Acute myeloid leukemia in adults: Overview

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. The leukemic cells interfere with production of normal blood cells, causing anemia, infection, bleeding, and other symptoms and complications.

This topic provides an overview of the evaluation, diagnosis, and management of AML in adults.

Details about specific aspects of AML in adults are presented separately:

●(See "Acute myeloid leukemia: Clinical manifestations, pathologic features, and diagnosis".)

●(See "Acute myeloid leukemia: Classification".)

●(See "Acute myeloid leukemia: Pathogenesis" and "Acute myeloid leukemia: Molecular genetics" and "Acute myeloid leukemia: Cytogenetic abnormalities".)

●(See "Acute myeloid leukemia: Risk factors and prognosis".)

●(See "Acute myeloid leukemia: Induction therapy in medically fit adults".)

●(See "Acute myeloid leukemia: Overview of complications" and "Acute myeloid leukemia: Involvement of the central nervous system".)

●(See "Acute myeloid leukemia in younger adults: Post-remission therapy".)

●(See "Pretreatment evaluation and prognosis of acute myeloid leukemia in older adults" and "Acute myeloid leukemia: Management of medically unfit adults".)

●(See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults" and "Initial treatment of acute promyelocytic leukemia in adults".)

EPIDEMIOLOGY — 

AML is the most common type of acute leukemia in adults. Nevertheless, AML is relatively rare, and it accounts for approximately 1 percent of adult cancers in the United States but nearly 2 percent of cancer-related deaths [1]. The median age at diagnosis is approximately 68 years, and the incidence increases with age. There is a modest predominance in males and a higher incidence in non-Hispanic White Americans than in other racial and ethnic groups. (See "Acute myeloid leukemia: Clinical manifestations, pathologic features, and diagnosis", section on 'Epidemiology'.)

AML has been associated with environmental factors (eg, genotoxic chemicals, radiation, tobacco, cytotoxic chemotherapy). In some patients, evolution to AML is preceded by evidence of clonal hematopoiesis manifested as myelodysplastic syndromes/neoplasms, myeloproliferative neoplasms, paroxysmal nocturnal hemoglobinuria, aplastic anemia, clonal hematopoiesis of indeterminate prognosis (CHIP), or clonal cytopenia of unknown significance (CCUS). (See "Acute myeloid leukemia: Pathogenesis" and "Acute myeloid leukemia: Clinical manifestations, pathologic features, and diagnosis", section on 'Epidemiology'.)

Uncommonly, AML in adults is associated with inherited genetic abnormalities, including mutations, duplications, or loss of tumor suppressor and/or deoxyribonucleic acid (DNA) damage repair genes (eg, trisomy 21; Fanconi anemia; Li-Fraumeni syndrome; Bloom syndrome; familial mutations of CEBPA, DDX41, RUNX1). Familial disorders may be associated with a personal or family history of other hematologic disorders (particularly thrombocytopenia or immune deficiencies), certain cancers and somatic syndromes, or other known genetic variants (figure 1). Guidelines for assessing familial genetic risk in patients with AML have been published [2]. (See "Familial disorders of acute leukemia and myelodysplastic syndromes".)

PATHOGENESIS — 

AML is a consequence of the malignant transformation of myeloid precursor cells.

Transformation of myeloid precursors results in one or more clones of neoplastic cells that can proliferate but are blocked in their ability to differentiate into mature blood cells and undergo programmed cell death (apoptosis). AML is maintained by a pool of self-renewing leukemic stem cells or committed progenitor cells that are more immature than the bulk population of leukemic cells. Curing AML requires the elimination of these self-renewing malignant cells along with their progeny, the bulk population of leukemic cells. (See "Acute myeloid leukemia: Pathogenesis", section on 'Leukemic stem cells'.)

Specific chromosomal abnormalities can be identified in more than one-half of cases of AML, including recurrent translocations, rearrangements, and gain or loss of entire chromosomes or portions of chromosomes. Some of these chromosomal translocations generate chimeric (ie, fusion) oncogenes. (See "Acute myeloid leukemia: Molecular genetics", section on 'Chromosomal translocations'.)

Point mutations and gene duplications, fusions, and deletions that are not detectable with routine karyotyping are seen in nearly all cases of AML. These abnormalities often affect genes that regulate cell growth, survival, and/or differentiation. Examples include alterations of genes that encode transcription factors, epigenetic regulators, tumor suppressors, DNA repair, signaling molecules, regulators of apoptosis and proliferation, and other mechanisms. In some adult patients, these genetic abnormalities originate in the germline. (See "Acute myeloid leukemia: Molecular genetics", section on 'Gene mutations'.)

PRESENTATION

Clinical manifestations — Most patients with AML have clinical manifestations, but some are asymptomatic and present with only laboratory abnormalities. Clinical findings include the following (see "Acute myeloid leukemia: Clinical manifestations, pathologic features, and diagnosis", section on 'Clinical presentation'):

●Signs and symptoms related to anemia (eg, weakness, dyspnea), thrombocytopenia (excess bleeding or bruising), and neutropenia (fever, infections) are common. (See "Acute myeloid leukemia: Clinical manifestations, pathologic features, and diagnosis", section on 'Clinical presentation'.)

●Headache or focal neurologic complaints (eg, due to cerebral hemorrhage, leukemic meningitis). (See "Acute myeloid leukemia: Involvement of the central nervous system".)

●Physical findings may include pallor, bleeding, or bruising. Occasional patients may manifest hepatomegaly, splenomegaly, or extramedullary masses or rash/leukemia cutis (myeloid sarcoma), but lymphadenopathy is rare. (See "Acute myeloid leukemia: Clinical manifestations, pathologic features, and diagnosis", section on 'Clinical presentation'.)

Adult patients rarely display phenotypic findings associated with germline predisposition to myeloid leukemia. (See "Familial disorders of acute leukemia and myelodysplastic syndromes".)

●Complete blood count with differential may exhibit pancytopenia (ie, decreased red blood cells, neutrophils, and/or platelets) or leukocytosis (due to circulating blasts). Serum chemistries may demonstrate hyperuricemia or other findings associated with tumor lysis syndrome or other metabolic complications. (See "Hyperleukocytosis and leukostasis in hematologic malignancies" and "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)

●Leukemic blasts in peripheral blood, bone marrow, and/or other tissues (eg, skin, other organs) may manifest Auer rods and prominent nucleoli (picture 1) among other findings. (See "Acute myeloid leukemia: Clinical manifestations, pathologic features, and diagnosis", section on 'Pathologic features'.)

Acute promyelocytic leukemia (APL) is a distinctive subtype of AML that should be suspected in younger patients (median age 40 to 50 years old) who present with bleeding or bruising without known trauma or out of proportion to known trauma, thrombocytopenia and/or pancytopenia, leukemic blasts with coarse or dense cytoplasmic granules (picture 2), low white blood cell (WBC) count, hypofibrinogenemia with disseminated intravascular coagulation (DIC), and/or few circulating myeloblasts. APL is a medical emergency that requires urgent management. Diagnosis and management of APL are discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults" and "Initial treatment of acute promyelocytic leukemia in adults".)

Complications/emergencies — AML may be associated with life-threatening complications and emergencies. Significant cytopenias are nearly universal as a result of the underlying disease or its treatment (eg, anemia, infection, bleeding). (See "Acute myeloid leukemia: Overview of complications" and "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Adjunctive care'.)

Certain complications are associated with particular subtypes of AML. As an example, DIC is most often associated with APL, but it can occur in other subtypes of AML, particularly acute monoblastic or monocytic leukemia. Further details regarding DIC and APL are presented separately. (See "Initial treatment of acute promyelocytic leukemia in adults" and "Molecular biology of acute promyelocytic leukemia" and "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults".)

Other complications are less predictable but may be related to the AML phenotype, comorbid illnesses, or complications of therapy. Further details regarding the diagnosis and management of complications and/or oncologic emergencies associated with AML include the following and are described separately. (See "Acute myeloid leukemia: Overview of complications".)

The following are examples of such emergencies and typical clinical presentations:

●Hyperleukocytosis/leukostasis (eg, respiratory and/or neurologic distress in a patient with AML and myeloblasts >50,000/microL, or any patient with AML and WBC >100,000/microL). (See "Acute myeloid leukemia: Overview of complications", section on 'Hyperleukocytosis and leukostasis'.)

●Metabolic abnormalities, including tumor lysis syndrome (eg, hyperkalemia, hyperphosphatemia, hyperuricemia, and/or renal insufficiency). (See "Acute myeloid leukemia: Overview of complications", section on 'Tumor lysis syndrome'.)

●Bleeding can be caused by severe thrombocytopenia, coagulation disorders, and/or DIC (eg, due to sepsis, severe liver disease, or the leukemia itself, particularly APL). (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults".)

●Involvement of the central nervous system, cranial nerves, or eyes; cerebral hemorrhage. (See "Acute myeloid leukemia: Involvement of the central nervous system", section on 'Clinical presentation' and "Acute myeloid leukemia: Involvement of the central nervous system".)

PRETREATMENT EVALUATION — 

Pretreatment evaluation identifies pathologic features and comorbidities that might alter management and affect prognosis.

Clinical and laboratory — Patients are evaluated clinically, and blood cells are examined by microscopy, cytochemical, immunophenotypic, and cytogenetic/molecular studies.

●Clinical evaluation – History and physical examination should identify clinical findings and comorbid conditions that may alter prognosis or complicate management.

Particular attention should be paid to medical comorbidities, such as diabetes, obesity, pulmonary disease, heart disease, renal insufficiency, liver disease, dental conditions, and drug allergies and interactions. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Pretreatment'.)

●Laboratory testing – Studies should include:

•Laboratory tests – Complete blood count (CBC) with differential, coagulation studies, serum chemistries, and viral serologies.

•Bone marrow – Bone marrow examination should include morphology (including the percentage of blasts), flow cytometry, karyotype, and molecular genetic testing to diagnose and classify AML.

•Other testing

-Chest radiography, electrocardiogram (EKG), and echocardiogram (or radionuclide ventriculogram) to assess left ventricular function and ejection fraction should be performed at baseline. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Pretreatment'.)

-Human leukocyte antigen (HLA) typing should be considered for patients who are potential candidates for hematopoietic cell transplantation. Typing should be done to identify HLA-matched platelet transfusions in patients who become refractory to platelet transfusions. (See "Acute myeloid leukemia in younger adults: Post-remission therapy", section on 'Unfavorable-risk disease'.)

Most patients require the placement of a central venous access catheter or PICC (peripherally inserted central catheter) line for chemotherapy, laboratory studies, and frequent transfusions.

Medical fitness — Management of AML often includes intensive treatment that requires adequate medical fitness.

Age, per se, is not an exclusion for intensive treatments, but caution is advised for patients ≥70 years because comorbid conditions increase with age. Patients >60 years old were excluded from many clinical trials of AML, but this should not preclude intensive treatment for medically fit individuals.

Fitness assessment includes the determination of the level of physical functioning (eg, performance status, measures of comorbidity) and cognitive function, especially in older adults or frail individuals. Performance status (table 1) and instruments for assessment of comorbidities (table 2) are discussed separately. (See "Pretreatment evaluation and prognosis of acute myeloid leukemia in older adults".)

Goals of care — AML is an aggressive malignancy that generally requires intensive and prolonged treatment. Management is guided by classification (subtype) of the AML and patient age, comorbid conditions, and preferences.

The goals of care should be determined by shared decision-making by clinicians and the patient, with input from loved ones, as discussed in detail separately. Discussion should acknowledge that AML is a life-ending disease for most patients while emphasizing the benefits of treatment for short- and long-term outcomes. (See "Acute myeloid leukemia: Management of medically unfit adults", section on 'Goals, benefits, and timing of treatment'.)

Goal setting is important for planning the treatment of AML:

●Achieving complete remission (CR), with resolution of life-threatening cytopenias and transfusion independence, is an appropriate goal for most patients with AML, since it is associated with prolongation of survival, improved quality of life, and is necessary for the cure of AML. Such management often requires intensive treatments, as discussed below. (See 'Intensive remission induction' below.)

●For some patients, treatment with the intent of achieving CR (or even modifying the disease course) is not possible because of advanced age, debility, coexisting medical problems, and/or prior treatment. Some younger and fit patients with adverse-risk AML may select less intensive chemotherapy to achieve a response prior to allogeneic hematopoietic cell transplantation. Lower-intensity approaches to treatment are discussed below. (See 'Less-fit or older patients' below.)

DIAGNOSIS AND CLASSIFICATION — 

AML should be suspected in an individual with circulating blast cells, acute onset of unexplained cytopenia-related symptoms (eg, bleeding, weakness, infection), or metabolic/oncologic emergencies such as tumor lysis syndrome or hyperleukocytosis.

Patients suspected of having AML should be referred urgently for expert evaluation and management.

Diagnostic criteria — Diagnosis of AML is based on documentation of ≥10 percent myeloblasts in bone marrow or blood that exhibit characteristic pathologic features or detection of a myeloid sarcoma (extramedullary collection of myeloblasts).

AML should be diagnosed and classified according to either the International Consensus Classification (ICC) [3] or the World Health Organization 5^th edition (WHO5) [4] criteria. These contemporary diagnostic systems should replace earlier schemes for diagnosis/classification (eg, WHO4, French-American-British [FAB] scheme).

Diagnostic criteria vary with the AML subtype and differ modestly between ICC and WHO5, as described below. (See 'Classification' below.)

Details of the morphologic and cytogenetic features of AML blasts are presented separately. (See "Acute myeloid leukemia: Clinical manifestations, pathologic features, and diagnosis".)

Classification — Both ICC and WHO5 emphasize cytogenetic/molecular features for classifying AML, but they have some important differences. Briefly, similarities and differences between ICC and WHO5 can be summarized as follows:

●Both ICC and WHO5

•Recognize cases with ≥10 percent blasts and defining genetic abnormalities (eg, t(15;17)/PML::RAR, t(8;21)/RUNX1::RUNX1T1, inv(16)/CBFB::MYH11, mutated NPM1) as AML.

•Require ≥20 percent blasts to diagnose AML with t(9;22)/BCR::ABL1 (to distinguish it from advanced phases of chronic myeloid leukemia).

•Recognize myeloid sarcoma as sufficient to diagnose AML.

●ICC – Distinctive features include:

•Cases with 10 to 19 percent blasts are classified as myelodysplastic syndromes/neoplasms (MDS)/AML.

•Cases without defining genetic abnormalities are designated as MDS/AML (if blasts are 10 to 19 percent) or AML, not otherwise specified (NOS; blasts ≥20 percent).

•Myeloid neoplasms with mutated TP53 or myelodysplasia-related cytogenetic abnormalities are distinct entities that are further defined as AML, MDS/AML, or MDS according to the blast percentage.

•The following diagnostic qualifiers are added when appropriate: therapy-related, progressing from MDS or MDS/myeloproliferative neoplasms (MPN), or germline predisposition.

●WHO5 – Distinctive features include:

•Cases of AML that lack a defining genetic abnormality are classified according to the state of differentiation as minimal differentiation, without maturation, with maturation, basophilic, myelomonocytic, monocytic, erythroid, and megakaryoblastic.

•WHO5 requires ≥20 percent blasts for AML with CEBP mutation.

Further details of the classification of AML are presented separately. (See "Acute myeloid leukemia: Classification".)

Differential diagnosis — AML in adults must be distinguished from other hematologic malignancies, causes of cytopenias, and syndromes associated with bleeding, infections, and certain metabolic syndromes.

●Hematologic malignancies – Clinical presentation and cellular morphology of other leukemias and MDS may resemble those of AML, but they can be distinguished by immunophenotype and karyotypic/molecular features.

•Other leukemias that must be distinguished from AML include acute lymphoblastic leukemia, advanced phases of chronic myeloid leukemia, blastic plasmacytoid dendritic cell neoplasm, acute leukemias of ambiguous lineage, leukemic phase of lymphoproliferative disease, hairy cell leukemia, large granular lymphocytosis, and others.

Diagnostic criteria for conditions are presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma" and "Chronic myeloid leukemia-blast phase: Diagnosis and treatment" and "Blastic plasmacytoid dendritic cell neoplasm" and "Mixed phenotype acute leukemia".)

•MDS and AML share certain clinical and pathologic features, and many experts consider them components of a spectrum of myeloid neoplasms. Indeed, ICC describes myeloid neoplasms with 10 to 19 percent blasts as MDS/AML, and WHO5 acknowledges the biologic and clinical similarities of MDS and AML [3,4]. The diagnosis and classification of MDS are discussed separately. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)

●Other causes of cytopenias – In some cases, the clinical presentation of AML is dominated by cytopenias, with few circulating blasts. Other causes of cytopenias include aplastic anemia, myelofibrosis, MDS, medications, nutritional deficiencies (eg, vitamin B12, folate, copper), bone marrow suppression (eg, alcohol, infection), sequestration from splenomegaly or hepatomegaly, autoimmune disorders (eg, Felty syndrome), hemophagocytic lymphohistiocytosis, and other conditions. (See "Approach to the adult with pancytopenia".)

●Other presentations

•Metabolic derangements – Tumor lysis syndrome can be caused by other proliferative malignancies, most notably very aggressive lymphomas. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)

•Leukocytosis – Marked elevation of the white blood cell count is described as a leukemoid reaction, which may be due to inflammatory or infectious processes; however, the blood smear reveals few, if any, myeloid blasts. (See "Hyperleukocytosis and leukostasis in hematologic malignancies".)

PROGNOSIS

Prognostic features — Outcomes in AML are associated with clinical and cytogenetic/molecular features.

●Clinical features – The likelihood of achieving a complete remission and/or long-term survival in AML is associated with age, performance status, medical comorbidities, prior myelodysplastic syndromes/neoplasms or myeloproliferative neoplasms, and exposure to cytotoxic agents and/or radiation therapy. (See "Acute myeloid leukemia: Risk factors and prognosis", section on 'Risk factors'.)

●Cytogenetic/molecular features – Outcomes are associated with certain cytogenetic/molecular features, and many of these are used to stratify risk and management of AML, as described below. (See 'Prognostic categories' below.)

Prognostic categories — The European LeukemiaNet stratifies individual cases as favorable, intermediate, or adverse risk based on the cytogenetic and molecular features of the myeloblasts [2].

●Favorable

•t(8;21)/RUNX1::RUNX1T1

•inv(16) or t(16;16)/CBFB::MYH11

•Mutated NPM1 without FLT3-ITD (internal tandem deletion)

•bZIP in-frame mutated CEBPA

●Intermediate

•Mutated NPM1 with FLT3-ITD

•Wild-type NPM1 with FLT3-ITD

•t(9;11)/MLLT3::KMT2A

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

●Adverse

•t(6;9)/DEK::NUP214

•t(v;11q23.3)/KMT2A-rearranged

•t(9;22)/BCR::ABL1

•t(8;16)/KAT6A::CREBBP

•inv(3) or t(3;3)/GATA2, MECOM (formerly EVI1)

•t(3q26.2;v)/MECOM-rearranged

•-5 or del(5q)

•-7

•-17/abn(17p)

•Complex karyotype

•Monosomal karyotype

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

•Mutated TP53

FIT, YOUNGER PATIENTS — 

Treatment of AML in fit, younger patients includes intensive remission induction therapy, assessment of response, and post-remission management.

Ideally, management should be at a medical center with clinicians experienced in treatment with intensive chemotherapy and the capacity for hematopoietic cell transplantation, if needed.

Assessment of fitness is discussed above. (See 'Medical fitness' above.)

Intensive remission induction — Treatment of AML in medically fit patients begins with intensive induction chemotherapy (table 3) that seeks to achieve a complete remission (CR).

●Administration – This generally includes a seven-day continuous infusion of cytarabine along with anthracycline treatment on days 1 to 3 (so-called "7+3" regimens). Selection and dosing of the anthracycline may vary with age and medical fitness. Liposomal daunorubicin-cytarabine (CPX-351) is an acceptable alternative for selected patients with therapy-related AML or secondary AML arising from a prior myelodysplastic syndrome/neoplasm. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Initial therapy'.)

For AML with mutated FLT3, midostaurin or quizartinib should be included in remission induction therapy, as discussed separately. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'AML with mutated FLT3'.)

For AML that expresses CD33, gemtuzumab ozogamicin may be added to 7+3 therapy, as discussed separately. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Gemtuzumab ozogamicin'.)

The initial response to induction therapy is determined by the evaluation of blood and bone marrow 14 to 21 days after initiation of therapy, as described below. (See 'Response to induction therapy' below.)

●Toxicity – Intensive remission induction therapy is highly toxic and typically entails hospitalization for several weeks. Toxicities include profound cytopenias, infections, bleeding/coagulation abnormalities, tumor lysis syndrome, electrolyte imbalances, mucositis with impaired nutritional status, and other complications. Treatment-related mortality increases with age and poor performance status.

●Outcomes – Depending upon age, patient characteristics, and prognostic features of the myeloblasts, 60 to 80 percent of younger adults achieve a CR with such regimens, but only approximately one-third of patients overall are ultimately cured of AML. Most patients who achieve CR do so after one course of induction therapy, but up to one-third of patients require two courses of induction therapy to achieve CR. Management of patients with persistent AML (ie, blasts >5 percent) is discussed below. (See 'Nadir marrow assessment' below.)

Details of intensive remission induction therapy for AML are presented separately. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Induction therapy'.)

Response to induction therapy — The initial response to remission induction therapy is judged by the morphologic response in blood and bone marrow.

Nadir marrow assessment — Bone marrow aspirate and biopsy are performed 14 to 21 days after beginning induction chemotherapy. The cellularity of the marrow biopsy and the percentage of blasts among nucleated cells are assessed by microscopy to determine if there has been adequate elimination of leukemia cells. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Nadir response assessment'.)

Further management is guided by the findings from the nadir marrow assessment:

●Blasts ≤5 percent – The patient is followed clinically to manage complications of cytopenias and other potential treatment-related complications. Bone marrow examination is repeated as blood counts recover (eg, >1000 neutrophils/microL, >100,000 platelets/microL), usually around four or five weeks after initiating treatment. (See 'Response assessment' below.)

Monitoring and management during the period of bone marrow hypoplasia are discussed separately. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Adjunctive care'.)

●Blasts >5 percent – If the marrow demonstrates substantial persistence of blasts in the presence of appropriate overall cellularity, a second cycle of induction therapy (sometimes using different drugs, doses, or schedules) may be given if tolerable, and a bone marrow examination is repeated as blood counts recover. Patients requiring a second course of induction therapy are generally considered primary refractory or poor risk and should be referred for early consideration of allogeneic stem cell transplantation if remission can be obtained.

Details of a second course of induction therapy are discussed separately. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Reinduction (second attempt)'.)

●Inconclusive – If the nadir results are inconclusive, bone marrow examination is generally repeated 7 to 10 days later, and management is guided by the findings, as described above. This situation most often occurs when the day 14 bone marrow has >5 percent blasts in a profoundly hypocellular marrow biopsy.

Response assessment — Blood and bone marrow are again evaluated as blood counts recover (eg, >1000 neutrophils/microL, >100,000 platelets/microL). This is generally ≥4 weeks from the start of induction therapy, but it may take up to 6 weeks if a second round of induction therapy is given.

Response to induction therapy is described as:

●CR – <5 percent blood and marrow blasts and none with Auer rods, plus recovery of neutrophils (ie, ≥1 x 10⁹/L) and platelets (ie, ≥100 x 10⁹/L).

●CR but incomplete recovery of neutrophil or platelet counts (CRi).

●Cytogenetic CR – Disappearance of any cells with an abnormal pretreatment karyotype.

●Refractory disease – Blasts >5 percent.

For patients with CR or CRi, measurable residual disease (MRD) should be assessed by flow cytometry or molecular techniques (if an AML-defining mutation is present). (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Measurable residual disease'.)

Post-remission management — Nearly all patients who achieve CR will relapse unless post-remission therapy is given. The goal of post-remission therapy is to eliminate residual disease and achieve long-term disease control and cure following induction chemotherapy.

Post-remission management is informed by the prognostic category according to pathologic features of the blasts, the level of MRD, and patient fitness. (See 'Prognosis' above.)

There are two phases to post-remission management:

●Consolidation phase – Consolidation therapy is an intensive treatment designed to eradicate residual AML cells that is given soon after achieving CR.

Consolidation therapy may include either cytarabine-based chemotherapy or hematopoietic cell transplantation (HCT).

•We favor allogeneic HCT for transplant-eligible patients who have a substantial risk for relapse, but there are no consensus criteria for selecting post-remission management.

In general, we favor allogeneic HCT for patients whose risk for relapse exceeds 35 percent. This generally includes patients with adverse prognostic features and/or persistent MRD (eg, >10^-4), but the decision to pursue allogeneic HCT must be individualized.

Patients with persistent MRD or adverse prognostic features who are not transplant-eligible because of comorbid conditions are managed as described below. Age alone is not a barrier to HCT when reduced-intensity preparative regimens are used, though patients older than 75 to 80 years are not commonly transplanted.

•For patients with MRD <10^-4 and either favorable or intermediate prognosis features, we generally treat with cytarabine-based consolidation chemotherapy. Some experts consider autologous HCT acceptable in this setting.

A more detailed consideration of consolidation phase management, including chemotherapy regimens and the addition of a targeted agent, is presented separately. (See "Acute myeloid leukemia in younger adults: Post-remission therapy".)

●Maintenance phase – Maintenance therapy describes lower-intensity treatment that is administered over a period of months to years following induction and/or consolidation phases.

Lower-intensity therapy, such as oral azacitidine and/or a targeted agent (for patients with a susceptible mutation), can be used for maintenance therapy in selected patients who are not eligible for HCT, as discussed separately. (See "Acute myeloid leukemia: Management of medically unfit adults", section on 'Post-remission management'.)

LESS-FIT OR OLDER PATIENTS — 

Lower-intensity treatments can provide control of AML, prolong survival, and lessen symptoms in patients who are unable to tolerate intensive remission induction therapy.

Lower-intensity treatments alone are unlikely to result in long-term disease control. In selected older or less-fit patients with adverse-risk AML, lower-intensity therapy can serve as a bridge to allogeneic hematopoietic cell transplantation (HCT).

●Administration – Lower-intensity therapy for AML is generally based on a hypomethylating agent (HMA; eg, azacitidine, decitabine) plus venetoclax (BCL2 inhibitor) or with a targeted agent (for patients with a susceptible mutation) [5]. Treatment can be either inpatient or outpatient.

Patients receiving venetoclax-based regimens must be monitored closely during the first week of therapy because of the risk of tumor lysis syndrome with kidney dysfunction.

Therapy is given in monthly cycles and is continued indefinitely until relapse or excessive toxicity. The choice of therapy is influenced by fitness, pathologic features of the blasts, and patient preference, as discussed separately. (See "Acute myeloid leukemia: Management of medically unfit adults".)

●Toxicity – HMA/venetoclax-based therapy is generally well-tolerated, but it is associated with tumor lysis syndrome (in the first week). Other toxicity includes cytopenias, neutropenic fever, pneumonia, and sepsis.

●Outcomes – HMA/venetoclax was superior to azacitidine alone in a phase 3 trial for AML in patients who were not candidates for intensive induction therapy or ≥75 years [5]. HMA/venetoclax is generally associated with overall survival of one to two years, but this is influenced by associated molecular features of the blasts.

MONITORING — 

Patients are monitored for relapse and for treatment-related adverse effects.

The patient is monitored by interim history, examination, and laboratory studies, including complete blood count, blood smear, and serum chemistries. The schedule for follow-up is individualized according to the treatment, comorbid conditions, and other clinical needs.

Details of monitoring are presented separately. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Monitoring'.)

RELAPSED/REFRACTORY DISEASE — 

Disease that recurs after the achievement of complete remission (CR) is described as relapsed AML. Refractory AML is leukemia that did not fully respond with CR to two cycles of remission induction therapy.

Relapsed or refractory (r/r) AML carries a grave prognosis, and management is guided by the clinical setting, analysis of the leukemic blasts, medical fitness, and the patient's values and preferences.

●Evaluation – Patients with suspected r/r AML should be evaluated as described above. (See 'Pretreatment evaluation' above.)

In addition:

•The immunophenotype, molecular, and cytogenetic studies of blasts must be repeated to determine if there are actionable targets that were not previously detected and/or treated (eg, IDH1 or IDH2 mutation, FLT3 mutations).

•All patients who may be candidates for transplantation should undergo human leukocyte antigen (HLA) typing and a search for related and/or unrelated donors in anticipation of potential allogeneic hematopoietic cell transplantation (HCT).

●Management – We strongly encourage enrollment in a clinical trial, when possible.

Allogeneic HCT is the only potentially curative approach to r/r AML at present. For patients who relapse after allogeneic HCT, donor lymphocyte infusion (DLI) may restore disease control.

Patients who are not candidates for allogeneic HCT or DLI should receive palliative management to control symptoms and potentially prolong survival. Examples include hydroxyurea to control symptoms associated with a rising blast count, intrathecal chemotherapy or radiation therapy to control central nervous system involvement, and management of tumor lysis syndrome.

Relapse >18 months after intensive induction therapy may again respond to the same regimen, though therapy should be informed by new cytogenetic/molecular abnormalities. Prompt referral for allogeneic HCT should be considered if remission is achieved.

Remission induction and consolidation for patients with r/r AML are discussed separately. (See "Treatment of relapsed or refractory acute myeloid leukemia".)

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 and other sources (eg, clinicaltrials.gov).

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".)

SUMMARY

●Description – Acute myeloid leukemia (AML) is a heterogeneous group of blood cancers that exhibit abnormal growth and differentiation caused by genetic and epigenetic changes in hematopoietic stem and/or progenitor cells. AML is the most common acute leukemia in adults.

●Clinical presentation – Most patients present with findings related to cytopenias (eg, fatigue, infections, bleeding), but some exhibit only laboratory abnormalities. (See 'Clinical manifestations' above.)

●Emergencies – Some patients present with hyperleukocytosis/leukostasis, tumor lysis syndrome (TLS), disseminated intravascular coagulation (DIC), central nervous system complications, or other emergencies that require urgent management. (See 'Complications/emergencies' above.)

Acute promyelocytic leukemia (APL) is a specific subtype of AML that often presents with hemorrhage and coagulopathy. APL requires immediate, distinctive treatment as discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults" and "Initial treatment of acute promyelocytic leukemia in adults".)

●Pretreatment evaluation – Pathologic features of the malignant cells and comorbid illnesses that might alter management and affect prognosis should be identified. (See 'Clinical and laboratory' above.)

●Fitness – Fitness for treatment is informed by performance status (table 1) and assessment of comorbid conditions (table 2). (See 'Medical fitness' above.)

●Goals of care – Shared decision-making by clinicians and the patient/family should establish goals of care. Long-term disease control/cure is an appropriate goal for many patients but easing symptoms and/or prolonging life may be more appropriate goals for those with significant comorbidities or advanced age. (See 'Goals of care' above.)

●Diagnosis – AML should be suspected in patients with circulating blasts, acute onset of unexplained cytopenia-related symptoms, or medical complications/emergencies (eg, TLS, DIC).

Diagnosis is based on the presence of ≥10 to 20 percent myeloblasts in bone marrow or blood that exhibit characteristic pathologic features or an extramedullary collection of myeloblasts (myeloid sarcoma). Diagnosis and classification of AML subtypes should use International Consensus Classification (ICC) or World Health Organization 5^th edition (WHO5) criteria. (See 'Diagnosis and classification' above.)

●Prognosis

•Outcomes are associated with age, fitness, and cytogenetic/molecular features. (See 'Prognostic features' above.)

•Prognostic risk is stratified as favorable, intermediate, or adverse, based on cytogenetics. (See 'Prognostic categories' above.)

●Fit, younger patients

•Remission induction – Seven-day continuous infusion of cytarabine plus an anthracycline on days 1 to 3 ("7+3" therapy), with or without a targeted agent for susceptible mutations, is usually given. Variations of this regimen are widely used. (See 'Intensive remission induction' above.)

•Response assessment – Examine blood/marrow at nadir (14 to 21 days after beginning treatment) to assess initial response; further management is guided by the findings. (See 'Nadir marrow assessment' above.)

Bone marrow is again assessed as blood counts recover (approximately four weeks after starting induction therapy). (See 'Response assessment' above.)

•Post-remission management – For complete remission (ie, <5 percent blasts), intensive consolidation chemotherapy or allogeneic hematopoietic cell transplantation (HCT) may be administered. This choice is guided by prognostic category, persistence of measurable residual disease, and patient fitness. (See 'Post-remission management' above.)

●Less-fit or older patients – Hypomethylating agent (eg, azacitidine, decitabine)-based therapy, with or without venetoclax or a targeted agent (for susceptible mutations) is usually given. (See 'Less-fit or older patients' above.)

●Monitoring – Clinical and laboratory assessments are used to monitor for relapse and treatment-related toxicity. (See 'Monitoring' above.)

●Relapsed/refractory AML – The prognosis is usually poor, and we encourage enrollment in a clinical trial.

Cytogenetic/molecular studies should be repeated to identify susceptible mutations, but only allogeneic HCT is curative at present. (See 'Relapsed/refractory disease' above.)