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Acute myeloid leukemia: Management of medically-unfit adults

Acute myeloid leukemia: Management of medically-unfit adults
Author:
Richard A Larson, MD
Section Editor:
Bob Lowenberg, MD, PhD
Deputy Editor:
Alan G Rosmarin, MD
Literature review current through: Dec 2022. | This topic last updated: Oct 11, 2022.

INTRODUCTION — Management of acute myeloid leukemia (AML) is informed by the individual's medical fitness for intensive antileukemic therapy. Importantly, medical fitness is based on performance status and physiologic function, but not on age per se; we do not apply age limits when judging medical fitness.

This topic discusses treatment of AML in medically-unfit adults.

The following topics are presented separately:

Overview of AML (see "Overview of acute myeloid leukemia in adults")

Pretreatment evaluation and prognosis of AML in older adults (see "Pretreatment evaluation and prognosis of acute myeloid leukemia in older adults")

Treatment of medically-fit adults with AML (see "Induction therapy for acute myeloid leukemia in medically-fit adults")

PRETREATMENT EVALUATION — Medical fitness is a key determinant of management of AML and informs the goals of care and choice of therapy. Medical fitness should be determined before initiating therapy for AML.

Clinical/laboratory evaluation — Pretreatment evaluation of the adult with AML should identify findings related to complications of AML and comorbid conditions that may influence the choice of therapy.

Clinical – The clinical evaluation assesses comorbid conditions and effects of cytopenias associated with AML. The history should evaluate symptoms associated with anemia (eg, dyspnea, weakness, palpitations) that may impair the quality of life; transfusion history should be documented. The patient should be examined for evidence of infections or excessive bleeding/bruising. Clinical manifestations of comorbid illnesses, including heart disease, pulmonary processes, nutritional deficits, and renal impairment should be documented.

Laboratory studies – Laboratory studies should include:

Complete blood count (CBC) and differential count

Prothrombin time (PT) and partial thromboplastin time (PTT)

Serum electrolytes, renal and liver function tests

Electrocardiogram (EKG)

If cytogenetic and molecular features of the leukemia were not determined at the time of diagnosis, they should be defined prior to selecting therapy using either peripheral blood or bone marrow. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Diagnosis' and "Classification of acute myeloid leukemia (AML)".)

Medical fitness — We classify patients with AML according to their fitness for treatment. Determination of medical fitness for patients with hematologic malignancies is based on assessment of performance status (PS) and medical fitness.

Assessment instruments – Assessment of medical fitness includes evaluation of:

Performance status – Eastern Cooperative Oncology Group (ECOG) performance scale (table 1).

Physiologic fitness – We assess physiologic fitness (eg, comorbid conditions, activities of daily living, physical performance tests, cognition), by the Charlson comorbidity index (CCI) (table 2).

Other measures of physiologic fitness are also acceptable, such as the Short Physical Performance Battery (SPPB; https://geriatrictoolkit.missouri.edu/SPPB-Score-Tool.pdf) [1].

For some older patients with AML, a comprehensive geriatric assessment and geriatric consultation may aid assessment of medical fitness [2,3]. For older patients with AML, a detailed assessment of medical fitness and its impact on clinical outcomes are discussed separately. (See "Pretreatment evaluation and prognosis of acute myeloid leukemia in older adults".)

Fitness categories – There are no clear distinctions between fitness categories and some measures of PS or physiologic fitness can apply to different categories. Importantly, fitness may change during the course of the disease and its treatment.

Assigning a fitness category – In selecting a fitness category, we seek to protect frail individuals from treatment that they are unlikely to tolerate, while not depriving patients of the opportunity to achieve remission and prolonged survival.

The following should be considered in judging medical fitness:

-Age, per se, does not determine medical fitness. However, because of age-related comorbidities, caution should be used when considering intensive therapy for patients ≥75 years old, as most outcomes data with intensive antileukemic therapy came from studies in younger, fit adults.

-Chronic comorbid conditions should be weighted more heavily than transient medical complications of the leukemia itself (eg, infection, heart failure exacerbated by anemia). The burden of AML can contribute to a lack of fitness and, in some cases, treatment may alleviate consequences/complications of AML and enhance the patient's ability to tolerate and benefit from subsequent treatment.

Categories – We categorize fitness as follows:

-Medically-fit – Medically-fit patients are those who are judged to be able to tolerate intensive treatment for AML, based on both of the following:

ECOG PS (table 1): 0 to 2

CCI (table 2): 0 to 2

For medically-fit patients who choose to receive intensive induction therapy for AML, management is discussed separately. (See "Induction therapy for acute myeloid leukemia in medically-fit adults".)

Some medically-fit patients may, for reasons of age or personal preference, choose to receive less intensive therapy, such as that for medically-unfit patients. (See 'Medically-unfit, but not frail' below.)

-Medically-unfit, but not frail – Patients who are medically-unfit but not frail are unlikely to tolerate intensive antileukemic therapy because of impaired PS or comorbid conditions. This fitness category includes a broad range of physical function. Some patients have only modest, recent, or transient impairment of functional status, while others have substantial comorbid illnesses, cognitive impairment, or other conditions that may affect their ability to tolerate treatment.

We judge patients to be medically-unfit but not frail if either of the following applies:

ECOG PS (table 1): 3

CCI (table 2): 3

Treatment for medically-unfit patients is described below. (See 'Medically-unfit, but not frail' below.)

-Frail – Frail patients are those whose debility or comorbid conditions would not permit treatment aimed at modifying the disease course, as reflected by both the following:

ECOG PS (table 1): ≥3

CCI (table 2): ≥3

Note that our use of the term frail for managing patients with hematologic malignancies may differ from other definitions of frailty. (See "Frailty", section on 'Concepts and definitions'.)

Management of frail patients with AML should focus primarily on providing supportive care to improve the quality of life by lessening symptoms caused by AML and comorbid conditions. It is important to carefully discuss the goals of care, likely outcomes, and available resources for personal and medical assistance. (See 'Frail patients' below and 'Goals, benefits, and timing of treatment' below.)

EMERGENCIES — Medical emergencies are encountered regularly in patients who present with AML. (See "Overview of the complications of acute myeloid leukemia".)

Acute promyelocytic leukemia (APL) – APL with t(15;17) is a unique category of AML that constitutes a medical emergency and requires urgent and specific treatment because of its distinctive clinical manifestations and complications.

APL is more likely in patients who present with bleeding or bruising, when leukemic blasts have coarse or dense cytoplasmic granules, and when there are few circulating leukemic cells or a low white blood cell count. The diagnosis is confirmed by detection of the PML-RARA fusion gene and/or an associated chromosomal translocation, as described separately. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults".)

The mainstay of therapy is prompt initiation of all-trans retinoic acid (ATRA), with or without arsenic trioxide. Medical fitness is generally not a barrier to such treatment and APL responds equally well across the age spectrum. Management of APL is presented separately. (See "Initial treatment of acute promyelocytic leukemia in adults".)

Hyperleukocytosis/leukostasis, which may be manifest as 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), can be diagnosed and managed as described separately. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors" and "Tumor lysis syndrome: Prevention and treatment".)

Bleeding/coagulation abnormalities may be caused by severe thrombocytopenia, disseminated intravascular coagulation, and other coagulopathies. (See "Hematopoietic support after hematopoietic cell transplantation", section on 'Platelet transfusion' and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)

Unexplained neurologic or visual findings may be manifestations of leukostasis (described above), thrombotic or hemorrhagic cerebrovascular accident, or leukemic involvement of the central nervous system. (See "Involvement of the central nervous system (CNS) with acute myeloid leukemia (AML)".)

GOALS, BENEFITS, AND TIMING OF TREATMENT

Goals of care – Goals of care are influenced by medical fitness and individual values. Age, per se, should not define or limit the goals of care. Determination of medical fitness is described above. (See 'Pretreatment evaluation' above.)

Medically-fit – For most medically-fit patients, the goal of care is to achieve long-term survival with the possibility of cure, as discussed separately. (See "Induction therapy for acute myeloid leukemia in medically-fit adults".)

Medically-unfit, but not frail – For most medically-unfit patients who are not frail, the goal is to achieve a remission as the most effective way to alleviate symptoms, improve the quality of life, and/or extend survival. It should be recognized that current therapies for this population have not been proven to achieve long-term survival or the possibility of cure. (See 'Medically-unfit, but not frail' below.)

Frail – For frail patients, the primary goals are relief of symptoms and improved quality of life through supportive care. The potential for harm resulting from more intensive therapy is likely to outweigh the benefits. (See 'Frail patients' below.)

Goals of care should be established in discussions between the patient and clinicians at the time of diagnosis and periodically through the course of the disease. Discussions should acknowledge that for most patients, AML will be a life-ending disease. Many patients overestimate their long-term prognosis and chance for cure, and they don't recall being offered more than one treatment [4,5]. Mutual understanding between the patient, family members, and practitioners facilitates conversations regarding goals of care, selection of therapy, health care proxies, do-not-resuscitate directives, and end-of-life decisions.

Benefits of treatment – Patients of any age who are medically-unfit but not frail can benefit from treatment of AML. Compared with supportive care alone, treatment of AML can relieve symptoms, improve the quality of life, and potentially extend survival.

Some clinicians and patients fear that treatment will cause more harm than good. However, the major causes of death from AML are infection and hemorrhage related to disease-associated cytopenias; treatment of the underlying AML is the most effective and efficient way to control those complications [6]. While some population-based studies have suggested that treatment only benefits patients ≤80 years, other studies have documented that treatment of selected patients in their 80s and 90s can achieve high rates of response and improved survival [7-10].

Compared with supportive care alone, treatment of AML is associated with improved quality of life, including fewer hospitalizations and less need for transfusions and antibiotics [8,11]. Improved outcomes are reported in prospective, retrospective, and population-based studies, even while recognizing that retrospective analyses may exhibit a bias that favors treatment for more medically fit and/or younger patients [7-9,11,12]. United States Surveillance, Epidemiology, and End Results (SEER)-Medicare data of 5480 patients ≥65 years (median age 78 years) reported improved survival in treated patients, compared with untreated patients (median six versus two months, respectively) [7].

Trials that compared lower-intensity treatment versus supportive care for medically-unfit patients with AML are discussed below. (See 'Preference for hypomethylating agents (HMA)' below.)

Timing of therapy – For most patients with AML, it is not harmful to temporarily delay treatment to permit an adequate diagnostic evaluation, assessment of fitness, medical stabilization, and management of complications.

An important exception is patients who are suspected of having acute promyelocytic leukemia (APL), for whom treatment should begin immediately, even before cytogenetic and/or molecular confirmation is available. Features that suggest the presence of APL are described above. (See 'Emergencies' above.)

Aside from APL, it is generally not harmful to delay treatment of AML by 96 hours or longer to stabilize the patient's condition and/or characterize the cytogenetic and molecular features of the AML cells. Infections, bleeding, hyperuricemia, renal dysfunction, anemia, and thrombocytopenia should be managed and comorbid conditions optimized to improve baseline physical function prior to initiating antileukemic therapy. Oral hydroxyurea can be used for cytoreduction if the peripheral blast count must be reduced during this time.

A retrospective study of 2263 patients with AML reported no differences in rates of remission, early death, or overall survival based on the time between diagnosis and initiation of treatment [13] and other studies have reported similar findings [14,15].

MEDICALLY-UNFIT, BUT NOT FRAIL — Classification of medical fitness is described above. (See 'Medical fitness' above.)

We encourage participation in a clinical trial, when possible. Examples of ongoing studies in the United States can be found at www.clinicaltrials.gov.

Supportive care for patients who are undergoing induction therapy for AML is discussed separately. (See "Induction therapy for acute myeloid leukemia in medically-fit adults", section on 'Monitoring and supportive care during therapy'.)

Preference for hypomethylating agents (HMA) — For patients who are medically-unfit but not frail, we suggest treatment that includes an HMA (eg, azacitidine, decitabine) rather than low-dose cytarabine (LoDAC), other single agents, or supportive care alone (algorithm 1). This suggestion is based on randomized trials that demonstrated superior outcomes with an HMA versus supportive care [16-18] and comparisons across prospective trials, which indicate that HMAs are associated with superior responses and similar toxicity compared with other single agents.

Some patients are not candidates for treatment with an HMA. Treatment options for patients who were previously treated with an HMA (eg, for prior myelodysplastic neoplasm/syndrome [MDS]) or who are ineligible for HMA therapy because of severe liver or kidney dysfunction (algorithm 1) are presented below. (See 'Alternative treatments' below.)

HMA versus supportive care – Phase 3 trials demonstrated that both azacitidine and decitabine are associated with superior survival and/or response rates compared with supportive care. Although no randomized trials in AML have directly compared HMAs with other single agents, comparisons across prospective studies suggest that HMAs are associated with superior outcomes compared with LoDAC.

A phase 3 trial of 488 patients ≥65 years old with newly diagnosed AML reported that azacitidine achieved superior survival compared with best supportive care (BSC) [17]. Each enrolled patient was preselected for a conventional care regimen (CCR; either LoDAC, intensive induction chemotherapy, or BSC); within each CCR subgroup, patients were randomly assigned to azacitidine versus the preselected CCR. Compared with the overall CCR cohort, azacitidine achieved marginally superior median overall survival (OS; 10 versus 7 months; hazard ratio [HR] 0.85; 95% CI 0.69-1.03) and one-year OS (47 versus 34 percent). Among those preselected for BSC, patients randomized to azacitidine achieved superior OS (6 versus 4 months; HR 0.60; 95% CI 0.38-0.95); OS did not differ between patients who were randomly assigned to azacitidine versus either LoDAC or intensive induction therapy. For patients treated with azacitidine, the rate of complete remission (CR) plus CR with incomplete hematologic recovery (CRi) was 28 percent and grade ≥3 adverse events (AEs) included febrile neutropenia (28 percent), thrombocytopenia (24 percent), pneumonia (19 percent), and anemia (16 percent).

In another phase 3 trial, azacitidine achieved superior OS compared with CCR; this trial included 113 patients with AML among 358 patients with either AML or high-risk MDS [16]. Compared with CCR (preselected as either LoDAC, intensive induction chemotherapy, or BSC), azacitidine was associated with superior median OS (25 versus 16 months, respectively; HR 0.47; 95% CI 0.28-0.79), two-year OS (50 versus 16 percent), and hematologic response (29 versus 12 percent). Grade ≥3 cytopenias were the most common serious AEs for all treatments.

A phase 3 trial randomly assigned 485 patients (median age 74 years) with AML and poor- or intermediate-risk cytogenetics to decitabine versus treatment choice (preselected BSC or low-dose cytarabine) [18]. The rate of CR plus CR without platelet recovery (CRp) was superior with decitabine (18 versus 8 percent), but OS was not significantly different (8 versus 5 months; HR 0.85; 95% CI 0.69-1.04). AEs of thrombocytopenia and neutropenia (27 and 24 percent, respectively) with decitabine were similar to those with low-dose cytarabine.

The choice of azacitidine versus decitabine and administration, AEs, and outcomes with these agents are discussed below. (See 'Selection of an HMA' below.)

HMA compared with other single agents – No randomized trials have directly compared an HMA versus LoDAC therapy, but comparisons between prospective studies suggest that HMAs are associated with longer survival and higher rates of response.

As examples, azacitidine and decitabine have been associated with CR in up to one-half of patients, with 6 to 12 month median OS [19-24]. By comparison, treatment with single-agent LoDAC (in a phase 3 trial that compared LoDAC alone with LoDAC plus venetoclax) reported 13 percent CR and 4 month median OS [25]. Details of these and other studies are presented below. (See 'Selection of an HMA' below and 'Low-dose cytarabine (LoDAC)' below.)

The US Food and Drug Administration (FDA) has not approved either azacitidine or decitabine for AML, but both are commonly used for off-label treatment of AML. The European Medicines Agency (EMA) has approved decitabine for treatment of AML and has approved azacitidine for treatment of AML that arose from MDS.

HMA plus venetoclax — In settings where venetoclax is available, we suggest treatment with an HMA (eg, either azacitidine or decitabine) plus venetoclax, rather than treatment with an HMA alone (algorithm 1). This suggestion is based on a randomized trial (VIALE-A), which reported that venetoclax plus azacitidine achieved superior survival compared with azacitidine alone [26], and other studies that reported addition of venetoclax to either azacitidine or decitabine was associated with improved response rates and comparable toxicity [27,28].

Treatment of patients with IDH1-mutated AML is discussed below. (See 'IDH1-mutated AML' below.)

Outcomes with venetoclax plus an HMAVenetoclax plus either azacitidine or decitabine is associated with superior outcomes, compared with an HMA alone; toxicity is only modestly increased by addition of venetoclax to either HMA.

Venetoclax plus azacitidine – A phase 3 trial (VIALE-A) of 431 patients with previously untreated AML reported that, compared with azacitidine plus placebo, azacitidine plus venetoclax achieved superior OS, higher rate of remission, more rapid and durable responses, and comparable quality of life, but it was associated with a higher incidence of febrile neutropenia [26]. Patients who were ≥75 years of age or had comorbid conditions that precluded intensive remission induction therapy were randomly assigned (2:1) to azacitidine plus venetoclax versus azacitidine plus placebo. With median follow-up of 21 months, azacitidine-venetoclax achieved superior OS (15 versus 10 months; HR 0.66; 95% CI 0.52-0.85), higher rate of CR (37 versus 18 percent), a higher composite score of CR plus CRi (65 versus 23 percent), and more transfusion-independence from red blood cells (60 versus 35 percent) and platelets (69 versus 50 percent). Grade ≥3 AEs that were more common with azacitidine-venetoclax included febrile neutropenia (42 versus 19 percent), neutropenia (42 versus 28 percent), and thrombocytopenia (45 versus 38 percent). AEs (of all grades) associated with azacitidine-venetoclax included nausea or vomiting (44 and 30 percent, respectively), constipation or diarrhea (43 and 41 percent), hypokalemia (29 percent), peripheral edema (24 percent), and infections (84 percent), but the incidence of AEs were only modestly increased compared with azacitidine plus placebo.

Other studies of azacitidine plus venetoclax reported similar rates of remission and toxicity [27,29].  

Venetoclax plus decitabineVenetoclax plus decitabine is associated with a toxicity profile and response rate that is similar to venetoclax plus azacitidine, but survival data are not yet available. Treatment of 145 patients with venetoclax plus either decitabine or azacitidine was associated with 67 percent CR plus CRi, 11 month median duration of response, and 18 month median OS; toxicity profiles and responses were similar for both regimens [27]. In a study of 31 patients treated with venetoclax plus decitabine, rates of CR and CRi were 54 and 8 percent, respectively; median duration of remission was five months [28].

Venetoclax as a single agent has only limited activity against AML; in a study of 32 patients with relapsed or refractory AML, venetoclax was associated with 19 percent response rate and 5 month median OS [30].

IDH1-mutated AML — For patients with mutated IDH1, we recommend treatment with azacitidine plus ivosidenib, rather than an HMA alone (algorithm 1), based on superior survival with the combination compared with azacitidine alone in the phase 3 AGILE trial [31].

Our approach in settings where treatment with azacitidine plus ivosidenib is not possible is:

Where ivosidenib is not available, we favor treatment with venetoclax plus an HMA. (See 'HMA plus venetoclax' above.)

For patients who can't use an HMA (eg, for comorbidities or prior HMA therapy), treatment with single-agent ivosidenib is acceptable. (See 'IDH inhibitors' below.)

Ivosidenib plus azacitidine achieved superior outcomes with similar toxicity compared with azacitidine plus placebo in a phase 3 trial in 146 patients with newly-diagnosed IDH1-mutated AML who were ineligible for intensive induction chemotherapy [31]. Compared with azacitidine plus placebo, ivosidenib plus azacitidine achieved superior median OS (24 versus 8 months; HR for death 0.44 [95% CI 0.27-0.73]), 12-month event-free survival (EFS; 37 versus 12 percent; HR 0.33 [95% CI 0.16-0.69]), and CR by 24 weeks (38 versus 11 percent). Grade ≥3 AEs included febrile neutropenia (28 percent with ivosidenib and azacitidine versus 34 percent with placebo and azacitidine), grade ≥3 neutropenia (27 versus 16 percent, respectively), bleeding (any grade; 41 versus 29 percent), infection (any grade; 28 versus 49 percent), and differentiation syndrome (any grade; 14 versus 8 percent).

Some experts consider azacitidine plus venetoclax acceptable for treatment of IDH1-mutated AML, based on subgroup analysis of limited numbers of patients in prospective trials. Although outcomes were similar for patients with mutated IDH1 who were treated with ivosidenib plus azacitidine compared with those treated using venetoclax plus azacitidine in two separate phase 3 trials, there were more patients with mutant IDH1 treated with azacitidine plus ivosidenib (72 patients in the AGILE trial) compared with the subset of patients with mutant IDH1 treated with azacitidine plus venetoclax (15 patients in the VIALE trial). AEs were comparable with both combinations.

Ivosidenib is approved by the US FDA for treatment of newly-diagnosed AML with an IDH1 mutation detected by an FDA-approved test in patients ≥75 years or who have comorbidities that preclude use of intensive induction chemotherapy. Ivosidenib is not yet approved by the EMA.

If venetoclax is not available — In settings where venetoclax is not available and IDH1 is not mutated, we generally treat with single-agent azacitidine or decitabine (algorithm 1).

The choice of azacitidine versus decitabine and administration, AEs, and outcomes with these agents are discussed below. (See 'Selection of an HMA' below.)

For patients with mutated IDH1, treatment with an HMA plus ivosidenib is discussed below. (See 'HMA plus ivosidenib' below.)

Patients ineligible for an HMA — For patients who were previously treated with an HMA (eg, for prior MDS) or who are ineligible for HMA therapy because of severe liver or kidney dysfunction, treatment options are presented below. (See 'Alternative treatments' below.)

FRAIL PATIENTS — We consider frail patients to be those whose debility or comorbid conditions would not permit treatment aimed at modifying the disease course of AML. (See 'Medical fitness' above.)

Some frail patients choose to receive supportive care alone, while others may favor treatment with a lower intensity regimen, such as low-dose cytarabine, single-agent IDH inhibitor (ie, ivosidenib for mutant IDH1 or enasidenib for mutant IDH2), or others. (See 'Supportive care' below and 'Alternative treatments' below.)

It is important to carefully discuss the goals of care, outcomes, and available resources (eg, assistance for personal and medical needs). (See 'Goals, benefits, and timing of treatment' above.)

TREATMENTS

Hypomethylating agents (HMAs) — Our preference for HMA-based therapy is discussed above. (See 'Preference for hypomethylating agents (HMA)' above.)

Selection of an HMA — Azacitidine and decitabine seem to have comparable efficacy for newly diagnosed AML and both agents are well-tolerated. Some patients and/or practitioners may favor one agent or based on schedule and/or method of administration.

Comparison of azacitidine with decitabineAzacitidine and decitabine have not been directly compared in randomized trials, but prospective and retrospective analyses indicate similar efficacy and toxicity profiles [16-24,32-36]; details of such studies are presented below. (See 'Azacitidine' below and 'Decitabine' below.)

A population-based survey of 2263 adults >65 years old with AML reported that patients who were treated with azacitidine or decitabine had similar median overall survival (OS; seven to eight months) and both achieved red blood cell transfusion-independence in approximately one-third of patients [33].

Differences in administration – Both azacitidine and decitabine are administered parenterally, but a patient may favor one or the other based on schedule and/or method of administration. Orally available HMAs are in development or approved for other indications, but their efficacy has not yet been reported for induction therapy of AML.

Some patients may favor decitabine because it is given intravenously (IV), which is convenient for patients who have venous access devices. Others may favor azacitidine because it requires less time in an infusion center and can be give subcutaneously; note that subcutaneous administration may cause pain or bruising in a patient who is thrombocytopenic.

Duration of treatment – In the absence of treatment intolerance, HMA administration can be continued until disease progression or for a fixed period (eg, one or two years). There are no data at present that compare open-ended treatment versus a predetermined course of therapy.

Azacitidine

AdministrationAzacitidine (75 mg/m2 subcutaneous) can be administered in an outpatient setting for 7 consecutive days in 28-day cycles [16]. Other azacitidine regimens (eg, 100 mg/m2 per day for 5 consecutive days in 28-day cycles) are more convenient and are also acceptable for treatment of AML [34]. Dose adjustment may be needed for patients with liver or kidney disease [37].

Monitoring – Complete blood count (CBC), liver chemistries, and renal function should be evaluated prior to each treatment cycle and as clinically indicated. We continue treatment for as long as the patient is responding and tolerating treatment, although it may be necessary to insert a brief interval between cycles or adjust doses to enable recovery of blood counts.

Response assessment is discussed below. (See 'Response assessment' below.)  

Toxicity – Grade ≥3 adverse events (AEs) include cytopenias and febrile neutropenia in one-quarter to one-third of patients and most will have at least one hospitalization for neutropenic fever during treatment. Growth factor support may be considered.

EfficacyAzacitidine is associated with a hematologic response in up to half of patients with AML. Compared with supportive care alone, azacitidine achieved longer survival, as discussed above. (See 'Preference for hypomethylating agents (HMA)' above.)

Among 35 patients treated with azacitidine for newly diagnosed AML, the rate of complete remission (CR)/CR with incomplete hematologic recovery (CRi) was 31 percent and median response duration was 13 months [19]. OS, event-free survival (EFS), and response rates from other studies are presented above. (See 'Preference for hypomethylating agents (HMA)' above.)

The European Medicines Agency (EMA) approved azacitidine for treatment of AML that arose from myelodysplastic neoplasm/syndrome (MDS). The US Food and Drug Administration (FDA) has not approved azacitidine for treatment of AML.

An oral preparation of azacitidine (CC-486) has been approved by the US FDA for post-remission maintenance therapy of AML, but it is not well-studied for induction therapy of AML; use of CC-486 for maintenance therapy is discussed below. (See 'Post-remission management' below.)

Decitabine

AdministrationDecitabine (20 mg/m2 IV daily over one hour) can be administered in an outpatient setting for 5 or 10 consecutive days, in 28-day cycles [18,20-22,32]. Decitabine can also be administered in the inpatient setting (eg, 15 mg/m2 IV over four hours every eight hours for three consecutive days, every six weeks) [23].

Dose adjustment may be needed for severe liver or kidney disease [38].

Monitoring – CBC, liver chemistries, and renal function should be evaluated prior to each cycle of therapy and as clinically indicated. Response to decitabine typically requires at least two cycles of therapy, and treatment should continue for as long as a benefit persists with tolerable side effects. Growth factor support and dose adjustment may be necessary.

Response assessment is discussed below. (See 'Response assessment' below.)  

Toxicity – Grade ≥3 AEs include cytopenias and febrile neutropenia in one-quarter to one-third of patients, and most patients will have at least one hospitalization for neutropenic fever during treatment. Growth factor support may be considered.

EfficacyDecitabine monotherapy for AML is associated with a hematologic response in up to one-half of patients and five to eight month median OS [18,20-24,32,35,36]. Compared with treatment for 5 consecutive days, treatment for 10 consecutive days may achieve higher response rates [21,22,24]. Decitabine appears to be effective in patients with AML with mutations in TP53 and/or unfavorable cytogenetic features [20]. Studies of decitabine for AML include:

A multicenter study reported that decitabine achieved clearance of bone marrow blasts in nearly half of 54 patients ≥60 years old [20]. Response rates were higher in patients with unfavorable-risk cytogenetics (67 percent of 43 patients) and TP53 mutation (100 percent of 21 patients), compared with intermediate-risk or favorable-risk cytogenetics (34 percent) and wild-type TP53 (41 percent). Maximum clinical response required at least two cycles of treatment. Other studies that used a similar 10-day decitabine regimen reported CR rates of 30 to 47 percent [21,22,24].

In a multicenter study of 227 older adults (median age 72 years) in which decitabine (135 mg/m2 total dose infused over 72 hours every six weeks) was administered to patients who were ineligible for intensive induction chemotherapy, the CR rate was 13 percent, median OS was 6 months, and one-year and two-year OS rates were 28 and 13 percent, respectively [23].

Addition of bortezomib to decitabine did not improve outcomes in a randomized phase 2 study [39], as described below. (See 'HMA plus other agents' below.)

Decitabine is approved for treatment of AML by the EMA but not by the US FDA. A fixed-dose oral agent (35 mg decitabine plus 100 mg cedazuridine, an inhibitor of cytidine deaminase in the gut and liver) is approved by the US FDA for treatment of MDS and chronic myelomonocytic leukemia but not for AML. (See "Chronic myelomonocytic leukemia: Management and prognosis", section on 'Hypomethylating agents'.)

HMA plus venetoclax — Randomized trials that included either azacitidine or decitabine plus venetoclax are discussed above. (See 'HMA plus venetoclax' above.)

Setting of care – We generally administer the first treatment of an HMA plus venetoclax in an inpatient setting, to monitor and manage the possibility of tumor lysis syndrome (TLS). Some patients with nearby housing and dependable transportation can be treated safely with daily outpatient visits. Although TLS is not well-documented with venetoclax for AML, it can occur with lymphoid malignancies.

Dosing and administrationVenetoclax plus either azacitidine or decitabine is administered in 28-day cycles [27,29]. Patients should be monitored clinically and biochemically for TLS and should receive adequate hydration and an anti-hyperuricemic agent. (See "Tumor lysis syndrome: Prevention and treatment".)

Either azacitidine or decitabine:

-Azacitidine 75 mg/m2 daily IV or subcutaneously for the first 7 days of each 28-day cycle. Other protocols for azacitidine administration are described above, but they have not been evaluated in combination with venetoclax. (See 'Azacitidine' above.)

or

-Decitabine 20 mg/m2 IV on days 1 to 5 of each 28-day cycle. (See 'Decitabine' above.)

Plus

Venetoclax – In cycle 1 only, venetoclax should be administered according to the following dose escalation schedule, to lessen the risk of TLS. Venetoclax should be taken orally with food. The dose of venetoclax should be reduced if it is administered with a moderate or strong CYP3A inhibitor (eg, antifungal azoles) [40].

-Cycle 1, day 1: 100 mg

-Cycle 1, day 2: 200 mg

-Cycle 1, days 3 to 28: 400 mg

We attempt to adhere to this protocol of 28 days of venetoclax administration to maximize the rate of CR.

Subsequent cycles can begin with 400 mg venetoclax daily.

In the event of substantial hematologic toxicity, venetoclax administration can be shortened to the first 21 days or 14 days of subsequent 28-day treatment cycles, although the efficacy of such schedules is not yet well-defined.

Monitoring – During the first treatment cycle, serum potassium, renal function tests, calcium, phosphate, and lactate dehydrogenase (LDH) should be obtained daily, until the threat of TLS has passed.

Prior to each treatment cycle, a CBC, liver chemistries, and renal and liver function tests should be obtained. Interval visits and CBCs may be required, guided by the degree of cytopenias and/or need for transfusion support.

Responses to venetoclax plus an HMA are relatively rapid. We perform bone marrow examination between day 14 and 21 with this therapy, as discussed below. (See 'Response assessment' below.)

We generally discontinue treatment if there is no meaningful response after three or four treatment cycles. We continue treatment for as long as the patient is responding and tolerating treatment, although adjustments to the dose or schedule of treatment may be needed, as described below. (See 'Post-remission management' below.)

Toxicity – The primary AEs of venetoclax plus an HMA are prolonged cytopenias, febrile neutropenia, and mild or moderate gastrointestinal effects (eg, nausea, vomiting, diarrhea), fatigue, and edema. Venetoclax plus an HMA should be used with caution in patients who have liver disease, renal dysfunction, or are receiving CYP3A inhibitors.

Venetoclax is approved by the US FDA in combination with an HMA in medically-unfit patients or those ≥75 years with newly diagnosed AML; venetoclax is not approved as a single agent for treatment of AML [28]. The EMA approved decitabine for treatment of AML and approved azacitidine for treatment of AML that arose from MDS; neither HMA is approved by the US FDA for treatment of AML.

HMA plus ivosidenib — Treatment with an HMA plus the IDH1 inhibitor, ivosidenib, in patients with IDH1-mutated AML is effective and well-tolerated. Details of a phase 3 trial that compared the combination to azacitidine alone are presented above. (See 'IDH1-mutated AML' above.)

Dosing and administrationIvosidenib (500 mg once daily orally) is administered in 28-day cycles along with azacitidine or decitabine, as described above. (See 'Azacitidine' above and 'Decitabine' above.)

Adverse effects – Treatment may cause hematologic AEs, QT prolongation, or differentiation syndrome (DS).  

OutcomesIvosidenib plus azacitidine achieved 24 month median OS, 38 percent CR, and was well-tolerated in patients with AML with mutant IDH1 [31], as discussed above. (See 'IDH1-mutated AML' above.)

In a multicenter study, azacitidine plus ivosidenib was associated with 82 percent 12-month OS, 78 percent overall response, and 61 percent CR among 23 patients with mutant IDH1 who were ineligible for intensive induction chemotherapy [41]. Among patients who achieved CR, 71 percent had undetectable measurable residual disease (MRD) by polymerase chain reaction (PCR). Grade ≥3 AEs included neutropenia, anemia, and thrombocytopenia (22, 13, and 13 percent, respectively) and QT prolongation in 13 percent. DS was reported in 17 percent, but none of the cases were grade ≥3.

HMA plus other agents — Compared with HMA monotherapy, no other agents besides venetoclax or ivosidenib have proven benefit when administered in combination with an HMA. Treatment with an HMA plus either venetoclax or ivosidenib is described above. (See 'HMA plus venetoclax' above and 'HMA plus ivosidenib' above.)

Other HMA-based combinations include:

Decitabine with sapacitabine – Alternating cycles of sapacitabine (an orally administered deoxycytidine analog) and decitabine was compared with decitabine alone in a phase 3 trial, which reported similar outcomes between trial arms [42]. Patients (≥70 years) with newly diagnosed AML who were unsuitable for intensive induction therapy were randomly assigned (241 patients in each arm) to single-agent decitabine (20 mg/m2 infusion on days 1 to 5 every 28 days) versus the same dose of decitabine every 8 weeks alternating with sapacitabine (300 mg by mouth twice daily on days 1 to 3 per week for 2 weeks every 8 weeks). Compared with decitabine alone, alternating decitabine/sapacitabine was associated with similar median OS (six months for each arm), one-year OS (34 to 35 percent), CR (17 percent for combination therapy versus 11 percent for decitabine alone), transfusions, and hospitalizations. Grade ≥3 hematologic AEs and grade ≥3 pneumonia, sepsis, and disease progression were similar in both arms.

Azacitidine plus gilteritinib – Treatment with azacitidine plus gilteritinib (FLT3 inhibitor) was associated with similar OS (9 to 10 months) and CR (14 to 16 percent), but higher overall response rate (ORR; 58 versus 27 percent), compared with azacitidine plus placebo, according to an abstract report of preliminary results of a phase 3 trial that included 123 patients with newly diagnosed AML who were ineligible for intensive treatment [43]. We await further data before using this combination outside of a clinical trial.

Decitabine plus bortezomib – In a randomized phase 2 study of 163 patients ≥60 years, compared with decitabine (20 mg/m2, days 1 to 10) alone, addition of bortezomib did not improve the rate of response or survival [39]. Outcomes did not differ between the study arms and, overall, the rate of CR plus CRi was 39 percent and median OS was 9 months. The most common AE was febrile neutropenia.

Alternative treatments — Alternative approaches may be appropriate for patients with severe liver or kidney dysfunction that precludes HMA-based therapy, for those who were previously treated with an HMA (eg, for prior MDS), and for selected frail patients.

Low-dose cytarabine (LoDAC) — LoDAC has limited therapeutic efficacy in AML, but we consider it acceptable for patients who are not candidates for HMA-based treatment and do not have an actionable mutation (eg, IDH mutation). However, LoDAC may be ineffective for patients with higher-risk AML (ie, adverse cytogenetic and/or molecular features).

We favor treatment with LoDAC combined with either venetoclax or glasdegib, based on superior outcomes compared with LoDAC monotherapy [25,44-46].

LoDAC combination therapy

LoDAC plus venetoclaxVenetoclax is an orally available inhibitor of BCL2 that is effective for initial treatment of AML in combination with LoDAC. Note that the following dose-escalation schedule for venetoclax differs from that used for venetoclax plus azacitidine. (See 'HMA plus venetoclax' above.)

To lessen the risk for TLS, when venetoclax is administered with LoDAC (20 mg/m2 once daily for 10 days in 28-day cycles), the following dose-escalation schedule should be used:

-Day 1: Venetoclax 100 mg

-Day 2: Venetoclax 200 mg

-Day 3: Venetoclax 400 mg

-Day 4 and beyond: Venetoclax 600 mg

Compared with LoDAC monotherapy, venetoclax plus LoDAC is associated with improved rates of remission and OS and an acceptable safety profile:

-In an international phase 3 trial of 211 patients with untreated AML, LoDAC plus venetoclax was associated with superior outcomes compared with LoDAC plus placebo [25]. Patients with medical comorbidities that precluded intensive induction chemotherapy and/or age ≥75 years were randomly assigned (2:1) to LoDAC plus venetoclax versus LoDAC plus placebo. With 18 month follow-up, median OS was superior in the venetoclax arm (8 versus 4 months; HR 0.70; 95% CI 0.50-0.98). Rates of CR plus CRi were 48 versus 13 percent, respectively, for venetoclax versus placebo, respectively. Key grade ≥3 AEs were febrile neutropenia (32 versus 29 percent), neutropenia (47 versus 16 percent), and thrombocytopenia (45 versus 37 percent).

-LoDAC plus venetoclax was associated with 54 percent CR plus CRi, 8 month median duration of remission, and 10 month median OS in a phase 1-2 study in 82 patients with newly diagnosed AML [46]. Response rates were more favorable in patients with intermediate-risk cytogenetics, de novo AML, and no prior HMA treatment.

Venetoclax is approved by the US FDA for use in combination with LoDAC in medically-unfit patients or those ≥75 years with newly diagnosed AML [28].

LoDAC plus glasdegibGlasdegib (an oral inhibitor of the hedgehog pathway) combined with LoDAC is effective for treatment of newly diagnosed AML [45]. Glasdegib does not have a demonstrated role as a single agent for de novo AML. Glasdegib can prolong the QT interval and may be associated with ventricular fibrillation and/or tachycardia, inhibitors and inducers of CYP3A4 should be avoided, and it is potentially teratogenic [47].

Glasdegib is given orally 100 mg daily along with LoDAC. An electrocardiogram (EKG) should be obtained prior to treatment with glasdegib, one week after initiation of treatment, and then once monthly for the next two months to assess QTc prolongation [45]. Strong inhibitors and inducers of CYP3A4 should be avoided for patients treated with glasdegib; if a moderate CYP3A4 inducer cannot be avoided, the glasdegib dose should be increased [45]. The FDA label warns of potential embryo-fetal death or severe birth defects. Male partners of fertile women should use a condom for ≥30 days after the last dose and patients receiving glasdegib should not donate blood or blood products for ≥30 days after the last dose to avoid risk of teratogenicity in fertile blood recipients.

The most common serious adverse reactions in patients receiving glasdegib with LoDAC were febrile neutropenia, pneumonia, hemorrhage, anemia, and sepsis (29, 23, 12, 7, and 7 percent, respectively) [45]. Studies of LoDAC plus glasdegib include:

-The BRIGHT AML 1003 study (NCT01546038) included 115 patients with newly diagnosed AML who were ≥75 years old or who had severe cardiac disease, renal impairment, or impaired performance status [45]. Patients were randomized 2:1 to receive glasdegib (100 mg daily) plus LoDAC (20 mg subcutaneously twice daily on days 1 to 10 of a 28-day cycle; 77 patients) versus LoDAC alone (38 patients). With median follow-up of 20 months, outcomes with glasdegib plus LoDAC were superior to LoDAC alone, with median OS 8 versus 4 months, respectively (HR: 0.46; 95% CI 0.30-0.71), and rates of CR were 18 versus 3 percent.

-LoDAC plus glasdegib achieved superior OS (9 versus 5 months) and CR (17 versus 2 percent), when compared with LoDAC alone, in a randomized, open label phase 2 study of 132 medically-unfit adults with AML or high-risk MDS [44]. Addition of glasdegib to LoDAC was more effective in patients with favorable or intermediate-risk cytogenetics than in those with poor-risk cytogenetics.

Glasdegib was approved by the US FDA, in combination with LoDAC, for treatment of newly diagnosed AML in medically-unfit adults or those ≥75 years old [45].

LoDAC plus clofarabine – Treatment with LoDAC plus clofarabine (20 mg/m2 daily for five days) was associated with 58 percent CR, 14 month median relapse-free survival, 13 month median OS, and 7 percent induction mortality rate at eight weeks in 60 patients ≥60 years [48].

Treatment with single-agent clofarabine is discussed below. (See 'Other agents' below.)

LoDAC monotherapy – We consider LoDAC monotherapy acceptable in settings where venetoclax and glasdegib are not available, for patients with significant cardiac dysrhythmias who cannot take glasdegib, and for patients who favor monotherapy for ease of administration or other reasons.

Single-agent LoDAC is generally administered subcutaneously 20 mg twice daily for 10 to 14 days every 28 days [49]. The dose may require adjustment for severe liver impairment. Moderate cytopenias and mild nausea and vomiting are the predominant AEs.

We generally continue treatment with LoDAC for as long as the patient is responding and tolerating treatment. (See 'Post-remission management' below.)

Outcomes with LoDAC monotherapy include:

In a multicenter trial, 217 patients with AML or high-risk MDS were randomly assigned to receive LoDAC (20 mg twice daily for 10 days) versus hydroxyurea; patients were also randomly assigned to receive all trans retinoic acid (ATRA) or no ATRA [49]. Compared with hydroxyurea, LoDAC resulted in a higher remission rate (18 versus 1 percent, respectively) and improved OS (HR 0.60; 95% CI 0.44-0.81); addition of ATRA had no effect. The median disease-free survival in patients who achieved a CR with LoDAC was eight months. Toxicity was generally mild, with the most common grade ≥3 toxicities being cardiac (10 percent), nausea/vomiting (6 percent), and diarrhea (4 percent). Induction death occurred in 26 percent of patients.

A multicenter trial randomly assigned 87 patients >65 years to LoDAC (10 mg/m2 every 12 hours for 21 days) versus intensive chemotherapy and reported that LoDAC achieved 32 percent CR and 22 percent partial response [50]. There was no difference in OS or remission duration between the two arms of the study, but intensive therapy was associated with a higher rate of CR (52 versus 32 percent) but more early deaths.

IDH inhibitors — IDH inhibitor monotherapy is acceptable for patients with an IDH mutation who are too frail for HMA-based therapy. For patients with IDH-mutated AML, IDH inhibitors are generally well-tolerated and can be associated with substantial hematologic responses [51,52]. Treatment with ivosidenib plus an HMA is discussed above. (See 'HMA plus ivosidenib' above.)

We generally continue treatment with an IDH inhibitor for as long as the patient continues to respond and the agent is tolerated. (See 'Post-remission management' below.)

IDH1 mutation – For IDH1-mutated AML, ivosidenib monotherapy is well-tolerated and can induce durable remissions and transfusion-independence. Ivosidenib is not available in all medical settings.

Ivosidenib is administered 500 mg once daily by mouth, with or without food; high-fat meals should be avoided. Grade ≥3 adverse reactions that were reported in ≥5 percent of patients include DS (which can be fatal if not treated promptly), prolonged QTc interval, and fatigue; rare cases of posterior reversible encephalopathy syndrome (PRES) and Guillain-Barré syndrome have been reported. (See "Treatment of relapsed or refractory acute myeloid leukemia", section on 'Remission re-induction' and "Differentiation syndrome associated with treatment of acute leukemia".)

A study that included 34 patients with previously untreated IDH1-mutant AML who were ineligible for intensive induction therapy (median age 76 years) reported that ivosidenib monotherapy achieved 30 percent CR plus 12 percent CRi [51]. Median OS was 13 months and 9 of 21 transfusion-dependent patients became transfusion-independent. Treatment was well-tolerated; grade ≥3 DS occurred in 9 percent but did not require treatment interruption.

Ivosidenib is approved by the US FDA for adults ≥75 years old with AML that has a susceptible IDH1 mutation detected by an FDA-approved diagnostic test [53].

IDH2 mutationEnasidenib is an inhibitor of IDH2 and is generally well-tolerated, but its efficacy for newly diagnosed AML is not well-defined and it is not available in all medical settings.

Enasidenib is administered 100 mg once daily by mouth for a minimum of six months (to allow time for clinical response) and should be continued until disease progression or unacceptable toxicity. The dose should be reduced for elevated bilirubin. Grade ≥3 AEs that are seen in ≥5 percent of patients include diarrhea, nausea, and DS (which can be fatal if not treated promptly). (See "Treatment of relapsed or refractory acute myeloid leukemia", section on 'Remission re-induction' and "Differentiation syndrome associated with treatment of acute leukemia".)

The efficacy of enasidenib for newly diagnosed AML with an IDH2 mutation is not well-defined, but treatment of relapsed or refractory AML in 23 evaluable patients ≥60 years achieved CR/CRi in 43 percent; azacitidine was added for some patients who did not achieve CR/CRi by cycle 5 [52].

Enasidenib is approved by the US FDA for adults with relapsed or refractory AML with an IDH2 mutation as detected by an FDA-approved test; it is not currently approved for treatment of newly diagnosed AML [54].

Other agents

Gemtuzumab ozogamicinGemtuzumab ozogamicin (GO) is an immunoconjugate that includes an anti-CD33 monoclonal antibody linked to calicheamicin.

GO administration – When used as a single agent for remission induction of AML, we treat with GO 6 mg/m2 on day 1 and 3 mg/m2 on day 8, and continue treatment for up to eight monthly cycles [55,56]. We restrict use of GO to patients with CD33-expressing leukemic blasts (although the threshold expression level has not been defined). The GO label includes a boxed warning about the risk of hepatotoxicity, including severe or fatal hepatic sinusoidal obstruction syndrome (hepatic veno-occlusive disease) [56].

For patients who achieve a CR, maintenance therapy with GO is described below. (See 'Post-remission management' below.)

Outcomes – Induction therapy with single-agent GO achieved one-year survival in about one-quarter of older adults with AML [56]. A trial that randomly assigned 237 patients ≥61 years to single-agent GO versus BSC reported that GO achieved superior median OS (5 versus 4 months; HR 0.69, 95% CI 0.53-0.90) and one-year OS (24 versus 10 percent) [55]. Rates of serious AEs were similar in both arms of the study.

GO is approved by the US FDA as a single agent for newly diagnosed AML [56]. Treatment with GO for de novo or relapsed/refractory AML in medically-fit adults is discussed separately. (See "Induction therapy for acute myeloid leukemia in medically-fit adults", section on 'Other agents'.)

Clofarabine – Single-agent clofarabine can achieve responses in medically-unfit patients with AML [57,58].

In a phase 3 trial, 406 medically-unfit adults with AML/high-risk MDS were randomly assigned to single-agent clofarabine versus LoDAC [59]. Compared with LoDAC, clofarabine achieved superior rates of overall response (38 versus 19 percent, respectively; HR 0.41 95% CI 0.3-0.6) and CR (22 versus 12 percent), but 13 percent two-year OS was not superior to LoDAC. Clofarabine caused greater myelosuppression and gastrointestinal and hepatic toxicity.

Clofarabine is not approved for treatment of AML by the US FDA or the EMA.

Treatment with clofarabine plus LoDAC is discussed above. (See 'Low-dose cytarabine (LoDAC)' above.)

GilteritinibGilteritinib is an oral inhibitor of mutant FLT3 that is used for treatment of relapsed or refractory AML, but its role for treatment of de novo AML is not defined at present. The FDA label for gilteritinib carries a warning about differentiation syndrome; other significant toxicities include posterior reversible encephalopathy syndrome (PRES), prolonged QT interval, and pancreatitis.

Gilteritinib monotherapy was superior to salvage chemotherapy in 247 adults with relapsed or refractory AML with a FLT3 mutation, as described separately [60]. (See "Treatment of relapsed or refractory acute myeloid leukemia", section on 'Targeted agents'.)

Outcomes of treatment with azacitidine plus gilteritinib are discussed above. (See 'HMA plus other agents' above.)

Supportive care — Management of the frail patient should focus primarily on supportive care to improve the quality of life by lessening symptoms caused by AML.

Hydroxyurea may be useful to avoid symptomatic leukostasis in patients with hyperleukocytosis (eg, >50,000 blasts/microL) or to manage discomfort from massive organomegaly. Management of leukostasis is discussed separately. (See "Hyperleukocytosis and leukostasis in hematologic malignancies".)

Supportive care for patients with AML includes transfusions with red blood cells and platelets, antibiotics to treat infections, growth factor support, and correction of coagulopathies. Prospective and retrospective studies report that, compared with supportive care alone, various treatments for AML are associated with improved survival, better relief of symptoms, and comparable days spent in the hospital, as described above. (See 'Goals, benefits, and timing of treatment' above.)

RESPONSE ASSESSMENT — We assess response to treatment based on history, physical examination, blood counts, and periodic bone marrow evaluation.

Schedule of assessment — The schedule for response assessment varies with the choice of therapy:

HMA combination therapy – For patients treated with a hypomethylating agent (HMA) plus venetoclax or ivosidenib, we assess response early in the first cycle (eg, day 14 to 21) because of high rates of early responses and the possible need to delay or modify dosing for persistent cytopenias in a leukemia-free marrow.

A second assessment is commonly performed after three cycles and then repeated every three cycles for patients in remission.

Other treatments – We assess response after every three cycles of therapy. However, we generally do not predefine a schedule of routine bone marrow examinations because, if blood counts return to near normal, we consider that there is little to learn from repeating a bone marrow biopsy. However, for patients with prolonged pancytopenia, a bone marrow biopsy may be helpful to distinguish residual or recurrent AML from treatment-related hypoplasia.

Response criteria — For medically-unfit patients, we judge response to treatment based on blood counts, transfusion needs, and relief of symptoms, as follows:

Hematologic complete remission (CR) – Normalization of the complete blood count (CBC), including absolute neutrophil count (ANC) ≥1000/microL and platelets ≥100,000/microL, transfusion-independence, and relief of AML-related symptoms.

CR with incomplete hematologic recovery (CRi) – Transfusion-independent and meets above criteria for CR, but without complete platelet recovery (usually) or ANC recovery.

Hematologic improvement – Improvements in CBC, but not to levels that define CR/CRi, with ongoing transfusion needs and/or inadequate symptom relief. Hematologic improvement is a reasonable goal for frail patients, in whom the goals are to reduce transfusion needs and/or provide symptomatic relief.

Refractory disease – No meaningful improvement in CBC, reduction of ongoing transfusion needs, and/or inadequate symptom relief.

For patients with partial response or refractory AML, management is discussed below. (See 'Relapsed or resistant AML' below.)

POST-REMISSION MANAGEMENT — Medical fitness and the patient's preferences should inform post-remission management.

We reassess fitness after completing initial therapy because some patients have improved fitness as the effects of AML and its complications respond to treatment. (See 'Pretreatment evaluation' above.)

Consolidation therapy – For patients who are medically-fit after achieving complete remission (CR; ie, ≤5 marrow and blood blasts), intensive consolidation therapy is an acceptable option. Consolidation therapy and its benefits and risks are discussed separately. (See "Post-remission therapy for acute myeloid leukemia in younger adults".)

For patients who remain medically-unfit or frail after achieving CR, we advise not treating with consolidation therapy because the adverse effects (AEs) generally outweigh the potential benefits. Medically-unfit patients may be candidates for maintenance therapy, as described below.

Maintenance therapy – For medically-unfit, but not frail patients who are responding and tolerating treatment, we generally continue treatment indefinitely as maintenance therapy, to prolong the response and/or extend survival. While some studies have arbitrarily stopped maintenance therapy after one or two years, the optimal duration of maintenance therapy is undefined and should be individualized. Some patients may favor observation rather than maintenance therapy, because they place greater emphasis on reducing the burdens or toxicity of continued treatment.

Over the course of maintenance therapy, recovery of blood counts may require dose reduction, increased intervals between cycles, and/or brief treatment interruptions. Examples of maintenance therapy in this setting include:

Hypomethylating agents (HMA) – Patients who were treated with an HMA can continue to receive that drug as maintenance therapy for as long as they are responding and tolerating treatment.

Importantly, the oral formulation of azacitidine is pharmacokinetically and pharmacodynamically distinct from injectable azacitidine; these distinct drugs should not be considered interchangeable [61,62].

-Oral azacitidine (CC-486) – Maintenance therapy with an oral formulation of azacitidine (CC-486) was associated with superior overall survival (OS) and relapse-free survival (RFS) when compared with placebo in newly diagnosed patients ≥55 years in first CR after intensive chemotherapy who were not eligible for allogeneic hematopoietic cell transplantation (HCT); importantly, this trial only included patients who achieved CR after intensive remission induction therapy (ie, medically-unfit patients were not included in the trial) [63]. In the multicenter QUAZAR trial, 472 patients were randomly assigned to CC-486 (300 mg orally once daily on days 1 to 14 of 28-day cycles) versus placebo. Compared with placebo, CC-486 achieved superior median OS (25 versus 15 months; HR 0.69; 95% CI 0.55-0.86) and RFS (10 versus 5 months). Maintenance therapy with CC-486 appears to delay relapse rather than prevent it, as the survival curves for CC-486 and placebo treatment in this study ultimately converged. Neutropenia was the most frequent grade ≥3 adverse event (41 versus 24 percent for CC-486 versus placebo, respectively); most other adverse effects were mild gastrointestinal symptoms (diarrhea, nausea, vomiting). Overall health-related quality of life was preserved during CC-486 treatment.

Oral azacitidine is approved by the US Food and Drug Administration (FDA) for continued treatment of AML in first CR or CR with incomplete hematologic recovery (CRi) following intensive induction chemotherapy in patients who are not able to complete intensive curative therapy [64]. No age limit is specified in the FDA label, but it is unclear if the benefits of CC-486 maintenance will extend to other patients (eg, <55 years, eligible for HCT) than those in the trial above.

-Parenteral azacitidine – In a study of parenteral azacitidine, 116 patients ≥60 years old who achieved CR or CRi were randomly assigned to observation versus azacitidine maintenance (50 mg/m2, subcutaneously, days 1 to 5, every four weeks) until relapse, for a maximum of 12 cycles [65]. Compared with observation, maintenance azacitidine was associated with superior 12-month disease-free survival (64 versus 42 percent), but OS did not differ between the groups.

IDH inhibitors – Treatment with an IDH inhibitor can continue for at least two years, if the patient has a continued response and is tolerating the agent [51].

Gemtuzumab ozogamicin – For patients who received gemtuzumab ozogamicin (GO), maintenance therapy with single-agent GO is an acceptable option. For maintenance therapy, single-agent GO is administered at 2 mg/m2 on day 1 every 4 weeks for up to 8 cycles [55,56].

FOLLOW-UP — We individualize follow-up according to clinical needs (eg, transfusion support), severity of symptoms, and informed by concerns on the part of the patient and clinicians. For the first two years, we generally schedule visits every one to three months, which include interval history and physical examination, complete blood count, and serum chemistries. We do not perform routine surveillance bone marrow examinations, unless warranted by a change in blood counts or other worrisome features.

RELAPSED OR RESISTANT AML — AML that recurs after an initial response (relapsed AML) or that fails to respond to induction therapy (resistant AML) has a poor prognosis in patients who are medically-unfit. Participation in a clinical trial is the preferred option.

Outside of a trial, there is no consensus regarding a preferred approach to management of relapsed or refractory AML. There is no evidence of benefit to treatment with a different hypomethylating agent (HMA; eg, azacitidine in a patient previously treated with decitabine, or vice versa) for patients who did not have an adequate response to the initial HMA.

We consider treatment with a targeted agent (if an actionable mutation is present), gemtuzumab ozogamicin (if available), or palliative management to be acceptable options. (See 'HMA plus ivosidenib' above and 'Other agents' above.)

Treatment of relapsed or refractory AML is discussed in greater detail separately. (See "Treatment of relapsed or refractory acute myeloid leukemia".)

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. Additionally, immunocompromised patients are candidates for a modified vaccination schedule (figure 1), other preventive strategies (including pre-exposure prophylaxis), and the early initiation of COVID-directed therapy. 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 – Management of acute myeloid leukemia (AML) is guided by fitness for leukemia therapy.

Pretreatment evaluation – Fitness is determined clinical evaluation, performance status (PS) (table 1), and physiologic function (table 2), rather than age, per se. (See 'Medical fitness' above.)

We categorize fitness as follows:

Medically-fit – Can tolerate intensive treatment for AML (eg, Eastern Cooperative Oncology Group [ECOG] PS 0 to 2 and Charlson comorbidity index [CCI] 0 to 2), as discussed separately. (See "Induction therapy for acute myeloid leukemia in medically-fit adults", section on 'Medically-fit patients'.)

Medically-unfit, but not frail – Unlikely to tolerate intensive therapy due to impaired PS (eg, ECOG PS 3) or significant comorbidities (eg, CCI 3), but able to tolerate lower-intensity treatments.

Frail – Debility or comorbidities (eg, ECOG PS ≥3 and CCI ≥3) that limit treatment aimed at modifying the disease course.

Medically-unfit, but not frail – For medically-unfit patients, we suggest treatment that includes a hypomethylating agent (HMA; eg, azacitidine, decitabine), rather than low-dose cytarabine, other agents, or supportive care alone (algorithm 1) (Grade 2C). Some experts consider low-dose cytarabine acceptable as front-line therapy. (See 'Medically-unfit, but not frail' above.)

In selected cases, a second agent may be added to an HMA:

If venetoclax is available – Where venetoclax is available, we suggest treatment with venetoclax plus an HMA, rather than an HMA alone (Grade 2B). (See 'HMA plus venetoclax' above.)

IDH1 mutation – For patients with IDH1-mutated AML, we recommend treatment with azacitidine plus ivosidenib, rather than an HMA alone (Grade 1B). Other experts consider venetoclax plus azacitidine acceptable in this setting, although this combination has been studied in fewer patients. (See 'HMA plus ivosidenib' above.)

If venetoclax is not available – We generally treat with single-agent azacitidine or decitabine. (See 'Hypomethylating agents (HMAs)' above.)

Not eligible for an HMA – For patients previously treated with an HMA (eg, for myelodysplastic neoplasm/syndrome [MDS]) or ineligible (eg, severe liver or kidney dysfunction), treatment options include low-dose cytarabine or a targeted agent (if appropriate according to mutation analysis). (See 'Alternative treatments' above.)

Marrow response monitoring – Varies according to treatment (see 'Response assessment' above):

HMA combination therapy – For patients treated with an HMA plus venetoclax or ivosidenib, we assess response early in the first cycle (eg, day 14 to 21) because of high rates of early responses and the possible need to delay or modify dosing for persistent cytopenias in a leukemia-free marrow.

A second assessment is commonly performed after three cycles and then repeated every three cycles for patients in remission.

Other treatments – We assess response after every three cycles of therapy.

Frail patients – For medically frail patients, the mainstay of management is supportive care to relieve symptoms and to improve the quality of life. Some frail patients may, instead, choose to receive lower-intensity treatments, as discussed above. (See 'Frail patients' above.)

Relapsed/refractory AML – Prognosis is poor and there is no consensus treatment. Approaches are discussed above. (See 'Relapsed or resistant AML' above.)

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