying disease and its treatment. Treatment should be administered in a center with the expertise and resources to manage AML.

The following features of induction therapy must be considered in managing a patient with AML:

●Goals of therapy – The goal of therapy for AML in medically fit patients is to achieve long-term survival and possible cure while limiting short-term and long-term adverse effects of treatment.

●Management – Treatment of AML is guided by medical fitness, clinical presentation, cytogenetics, and molecular features of the leukemic blasts:

•Fitness – Medical fitness is judged by performance status and comorbid conditions. There is no specific age threshold, but many centers limit intensive induction therapy for AML to patients either ≤70 or ≤75 years with adequate organ function. (See 'Medical fitness' below.)

•Classification and risk stratification – The AML subtype should be identified, and the risk category determined, as these features will affect induction therapy and postremission treatment, as well as outcomes. (See 'Classification and risk stratification' below.)

•Timing – Induction therapy should begin promptly, but it is more important to perform an adequate diagnostic work-up, stabilize the patient's condition, and control disease complications/emergencies than it is to start chemotherapy immediately [1,2]. However, for patients who are medically unstable due to complications or emergencies associated with the leukemia, prompt initiation of induction therapy may be the most efficient means of medical stabilization.

●Induction therapy

•The mainstay of induction therapy for medically fit adults with AML is intensive treatment with cytarabine plus an anthracycline. Induction therapy differs for patients with or without FLT3 mutation. (See 'Initial therapy' below.)

•Other acceptable regimens for AML induction therapy are discussed below. (See 'Alternative induction regimens' below.)

•For patients who are unlikely to tolerate such intensive treatment, treatments that can alleviate symptoms, improve the quality of life, and prolong survival are discussed separately. (See "Acute myeloid leukemia: Management of medically unfit adults".)

•Management of special scenarios, including limited cardiac function, pregnancy, and others are discussed below. (See 'Special scenarios' below.)

●Adjunctive care – Clinical assessment, symptom management, and administration of blood products and antimicrobial agents to manage the prolonged cytopenias and infections associated with induction therapy are discussed below. (See 'Adjunctive care' below.)

●Response to induction therapy – Evaluation of the response to therapy is needed to choose postremission management or treat refractory disease.

•The initial response to therapy is evaluated at the hematologic nadir. (See 'Nadir response assessment' below.)

•Findings from the nadir assessment determine if a reinduction course will be administered. (See 'Reinduction (second attempt)' below.)

•Remission status is determined after hematologic recovery and is judged by bone marrow findings; clinical and hematologic parameters; and assessment of measurable residual disease. (See 'Remission status' below.)

●Medical emergencies – Hyperleukocytosis/leukostasis; tumor lysis syndrome; bleeding and coagulation disorders; and neurologic complications are discussed below. (See 'Emergencies' below.)

●Postremission management

•Monitoring for relapse and complications of therapy is discussed below. (See 'Monitoring' below.)

•Consolidation and/or maintenance therapy are important aspects of long-term control/cure of AML and are discussed separately. (See "Acute myeloid leukemia in younger adults: Post-remission therapy".)

PRETREATMENT — The patient is evaluated for AML-related complications and emergencies and assessed for comorbidities that may affect the ability to tolerate intensive therapy.

Clinical evaluation — The history and physical examination should evaluate comorbid illnesses (eg, heart disease, liver or kidney dysfunction, uncontrolled diabetes mellitus) and other conditions (eg, prior hematologic and oncologic disorders or cytotoxic therapy) that might affect management.

●Organ function

•Heart disease – Special attention to cardiac function is required because of the large volumes of intravenous (IV) fluids administered during remission induction therapy and the routine use of anthracyclines.

Management for patients with congestive failure or dysrhythmias that might preclude anthracycline use is discussed below. (See 'Limited cardiac function' below.)

•Liver disease – Liver disease may affect the dose and schedule of anthracycline administration.

•Kidney disease – Renal insufficiency might affect the schedule and dose of cytarabine and influence management of tumor lysis syndrome.

●Drug allergies – History of allergies to antibiotics and other drugs should be noted since virtually every patient will require antibiotic therapy.

●Infections – History of active infections or latent infections that can reactivate or worsen in the setting of immunosuppression should be reviewed, including hepatitis B virus, hepatitis C virus, herpes simplex virus, cytomegalovirus, human immunodeficiency virus (HIV), and tuberculosis.

●Alloimmunization – Alloantibodies arising from prior transfusions or multiple pregnancies may presage transfusion reactions or other complications of red blood cell or platelet transfusions. (See "Refractoriness to platelet transfusion", section on 'Factors associated with platelet refractoriness'.)

●Prior hematologic or malignant disorders – Distinctive management may be required for patients with a preexistent hematologic condition, prior cytotoxic therapy, or a familial/germline disorder that predisposes to AML.

•Secondary leukemia – Secondary AML refers to AML that arises from a prior hematologic condition (eg, myelodysplastic syndromes/neoplasms, myeloproliferative neoplasms). Management is discussed below. (See 'Secondary and therapy-related AML' below.)

•Therapy-related myeloid neoplasms – Patients with AML who previously received cytotoxic agents or radiation therapy are considered to have therapy-related myeloid neoplasms. Such patients may require special management, especially if there is chronic organ injury from their primary disorder or unfavorable disease biology (eg, TP53 mutation) associated with prior treatment. (See "Therapy-related myeloid neoplasms: Management and prognosis".)

•Germline or familial predisposition – AML in the setting of a familial/inherited disorder may require distinctive management.

These conditions may be suspected if there is personal or family history of prior hematologic or other malignancies, unexplained cytopenias, certain somatic stigmata (eg, congenital limb anomalies, deafness, premature graying, skin or nail abnormalities, unexplained organ dysfunction), or genetic abnormalities involving RUNX1, ETV6, GATA2, or DDX41.

Evaluation and diagnosis of germline disorders are discussed separately. (See "Familial disorders of acute leukemia and myelodysplastic syndromes".)

Laboratory studies — The following laboratory studies should be performed (table 1):

●Hematology

•Complete blood count with white blood cell (WBC) differential count.

•Review of blood smear (≥200 nucleated cells).

●Coagulation – Prothrombin time/international normalized ratio, activated partial thromboplastin time, fibrinogen.

●Chemistries – Electrolytes, glucose, renal function tests, calcium, phosphorus, uric acid, liver function tests, albumin, total protein, and lactate dehydrogenase.

●Infectious – Serologic testing for hepatitis A, B, and C; HIV; herpes simplex virus; cytomegalovirus; varicella zoster virus.

●Human leukocyte antigen typing – Human leukocyte antigen (HLA) typing should be performed for patients who may be candidates for hematopoietic cell transplantation (HCT). HLA class I typing should be performed in case of refractoriness to platelet transfusion due to HLA alloantibodies.

●Urine analysis – If clinically warranted.

Other evaluation and management

●Cardiac

•Electrocardiogram – Arrhythmias and baseline prolongation of the QTc interval should be noted.

•Ejection fraction – Echocardiogram or radionuclide ventriculography is performed to assess cardiac function. (See "Tests to evaluate left ventricular systolic function".)

Management of otherwise-fit patients with impaired cardiac function is discussed below. (See 'Limited cardiac function' below.)

●Neurologic – Routine screening with a lumbar puncture (LP) is not indicated for patients who are asymptomatic at the time of diagnosis.

Evaluation and management for patients with unexplained neurologic abnormalities at diagnosis are discussed separately. (See "Involvement of the central nervous system (CNS) with acute myeloid leukemia (AML)".)

Some experts suggest performing a diagnostic LP for patients with high-risk features for central nervous system (CNS) involvement (eg, WBC count >100,000/microL or AML with monocytic features).

The CNS should be reevaluated after achieving systemic remission. (See 'Response evaluation' below.)

●Central venous catheter – A central venous access catheter, such as a percutaneous IV central catheter, with two or three independent lumens should be implanted. Use of fully implantable devices should be avoided during induction chemotherapy because of the higher risks of bleeding or infection and impediments to rapid removal in the event of an infection. (See "Central venous access in adults: General principles".)

●Dental evaluation – A professional dental evaluation may be warranted, especially for patients with poor dentition/dental health, to identify and address possible infectious foci.

●Chest radiograph

●Fertility – People with childbearing potential should receive counseling about the potential effect of treatment on fertility and options for fertility preservation. Individuals of childbearing potential should have a serum pregnancy test. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)

Medical fitness — Medical fitness is determined by the patient's performance status and the nature and severity of comorbid conditions. Fitness for intensive therapy is not determined by chronologic age per se.

There are no absolute criteria for classification of fitness, and the assessment should consider both preexistent conditions and the effects of the leukemia itself. We attempt to address medical comorbidities and/or improve the patient's clinical status before excluding an individual as a candidate for intensive treatment.

We do not apply an upper age limit for intensive treatment of AML, but caution is warranted for patients ≥75 years. Clinical trials have applied various criteria for inclusion, and the upper limit for inclusion has increased over time.

We use the following instruments to judge medical fitness:

●Performance status – The following instruments and scores (table 2) are generally acceptable for assessing fitness for intensive induction therapy:

•Eastern Cooperative Oncology Group performance status (ECOG PS) – 0 to 1

•Karnofsky performance status (KPS) – ≥80

●Comorbidities – To assess the significance of comorbid conditions, we use the hematopoietic cell transplantation specific comorbidity index (HCT-CI) (table 3), which was originally designed to predict outcomes in patients undergoing HCT [3].

Geriatric consultation can be helpful to assess patients who may be at increased risk for treatment-related complications. Examples include patients with impaired performance status (eg, ECOG PS ≥2, KPS <80), significant comorbidities (eg, HCT-CI ≥3), or age ≥75 years. (See "Pretreatment evaluation and prognosis of acute myeloid leukemia in older adults".)

CLASSIFICATION AND RISK STRATIFICATION — AML should be analyzed and categorized using a contemporary classification scheme and the prognosis evaluated.

Pathology — Bone marrow aspirate and biopsy should be performed and analyzed with microscopy, cytogenetics, and molecular testing.

●Microscopy – The percentage of blasts is determined by counting ≥500 nucleated cells. Myeloblasts, monoblasts, and megakaryoblasts are included in the blast count. Monoblasts and promonocytes but not abnormal monocytes are counted as blast equivalents for cases of AML with monocytic or myelomonocytic differentiation.

●Immunophenotype – Flow cytometry should include markers of hematopoietic precursors, myeloid differentiation and maturation, monocytes, megakaryocytes, erythroid cells, T lymphocytes, and B lymphocytes.

●Cytogenetics – Chromosome banding of ≥20 metaphases is required to define a normal karyotype and is preferred for an abnormal karyotype. Blood specimens with circulating blasts can be used to define the karyotype.

If there are no analyzable metaphases, fluorescence in-situ hybridization is acceptable for detecting genetic abnormalities (eg, RUNX1::RUNX1T1, CBFB::MYH11, KMT2A, and MECOM gene fusions) or myelodysplasia-related chromosomal abnormalities (eg, loss of chromosome 5q, 7q, or 17p).

●Genetic analysis – Screening for acquired gene mutations and for inherited gene variants of potential pathogenic significance is required to diagnose and classify AML and to identify actionable therapeutic targets. Gene panel testing is preferred where available.

Testing should include:

•Gene rearrangements – PML::RARA, CBFB::MYH11, RUNX1::RUNX1T1, KMT2A rearrangements, BCR::ABL1.

•Actionable mutations – FLT3 (including internal tandem duplications [ITD] and of tyrosine kinase domain [TKD] mutations), IDH1, IDH2.

•Other mutations with prognostic relevance – NPM1, CEBPA, DDX41, TP53; ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2.

AML classification — Two revised classification schemes for hematologic malignancies were published in 2022. These models differ in important ways from each other and from earlier classification schemes. Examples of important changes include the blast thresholds to diagnose AML, newly defined genetic subtypes, and new labels and organization for certain subtypes of AML:

●International Consensus Classification (ICC) [4].

●World Health Organization 5^th edition (WHO5) [5].

Both ICC and WHO5 rely heavily on cytogenetic and molecular features of AML, and use of either scheme is preferred over earlier classification models. Details of AML classification are discussed separately. (See "Acute myeloid leukemia: Classification".)

ICC and WHO5 apply the same criteria for diagnosis of acute promyelocytic leukemia with t(15;17)(q24.1;q21.2)/PML::RARA, which requires distinctive management that differs from treatment of other categories of AML. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults" and "Initial treatment of acute promyelocytic leukemia in adults".)

ICC and WHO5 apply different labels and diagnostic criteria for certain categories of AML including:

●Secondary AML

●Therapy-related myeloid neoplasms

●Mixed phenotype acute leukemia

●Myeloid neoplasms with germline predisposition

Details of AML nosology are presented separately. (See "Acute myeloid leukemia: Classification".)

European LeukemiaNet risk stratification — The European LeukemiaNet (ELN) stratification scheme uses cytologic and molecular features of the leukemia to categorize prognosis as follows [6]:

●Favorable

•t(8;21)(q22;q22.1)/RUNX1::RUNX1T1

•inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/CBFB::MYH11

•Mutated NPM1 without FLT3-ITD

•bZIP in-frame mutated CEBPA

●Intermediate

•Mutated NPM1 with FLT3-ITD

•Wild-type NPM1 with FLT3-ITD (without adverse-risk genetic lesion)

•t(9;11)(p21.3;q23.3)/MLLT3::KMT2A

•Cytogenetic and/or molecular abnormalities not classified as favorable or adverse

●Adverse

•t(6;9)(p23;q34.1)/DEK::NUP214

•t(v;11q23.3)/KMT2A-rearranged

•t(9;22)(q34.1;q11.2)/BCR::ABL1

•t(8;16)(p11;p13)/KAT6A::CREBBP

•inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/GATA2, MECOM (EVI1)

•t(3q26.2;v)/MECOM (EVI1)-rearranged

•-5 or del(5q); -7; -17/abn(17p)

•Complex karyotype or monosomal karyotype

•Mutated ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2

•Mutated TP53

The ELN prognostic category may influence the choice of induction therapy and it guides postremission management of AML.

INDUCTION THERAPY — The backbone of intensive induction therapy for AML is cytarabine plus an anthracycline. There are several acceptable regimens as discussed below. (See 'Initial therapy' below.)

Special scenarios that may affect selection of induction therapy are discussed below. (See 'Special scenarios' below.)

Initial therapy — Induction therapy is stratified according to the presence or absence of mutated FLT3:

●(See 'AML without mutated FLT3' below.)

●(See 'AML with mutated FLT3' below.)

AML without mutated FLT3 — For newly diagnosed AML without mutated FLT3, we recommend treatment with a seven-day continuous infusion of cytarabine plus an anthracycline for three days (so-called "7+3 therapy"), based on the favorable balance of outcomes and toxicity.

●Administration – The regimen that is most often used is:

•Cytarabine – 100 to 200 mg/m²/day by continuous intravenous (IV) infusion for days 1 to 7

•Anthracycline

-Daunorubicin – 60 to 90 mg/m² IV on days 1 to 3

or

-Idarubicin – 12 mg/m² IV on days 1 to 3

●Adverse effects – Treatment with "7+3 therapy" generally causes three to five weeks of profound cytopenias with a risk of life-threatening infections and bleeding. Many patients will experience nausea and vomiting, mucositis/stomatitis, alopecia, and diarrhea. Cytarabine may cause a flu-like syndrome (including fever and/or rash), and daunorubicin can be associated with infusion reactions and cardiac arrhythmias. These and other adverse effects (AEs) are discussed in more detail separately. (See 'Adjunctive care' below and "Infusion reactions to systemic chemotherapy", section on 'Anthracyclines and related agents' and "Infusion reactions to systemic chemotherapy", section on 'Cytarabine'.)

●Outcomes – Regimens using cytarabine plus anthracycline have been standard induction therapy for AML for many years. Randomized trials that examined the dose, schedule, and choice of agents in "7+3 therapy" reported similar outcomes using cytarabine plus either daunorubicin, idarubicin, or the anthracenedione mitoxantrone. Replacement of infusional cytarabine by high-dose cytarabine (HiDAC) was associated with increased toxicity without improved efficacy.

•Daunorubicin dose – Higher doses of daunorubicin (eg, 60 mg/m² or 90 mg/m²) are more efficacious but not more toxic compared with daunorubicin 45 mg/m².

A systematic review and meta-analysis that included 29 randomized trials reported that higher-dose daunorubicin was associated with reduced rates for remission failure (relative risk [RR] 0.75; 95% CI 0.60-0.94) and overall mortality (RR 0.83; 95% CI 0.75-0.93) but similar rates of early death [7].

In the Eastern Cooperative Oncology Group (ECOG) 1900, 330 patients <60 years old with favorable/intermediate-risk AML were randomly assigned to treatment with daunorubicin 90 mg/m² versus 45 mg/m² [8]. Compared with the lower dose, higher-dose daunorubicin achieved superior median overall survival (OS; 34 versus 21 months) and more complete remissions (CR; 71 versus 57 percent); both trial arms had similar rates of grade ≥3 AEs, including cardiac and hematopoietic toxicity.

Other randomized trials evaluated daunorubicin 90 mg/m² in AML induction therapy. Compared with 45 mg/m², the 90 mg/m² dose achieved superior five-year OS (47 versus 35 percent) and CR (83 versus 72 percent) [9]. In another randomized trial, OS, relapse-free survival, CR, and AEs were similar with daunorubicin 90 mg/m² versus 60 mg/m² [10]; however, retrospective analysis of this trial reported that the higher dose of daunorubicin was associated with improved outcomes only for the subset of patients with FLT3 mutation [11], as described below. (See 'AML with mutated FLT3' below.)

•Daunorubicin versus idarubicin – Daunorubicin and idarubicin are associated with similar outcomes.

A systematic review and meta-analysis reported no difference between daunorubicin and idarubicin with regard to overall mortality or early death [7].

The three-arm Acute Leukemia French Association (ALFA)-9801 trial randomly assigned 468 patients 50 to 70 years old to daunorubicin 80 mg/m² once daily for three days versus idarubicin 12 mg/m² once daily for three days versus idarubicin 12 mg/m² once daily for four days; rates of CR were 70, 83, and 78 percent, respectively, but OS, event-free survival (EFS), and relapse incidence did not differ between arms [12].

•Cytarabine dose – Comparable outcomes and toxicity were achieved with a seven-day continuous infusion of cytarabine 100 mg/m²/day versus cytarabine 200 mg/m²/day [13]. Compared with HiDAC plus an anthracycline, "7+3 therapy" using either dose of infusional cytarabine achieved similar outcomes but less toxicity [14-16].

There is no evidence that alternative induction regimens are associated with better outcomes or less toxicity than "7+3 therapy" in this setting, as discussed below. (See 'Alternative induction regimens' below.)

For patients with secondary AML, therapy-related AML, or adverse cytogenetic features, some experts favor induction using CPX-351 (liposome-encapsulated cytarabine plus daunorubicin), as discussed below. (See 'Secondary and therapy-related AML' below.)

For CD33-positive AML with intermediate or favorable cytogenetic features, some experts add gemtuzumab ozogamicin (GO) to "7+3 induction therapy," as discussed below. (See 'Gemtuzumab ozogamicin' below.)

AML with mutated FLT3 — For patients with FLT3-mutated AML, we recommend addition of either midostaurin (for any FLT3 mutation) or quizartinib (for FLT3 with internal tandem repeats [ITD]) to intensive induction chemotherapy.  

●Administration

•Midostaurin – Administered orally 50 mg twice daily on days 8 through 21. Cytarabine and an anthracycline are administered, as described above. (See 'AML without mutated FLT3' above.)

Strong CYP3A4 activators and inhibitors may alter exposure to midostaurin and its active metabolites; alternatives to agents that strongly affect CYP3A4 should be considered.

•Quizartinib – Administered 35.4 mg orally once daily on days 8 to 21 of "7+3" therapy.

A boxed warning for quizartinib notes QT prolongation, torsades de pointes, and cardiac arrest. The QT interval should be assessed prior to initiating quizartinib and periodically during treatment. Hypokalemia and hypomagnesemia should be corrected. Treatment should not be initiated if the QT interval (corrected by Fridericia's formula [QTcF]) is >450 ms. The dose of quizartinib should be reduced when used concomitantly with strong CYP3A inhibitors.

The US Food and Drug Administration (FDA) and the European Medicines Agency approved midostaurin in combination with chemotherapy for newly diagnosed AML with mutated FLT3 in adults. The FDA approved quizartinib in combination with "7+3" induction therapy for AML that is positive for FLT3-ITD but not for other FLT3 mutations; quizartinib is available only through a Risk Evaluation and Mitigation Strategy (REMS) in the US [17].

●Adverse effects – In phase 3 trials that compared either midostaurin or quizartinib versus placebo as components of induction therapy, there were similar rates of grade ≥3 febrile neutropenia, infections, nausea, and mucositis in both treatment arms [18-20].

●Outcomes

•Midostaurin – In the CALGB 10603/RATIFY trial, 717 adults (<60 years) who had AML with FLT3-internal tandem duplications (ITD; 77 percent) or FLT3-tyrosine kinase domain (TKD) mutations (23 percent) were randomly assigned to 7+3 chemotherapy plus either midostaurin or placebo [18]. With median follow-up of 59 months compared with placebo, midostaurin achieved superior median OS (75 versus 26 months), four-year OS (51 versus 44 percent), median EFS (8 versus 3 months), and four-year EFS (28 versus 21 percent). The two trial arms had similar rates of CR, time to recovery of neutrophils and platelets, grade ≥3 toxicity, and treatment-related deaths.

A phase 2 study reported that addition of midostaurin to 7+3 chemotherapy was also beneficial in older patients (61 to 70 years) [21].

•Quizartinib – Addition of quizartinib to "7+3" induction therapy achieved better survival than adding placebo to "7+3" therapy, among 539 patients with FLT3 ITD-positive AML in the phase 3 QuANTUM-First trial [20].Patients subsequently received consolidation with HiDAC plus either quizartinib or placebo, allogeneic hematopoietic cell transplantation (HCT), or both, followed by continuation of single-agent quizartinib or placebo for up to three years. Median OS was 32 months with quizartinib compared with 15 months with placebo (HR 0.78 [95% CI 0.62-0.98]). The most common grade ≥3 AEs were febrile neutropenia, hypokalemia, and pneumonia in both groups and neutropenia in the quizartinib group; at least one grade ≥3 AE occurred in approximately 90 percent of patients in both arms.

Nadir response assessment — Bone marrow examination is performed at the hematologic nadir (usually day 14 to 22). For patients receiving midostaurin (days 8 to 21), the nadir assessment should be performed on day 22. Further management is guided by the findings:

●Hypoplasia – For bone marrow that reveals hypoplasia (ie, <20 percent cellularity) and clearance of blasts (ie, <5 percent of residual cellularity), monitoring of blood counts and adjunctive care continues until recovery of blood counts. (See 'Adjunctive care' below.)

●Persistent blasts – For bone marrow that is not hypoplastic and/or has blasts ≥5 percent, a second cycle of induction therapy should be administered without delay if the patient can tolerate it. (See 'Reinduction (second attempt)' below.)

If the findings from the nadir study are ambiguous, a bone marrow examination should be repeated five to seven days later.

Reinduction (second attempt) — For patients with persistent AML on the nadir bone marrow examination, we suggest reinduction therapy rather than observation.

Reinduction generally uses cytarabine, with or without an anthracycline or other agents, but doses and schedules vary among institutions, and there is no consensus.

Examples of reinduction regimens include:

●Repeat treatment with an anthracycline plus infusional cytarabine – Various protocols have been used for reinduction, including repeat treatment with "7+3" or variants of the initial induction regimen. (See 'Initial therapy' above.)

In some settings, reinduction may include a shorter course (eg, five days of cytarabine infusion plus two days of an anthracycline) and/or a lower dose of the anthracycline (eg, daunorubicin 45 mg/m² or idarubicin 10 mg/m²).

●Other cytarabine-based treatment – An intermediate-dose cytarabine-containing regimen (eg, FLAG [fludarabine, cytarabine, and granulocyte colony-stimulating factor (G-CSF)]) or HiDAC alone may be used for reinduction.

HiDAC is generally limited to patients ≤60 years because of the increased risk of neurotoxicity in older patients, and the dose may be adjusted based on renal function. (See "Acute myeloid leukemia in younger adults: Post-remission therapy", section on 'Administration of consolidation HiDAC'.)

For older patients with residual disease or those who cannot tolerate another course of anthracycline/cytarabine, some clinicians switch to a hypomethylating agent plus venetoclax, based on efficacy in previously untreated older patients with AML and relapsed/refractory disease [22-25].

REMISSION STATUS — The response to induction therapy is determined by evaluation of bone marrow, blood, and/or extramedullary sites (if involved) after recovery of hematopoiesis.

Response evaluation

●Bone marrow – Bone marrow aspirate and biopsy is performed when the absolute neutrophil count (ANC) is ≥1 x 10⁹/L (≥1000/microL) and platelet count is ≥100 x 10⁹/L (≥100,000/microL). This is generally four or more weeks after starting induction therapy, although the timing varies according to whether the patient received one or two cycles of induction therapy.

●Extramedullary involvement – For patients with central nervous system (CNS) involvement at diagnosis, the CNS should also be reevaluated with imaging and/or lumbar puncture, as discussed separately. (See "Involvement of the central nervous system (CNS) with acute myeloid leukemia (AML)".)

Similarly, patients with extramedullary tumor masses (ie, myeloid sarcoma) should have post-therapy imaging and if necessary, biopsy, to confirm remission.

Remission criteria — Following are remission criteria; note that outcomes are modified to incorporate measurable residual disease (MRD) status if evaluated.

●Complete remission (CR) – Bone marrow blasts <5 percent and none with Auer rods; no circulating blasts or blasts with Auer rods; absence of extramedullary disease; ANC ≥1 x 10⁹/L (≥1000/microL); platelet count ≥100 x 10⁹/L (100,000/microL)

●CR with partial hematologic recovery (CRh) – ANC ≥0.5 x 10⁹/L and platelet count ≥50 x 10⁹/L; all other CR criteria are met.

●CR with incomplete hematologic recovery (CRi) – CRi can be used to describe patients who meet all CR criteria except for residual neutropenia (<1 x 10⁹/L) or thrombocytopenia (platelets <100 x 10⁹/L).

●Refractory AML – Not meeting criteria for CR, CRh, or CRi after two cycles of intensive induction therapy.

Measurable residual disease — MRD can provide a quantitative method to define a deeper remission than morphologic criteria alone, and it can refine postremission relapse risk assessment and identify impending relapse.

MRD has prognostic value for overall survival (OS) and relapse based on a systematic meta-analysis and various studies [26-31]. However, a negative assay simply indicates that disease is below the threshold of the assay; it does not indicate complete eradication of the leukemia, since relapse can still occur in a small minority of MRD-negative patients, and conversely, not all MRD-positive patients inevitably relapse.

Multiparameter flow cytometry (MFC) and quantitative polymerase chain reaction (qPCR) are the most common methods for assessing MRD [32]. Next-generation sequencing (NGS) and digital PCR are emerging technologies for assessing MRD, but they are not currently standard approaches in clinical practice [33]. The preferred technique varies among institutions and with pathologic aspects of the case. MFC is more broadly applicable (eg, up to 90 percent of cases), but it is slightly less sensitive than qPCR, which is applicable in up to one-half of cases of AML [6].

Standards for MRD analysis, MRD thresholds, and definitions of MRD response have been published [34].

For patients with CR or CRh with negative MRD, the outcome can be labeled CR_MRD- or CRh_MRD-, respectively.

MRD by multiparameter flow cytometry — Multiparameter flow cytometry (MFC) is the most common method for assessing MRD in clinical practice. It can be used in nearly all cases of AML, and it provides sensitivity of 10^-3 to 10^-4.

Persistent blasts are distinguished from normal hematopoietic cells according to a leukemia-associated immunophenotype or a "different from normal" immunophenotype. MFC evaluation for leukemic stem cells is investigational and not widely used in clinical practice.

A set of "core" markers should include: CD34, CD117, CD45, CD33, CD13, CD56, CD7, and HLA-DR. If the blasts exhibit monocytic features, CD64, CD11b, and CD4 should be added.

Molecular MRD — Polymerase chain reaction (PCR) can detect MRD in blood or bone marrow. The sensitivity is 10^-4 to 10^-5 in marrow, but it is generally one order of magnitude less sensitive in blood.

Leukemia-related abnormalities that are suitable for qPCR monitoring include mutated NPM1; CBFB::MYH11, RUNX1::RUNX1T1, KMT2A::MLLT3, DEK::NUP214, and BCR::ABL1 gene fusions; and WT1 expression [34]. Detection of MRD by qPCR has been best validated with AML that has NPM1 mutation, CBFB::MYH11, or RUNX1::RUNX1T1 [35].

MRD detection by NGS is not broadly used in clinical practice. If used, error-corrected targeted panel-based approaches are preferred. Care must be taken to recognize and exclude germline mutations (eg, DDX41) or mutations associated with preexisting clonal hematopoiesis of indeterminate potential (CHIP; eg, DNMT3A, TET2, ASXL1), as these are not considered to reflect MRD for AML [36].

ADJUNCTIVE CARE — Patients undergoing intensive remission induction therapy require careful monitoring and adjunctive care for manifestations of the underlying leukemia and treatment-associated complications. Induction therapy generally causes three to five weeks of profound cytopenias and may cause life-threatening infections, organ dysfunction, and other complications.

●Clinical monitoring – The patient should be examined at least daily for infusion reactions, tumor lysis syndrome (TLS; especially with high blast counts), nausea/vomiting, mucositis, diarrhea, infections, and other complications of therapy. It is important to recognize that clinical findings of infection may be blunted or absent during periods of profound neutropenia. Careful attention is paid to fluid balance and daily weights, and diuretics may be necessary.

●Laboratory studies – We perform the following laboratory studies:

•Complete blood count with differential – Complete blood count (CBC) with differential count should be performed daily until recovery of white blood cell count to ≥500/microL and platelet transfusion independence is achieved. The frequency of CBCs can then be reduced (eg, to every other day), as clinically appropriate.

•Coagulation studies – Prothrombin time/international normalized ratio and partial thromboplastin should be monitored at least weekly or more frequently if clinically indicated. Fibrinogen should be measured early in remission induction because disseminated intravascular coagulation (DIC) can be triggered by chemotherapy. Patients with clinical or laboratory evidence of DIC, serum fibrinogen, fibrin degradation products (FDPs), and/or other tests should be monitored at least daily until DIC has resolved. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Treatment'.)

•Chemistry profile – Chemistry profile, including electrolytes, blood urea nitrogen (BUN), creatinine, uric acid, calcium, phosphorus, and liver function tests, including lactate dehydrogenase, should be performed at least daily until the risk of TLS has passed. The frequency of testing can then be adjusted as clinically appropriate. Close monitoring of BUN and creatinine may be required throughout the hospitalization for patients who are receiving nephrotoxic agents, such as certain antibiotics. Elevated serum lysozyme levels may lead to renal tubule damage/dysfunction in patients with monocytic/monoblastic leukemia.

●Symptom management

•Nausea/vomiting and other gastrointestinal toxicity – Effective management of nausea and vomiting enhances patient comfort, improves oral hydration and nutritional status, and can reduce the risk of gastrointestinal bleeding or a Mallory-Weiss tear from forceful vomiting.

Management of severe nausea and vomiting is described separately. (See "Prevention of chemotherapy-induced nausea and vomiting in adults", section on 'Induction therapy for acute leukemia'.)

Induction chemotherapy can damage gastrointestinal epithelial cells and cause painful oral mucositis and diarrhea. Pain may also limit the ability to take oral fluids and nutrition, exacerbating fluid imbalances and impaired nutrition. Breakdown of the mucosal barrier predisposes to viral, bacterial, and fungal (mostly Candida albicans) superinfection, particularly as the hematologic nadir is reached. Management of chemotherapy-induced mucositis and diarrhea are presented separately. (See "Oral toxicity associated with systemic anticancer therapy", section on 'Treatment of established mucositis'.)

•Cytopenias – Profound and prolonged cytopenias are universal with intensive remission induction therapy, and transfusion of red blood cells (RBCs) and platelets should be provided as needed. Granulocyte colony-stimulating factor (G-CSF; filgrastim) and other myeloid growth factors are not routinely administered.

-Transfusions – There is no consensus threshold for transfusion of RBCs or platelets. We generally transfuse RBCs when the patient has anemia-associated symptoms (eg, profound fatigue, dyspnea) and aim to maintain the hemoglobin ≥7 g/dL, but this may vary with age, symptoms, comorbid conditions, and institutional approach. We transfuse platelets prophylactically for patients with platelet counts <10,000/microL or for overt bleeding, such as oral purpura. For patients who are not bleeding, there is no benefit in transfusing multiple platelet units beyond a single platelet pheresis unit daily [37,38]. (See "Indications and hemoglobin thresholds for RBC transfusion in adults" and "Platelet transfusion: Indications, ordering, and associated risks", section on 'Leukemia, chemotherapy, and HSCT'.)

All patients should receive leukoreduced blood products to decrease febrile nonhemolytic transfusion reactions, alloimmunization, and other complications. Irradiated blood products are required for individuals who may be candidates for hematopoietic cell transplantation (HCT) to prevent transfusion-associated graft-versus-host disease (ta-GVHD). For cytomegalovirus (CMV)-negative patients who are candidates for HCT, blood products should be leukoreduced or from CMV-negative donors. (See "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion", section on 'Pre-storage leukoreduction' and "Transfusion-associated graft-versus-host disease".)

-Growth factors – In a randomized trial, G-CSF hastened neutrophil recovery but did not lead to differences in the number, severity, or duration of infections [39]. Treatment with G-CSF has been reported to have variable but uncertain effects on the rate of relapse and/or survival in subsets of patients with AML [40-43]. Long-term safety of myeloid growth factors for patients with AML is undefined.

•Fever/infection – Prevention of infections is critical given the substantial morbidity and mortality in these patients. The prolonged and profound neutropenia associated with induction therapy is frequently accompanied by fever, a high risk of bacterial or fungal infection, and viral reactivation. Even though most infections during induction therapy are due to endogenous flora, precautions should be taken to limit exposure to exogenous pathogens.

Fever or other infectious findings in a neutropenic patient require prompt evaluation and administration of empiric, broad-spectrum parenteral antibiotics. The choice of antibiotics should be tailored to the most likely organisms and institutional drug resistance patterns. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)".)

-General measures – Careful hand hygiene, prohibition against sick visitors, and other precautions are used to limit infections. Most methods to reduce the risk of infection have not been rigorously tested but are applied because they are relatively simple and may reduce exposure to potential pathogens. (See "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults", section on 'General precautions'.)

No benefit was reported from implementation of a "neutropenic diet" (ie, elimination of raw fruits and vegetables) on survival or infections, according to a meta-analysis and randomized trials [44-46].

-Prophylaxis – There is no consensus for use and/or choice of prophylactic antibiotics, antifungals, and antiviral agents during remission induction therapy. Some institutions administer prophylactic fluoroquinolones and/or antifungals, but the potential benefit varies according to the local flora and results of surveillance cultures and must be weighed against the risk of selecting for drug-resistant organisms [47].

The American Society of Clinical Oncology and the Infectious Disease Society of America recommend that severely neutropenic patients undergoing intensive chemotherapy receive prophylactic antibacterial and antifungal therapy and that patients who are seropositive for hepatitis B core antibody or herpes simplex virus with leukemia receive antiviral prophylaxis [48,49]. Management of antimicrobial prophylaxis is discussed separately. (See "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults" and "Prophylaxis of invasive fungal infections in adults with hematologic malignancies".)

MONITORING — Most medically fit patients who achieve complete remission after induction therapy proceed to postremission management and subsequent monitoring for relapse and treatment-related complications, as described separately. (See "Treatment of relapsed or refractory acute myeloid leukemia".)

For patients who do proceed to postremission therapy, there is no consensus about timing of follow-up bone marrow examinations. If the complete blood count remains normal, it is reasonable to repeat a bone marrow examination two to three months after the completion of treatment, since most relapses are signaled by a decline in the platelet count or the appearance of leukemic blasts in the blood smear.

ALTERNATIVE INDUCTION REGIMENS

FLAG-Ida — FLAG-Ida (fludarabine, cytarabine, G-CSF [granulocyte colony-stimulating factor], idarubicin) is used by some experts for patients with intermediate or adverse prognosis AML.

●Administration – FLAG-Ida consists of intravenous (IV) fludarabine 30 mg/m² on days 2 to 6, high-dose cytarabine (HiDAC; 1500 to 2000 mg/m² IV over three hours starting four hours after fludarabine infusion on days 2 to 6), idarubicin 10 mg/m² IV on days 2 to 4, and G-CSF 5 microg/kg subcutaneously on days 1 to 5. Additional G-CSF may be administered starting on seven days after the end of chemotherapy until the white blood cell count is >500/microL.

The following dose adjustments should be considered for patients >60 years: fludarabine 20 mg/m², cytarabine 500 to 1000 mg/m², and idarubicin 8 mg/m².

●Outcomes – There is no evidence that FLAG-Ida is associated with better outcomes than induction with cytarabine/anthracycline.

In the MRC AML 15 trial, younger patients (median 49 years) were randomly assigned to FLAG-Ida versus two induction courses of daunorubicin/cytarabine, with or without etoposide; patients receiving FLAG-Ida or daunorubicin/cytarabine (without etoposide) were also randomly assigned to receive a single dose of gemtuzumab ozogamicin (GO) during the first induction cycle [50]. Patients were then randomly assigned to different consolidation regimens (HiDAC versus amsacrine, cytarabine, etoposide, then mitoxantrone/cytarabine). There was no difference in complete remission (CR) rate between patients who received induction therapy with FLAG-Ida versus daunorubicin/cytarabine/etoposide (84 versus 81 percent, respectively), but FLAG-Ida was associated with a decreased relapse rate (38 versus 55 percent).

CPX-351 — CPX-351 is a liposomal formulation that encapsulates cytarabine/daunorubicin in a 5:1 fixed molar ratio [51]. Treatment with CPX-351 for secondary AML and therapy-related AML is discussed below. (See 'Secondary and therapy-related AML' below.)

CPX-351 is given 100 units/m² as a 90-minute IV infusion on days 1, 3, and 5. For patients with persistent blasts or without hypoplastic bone marrow on day 14, reinduction (second induction) with the same dose of CPX-351 is given on days 1 and 3.

Gemtuzumab ozogamicin — Gemtuzumab ozogamicin (GO) is an anti-CD33 monoclonal antibody linked to calicheamicin that has yielded mixed results when added to "7+3 therapy" for CD33-positive AML, but treatment is associated with increased toxicity.

●Administration – GO is given IV at 3 mg/m² (capped at 5 mg) on days 1, 4, and 7 of induction therapy; a single dose of GO on day 1 of induction may also be efficacious [52-54].

Various doses and schedules have been used when combining GO with chemotherapy, and higher doses appear to be associated with increased risks [52,55].

The threshold of CD33 expression for efficacy of GO is not well-defined.

●Outcomes – Addition of GO to AML induction therapy was beneficial for certain subsets of patients in a meta-analysis, but individual randomized trials provided mixed results:

•A meta-analysis of five studies reported that addition of GO to "7+3 induction therapy" was associated with better outcomes in some prognostic subsets of patients [52]. For patients with favorable- or intermediate-risk cytogenetics, addition of GO to cytarabine/anthracycline induction therapy was associated with better five-year overall survival (OS) (hazard ratio [HR] 0.90 [95% CI 0.82-0.98]) and reduced risk of relapse (HR 0.81 [95% CI 0.73-0.90]), but it was not associated with more favorable rates of response (CR plus CR with incomplete hematologic recovery [CRi]). No benefit for GO was observed for patients with adverse-risk karyotypes.

•The multicenter, phase 3 ALFA-0701 trial of 271 patients (age 50 to 70 years) reported superior event-free survival (EFS) (ie, induction failure, relapse, or death) with GO plus "7+3 therapy" compared with "7+3" alone (17 versus 10 months, respectively; HR 0.56 [95% CI 0.42-0.76]), but there was no difference in OS [56,57]. In a follow-up study, the benefit of GO was limited to patients with favorable- or intermediate-risk cytogenetic findings and those with FLT3 or KRAS mutations [58].

•A trial (AMLSG 09-09) that randomly assigned 588 patients with NPM1-mutated AML to idarubicin, cytarabine, etoposide, and all-trans retinoic acid, with or without GO, reported that GO was associated with a lower cumulative incidence of relapse and a greater proportion of patients with undetectable measurable residual disease (MRD), but there were more early deaths (10 versus 6 percent), primarily due to infections and no difference in EFS [59,60].

•In the MRC AML 15 trial, in patients ≤60 years, addition of GO to induction therapy was well tolerated, and there were no differences in relapse-free survival or OS between arms that received or did not receive GO [53]. Benefits were seen in patients with favorable-risk cytogenetics, with a trend toward benefit for those with intermediate-risk cytogenetics.

•GO has been associated with mixed results in older patients with AML. In a trial of older patients with AML (median 67 years), addition of GO to induction therapy using either cytarabine/anthracycline or daunorubicin/clofarabine did not improve CR rate or substantially increase toxicity, but it did achieve improved survival and fewer relapses [54]. In another trial, addition of GO provided no benefit, but it was associated with increased toxicity.

GO is approved by the US Food and Drug Administration in combination with "7+3 therapy" for treatment of adults with newly diagnosed CD33-positive AML.

The GO label includes a boxed warning about hepatotoxicity, including severe or fatal hepatic sinusoidal obstruction syndrome (also called veno-occlusive disease). Other toxicities include infusion-related reactions (including anaphylaxis), hemorrhage, and teratogenicity.

Other regimens — There is no conclusive evidence that other induction regimens are superior to "7+3 therapy." As an example, a phase 3 trial reported comparable rates of CR (approximately 80 percent) using the following three regimens: cytarabine and daunorubicin; etoposide, cytarabine, and daunorubicin; or FLAG (fludarabine, cytarabine, and G-CSF) [50].

Aside from the benefit of adding midostaurin for FLT3-mutated AML and a possible benefit from adding GO for CD33-positive AML, there is no persuasive evidence of benefit from adding other agents to a cytarabine/anthracycline backbone. Effects of midostaurin and GO are discussed above. (See 'AML with mutated FLT3' above and 'Gemtuzumab ozogamicin' above.)

Examples of other AML induction regimens include:

●Mitoxantrone-cytarabine – Mitoxantrone is an anthracenedione that has been used in place of an anthracycline for induction therapy. Mitoxantrone 12 mg/m² IV on days 1, 2, and 3 (replacing an anthracycline) is given along with a seven-day cytarabine infusion. (See 'Initial therapy' above.)

There is no evidence that mitoxantrone-based induction is more effective or less toxic than an anthracycline for induction therapy.

•The AML-10 trial randomly assigned 2157 patients with AML to cytarabine and etoposide plus either daunorubicin, mitoxantrone, or idarubicin [61]. This EORTC/GIMEMA (European Organisation for Research and Treatment of Cancer/Gruppo Italiano Malattie Ematologiche dell’Adultorate) trial reported that the rate of CR was similar in all three trial arms. Long-term survival was inferior for patients who received induction therapy with daunorubicin compared with mitoxantrone or idarubicin, but this finding was confounded by different rates of transplantation between trial arms.

•Other trials that compared mitoxantrone with daunorubicin for induction therapy also did not indicate that mitoxantrone was associated with a greater benefit than anthracyclines [62-67].

●Other third agents – None of the following agents have proven benefit when added to AML induction therapy:

•Venetoclax – A phase 2 study of 33 patients reported that adding venetoclax 100 mg on day 4, 200 mg on day 5, and 400 mg on days 6 to 11 to "7+3 therapy" was associated with CR_MRD- (CR with undetectable MRD) in 97 percent [68]. Grade ≥3 adverse effects (AEs) included neutropenia, thrombocytopenia, and anemia in 100 percent of patients, febrile neutropenia in 55 percent, pneumonia in 21 percent, and sepsis in 12 percent; there were no treatment-related deaths. Estimated one-year OS and EFS were 97 and 72 percent, respectively.

Addition of venetoclax to FLAG-Ida in 45 patients was associated with 89 percent composite CR (ie, CR, CR with partial hematologic recovery [CRh], and CR with incomplete hematologic recovery [CRi]), including 82 percent with negative MRD; estimated 24-month OS and EFS were 76 and 64 percent, respectively [69].

We await results of an ongoing phase 3 HOVON/AMLSG of induction and consolidation chemotherapy with venetoclax.

•Cladribine – Addition of the purine analog, cladribine (2-CdA), to "7+3 therapy" was associated with improved survival and response rate in two randomized trials, but the results should be further validated before using this regimen in clinical practice.

In a randomized trial of 652 adults with AML, compared with "7+3" alone, cladribine plus "7+3" achieved superior OS (45 versus 33 percent, respectively) and CR (68 versus 56 percent, respectively) [70]. However, these findings should be independently validated because of the relatively low rates of CR (56 percent) and median OS (14 months) in the control arm. An earlier phase 3 trial by the same group demonstrated similar benefits for cladribine [71]. Toxicity with the addition of cladribine was similar to that with "7+3 therapy" in other studies.

•Clofarabine – A HOVON/SAKK trial evaluated cytarabine/idarubicin induction with or without clofarabine (10 mg/m² on days 1 to 5) in patients with AML (18 to 65 years) [72]. OS and EFS did not differ between trial arms; however, patients treated with clofarabine had fewer relapses but more deaths in remission. Subset analysis reported that patients with European LeukemiaNet intermediate-risk (primarily wild-type NPM1/FLT3-internal tandem duplications [ITD]-negative) clofarabine was associated with improved four-year EFS (40 versus 18 percent for the control arm).

•Other agents – Addition of fludarabine, topotecan, thioguanine, or vorinostat to "7+3 therapy" did not improve outcomes [62,72-82].

SPECIAL SCENARIOS

Emergencies — A life-threatening medical emergency may be seen at the time of presentation, or it can emerge during induction therapy. The most common emergencies are:

●Hyperleukocytosis – A white blood cell (WBC) count >100 x 10⁹/L (100,000/microL) is associated with increased mortality during induction therapy due to clinical leukostasis, hemorrhage, neurologic dysfunction, and other complications.

●Clinical leukostasis – Clinical manifestations of leukostasis, such as neurologic dysfunction or hypoxia, constitute a medical emergency and require immediate intervention.

The patient should be treated with hydroxyurea (up to 50 to 60 mg/kg per day to reduce the WBC count to <25 x 10⁹/L) or planned induction therapy should begin promptly. The risk of bleeding increases as perfusion is restored to ischemic capillary beds (eg, in the brain); rigorous platelet transfusion support may be necessary. Other urgent interventions include a restrictive transfusion policy for red blood cells (RBCs) and consideration of leukapheresis and/or dexamethasone, as discussed separately. (See "Hyperleukocytosis and leukostasis in hematologic malignancies".)

●Tumor lysis syndrome – Tumor lysis syndrome (TLS) and associated metabolic disorders (eg, hyperkalemia, hyperphosphatemia, hyperuricemia, renal insufficiency) are more common in patients with hyperleukocytosis. Management of TLS is discussed separately. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors" and "Tumor lysis syndrome: Prevention and treatment".)

●Bleeding/coagulation abnormalities – Bleeding may be associated with severe thrombocytopenia, disseminated intravascular coagulation (DIC), and other coagulopathies. (See "Hematopoietic support after hematopoietic cell transplantation", section on 'Platelets' and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Treatment'.)

DIC is especially common in patients with acute promyelocytic leukemia, which requires distinctive and urgent management. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults" and "Initial treatment of acute promyelocytic leukemia in adults".)

●Neurologic abnormalities – Patients with new or unexplained neurologic findings (eg, headache, confusion, cranial neuropathy) require urgent evaluation.

Magnetic resonance imaging (MRI) should be performed urgently for patients with neurologic findings consistent with central nervous system (CNS) bleeding, leptomeningeal disease, and/or mass lesions. Computed tomography (CT) is acceptable if there is a contraindication to MRI (eg, implanted metallic devices).

Lumbar puncture (LP) should be performed after bleeding and mass lesions have been excluded and with correction of a coagulopathy or severe thrombocytopenia. Administration of one dose of intrathecal chemotherapy (methotrexate or cytarabine) should be considered at the time of the diagnostic LP.

Detailed evaluation of patients with neurologic findings in the setting of newly diagnosed AML is discussed separately. (See "Involvement of the central nervous system (CNS) with acute myeloid leukemia (AML)", section on 'Evaluation'.)

Management of CNS involvement with AML is discussed separately. (See "Involvement of the central nervous system (CNS) with acute myeloid leukemia (AML)".)

Limited cardiac function — For patients with limited heart function who are otherwise medically fit to receive intensive treatments, non-anthracycline-containing induction regimens may be considered.

All adults should have an echocardiogram or radionuclide ventriculogram prior to initiating induction therapy. We generally avoid anthracyclines in patients with a baseline left ventricular ejection fraction of <40 percent.

Alternative, non-anthracycline-containing regimens may be considered. However, remission induction is associated with administration of large amounts of intravenous fluids, and cardiac function must be carefully monitored and managed. The use of anthracyclines in patients with heart disease is discussed in detail separately. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)

There is no consensus for patients who cannot tolerate an anthracycline-based regimen, but options include:

●Venetoclax plus azacitidine or decitabine (see "Acute myeloid leukemia: Management of medically unfit adults", section on 'HMA plus venetoclax')

●FLAG (fludarabine, cytarabine, G-CSF [granulocyte colony-stimulating factor]) [83]

●CLAG (cladribine, cytarabine, G-CSF) [84,85]

●Clofarabine-based combinations [72,86-88]

Other options for patients with limited cardiac function include targeted agents for actionable mutations (eg, gemtuzumab ozogamicin [GO] for CD33-positive AML, IDH inhibitors for IDH mutations) are discussed separately. (See "Acute myeloid leukemia: Management of medically unfit adults".)

A retrospective study reported similar outcomes with three regimens (FLAG; clofarabine plus cytarabine; topotecan plus cytarabine) among 52 patients with de novo or relapsed/refractory AML and limited cardiac function [89]. For de novo AML, the complete remission (CR) rate was 63 percent, while cardiovascular and hematologic adverse effects (AEs) were moderate.

A retrospective study of FLAG in 40 patients with AML reported 70 percent overall response rate (ORR) and only one death during induction [90]. In a study of FLAG induction in 24 patients ≥60 years, outcomes included 58 percent CR, 16 percent CR with incomplete platelet recovery, 12 percent deaths from infections with neutropenia but no other grade ≥3 AEs or significant mucositis [91]. Addition of low-dose GO to FLAG (FLAG-GO) was effective for AML with core-binding factor (CBF) mutations (eg, AML with inv(16) or t(8;21)) [92]. Among 45 patients (median 48 years) with AML with CBF mutations, three-year overall survival (OS) and relapse-free survival were 85 and 78 percent, respectively, with 91 percent CR and 5 percent induction deaths.

Secondary and therapy-related AML — For patients with secondary AML (ie, arising from a prior myeloid neoplasm) or therapy-related AML, we favor CPX-351 induction therapy, but induction using cytarabine/anthracycline ("7+3") or FLAG-Ida is acceptable.

Two randomized trials directly compared CPX-351 with other intensive induction regimens for secondary AML, therapy-related AML, or AML with adverse cytogenetic features:

●CPX-351 was superior to cytarabine/anthracycline ("7+3 therapy") induction in a phase 3 trial of 309 patients with treatment-related or secondary AML or de novo AML with myelodysplasia-related cytogenetic abnormalities [93]. Compared with "7+3 therapy," CPX-351 achieved superior five-year OS (18 versus 10 percent; hazard ratio [HR] 0.70 [95% CI 0.55-0.91]) and longer median OS (nine versus six months). There were 5 percent treatment-related deaths in both cohorts, but there was a trend toward higher 30-day mortality with "7+3 therapy" (11 versus 6 percent). More patients treated with CPX-351 were able to proceed to allogeneic transplantation.

●There was no difference in survival between CPX-351 versus FLAG-Ida in younger adults with AML with adverse cytogenetic features or high-risk myelodysplastic syndromes (MDS); 20 percent of patients had secondary AML, 49 percent had de novo AML, and 30 percent had high-risk MDS [94]. There was no difference in OS (13.3 versus 11.4 months) or event-free survival, but relapse-free survival was longer with CPX-351 (median 22.1 versus 8.4 months; HR 0.58 [95% CI 0.36-0.95]), while there was a trend higher ORR with FLAG-Ida. Grade ≥3 nonhematologic AEs were similar in both arms, but FLAG-Ida was associated with slower recovery of neutrophils and platelets, resulting in longer hospitalizations and increases in intravenous antibiotic use and transfusions.

Other aspects of management of therapy-related AML are described separately. (See "Therapy-related myeloid neoplasms: Management and prognosis", section on 'Medical therapy'.)

Pregnancy — If AML is detected during the first trimester and requires urgent treatment, immediate termination of pregnancy followed by treatment of the leukemia is advisable, as combination chemotherapy given during this time is associated with an unacceptably high incidence of fetal abnormalities and/or fetal loss [95].

Management of patients diagnosed later in pregnancy (eg, late in the second trimester or during the third trimester) poses a difficult therapeutic dilemma [96]. If the leukemia is relatively indolent, it is sometimes possible to manage patients conservatively with leukapheresis and/or transfusion, with induction of labor and delivery of a viable fetus as soon as possible. However, the hazard of delayed therapy until delivery may pose a significant risk to the mother, and it is generally difficult or impossible to predict whether the AML will take an indolent course.

There have been many reports of patients treated with chemotherapy later in their pregnancies, most of whom did not abort [95,97-101]. There have been no reports of leukemia occurring in the children, nor an increased incidence of fetal abnormalities in infants who have been exposed to intensive chemotherapy during the later stages of gestation. A literature review of 160 pregnant patients treated with anthracyclines for a variety of malignancies reported no apparent impact on delivered infants in 73 percent of patients [95]. Unfavorable fetal outcomes included fetal death (9 percent), prematurity (6 percent), and malformations (3 percent).

Chemotherapeutic agents used for AML induction therapy are potentially teratogenic and may affect fertility; contraception should be used for individuals who are considering pregnancy. As an example, the US Food and Drug Administration label for idarubicin advises contraception for ≥6.5 months after the last dose for females and ≥3.5 months for male partners of fertile females [102]. Patients should seek advice for fertility preservation before treatment when possible.

Extramedullary disease — Myeloid sarcoma refers to an extramedullary mass of myeloid blasts, and it is sufficient to establish a diagnosis of AML [4,5]. Up to 10 percent of patients with AML have extramedullary involvement (eg, leukemia cutis, myeloid sarcoma) at some point during the disease course. Evaluation of patients with extramedullary AML (with or without evidence of AML in marrow) is similar to that for patients with overt AML [103]. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia".)

Specific aspects of the evaluation and management of extramedullary disease include:

●Imaging – Imaging can characterize extramedullary involvement, aid in radiation treatment planning, and assess response to therapy [104]. Positron emission tomography/CT may be preferred over CT alone for radiation therapy (RT) planning [105-107]. MRI with gadolinium can be used to assess CNS involvement.

●Biopsy – Patients with suspected extramedullary involvement in a location amenable to biopsy should undergo a biopsy of the involved tissue. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Pathologic features'.)

●Radiation therapy – RT can be incorporated into treatment, either before induction chemotherapy (eg, for compression of vital structures) or as consolidation after induction chemotherapy (eg, for persistent extramedullary involvement after chemotherapy). Myeloblasts are radiation sensitive, and doses >20 Gy are generally adequate.

Treatment of myeloid sarcoma is like that for other AML. Given the rarity of this condition, there is a paucity of data regarding the role of RT in this setting. Remission induction chemotherapy (with or without RT) achieves survival rates similar to those seen in patients with AML without extramedullary disease [108,109]. Without systemic remission induction chemotherapy, patients presenting with myeloid sarcoma will almost always progress to systemic disease, usually within three to six months [110].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute myeloid leukemia".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Acute myeloid leukemia (AML) (The Basics)" and "Patient education: Leukemia in adults (The Basics)")

●Beyond the Basics topics (see "Patient education: Acute myeloid leukemia (AML) treatment in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Description – Acute myeloid leukemia (AML) refers to aggressive malignancies of bone marrow myeloid precursor cells that interfere with production of normal blood cells, causing fatigue, weakness, infection, bleeding, and other symptoms and complications.

Diagnosis and classification of AML are discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia".)

●Pretreatment evaluation – Evaluation includes AML-associated complications/emergencies, performance status (table 2), medical fitness, and medical comorbidities (table 3) that might affect tolerance for intensive induction therapy. (See 'Pretreatment' above.)

●Classification – AML is categorized using a contemporary classification scheme, and prognosis is estimated using the European LeukemiaNet model. (See 'Classification and risk stratification' above.)

●Induction therapy – Induction therapy should begin promptly, but clinical stabilization of emergencies/complications and diagnostic work-up are most important and should not be delayed.

Induction therapy is stratified as follows:

•AML without mutated FLT3 – For AML without mutated FLT3, we recommend treatment with a seven-day continuous infusion of cytarabine plus an anthracycline for three days ("7+3 therapy") (Grade 1B) (see 'AML without mutated FLT3' above):

-Cytarabine 100 to 200 mg/m² daily as a continuous infusion for 7 days

-Daunorubicin 60 to 90 mg/m² on days 1 to 3 or idarubicin 12 mg/m² on days 1 to 3

Acceptable alternatives are discussed. (See 'Alternative induction regimens' above.)

•For AML with mutated FLT3 – For patients with FLT3-mutated AML, we recommend addition of either midostaurin (for any FLT3 mutation) or quizartinib (for FLT3 with internal tandem repeats) to intensive induction chemotherapy (Grade 1B). (See 'AML with mutated FLT3' above.)

●Response – Bone marrow examination at hematologic nadir (days 14 to 22) guides further management (see 'Nadir response assessment' above):

•Hypoplasia – For hypoplasia (ie, <20 percent cellularity) and clearance of blasts (ie, <5 percent) in the nadir marrow, we suggest monitoring until recovery of blood counts (Grade 2C). (See 'Adjunctive care' above.)

•Persistent blasts – For persistent blasts and cellularity, we suggest reinduction therapy without delay (when tolerable), rather than observation (Grade 2C). (See 'Reinduction (second attempt)' above.)

●Remission status – Bone marrow, blood, and/or extramedullary sites are evaluated at the time of hematologic recovery; criteria are presented above (see 'Remission criteria' above):

•Complete remission

•CR with partial hematologic recovery (CRh)

•CR with incomplete hematologic recovery (CRi)

•No response (refractory AML)

●Measurable residual disease (MRD) – We assess MRD by multicolor flow cytometry or molecular techniques to refine the remission status and aid selection of postremission management. (See 'Measurable residual disease' above.)

●Adjunctive care – Monitor for complications and medical needs (eg, transfusions, antimicrobials). (See 'Adjunctive care' above.)

●Alternative induction regimens – Include:

•FLAG-Ida (fludarabine, cytarabine, G-CSF [granulocyte colony-stimulating factor], idarubicin) (see 'FLAG-Ida' above)

•CPX-351 (liposome-encapsulated cytarabine/daunorubicin) (see 'CPX-351' above)

•Gemtuzumab ozogamicin (see 'Gemtuzumab ozogamicin' above)

●Special scenarios – Management of medical emergencies and patients with limited cardiac function, secondary/treatment-related AML, and pregnancy. (See 'Special scenarios' above.)