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Acute Myeloid Leukemia (AML)

(Acute Myelocytic Leukemia; Acute Myelogenous Leukemia)

By

Ashkan Emadi

, MD, PhD, University of Maryland;


Jennie York Law

, MD, University of Maryland, School of Medicine

Last full review/revision May 2020
Click here for Patient Education
Topic Resources

In acute myeloid leukemia (AML), malignant transformation and uncontrolled proliferation of an abnormally differentiated, long-lived myeloid progenitor cell results in high circulating numbers of immature blood cells and replacement of normal marrow by malignant cells. Symptoms include fatigue, pallor, easy bruising and bleeding, fever, and infection; symptoms of extramedullary leukemic infiltration are present in only about 5% of patients (often as skin manifestations). Examination of peripheral blood smear and bone marrow is diagnostic. Treatment includes induction chemotherapy to achieve remission and postremission chemotherapy (with or without stem cell transplantation) to avoid relapse.

The American Cancer Society estimates that in the United States in 2020 there will be about 19,940 new cases of acute myeloid leukemia (AML) and 11,180 deaths, almost all in adults. AML is slightly more common among men than women, but the average lifetime risk in both sexes is about 0.5% (1 in 200 Americans).

AML comprises about 25% of childhood leukemias, often developing in infancy. However, the incidence of AML increases with age; it is the most common acute leukemia in adults, with a median age of onset of 68 years. AML also may occur as a secondary cancer after chemotherapy or radiation therapy for a different type of cancer. Secondary AML is difficult to treat with chemotherapy alone.

Pathophysiology of AML

Similar to acute lymphoblastic leukemia Acute Lymphoblastic Leukemia (ALL) Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer; it also strikes adults of all ages. Malignant transformation and uncontrolled proliferation of an abnormally differentiated... read more Acute Lymphoblastic Leukemia (ALL) , acute myeloid leukemia is caused by a series of acquired genetic aberrations. Malignant transformation usually occurs at the pluripotent stem cell level, although it sometimes involves a committed stem cell with more limited capacity for self-renewal. Abnormal proliferation, clonal expansion, aberrant differentiation, and diminished apoptosis (programmed cell death) lead to replacement of normal blood elements with malignant cells.

Classification of AML

Acute myeloid leukemia has a number of subtypes and precursor neoplasms that are distinguished from each other by morphology, immunophenotype, cytochemistry, and genetic abnormalities (see also The 2016 World Health Organization [WHO] Classification of myeloid neoplasms) all of which have important implications for prognosis and treatment. Seven classes are described in the WHO classification, including

  • AML with recurrent genetic abnormalities

  • AML with myelodysplasia-related changes (AML-MRC)

  • Therapy-related AML (t-AML)

  • AML, not otherwise specified (NOS)

  • Myeloid sarcoma

  • Myeloid proliferations related to Down syndrome

  • Blastic plasmacytoid dendritic cell neoplasm

Morphologic criteria from the previous French-American-British (FAB) classification system are used for subtypes that are not otherwise specified (NOS).

Acute promyelocytic leukemia (APL) is a subtype of AML with recurrent genetic abnormalities. APL is a particularly important subtype, representing 10 to 15% of all cases of AML, striking a younger age group (median age 31 years) and particular ethnicity (Hispanics). Patients commonly present with a coagulation disorder (eg, disseminated intravascular coagulation Disseminated Intravascular Coagulation (DIC) Disseminated intravascular coagulation (DIC) involves abnormal, excessive generation of thrombin and fibrin in the circulating blood. During the process, increased platelet aggregation and coagulation... read more [DIC]).

Therapy-related AML (t-AML) is a subtype of AML caused by prior treatment with certain antineoplastic drugs (eg, alkylating agents and topoisomerase II inhibitors). Most t-AMLs occur 3 to 10 years after initial therapy, with a longer latency for alkylating agents and hydroxyurea (mean latency 5 to 7 years) than for topoisomerase II inhibitors (mean latency 6 months to 3 years). Alkylating agents cause chromosomal deletions and unbalanced translocations. Hydroxyurea causes del(17)p and also inhibits TP53 activation. Topoisomerase II inhibitors lead to balanced chromosomal translocations.

Myeloid sarcoma is characterized by extramedullary myeloblastic infiltration of skin (leukemia cutis), gingiva, and other mucosal surfaces.

Symptoms and Signs of AML

Symptoms of acute myeloid leukemia may be present for only days to weeks before diagnosis. The most common presenting symptoms are due to disrupted hematopoiesis with ensuing

  • Anemia

  • Thrombocytopenia

  • Granulocytopenia

Anemia can manifest with fatigue, weakness, pallor, malaise, dyspnea on exertion, tachycardia, and exertional chest pain.

Thrombocytopenia can cause mucosal bleeding, easy bruising, petechiae/purpura, epistaxis, bleeding gums, and heavy menstrual bleeding. Hematuria and gastrointestinal bleeding are uncommon. Patients can present with spontaneous hemorrhage, including intracranial or intra-abdominal hematomas.

Granulocytopenia (neutropenia) can lead to a high risk of infections, including those of bacterial, fungal, and viral etiologies. Patients may present with fevers and a severe and/or recurrent infection. The cause of fever often is not found, although granulocytopenia may lead to a rapidly progressing and potentially life-threatening bacterial infection.

Leukemia cutis can have various appearances, including papules or nodules, and plaques, and may be erythematous, brown, hemorrhagic, or violaceous/gray-blue.

Leukemic cell infiltration of other organ systems tends to be less common and severe in AML than in ALL, however:

  • Infiltration can enlarge the liver, spleen, and lymph nodes.

  • Bone marrow and periosteal infiltration may cause bone and joint pain.

  • Meningeal infiltration can result in cranial nerve palsies, headache, visual or auditory symptoms, altered mental status, and transient ischemic attack/stroke.

Diagnosis of AML

  • Complete blood count (CBC) and peripheral blood smear

  • Bone marrow examination

  • Histochemical studies, cytogenetics, immunophenotyping, and molecular biology studies

A diagnosis of acute myeloid leukemia is made when myeloid blast cells are ≥ 20% of marrow nucleated cells or ≥ 20% of nonerythroid cells when the erythroid component is > 50%, or at any blast percentage in the presence of recurrent cytogenetic abnormalities [t(8;21), t(15;17), inv(16) or t(16;16)]. Diagnosis can be made by the same criteria using peripheral blood.

CBC and peripheral smear are the first tests done; pancytopenia and peripheral blasts suggest acute leukemia. Blast cells in the peripheral smear may approach 90% of white blood cell (WBC) count.

Bone marrow examination (aspiration and needle biopsy) is routinely done. Blast cells in the bone marrow are classically between 25 and 95%.

Histochemical studies, cytogenetics, immunophenotyping, and molecular biology studies help distinguish the blasts of ALL from those of AML or other diseases. Histochemical studies include staining for myeloperoxidase, which is positive in cells of myeloid origin. Crystallization of myeloperoxidase-rich granules leads to formation of Auer rods (linear azurophilic inclusions in the cytoplasm of blast cells), which are pathognomic for AML. Detection of specific immunophenotypical markers (eg, CD13, CD33, CD34, CD117) is essential in classifying the acute leukemias.

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Less common cytogenetic abnormalities include

  • t(9;11)(p22.3;q23.3) MLLT3-KMT2A

  • t(1;22)(p13.3;q13.1) RBM15-MKL1

  • t(6;9)(p23;q34.1) DEK-NUP214

  • inv(3)(q21.3q26.2)

Other laboratory findings may include hyperuricemia, hyperphosphatemia, hyperkalemia, hypocalcemia, and elevated lactic dehydrogenase. These findings indicate a tumor lysis syndrome Tumor Lysis and Cytokine Release Syndromes Adverse effects are common in patients receiving any cancer therapy. Patients may also have adverse effects resulting from their cancer. Successfully managing these adverse effects is important... read more . Elevated serum hepatic transaminases and/or creatinine and hypoglycemia may also be present.

CT of the head is done in patients with CNS symptoms. Echocardiography or multi-gated acquisition (MUGA) scan is typically done to assess baseline cardiac function prior to giving anthracyclines, which are cardiotoxic.

Prognosis for AML

Remission induction rate ranges from 50 to 85%. Long-term disease-free survival is about 20 to 40% overall but is 40 to 50% in younger patients treated with intensive chemotherapy or stem cell transplantation.

Prognostic factors help determine treatment protocol and intensity; patients with strongly negative prognostic features are usually given intense forms of therapy followed by allogeneic stem cell transplantation. In these patients, the potential benefits of intense therapy are thought to justify the increased treatment toxicity.

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Molecular genetic abnormalities are also important in refining prognosis and therapy in AML. Many different mutations exist; these are categorized into groups based on their effect on prognosis and treatment. Patients with AML average 5 recurrent gene mutations. Patients with mutations in NPM1, which codes for the protein nucleophosmin, or in CEBPA have a more favorable prognosis. Mutations in FLT3, on the other hand, have a poorer prognosis (including in patients who also have an otherwise favorable NPM1 mutation).

Minimal residual disease is defined as having < 0.1 to 0.01% (based on the assay used) leukemic cells in bone marrow. In AML, minimal residual disease can be assessed by multiparameter flow cytometry detection of leukemia-associated immunophenotype or by mutation-specific polymerase chain reaction (PCR). These tools are prognostically accurate but are not quite ready for use in clinical practice.

Treatment of AML

  • For medically fit patients: Chemotherapy (induction and consolidation) with or without allogeneic hematopoietic stem cell transplantation

  • For medically frail patients: Less intensive therapies

  • For all: Supportive care

Treatment of acute myeloid leukemia depends on the patient's overall medical condition. Medically fit patients tend to be younger and have lower-risk cytogenetic abnormalities, better functional status, and fewer comorbidities than medically frail patients.

Because treatment of AML is complex and evolving, it is best done at the most specialized center available, particularly during critical phases (eg, remission induction); clinical trials are the first choice when available.

Medically fit patients with AML

In medically fit patients, initial treatment is induction chemotherapy to try to induce complete remission. Patients in remission then undergo consolidation therapy that may include allogeneic hematopoietic stem cell transplantation.

Complete remission is defined as < 5% blast cells in the bone marrow, absolute neutrophil count > 1000/mcL (> 1 × 109/L), platelet count > 100,000/mcL (> 100 × 109/L), and independence from blood transfusion.

The basic induction regimen (known as 7+3) includes cytarabine by continuous IV infusion for 7 days and daunorubicin or idarubicin given IV for 3 days during this time. Treatment usually results in significant myelosuppression, with infection or bleeding. There is significant latency before marrow recovery. During this time, meticulous preventive and supportive care Supportive care In acute myeloid leukemia (AML), malignant transformation and uncontrolled proliferation of an abnormally differentiated, long-lived myeloid progenitor cell results in high circulating numbers... read more Supportive care are vital.

Complete remission rates with 7+3 are about 70 to 85% (favorable genetics), 60 to 75% (intermediate genetics), and 25 to 40% (adverse genetics); complete remission rates also depend on patient-specific and other disease risk factors (eg, secondary vs de novo AML). However, most patients who achieve a CR with 7+3 (or another conventional induction regimen) ultimately relapse.

Re-induction is usually recommended for patients with residual leukemia on day 14, although there is no high-quality evidence that it improves outcome. Residual leukemia is defined variably as bone marrow blasts > 10% with bone marrow cellularity > 20%. The various recommended re-induction regimens include different dosages of cytarabine. Some include anthracyclines with or without a third agent.

Several drugs can be used with or instead of traditional 7+3 chemotherapy. Addition of midostaurin, a kinase inhibitor, to chemotherapy appears to prolong survival in certain patients (eg, adults < 60 with newly diagnosed FLT3 mutated AML—1 Treatment references In acute myeloid leukemia (AML), malignant transformation and uncontrolled proliferation of an abnormally differentiated, long-lived myeloid progenitor cell results in high circulating numbers... read more Treatment references ). Gemtuzumab ozogamicin (a CD33 directed antibody-drug conjugate) can be combined with chemotherapy in patients with newly diagnosed CD33-positive AML. Gemtuzumab ozogamicin is also sometimes used as monotherapy for induction and consolidation.

A consolidation phase follows remission in many regimens. This can be done with the same drugs used for induction or other drugs. High-dose cytarabine regimens may lengthen remission duration, particularly when given for consolidation in patients < 60 years old. For patients with favorable cytogenetic non-APL AML in first complete remission, consolidation with high-dose cytarabine is considered standard post-induction therapy.

A liposomal combination of daunorubicin and cytarabine is available for the treatment of adults with newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC). This combination showed superiority in overall survival compared with the standard-of-care cytarabine plus daunorubicin (7+3 regimen) in patients 60 to 75 years of age with newly diagnosed t-AML or AML-MRC (2 Treatment references In acute myeloid leukemia (AML), malignant transformation and uncontrolled proliferation of an abnormally differentiated, long-lived myeloid progenitor cell results in high circulating numbers... read more Treatment references ).

Allogeneic stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers (leukemias, lymphomas, myeloma) and other hematologic disorders... read more done during the first complete remission can generally improve outcome in patients with intermediate or adverse-risk cytogenetics. Generally, it takes 6 to 12 weeks to prepare for stem cell transplant. Recommendations are to proceed with standard high-dose cytarabine consolidation chemotherapy while awaiting definitive stem cell transplantation. Conditions that may render patients ineligible for allogenic stem cell transplantation include poor overall performance status and moderate to severe impairment of pulmonary, liver, kidney, or cardiac function.

In APL and some other cases of AML, disseminated intravascular coagulation Disseminated Intravascular Coagulation (DIC) Disseminated intravascular coagulation (DIC) involves abnormal, excessive generation of thrombin and fibrin in the circulating blood. During the process, increased platelet aggregation and coagulation... read more (DIC) may be present when leukemia is diagnosed and may worsen as leukemic cell lysis releases procoagulant chemicals. In APL [with the translocation t(15;17)], all-trans retinoic acid (tretinoin) corrects the DIC in 2 to 5 days; combined with daunorubicin or idarubicin, this regimen can induce remission in 80% to 90% of patients and bring about long-term survival in 65% to 70%. Arsenic trioxide is also very active in APL. Targeted therapy with tretinoin and arsenic trioxide without conventional cytotoxic chemotherapy is very well tolerated and has been extremely successful in APL with a 100% complete remission rate and > 90% cure rate (3 Treatment references In acute myeloid leukemia (AML), malignant transformation and uncontrolled proliferation of an abnormally differentiated, long-lived myeloid progenitor cell results in high circulating numbers... read more Treatment references ).

Medically frail patients with AML

In older and medically frail patients, initial therapy is typically less intensive.

Because the median age for diagnosis of AML is 68, most newly diagnosed patients are considered older. Older patients are more likely to have comorbidities that limit their therapeutic options. Older patients also are much more likely to have high-risk cytogenetic abnormalities (eg, complex karyotype, monosomy 7), secondary AML arising from myelodysplastic syndrome Myelodysplastic Syndrome (MDS) The myelodysplastic syndrome (MDS) is group of disorders typified by peripheral cytopenia, dysplastic hematopoietic progenitors, a hypercellular or hypocellular bone marrow, and a high risk... read more or myeloproliferative neoplasms Overview of Myeloproliferative Neoplasms Myeloproliferative neoplasms are clonal proliferations of bone marrow stem cells, which can manifest as an increased number of platelets, red blood cells (RBCs), or white blood cells (WBCs)... read more , or AML with multidrug resistance.

Although intensive chemotherapy is typically denied to older patients solely based on their age, it nevertheless improves rate of complete remission and overall survival in patients < 80, particularly those with favorable-risk karyotypes. Achieving complete remission also improves quality of life by reducing hospitalizations, infections, and transfusion requirements.

The DNA methyltransferase inhibitors decitabine and azacitidine are pyrimidine nucleoside analogs that modulate DNA by reducing methylation of the promoter region of tumor suppressor genes. They have improved clinical outcomes in elderly patients with de novo AML as well as those with s-AML (AML preceded by myelodysplastic syndrome), t-AML (therapy-related AML) and AML harboring TP53 mutations. One of these drugs can be given alone as first-line treatment for many older patients, particularly those with compromised functional/performance status, organ dysfunction, and tumor biology (eg, karyotype, molecular aberrations) that predict poor response to intensive chemotherapy.

Venetoclax is an inhibitor of anti-apoptotic protein BCL-2 and is used in combination with azacitidine or decitabine or low-dose cytarabine for the treatment of newly diagnosed AML in adults who are ≥ 75 years, or who have comorbidities that preclude use of intensive induction chemotherapy. Further study is needed to confirm these response rates, and continued recommendation for this indication. Glasdegib is a hedgehog pathway inhibitor used, in combination with low-dose cytarabine, for treatment of newly diagnosed AML in patients ≥ 75 years or who have comorbidities that preclude use of intensive induction chemotherapy.

Following induction therapy and provided their performance status is appropriate, older patients may undergo allogeneic hematopoietic stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers (leukemias, lymphomas, myeloma) and other hematologic disorders... read more . Allogeneic hematopoietic stem cell transplantation prolongs survival in elderly patients. If patients are not candidates for full intensity regimens, reduced intensity (non-myeloablative) regimens can be used. Older and frail patients who do not undergo transplantation usually proceed to consolidation chemotherapy (eg, cytarabine or combined cytarabine and anthracycline at lower doses than used for induction).

Relapsed or resistant AML

Patients who have not responded (are resistant) to treatment and patients who have relapsed generally have a poor prognosis. A second remission can be achieved in 30% to 70% of patients who relapsed following a first remission. These second remissions are achieved more readily in patients with initial remissions > 1 year and/or with favorable cytogenetics and are generally shorter in duration than first remissions.

Patients with relapsed or resistant AML may be candidates for allogeneic stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers (leukemias, lymphomas, myeloma) and other hematologic disorders... read more preceded by re-induction salvage chemotherapy. Many salvage chemotherapeutic regimens include various dosages of cytarabine combined with drugs such as idarubicin, daunorubicin, mitoxantrone, etoposide, antimetabolites (eg, cladribine, clofarabine, fludarabine), and asparaginase. Regimens containing decitabine and azacitidine are sometimes used.

Donor lymphocyte infusion is another option in relapsed or resistant AML if initial allogeneic stem cell transplant is unsuccessful. Other novel treatment strategies include enasidenib, an isocitrate dehydrogenase-2 (IDH2) inhibitor, or ivosidenib, an isocitrate dehydrogenase-1 (IDH1) inhibitor, that may be useful for adult patients with relapsed or refractory AML who have an IDH2 or an IDH1 mutation, and gemtuzumab ozogamicin as monotherapy for relapsed or refractory AML.

Gilteritinib is a kinase inhibitor used for the treatment of adult patients who have relapsed or refractory AML with a FLT3 mutation. In the phase 3 study, patients randomized to receive gilteritinib had significantly longer survival than patients treated with chemotherapy (Hazard ratio 0.64; 95% CI: 0.49 - 0.83) (4 Treatment references In acute myeloid leukemia (AML), malignant transformation and uncontrolled proliferation of an abnormally differentiated, long-lived myeloid progenitor cell results in high circulating numbers... read more Treatment references ).

Chimeric antigen receptor T (CAR-T) cells targeting CD123 or CD33 and antibody-drug conjugates targeting CD33 have also been used in clinical trials.

Supportive care

Supportive care is similar in the acute leukemias and may include

  • Transfusions

  • Antimicrobials

  • Hydration and urine alkalinization

  • Psychologic support

Transfusions of red blood cells and platelets are administered as needed to patients with anemia or bleeding. Prophylactic platelet transfusion is done when platelets fall to < 10,000/mcL (< 10 × 109/L). Anemia (hemoglobin < 7 or 8 g/dL [< 70 or 80 g/L]) is treated with transfusions of packed red blood cells. Granulocyte transfusions are not routinely used.

Antimicrobials are often needed for prophylaxis and treatment because patients are immunosuppressed; in such patients, infections can progress quickly with little clinical prodrome. After appropriate studies and cultures have been done, febrile patients with neutrophil counts < 500/mcL (< 0.5 × 109/L) should begin treatment with a broad-spectrum bactericidal antibiotic that is effective against gram-positive and gram-negative organisms (eg, ceftazidime, piperacillin and tazobactam, meropenem). Fungal infections, especially pneumonias, are becoming more common; these are difficult to diagnose, so chest CT to detect fungal pneumonia should be done early (ie, within 72 hours of presentation with neutropenic fever depending on the degree of suspicion). Empiric antifungal therapy should be given if antibacterial therapy is not effective within 72 hours. In patients with refractory pneumonitis, Pneumocystis jirovecii infection Pneumocystis jirovecii Pneumonia Pneumocystis jirovecii is a common cause of pneumonia in immunosuppressed patients, especially in those infected with human immunodeficiency virus (HIV) and in those receiving systemic corticosteroids... read more Pneumocystis jirovecii Pneumonia or a viral infection should be suspected and confirmed by bronchoscopy and bronchoalveolar lavage and treated appropriately. Posaconazole, a 2nd-generation triazole antifungal agent, is indicated for primary prophylaxis in patients age > 13 years who are at high risk of developing invasive Aspergillus or Candida infections because of immunosuppression. Acyclovir or valacyclovir prophylaxis is generally recommended for all patients.

Hydration and allopurinol or rasburicase are used for treatment of hyperuricemia, hyperphosphatemia, hypocalcemia, and hyperkalemia (ie, a tumor lysis syndrome Tumor Lysis and Cytokine Release Syndromes Adverse effects are common in patients receiving any cancer therapy. Patients may also have adverse effects resulting from their cancer. Successfully managing these adverse effects is important... read more ) caused by the rapid lysis of leukemic cells during initial therapy in AML.

Psychologic support may help patients and their families with the shock of illness and the rigors of treatment for a potentially life-threatening condition.

Treatment references

Key Points

  • Acute myeloid leukemia (AML) is the most common acute leukemia in adults.

  • There are a number of subtypes, typically involving very immature myeloid cells.

  • Chromosomal and molecular genetic abnormalities are common and have implications for prognosis and treatment.

  • In medically fit patients, treat with induction and consolidation chemotherapy followed by allogeneic hematopoietic stem cell transplantation (in patients with intermediate and unfavorable genetic features).

  • In medically frail patients, treat with less intensive regimens such as DNA methyltransferase inhibitors and consider allogeneic hematopoietic stem cell transplantation.

  • In relapsed and/or resistant patients, treat with salvage chemotherapy followed by allogeneic hematopoietic stem cell transplantation when feasible, or use targeted therapies.

More Information

The following is an English-language resource that may be useful. Please note that THE MANUAL is not responsible for the content of this resource.

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