INTRODUCTION — Acute myeloid leukemia (AML) comprises a heterogeneous group of aggressive blood cell cancers that arise from clonal expansion of malignant hematopoietic precursor cells in the bone marrow. AML cells interfere with production of normal blood cells, causing weakness, infection, bleeding, and other symptoms and complications. Remission induction therapy is given with the goal of reducing the leukemic burden and restoring normal bone marrow function. Remission induction therapy differs according to the patient's medical fitness and certain pathologic features of the leukemic cells.
Importantly, there is no consensus regarding criteria for medical fitness and no upper age limit. However, because of age-related comorbidities, caution should be used when considering intensive chemotherapy for patients who are ≥70 to 75 years old.
Induction therapy for medically-fit adults with de novo AML will be reviewed here.
Other topics related to initial management of AML are provided separately:
●(See "Overview of acute myeloid leukemia in adults".)
●(See "Acute myeloid leukemia: Management of medically-unfit adults".)
●(See "Therapy-related myeloid neoplasms: Management and prognosis".)
●(See "Initial treatment of acute promyelocytic leukemia in adults".)
●(See "Familial disorders of acute leukemia and myelodysplastic syndromes".)
●(See "Mixed phenotype acute leukemia".)
MEDICAL FITNESS — Medical fitness must be assessed prior to treatment for AML because it has an important role in selection of therapy. There is no consensus regarding the optimal method for assessing medical fitness and, importantly, there is no explicit age limit for intensive treatment.
Medical fitness is primarily determined by performance status (PS) and the nature and severity of medical comorbidities. We do not apply an upper age limit when judging medical fitness or for treatment with intensive therapies. However, because of age-related comorbidities, caution should be used when considering intensive chemotherapy for patients ≥70 to 75 years old, as most outcome data related to intensive regimens come from studies in younger adults (eg, <60 to 65 years old).
Scores that correspond to medical fitness, using acceptable instruments for assessment include:
●Performance status – We consider the following measures of PS (table 1) to be acceptable for intensive treatment of AML:
•Eastern Cooperative Oncology Group (ECOG) PS: 0 to 1
•Karnofsky PS (KPS): ≥80
●Comorbidity – The hematopoietic cell transplantation specific comorbidity index (HCT-CI) (table 2) was designed to predict outcomes in patients undergoing HCT [1]. Some centers use the HCT-CI as an instrument for assessing medical fitness in patients with AML.
We generally consider patients with ECOG PS ≥2, KPS <80, or HCT-CI ≥3 to be medically-unfit or frail. We attempt to address medical comorbidities and/or improve PS prior to excluding an individual as a candidate for intensive treatment. For such patients, we suggest further evaluation as described for medically-unfit adults with AML. (See "Pretreatment evaluation and prognosis of acute myeloid leukemia in older adults" and "Acute myeloid leukemia: Management of medically-unfit adults".)
Management of medically-fit patients is discussed below. (See 'Medically-fit patients' below.)
For other patients (eg, medically unfit/frail, limited cardiac function), management is discussed below. (See 'Special scenarios' below.)
PRETREATMENT EVALUATION AND MANAGEMENT — Because of the intensive nature of remission induction chemotherapy for AML, particular attention should be paid to underlying conditions or comorbid illnesses that could complicate AML or its management [2]. All cases of AML should be classified according to World Health Organization (WHO) criteria, which is described separately (table 3).
History and physical examination — The medical history and physical examination should investigate potential conditions that may have contributed to development of AML (eg, prior hematologic disorders or cytotoxic therapy) and evaluate comorbid illnesses or other conditions (eg, heart disease, liver or kidney dysfunction, uncontrolled diabetes mellitus) that might complicate management [2]. Clinical evaluation should include the following:
●Prior hematologic or malignant disorders – History of a pre-existent hematologic condition (eg, myelodysplastic syndrome, myeloproliferative neoplasm) indicates secondary AML, while prior treatment with cytotoxic chemotherapy or radiation therapy points to a therapy-related myeloid neoplasm. Compared with primary (de novo) AML, these categories of AML are generally associated with inferior prognosis and may require distinctive management, as described separately. (See "Prognosis of acute myeloid leukemia", section on 'Antecedent hematologic disorders' and "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis".)
AML that arises in the setting of an inherited disorder (eg, Fanconi anemia, familial platelet disorder) has distinctive management concerns. An inherited cause for AML may be suspected if there is personal or family history of hematologic malignancy or other cancers, unexplained prior cytopenias, recurrent or atypical infections, or certain somatic stigmata (eg, congenital limb anomalies, deafness, premature graying, skin or nail abnormalities, or unexplained organ dysfunction). Genetic abnormalities involving RUNX1, ETV6, or GATA2 may also raise suspicion regarding a germline predisposition for developing AML in the appropriate clinical context. (See "Familial disorders of acute leukemia and myelodysplastic syndromes".)
●Organ dysfunction
•Heart disease – Special attention is required for the large volumes of intravenous fluids administered during remission induction therapy. A history of congestive failure or dysrhythmias may preclude use of anthracyclines, which are commonly used in intensive remission regimens. (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 – A history of active infections or latent infections that can reactivate or worsen in the setting of immunosuppression should be reviewed. This includes hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex virus (HSV), cytomegalovirus (CMV), human immunodeficiency virus (HIV), and tuberculosis. Individual behaviors or exposures that increase the likelihood of certain infections (eg, risk for sexually transmitted infections, residence in area where specific pathogens are endemic, mold in home) and vaccination status should be reviewed.
●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'.)
Laboratory studies — We suggest the following pretreatment studies in patients with AML (table 4):
●Hematology – Complete blood count with differential.
●Coagulation tests – Prothrombin time (PT)/international normalized ratio (INR), activated partial thromboplastin time (aPTT), fibrinogen.
●Chemistries – Electrolytes, glucose, renal function tests, calcium, phosphorus, uric acid, liver function tests, albumin, total protein, and lactate dehydrogenase (LDH).
●Infectious – Screening tests should be performed for hepatitis A, B, and C; HIV; HSV; and CMV.
●HLA typing – Human leukocyte antigen (HLA) typing should be performed for patients who may be candidates for hematopoietic cell transplantation. HLA class I typing should be performed in case of refractoriness to platelet transfusion due to HLA alloantibodies.
●Urine analysis
Other evaluation and management
●Cardiac evaluation – We suggest an electrocardiogram (EKG), with attention to arrhythmias and baseline prolongation of the QTc interval, plus an echocardiogram or radionuclide ventriculography (RVG; also called multiple gated cardiac blood pool scanning [MUGA]) to assess cardiac function, ejection fraction, and wall motion abnormalities. (See "Tests to evaluate left ventricular systolic function".)
Remission induction therapy for patients with impaired cardiac function is discussed below. (See 'Limited cardiac function' below.)
●Neurologic evaluation – Routine screening with a lumbar puncture (LP) is not indicated for asymptomatic patients at the time of diagnosis. Some experts suggest performing a diagnostic LP for patients with high-risk features for central nervous system (CNS) involvement (eg, white blood cell count >100,000/microL, or AML with monocytic features). For patients with neurologic findings at the time of diagnosis, the evaluation and management are discussed separately. (See "Involvement of the central nervous system (CNS) with acute myeloid leukemia (AML)".)
Re-evaluation of the status of the CNS after achieving systemic remission is discussed below. (See 'Remission assessment' below.)
●Central venous catheter – A central venous access catheter, such as a percutaneous intravenous central catheter (PICC), with two or three independent ports should be implanted. Use of fully implantable devices should be avoided during induction chemotherapy because of the higher risks of bleeding or infection and associated impediments to rapid removal in event of infection. (See "Central venous access: General principles".)
●Dental evaluation – We suggest a professional dental evaluation to identify and address possible infectious foci.
●Chest radiograph
●Fertility – Men and women with child-bearing potential should receive counseling about the potential effect of treatment on their fertility and options for fertility-preserving measures. Women of child-bearing potential should have a serum pregnancy test. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)
WHO CATEGORY AND ELN RISK STRATIFICATION — The leukemia should be classified according to the World Health Organization (WHO) category of AML and European LeukemiaNet (ELN) risk stratification.
●WHO category – WHO category of AML (table 3) is determined by morphology, immunophenotype, cytogenetics, and molecular analysis of bone marrow, peripheral blood, or myeloid sarcoma (if present) [3,4]. WHO classification has superseded FAB (French American British) classification, which was based on morphology and cytochemical staining. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Diagnosis'.)
Management of patients with the following WHO categories of AML is discussed separately:
•Acute promyelocytic leukemia (APL) (see "Initial treatment of acute promyelocytic leukemia in adults")
•Therapy-related myeloid neoplasms and secondary AML (see "Therapy-related myeloid neoplasms: Management and prognosis")
•Mixed phenotype acute leukemia (MPAL) (see "Mixed phenotype acute leukemia")
•Myeloid neoplasms with germline predisposition (see "Familial disorders of acute leukemia and myelodysplastic syndromes")
●ELN risk stratification – ELN prognostic stratification (table 5) classifies AML into favorable, intermediate, and adverse categories, based on cytologic and molecular features of the leukemia [2].
EMERGENCIES — Medical emergencies are encountered regularly in patients with AML. (See "Overview of the complications of acute myeloid leukemia".)
Details regarding the diagnosis and management of the following complications and/or oncologic emergencies associated with AML are described separately:
●Acute promyelocytic leukemia (APL) requires urgent, distinctive management (see "Initial treatment of acute promyelocytic leukemia in adults")
●Hyperleukocytosis/leukostasis (eg, respiratory and/or neurologic distress in a patient with AML and myeloblasts >50,000/microL, or any patient with AML and myeloblasts >100,000/microL) (see "Hyperleukocytosis and leukostasis in hematologic malignancies")
●Metabolic abnormalities, including tumor lysis syndrome (eg, hyperkalemia, hyperphosphatemia, hyperuricemia, and/or renal insufficiency) (see "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors" and "Tumor lysis syndrome: Prevention and treatment")
●Bleeding/coagulation abnormalities (eg, severe thrombocytopenia, disseminated intravascular coagulation) (see "Hematopoietic support after hematopoietic cell transplantation", section on 'Platelet transfusion' and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Treatment')
●Unexplained neurologic or visual symptoms (see "Involvement of the central nervous system (CNS) with acute myeloid leukemia (AML)")
GOALS AND TIMING OF TREATMENT
●Goals of care – The goals of care should be established in discussions between the patient and clinicians. Medical fitness, age, features of the leukemic cells, and individual values and preferences should be considered in establishing the goals of care:
•For medically-fit patients, the goal of treatment is to achieve long-term survival with the possibility of cure; this generally requires achievement of complete remission, as described below. (See 'Medically-fit patients' below.)
•For medically-unfit or frail patients, the goals of care are to prolong life, alleviate symptoms, and/or improve quality of life, as described below. (See 'Unfit or frail patients' below.)
●Timing of treatment – Treatment of AML should begin promptly, but it is more important to perform an adequate diagnostic work-up (including molecular testing), stabilize the patient's condition, and control complications (eg, infection, bleeding, hyperuricemia, renal dysfunction, anemia, thrombocytopenia) than it is to start chemotherapy immediately [5,6].
The diagnosis of acute promyelocytic leukemia (APL) must be excluded promptly (eg, using fluorescence in situ hybridization [FISH] or genetic testing) to enable the necessary urgent and distinctive management. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults", section on 'Genetic features'.)
If the peripheral blast count must be reduced while awaiting molecular results or managing complications, oral hydroxyurea can be used for cytoreduction. (See "Overview of the complications of acute myeloid leukemia".)
MEDICALLY-FIT PATIENTS — For patients with AML, we favor participation in a clinical trial, when possible. Outside of a clinical trial, the choice of treatment is based on medical fitness and certain cytogenetic/molecular features of the AML cells. As discussed above, medical fitness is determined by performance status (PS) and/or comorbid illnesses, rather than chronological age, per se. (See 'Medical fitness' above.)
For patients with significant comorbidities (eg, heart failure, uncontrolled diabetes mellitus) and/or medical complications (eg, infection, bleeding, hyperuricemia, renal dysfunction, anemia, thrombocytopenia), we attempt to ameliorate the patient's condition prior to beginning intensive chemotherapy. Such stabilization may result in improved PS. (See 'Goals and timing of treatment' above.)
For patients who are medically-unfit, frail, or have limited cardiac function, management is described below. (See 'Unfit or frail patients' below and 'Limited cardiac function' below.)
Choice of regimen — For medically-fit patients, we recommend remission induction therapy with a seven-day continuous infusion of cytarabine plus an anthracycline for three days (so-called "7+3 therapy") rather than treatment with high dose cytarabine or other remission induction regimens. This recommendation is based on the more favorable balance of outcomes and toxicity with 7+3 therapy.
Details of 7+3 therapy are presented below. For patients with FLT3-mutated AML, including FLT3 internal tandem duplication (ITD) or tyrosine kinase domain (TKD) mutations, we suggest adding a targeted agent to 7+3 therapy. (See '7+3 therapy (cytarabine plus anthracycline)' below and 'Adding a third agent to 7+3' below.)
7+3 therapy (cytarabine plus anthracycline) — The preferred approach for remission induction is a 7-day continuous infusion of cytarabine and anthracycline treatment on days 1 to 3, which is commonly referred to as "7+3 therapy." Details of the cytarabine dose and the choice and dose of anthracycline (ie, daunorubicin, idarubicin) vary between institutions and no single protocol for 7+3 therapy has proven to offer a superior balance of outcomes and toxicity.
For medically fit patients, we suggest treatment as follows:
●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
Additional management for patients with FLT3-mutated AML is discussed below. (See 'Adding a third agent to 7+3' below.)
Treatment with 7+3 therapy generally achieves a complete remission (CR) rate of 60 to 80 percent for patients <60 to 65 years old [2,7,8]. Long-term outcomes are influenced by cytogenetic/molecular features (table 5) and post-remission management. (See "Post-remission therapy for acute myeloid leukemia in younger adults".)
Patients require aggressive intravenous hydration; monitoring for cardiac, renal, and liver dysfunction; blood product support; and surveillance for infections. Treatment with 7+3 therapy generally causes three to five weeks of profound cytopenias and associated risks 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 are discussed in more detail separately. (See 'Monitoring and supportive care during therapy' below and "Infusion reactions to systemic chemotherapy", section on 'Anthracyclines and related agents' and "Infusion reactions to systemic chemotherapy", section on 'Cytarabine'.)
Bone marrow examination should be performed 14 to 21 days after initiation of therapy to assess the initial response to therapy and determine whether a second induction course is needed, as described below. (See 'Initial response to therapy' below.)
Approximately four to five weeks after the start of therapy, when sufficient time has passed for recovery of normal blood counts, another bone marrow examination is performed to determine whether the patient has achieved remission. (See 'Remission assessment' below and "Remission criteria in acute myeloid leukemia and monitoring for residual disease".)
Broadly, findings from randomized trials that examined the dose, schedule, and choice of agents have found that outcomes are similar between daunorubicin and idarubicin; higher dose daunorubicin (ie, 60 or 90 mg/m2/d) is more efficacious but not more toxic than lower dose (ie, 45 mg/m2/d) daunorubicin; and, compared with infusional cytarabine, high dose cytarabine (HiDAC) is associated with increased toxicity without an improvement in efficacy. Examples of informative studies follow:
●Daunorubicin dose – Higher doses of daunorubicin (eg, 60 mg/m2 or 90 mg/m2) are more efficacious than 45 mg/m2. In ECOG 1900, 330 patients <60 years old with favorable/intermediate-risk AML were randomly assigned to three once daily doses of daunorubicin 90 mg/m2 versus 45 mg/m2 [9]. Compared with the lower dose, higher dose daunorubicin achieved a superior rate of CR (71 versus 57 percent) and median overall survival (OS; 34 versus 21 months); there were similar rates of severe (grade ≥3) adverse events, including cardiac and hematopoietic toxicity. Another phase 3 trial also reported higher rates of CR (83 versus 72 percent) and five-year OS (47 versus 35 percent) with 90 mg/m2 compared with 45 mg/m2 [10]. In a phase 3 trial that compared daunorubicin 90 mg/m2 versus 60 mg/m2, rates of CR and toxicity were similar; with median follow-up 28 months, the higher dose arm achieved superior OS and relapse-free survival (RFS) for patients with FLT3 mutation, but not for others [11,12]. 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 not for early death [13].
●Daunorubicin versus idarubicin – The three-arm ALFA-9801 trial randomly assigned 468 patients 50 to 70 years old (median age 60 years) 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 versus 83 versus 78 percent, respectively, but OS, event-free survival (EFS), and relapse incidence did not differ between arms [14]. A systematic review and meta-analysis reported no difference between daunorubicin and idarubicin with regard to overall mortality or early death [13].
●Cytarabine dose – We suggest a cytarabine dose of 100 mg/m2/day or 200 mg/m2/day for seven-day continuous infusion; the two doses are associated with comparable outcomes and toxicity [15]. Compared with high dose cytarabine (HiDAC) plus an anthracycline, 7+3 therapy using either dose of infusional cytarabine achieves similar outcomes but with less toxicity [16-18].
For patients with limited cardiac function, HiDAC alone or combined with a non-cardiotoxic agent is acceptable as remission induction therapy. (See 'Limited cardiac function' below.)
Adding a third agent to 7+3 — Addition of a targeted agent to 7+3 therapy is an option for patients with a suitable mutation.
Inhibitors of mutated FLT3 — Mutations in FLT3 due to internal transmembrane duplications (FLT3-ITD) or changes in the activating loop of the kinase domain (FLT3-TKD) are common in AML. A high mutation fraction of FLT3-ITD molecules on the surface of leukemia cells is associated with adverse outcomes and short remissions.
For patients with FLT3 mutant AML, we suggest adding midostaurin to 7+3 therapy rather than 7+3 therapy alone, based on superior outcomes and modest incremental toxicity.
In the phase 3 CALGB 10603/RATIFY trial, 717 adults <60 years old with AML associated with FLT3-ITD (77 percent) or FLT3-TKD (23 percent) mutations were randomly assigned to 7+3 chemotherapy plus midostaurin (50 mg orally twice daily on days 8 through 21) versus placebo [19]. With median follow-up of 59 months, when 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 arms had similar rates of CR, time to recovery of neutrophils and platelets, severe (grade 3/4) toxicity, and treatment-related deaths.
A multicenter phase 2 trial reported that addition of the multi-kinase inhibitor, sorafenib, to 7+3 improved median EFS (21 versus 9 months, respectively) and three-year EFS (40 versus 22 percent) but was associated with increased toxicity (eg, fever, diarrhea, bleeding, cardiac events, hand-foot syndrome, and rash) [20].
The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have approved midostaurin in combination with chemotherapy for the treatment of adult patients with newly diagnosed AML who have a mutation of FLT3 [21].
Other agents — There is some evidence that gemtuzumab ozogamicin (GO) may improve outcomes when added to 7+3 therapy, but no persuasive evidence that addition of other targeted agents or chemotherapy to 7+3 therapy provides a more favorable balance of outcomes and toxicity.
●Gemtuzumab ozogamicin – GO is an immunoconjugate (anti-CD33 monoclonal antibody linked to calicheamicin) that may improve outcomes when added to 7+3 therapy for CD33-positive AML, but treatment is associated with increased toxicity. The threshold of CD33 expression for efficacy of GO is not well-defined. Informative studies include:
•A meta-analysis that included 3325 adult patients in five randomized trials concluded that, compared with intensive induction therapy alone, addition of GO improved certain outcomes for patients with favorable- or intermediate-risk cytogenetics [22]. For patients with favorable- or intermediate-risk cytogenetics, addition of GO reduced the risk of relapse (hazard ratio [HR] 0.81; 95% CI 0.73-0.90) and improved five-year OS (HR 0.90; 95% CI 0.82-0.98) but was not associated with more favorable rates of CR or CR with incomplete hematologic recovery (CRi). A benefit for GO was not observed for patients with adverse-risk karyotypes.
•The multicenter, phase 3 ALFA-0701 trial of 271 patients (age 50 to 70 years) reported superior EFS (ie, induction failure, relapse, or death by any signaling cause) with GO plus 7+3 therapy versus with 7+3 alone (17 versus 10 months; HR 0.56, 95% CI 0.42-0.76), but there was no difference in OS [23]. In a follow-up study, the benefit of GO was found to be confined to patients with favorable- or intermediate-risk cytogenetic findings and those with mutations of signaling molecules (eg, FLT3, KRAS) [24].
•A trial that randomly assigned 588 patients with NPM1-mutated AML to idarubicin, cytarabine, etoposide, and all-trans retinoic acid, with or without GO, reported that addition of GO was associated with a lower cumulative incidence of relapse and a greater proportion of patients who achieved undetectable measurable residual disease (MRD), but no difference in EFS and a higher rate of early death (10 versus 6 percent; primarily due to infections) [25,26].
GO was approved by the FDA in combination with 7+3 therapy for treatment of adults with newly diagnosed CD33+ AML [27]. The GO label includes a boxed warning about hepatotoxicity, including severe or fatal hepatic sinusoidal obstruction syndrome (also known as veno-occlusive disease). Other toxicities include infusion-related reactions (including anaphylaxis), hemorrhage, and teratogenicity. A variety of doses and schedules have been used when combining GO with chemotherapy, and higher doses appear associated with increased risks [2,22].
Use of GO as a single agent for induction therapy in medically-unfit patients and for relapsed/refractory AML is described separately. (See "Acute myeloid leukemia: Management of medically-unfit adults".)
●Other agents – There is no conclusive evidence that adding other agents to 7+3 therapy is beneficial. Examples of studies include:
•Etoposide – A phase 3 trial reported that comparable rates of CR (approximately 80 percent) were achieved with the following three regimens: cytarabine and daunorubicin versus etoposide, cytarabine, and daunorubicin versus fludarabine, HiDAC, idarubicin, and granulocyte colony-stimulating factor (so-called FLAG therapy) [28].
•Cladribine – Two multicenter Polish trials reported that addition of the purine analog, cladribine (2-CdA), to 7+3 therapy improved response and survival in AML. In a randomized trial of 652 adults with AML, compared with 7+3 alone, cladribine plus 7+3 achieved superior CR (68 versus 56 percent, respectively) and OS (45 versus 33 percent) [29]. 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 [30]. Toxicities were similar to those seen in other studies of 7+3 therapy.
•Oblimersen (antisense BCL2 oligonucleotide) – The investigational agent, oblimersen (G3139), which targets BCL2, did not affect outcomes or toxicity, according to a phase 3 trial in which 506 adults ≥60 years were randomly assigned to 7+3 therapy with or without oblimersen [31]. Among the entire population, estimated one-year OS and two-year OS were approximately 40 percent and 20 percent, respectively. Addition of oblimersen (7 mg/m2 /day on days 1 to 10 during induction and days 1 to 8 in consolidation) did not affect rates of CR, EFS, or toxicity.
•Other chemotherapy agents – No clinical benefits were demonstrated in most studies that added potentially non-cross-resistant drugs (eg, fludarabine, etoposide, topotecan, thioguanine, vorinostat, clofarabine) to a 7+3 regimen [32-43].
Initial response to therapy — A bone marrow examination on day 14 of treatment provides an assessment of the clearance of blast cells and a preview of the response to induction therapy. Practices vary with regard to the response to these results, as described below.
Findings from the day 14 examination may be classified as follows, but note that the definitions are neither strict nor universally agreed-upon:
●Hypoplastic – Bone marrow cellularity <5 to 20 percent and <5 percent blasts
●Indeterminate – Bone marrow cellularity <5 to 20 percent with ≥5 percent blasts
●Persistent leukemia – Some clearing of leukemia or no response, but cellularity ≥20 percent
Institutions vary in their responses to findings of the day 14 bone marrow examination. The response should be guided by the clinical research protocol (if applicable) or by institutional approach.
●For some centers, all medically-fit patients receive a second cycle of the same induction therapy, but those with persistent disease may receive more intensive/alternate treatment (eg, high dose cytarabine [HiDAC] plus mitoxantrone; mitoxantrone, etoposide, and cytarabine [MEC], other regimen) [2]. (See '7+3 therapy (cytarabine plus anthracycline)' above and "Treatment of relapsed or refractory acute myeloid leukemia", section on 'Remission re-induction'.)
●Other centers use the following approach, guided on the day 14 marrow results:
•Hypoplastic – Observation for two to four weeks until recovery of blood counts. If pancytopenia persists, then repeat bone marrow biopsy. (See 'Remission assessment' below.)
•Indeterminate – Repeat the bone marrow examination one to two weeks later, with subsequent management guided by whether the repeat study demonstrates hypoplasia (described above) versus persistent leukemia (below).
•Persistent leukemia – Repeat treatment with 7+3 therapy, or treat with a more intensive or alternate induction therapy (eg, HiDAC-based therapy, hypomethylating agent plus venetoclax, other regimen). (See "Treatment of relapsed or refractory acute myeloid leukemia", section on 'Remission re-induction'.)
MONITORING AND SUPPORTIVE CARE DURING THERAPY — Careful monitoring and supportive care are critical for successful induction therapy of AML. Intensive remission induction therapy generally produces 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 once per day to assess the patient for infusion reactions, tumor lysis syndrome (TLS), 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 to fluid balance, including use of diuretics may be necessary, and daily weights can be helpful.
Laboratory — Laboratory studies should be monitored for cytopenias, bleeding disorders, TLS, organ dysfunction, infections, and other complications of therapy. We suggest the following:
●Complete blood count (CBC) with differential – CBC with differential count should be performed daily until recovery of white blood cell (WBC) 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 (PT)/international normalized ratio (INR) and partial thromboplastin time (aPTT) should be monitored at least weekly, or more frequently as clinically indicated. Fibrinogen should be measured early in the course of remission induction therapy, because disseminated intravascular coagulation (DIC) can be triggered by chemotherapy. For patients with clinical or laboratory evidence of DIC, serum fibrinogen, fibrin degradation products (FTPs), and/or other tests should be monitored at least daily until DIC has resolved.
●Chemistry profile – Chemistry profile including electrolytes, blood urea nitrogen (BUN), creatinine, uric acid, calcium, phosphorus, and liver function tests (including lactate dehydrogenase [LDH]) 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.
Bone marrow examinations — Bone marrow examination should be performed two to three weeks after beginning induction therapy to assess the initial response to therapy; additional examinations may be needed if the bone marrow is not hypoplastic at that time, as described above. (See 'Initial response to therapy' above.)
Bone marrow examination should again be performed to determine if the patient has achieved remission, when the platelet count and WBC count are improving (generally four or five weeks after starting therapy). (See 'Remission assessment' below.)
Supportive care
Nausea/vomiting, other GI toxicity — Effective management of nausea and vomiting improves patient comfort, improves oral hydration and nutritional status, and can reduce the risk of gastrointestinal (GI) bleeding or a Mallory-Weiss tear from forceful vomiting.
Nausea and vomiting may be severe. Management is described separately. (See "Prevention of chemotherapy-induced nausea and vomiting in adults", section on 'Induction therapy for acute leukemia'.)
Induction chemotherapy can damage GI 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 (RBC) and platelets should be provided as needed. Granulocyte colony-stimulating factor (G-CSF; filgrastim) and other myeloid growth factors are not routinely administered.
There is no consensus regarding a threshold for transfusion of RBCs or platelets. We generally transfuse RBCs when the patient has symptoms associated with anemia (eg, profound fatigue, dyspnea) and aim to maintain the hemoglobin between 8 and 9 g/dL, but this may vary depending on the patient's age, symptoms, and comorbid conditions. We transfuse platelets prophylactically for patients with platelet counts <10,000/microL or for signs of 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 [44,45]. (See "Indications and hemoglobin thresholds for red blood cell transfusion in the adult" and "Platelet transfusion: Indications, ordering, and associated risks", section on 'Leukemia, chemotherapy, and HSCT'.)
All patients should receive leukoreduced blood products to reduce febrile nonhemolytic transfusion reactions (FNHTRs), alloimmunization, and other complications. Irradiated blood products are required for any individuals who may be candidates for hematopoietic cell transplantation to prevent transfusion-associated graft-versus-host disease (ta-GVHD). For cytomegalovirus (CMV)-negative patients who are candidates for hematopoietic cell transplantation, 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".)
Long-term safety of myeloid growth factors remains to be determined for patients with AML. In a randomized trial, G-CSF hastened neutrophil recovery but did not lead to differences in the number, severity, or duration of infections [46]. 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 [47-50].
Fever/infection — Prevention of infections is a critical aspect of management, given the substantial morbidity and mortality in these patients. The prolonged and profound neutropenia associated with induction therapy is frequently accompanied by fever and a high risk of infection with bacteria or fungi 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.
Key measures generally include careful hand hygiene (which is often overlooked), use of a high-efficiency particulate air (HEPA)-filtered room, neutropenic diet, avoidance of fresh or dried plants and flowers, and other precautions. We advise our patients to avoid raw berries and vegetables grown in dirt and to limit intake of raw fruits and raw vegetables (eg, salad) to those that can be easily peeled (eg, bananas, oranges). Sick visitors are prohibited. Most methods to reduce the risk of infection have not been rigorously tested, but they are routinely applied because they are relatively simple and are likely to reduce exposure to potential pathogens. (See "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults", section on 'General precautions'.)
There is no consensus regarding use and/or choice of prophylactic antibiotics, antifungals, and antiviral agents during remission induction therapy and practices vary. 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 [51]. The American Society of Clinical Oncology (ASCO) and the Infectious Disease Society of America (IDSA) 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 (HSV) with leukemia receive antiviral prophylaxis [52,53]. 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".)
Development of fever or other infectious findings in a neutropenic patient is a medical emergency. The patient requires prompt evaluation and administration of empiric, broad-spectrum parenteral antibiotics; choice of antibiotics should be tailored to the most likely organisms and resistance patterns of the institution. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)".)
The utility of a neutropenic diet was examined in a trial of 153 patients who were undergoing induction therapy for newly diagnosed AML and randomly assigned to diets either containing raw fruits or vegetables (raw diet) or not (cooked diet) [54]. There was no difference in overall survival or rates of major infections between the two diets.
REMISSION ASSESSMENT — Determination of whether a patient has achieved remission is based on a bone marrow examination when blood counts are recovering. We suggest performing the bone marrow examination when the absolute neutrophil count (ANC) is >1000/microL and platelet count >100,000/microL. This is generally four or more weeks after starting therapy, but the timing will vary according to whether the patient received one or two cycles of induction therapy.
Bone marrow morphology and percentage of blasts and peripheral blood counts are used to define complete remission (CR), CR with incomplete hematologic recovery, partial response, or induction failure. Cytogenetic response is based on repeat karyotype and/or fluorescence in situ hybridization (FISH) in patients with findings at the time of diagnosis. Flow cytometry and molecular studies may be applied to detect measurable residual disease (MRD), as described separately. (See "Remission criteria in acute myeloid leukemia and monitoring for residual disease", section on 'Definition of complete remission (CR)'.)
For patients who had evidence of central nervous system (CNS) involvement at the time of diagnosis, the CNS should also be re-evaluated with imaging and/or lumbar puncture (LP), as discussed separately. (See "Involvement of the central nervous system (CNS) with acute myeloid leukemia (AML)".)
Post-remission management of AML (ie, remission consolidation therapy) and treatment of patients with persistent leukemia are discussed separately. (See "Post-remission therapy for acute myeloid leukemia in younger adults" and "Treatment of relapsed or refractory acute myeloid leukemia".)
SPECIAL SCENARIOS
Limited cardiac function — Patients with a congestive failure or other impaired cardiac function may not be able to tolerate the cardiotoxicity of an anthracycline. We generally avoid use of anthracyclines in patients with a baseline ejection fraction <40 percent. The use of anthracyclines in patients with cardiac disease is discussed in detail separately. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)
For patients with impaired cardiac function who are otherwise fit enough to receive intensive therapy, cytarabine-based regimens alone or combined with non-cardiotoxic agents offer potentially curative therapy. Nevertheless, remission induction therapy is associated with administration of large amounts of intravenous fluids, and cardiac function must be carefully monitored and managed.
Options for remission induction therapy include:
●Actionable mutations – Infusional cytarabine plus midostaurin (for mutated FLT3), gemtuzumab ozogamicin (for CD33+ AML), or IDH inhibitors (for IDH mutations). Fludarabine, cytarabine, granulocyte stimulating factor and gemtuzumab ozogamicin is a very effective, non-anthracycline-containing induction therapy for newly diagnosed patients with core-binding factor AML (eg, AML with inv(16) or t(8;21)) [55].
●High dose cytarabine – High dose cytarabine (HiDAC) alone or combined with other agents (eg, fludarabine, etoposide, vorinostat) [28,56,57]. Various doses and schedules of HiDAC have been described, with cytarabine doses ranging between 5 and 36 g/m2 per course. The risks for renal and neurologic function must be closely monitored for patients receiving HiDAC, as discussed separately. (See "Post-remission therapy for acute myeloid leukemia in younger adults", section on 'Administration of consolidation HiDAC'.)
●Clofarabine – Various clofarabine-containing regimens have been administered as induction therapy, none of which is clearly superior with regard to overall survival [43,58-61].
Other treatment options for patients with impaired cardiac function are discussed below and separately. (See 'Unfit or frail patients' below and "Treatment of relapsed or refractory acute myeloid leukemia", section on 'Intensive chemotherapy'.)
Unfit or frail patients — We consider medically-unfit patients to be those who cannot tolerate intensive therapy. We consider frail patients to be those who cannot tolerate any toxic antileukemic therapy. Assessment of unfitness and frailty is described above. (See 'Medical fitness' above.)
For medically-unfit and frail patients, the goals of care are to prolong life, alleviate symptoms, and/or improve quality of life. For patients with impaired performance status (eg, ECOG ≥2 or KPS <80) (table 1) or substantial comorbid illness (eg, HCT-CI ≥3 ) (table 2), we suggest further evaluation and management as described for medically-unfit adults with AML. (See "Pretreatment evaluation and prognosis of acute myeloid leukemia in older adults" and "Acute myeloid leukemia: Management of medically-unfit adults".)
For patients who are not medically fit for intensive treatment, acceptable treatment options include lower intensity therapies, such as azacitidine, decitabine, or low dose cytarabine, any of which can be administered alone or in combination with venetoclax (inhibitor of BCL2); IDH inhibitors (eg, ivosidenib, enasidenib) if IDH1 or IDH2 mutations are present; or other targeted therapies (eg, glasdegib). These treatments are relatively well-tolerated and can improve blood counts, relieve symptoms, improve quality of life, and/or extend survival, but they generally do not achieve long-term disease control. Lower intensity therapies for AML are discussed in detail separately. (See "Acute myeloid leukemia: Management of medically-unfit adults".)
For frail patients, we generally focus on supportive care to alleviate symptoms. (See "Acute myeloid leukemia: Management of medically-unfit adults".)
Secondary AML — Secondary AML refers to AML that arises in a patient with prior myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN). Compared with primary (de novo) AML, secondary AML is generally associated with inferior prognosis and may require distinctive management.
Management of secondary AML is similar to that of therapy-associated myeloid neoplasms, as 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 [62]. Caution is advised regarding the importance of contraception for women and men who were previously treated for AML, as described below.
Management of patients diagnosed later in pregnancy (eg, late in the second trimester or during the third trimester) poses a difficult therapeutic dilemma [63]. 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 pregnancy, the majority of whom have not aborted [62,64-68]. 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 the delivery of normal infants in 73 percent of patients [62]. Common 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 men and women 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 women and ≥3.5 months for male partners of fertile women [69]. Both men and women should seek advice for fertility preservation before treatment.
Central nervous system (CNS) disease — For patients with neurologic findings (eg, headache, confusion, cranial neuropathy) and certain higher-risk features, we suggest evaluation for potential CNS involvement. For patients with neurologic findings consistent with CNS bleeding, leptomeningeal disease, and/or mass lesions, magnetic resonance imaging (MRI) should be performed urgently. Computed tomography (CT) is acceptable if there is a contraindication to MRI (eg, implanted metallic devices). Lumbar puncture (LP) should be performed after correction of any coagulopathy or severe thrombocytopenia and bleeding and mass lesions have been excluded. 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)".)
Other extramedullary disease — Up to 10 percent of patients with AML will have extramedullary (eg, leukemia cutis, myeloid sarcoma) involvement at some point during the disease course. Evaluation of patients with extramedullary AML (with or without evidence of AML on bone marrow biopsy) is similar to that for patients with overt AML [70]. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia".)
Specific aspects of the evaluation and management of extramedullary disease include:
●Imaging can determine the extent of extramedullary involvement, aid in radiation treatment planning, and assess response to therapy [71]. Combined positron emission tomography (PET)/CT may be preferred over CT alone for radiation therapy (RT) planning [72-74]. MRI with gadolinium can assess CNS involvement. (See "Involvement of the central nervous system (CNS) with acute myeloid leukemia (AML)".)
●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'.)
●RT may be incorporated into the treatment approach, either before induction chemotherapy for patients with compression of vital structures, or as consolidation after induction chemotherapy for patients with persistent extramedullary involvement after chemotherapy. Myeloblasts are radiation sensitive, and doses >20 Gy are generally adequate.
Without systemic remission induction chemotherapy, patients presenting with myeloid sarcoma will almost always progress to systemic disease, usually within three to six months [75]. In comparison, treatment with remission induction chemotherapy, with or without RT, achieves survival rates similar to those seen in patients with AML without extramedullary disease [76,77]. Given the rarity of this condition, there is a paucity of data regarding the role of RT in this setting.
CLINICAL TRIALS — Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)
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 5th to 6th 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 10th to 12th 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 hematologic malignancies of bone marrow myeloid precursor cells that interfere with production of normal blood cells, causing 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 – History, physical examination, laboratory studies, and clinical testing are used to evaluate heart, lung, liver, and kidney disease that may affect tolerance for intensive treatment. (See 'Pretreatment evaluation and management' above.)
●Medical fitness – Fitness is determined by performance status (table 1) and the nature and severity of medical comorbidities (table 2). There is no age threshold for receiving intensive treatment, but patients ≥70 years are more likely to have limiting comorbid conditions.
●Emergencies, goals, and timing of therapy
•Emergencies – AML is often associated with life-threatening emergencies. (See 'Emergencies' above.)
•Timing of therapy – Treatment should begin promptly, but clinical stabilization and emergencies/complications should first be addressed. (See 'Goals and timing of treatment' above.)
•Goals – Goals of care are based on fitness for intensive treatment:
-Medically-fit – For fit patients, the goal of treatment is to achieve long-term survival with the possibility of cure.
-Unfit or frail – Goals are to prolong life, alleviate symptoms, and/or improve quality of life.
●Remission induction therapy
•7+3 regimen – For medically-fit patients, we recommend remission induction therapy with a seven-day continuous infusion of cytarabine plus three days of an anthracycline (so-called "7+3" therapy) (Grade 1B). (See '7+3 therapy (cytarabine plus anthracycline)' above.)
7+3 therapy includes:
-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
Induction chemotherapy is toxic and requires careful monitoring and management of cytopenias, infections, bleeding, tumor lysis syndrome, electrolyte imbalances, and other complications.
•Third agents – For patients with FLT3 mutant AML, we suggest adding midostaurin to 7+3 therapy, rather than 7+3 therapy alone (Grade 2B). (See 'Inhibitors of mutated FLT3' above.)
●Response assessment
•Nadir bone marrow (BM) examination – BM examination on approximately day 14 assesses clearance of blasts and may guide further induction therapy. (See 'Initial response to therapy' above.)
•Recovery BM – BM morphology is again reviewed as blood counts recover (eg, ≥4 weeks after beginning therapy) to evaluate remission; in some cases, this is supplemented by analysis for measurable residual disease (MRD) using flow cytometry and/or molecular techniques. (See 'Remission assessment' above.)
●Special scenarios – Remission induction therapy is modified for patients with limited cardiac function, pregnant individuals, and other specific scenarios. (See 'Special scenarios' above.)
