Acute myeloid leukemia (AML) is a malignant disease of the bone marrow in which hematopoietic precursors are arrested in an early stage of development. Most AML subtypes are distinguished from other related blood disorders by the presence of more than 20% blasts in the bone marrow.
The underlying pathophysiology in AML consists of a maturational arrest of bone marrow cells in the earliest stages of development. (See Pathophysiology.) Several factors have been implicated in the causation of AML, including antecedent hematologic disorders, familial syndromes, environmental exposures, and drug exposures. However, most patients who present with de novo AML have no identifiable risk factor. (See Etiology.)
Patients with AML present with symptoms resulting from bone marrow failure, symptoms resulting from organ infiltration with leukemic cells, or both. The time course is variable. (See Presentation.) The workup for AML includes blood tests, bone marrow aspiration and biopsy (the definitive diagnostic tests), and analysis of genetic abnormalities. (See Workup.)
Current standard chemotherapy regimens cure only a minority of patients with AML. Consequently, all patients should be evaluated for entry into well-designed clinical trials. If a clinical trial is not available, the patient can be treated with standard therapy. (See Treatment.) Readmission is frequently required for the management of toxic effects of chemotherapy.
Go to Oncology Decision Point for expert commentary on AML treatment decisions and related guidelines.
The underlying pathophysiology in AML consists of a maturational arrest of bone marrow cells in the earliest stages of development. The mechanism of this arrest is under study, but in many cases, it involves the activation or inactivation of genes through chromosomal translocations and other genetic and/or epigenetic abnormalities.[1, 2, 3]
This developmental arrest results in 2 disease processes. First, the production of normal blood cells markedly decreases, which results in varying degrees of anemia, thrombocytopenia, and neutropenia. Second, the rapid proliferation of the abnormal myeloblasts, along with a reduction in their ability to undergo programmed cell death (apoptosis), results in their accumulation in the bone marrow, the blood, and, frequently, the spleen and liver.
Several factors have been implicated in the causation of AML, including antecedent hematologic disorders, familial syndromes, environmental exposures, and drug exposures. However, most patients who present with de novo AML have no identifiable risk factor.
The most common risk factor for AML is the presence of an antecedent hematologic disorder, the most common of which is myelodysplastic syndrome (MDS). MDS is a bone marrow disease of unknown etiology that occurs most often in older patients and manifests as progressive cytopenias that occur over months to years. Patients with low-risk MDS (eg, MDS with ringed sideroblasts) generally do not develop AML, whereas patients with high-risk MDS (eg, MDS with excess blasts) frequently do.
Other antecedent hematologic disorders that predispose patients to AML include aplastic anemia and myeloproliferative disorders, especially myelofibrosis.
Some congenital disorders that predispose patients to AML include Bloom syndrome, Down syndrome, congenital neutropenia, Fanconi anemia, and neurofibromatosis. Usually, these patients develop AML during childhood; rarely, they may present in young adulthood.
More subtle genetic disorders, including polymorphisms of enzymes that metabolize carcinogens, also predispose patients to AML. For example, polymorphisms of NAD(P)H:quinone oxidoreductase (NQO1), an enzyme that metabolizes benzene derivatives, are associated with an increased risk of AML.[4] Particularly increased risk exists for AML that occurs after chemotherapy for another disease or for de novo AML with an abnormality of chromosomes 5, 7, or both.
Likewise, polymorphisms in glutathione S-transferase are associated with secondary AML after chemotherapy for other malignancies.[5]
Germline mutations in the gene AML1 (RUNX1, CBFA2) occur in the familial platelet disorder with predisposition for AML, an autosomal dominant disorder characterized by moderate thrombocytopenia, a defect in platelet function, and propensity to develop AML.[6] Mutation of CEBPA (the gene encoding CCAAT/enhancer binding protein alpha, a granulocytic differentiation factor and member of the bZIP family) was described in a family with 3 members affected by AML.[7]
Holme et al studied 27 families with familial MDS/AML. All of the families were screened for RUNX1, CEBPA, TERC, TERT, GATA2, TET2, and NPM1 mutations. Five of the 27 families had telomerase mutations (3 TERT, 2 TERC), one had a RUNX1 mutation, and four had heterozygous GATA2 mutations.[8]
Gao et al reviewed GATA2 mutations associated with familial AML-MDS.[9] GATA2 is a transcription factor crucial for hematopoietic differentiation and lymphatic formation. Germline GATA2 mutations are involved in a rare group of complex syndromes with overlapping clinical features of immune deficiency, lymphedema, and propensity to AML or MDS.
With the routine use of expanded next-generation genetic panels on bone marrow, and with confirmation on nonhematopoietic tissues, many more patients are being diagnosed with germline mutations that predisposed them to AML. Among these genes are DDX41, SRP72, ANKRD26, and ETV6.[10] The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia now includes a subtype "Myeloid neoplasms with germ line predisposition".[1] Thus, to properly classify patients with AML, these genes must be included in nextgen panels.
Some hereditary cancer syndromes, such as Li-Fraumeni syndrome, can manifest as leukemia. However, cases of leukemia are less common than the solid tumors that generally characterize these syndromes.
Several studies demonstrate a relationship between radiation exposure and leukemia. Early radiologists (before the use of appropriate shielding) were found to have an increased likelihood of developing leukemia. Patients receiving therapeutic irradiation for ankylosing spondylitis were at increased risk of leukemia. Survivors of the atomic bomb explosions in Japan were at a markedly increased risk for the development of leukemia.
Persons who smoke tobacco have a small but statistically significant (odds ratio, 1.5) increased risk of developing AML.[11] In several studies, the risk of AML was slightly increased in people who smoked compared with those who did not smoke.
Exposure to benzene is associated with aplastic anemia and pancytopenia. These patients often develop AML. Many of these patients have the erythroleukemia subtype of AML (AML-M6). Exposure to soot, creosote, inks, dyes, and tanning solutions and coal dust have also been associated with AML.[12]
As more patients with cancer survive their primary malignancy and more patients receive intensive chemotherapy (including bone marrow transplantation [BMT]), the number of patients with AML increases because of exposure to chemotherapeutic agents. For example, the cumulative incidence of acute leukemia in patients with breast cancer who were treated with doxorubicin and cyclophosphamide as adjuvant therapy was 0.2-1.0% at 5 years.[13]
Patients with previous exposure to chemotherapeutic agents can be divided into 2 groups: (1) those with previous exposure to alkylating agents and (2) those with exposure to topoisomerase-II inhibitors. The typical latency period between drug exposure and acute leukemia is approximately 3-5 years for alkylating agents/radiation exposure, but it is only 9-12 months for topoisomerase inhibitors.
Patients with a previous exposure to alkylating agents, with or without radiation, often have a myelodysplastic phase before the development of AML. Cytogenetics testing frequently reveals -5 and/or -7 (5q- or monosomy 7).
Patients with a previous exposure to topoisomerase-II inhibitors do not have a myelodysplastic phase. Cytogenetics testing reveals a translocation that involves band 11q23. Less commonly, these patients develop leukemia with other balanced translocations, such as inversion 16 or t(15;17).[14]
The American Cancer Society (ACS) estimates that 19,940 new cases of AML (11,090 in men, 8850 in women) will occur in the United States in 2020.[15] AML is more commonly diagnosed in developed countries, and it is more common in whites than in other populations.
The prevalence of AML increases with age. The median age of onset is approximately 70 years. However, AML affects all age groups.
AML is more common in men than in women, especially in older patients. This is likely because MDS is more common in men, and advanced MDS frequently evolves into AML. Some have proposed that the higher prevalence of AML in men may be related to occupational exposures (see Etiology).
The ACS estimates that in 2020, 11,180 deaths from AML will occur in the United States. Of those, 6470 are expected to occur in men and 4710 in women.[15]
The prognosis depends on several factors. Increasing age is an adverse factor, because older patients more frequently have a previous antecedent hematologic disorder and/or poor-risk cytogenetic and molecular markers that make the leukemia resistant to chemotherapy. Older patients also frequently have comorbid medical conditions that compromise the ability to tolerate full doses of chemotherapy. A previous antecedent hematologic disorder (most commonly, MDS) is associated with a poor outcome of therapy.
Findings from cytogenetic analysis of the bone marrow constitute one of the most important prognostic factors. Patients with t(8;21), t(15;17), or inversion 16 have the best prognosis, with long-term survival rates of approximately 65%. Patients with normal cytogenetic findings have an intermediate prognosis and have a long-term survival rate of approximately 35%. Patients with poor-risk cytogenetic findings (especially -7, -5, or monosomal karyotype) have a poor prognosis, with a long-term survival rate of less than 10%.[16]
Other cytogenetic abnormalities, including +8, 11q23, and miscellaneous, have been reported to confer intermediate risk in some series and poor risk in others.
The presence of an FLT3 mutation is associated with a poorer prognosis. Biallelic mutations in CEBPA are associated with a longer remission duration and longer overall survival.[17] Mutations in NPM are associated with an increased response to chemotherapy. Patients with TP53 mutations have a particularly poor prognosis.[18]
A study by Metzeler et al determined that TET2 mutations had an adverse prognostic impact in an otherwise favorable-risk patient subset, using the European LeukemiaNet (ELN) molecular-risk classification of patients with primary cytogenetically normal AML.[19]
In adults, treatment results are generally analyzed separately for younger (18-60 y) patients with AML and for older patients (>60 y). With current standard chemotherapy regimens, approximately 40-45% of adults younger than 60 years survive longer than 5 years and are considered cured. Results in older patients are more disappointing, with fewer than 10% surviving over the long term. Overall, cure rates for younger patients have improved over the past few decades, but little progress has been made in improving the survival of older patients.[20]
The prognosis of therapy-related AML is particularly poor, with 5-year survivals of approximately 10%. The prognosis is better for the subset of patients with therapy-related AML who have favorable cytogenetic abnormalities.[21, 22]
A study by Varadarajan et al found that having ever smoked decreased overall survival in patients with AML.[23] Crysandt and colleagues found that in younger patients with de novo AML, overweight and obesity were risk factors for an impaired response to induction therapy and shorter disease-free and overall survival.[24]
Death in patients with AML may result from uncontrolled infection or hemorrhage. This may happen even after use of appropriate blood product and antibiotic support.
Patients with AML should be instructed to call their healthcare providers immediately if they develop a fever or have signs of bleeding.
For patient education resources, see the Blood and Lymphatic System Center and the Skin, Hair, and Nails Center, as well as Leukemia and Bruises.
Patients with acute myeloid leukemia (AML) present with signs and symptoms resulting from bone marrow failure, organ infiltration with leukemic cells, or both. The time course is variable. Some patients, particularly younger ones, present with acute symptoms that develop over a few days to 1-2 weeks. Others have a longer course, with fatigue or other symptoms lasting from weeks to months. A longer course may suggest an antecedent hematologic disorder, such as myelodysplastic syndrome (MDS).
Symptoms of bone marrow failure are related to anemia, neutropenia, and thrombocytopenia. The most common symptom of anemia is fatigue. Patients often retrospectively note a decreased energy level over past weeks. Other symptoms of anemia include dyspnea on exertion; dizziness; and, in patients with coronary artery disease, anginal chest pain. In fact, myocardial infarction may be the first presenting symptom of acute leukemia in an older patient.
Patients with AML often have decreased neutrophil levels despite an increased total white blood cell (WBC) count. Patients generally present with fever, which may occur with or without specific documentation of an infection. Patients with the lowest absolute neutrophil counts (ANCs) (ie, < 500 cells/µL, especially < 100 cells/µL) have the highest risk of infection. See the Absolute Neutrophil Count calculator.
Patients often have a history of upper respiratory infection symptoms that have not improved despite empiric treatment with oral antibiotics.
Patients may present with bleeding gums and multiple ecchymoses. Bleeding may be caused by thrombocytopenia, coagulopathy that results from disseminated intravascular coagulation (DIC), or both. Potentially life-threatening sites of bleeding include the lungs, gastrointestinal (GI) tract, and central nervous system.
Alternatively, disease manifestations may be the result of organ infiltration with leukemic cells. The most common sites of infiltration include the spleen, liver, gums, and skin. Infiltration occurs most commonly in patients with the monocytic subtypes of AML. Patients with splenomegaly note fullness in the left upper quadrant and early satiety. Patients with gum infiltration often present to their dentist first. Gingivitis due to neutropenia can cause swollen gums, and thrombocytopenia can cause the gums to bleed.
Patients with markedly elevated WBC counts (>100,000 cells/µL) can present with symptoms of leukostasis (ie, respiratory distress and altered mental status). Leukostasis is a medical emergency that calls for immediate intervention. Patients with a high leukemic cell burden may present with bone pain caused by increased pressure in the bone marrow.
Physical signs of anemia, including pallor and a cardiac flow murmur, are frequently present in AML patients. Fever and other signs of infection can occur, including lung findings of pneumonia.
Patients with thrombocytopenia usually demonstrate petechiae, particularly on the lower extremities. The petechiae are small, often punctate, hemorrhagic rashes that are not palpable. Areas of dermal bleeding or bruises (ie, ecchymoses) that are large or present in several areas may indicate a coexistent coagulation disorder (eg, DIC). Purpura is characterized by flat bruises that are larger than petechiae but smaller than ecchymoses.
Signs relating to organ infiltration with leukemic cells include hepatosplenomegaly and, to a lesser degree, lymphadenopathy. Occasionally, patients have skin rashes due to infiltration of the skin with leukemic cells (leukemia cutis). Chloromata are extramedullary deposits of leukemia. Rarely, a bony or soft-tissue chloroma may precede the development of marrow infiltration by AML (granulocytic sarcoma).
Signs relating to leukostasis include respiratory distress and altered mental status.
The workup for acute myeloid leukemia (AML) includes the following:
Immunophenotyping by flow cytometry of bone marrow or peripheral blood samples can be used to help distinguish AML from acute lymphocytic leukemia (ALL) and further classify the subtype of AML. Cytogenetic studies performed on bone marrow provide important prognostic information and can guide treatment by confirming a diagnosis of acute promyelocytic leukemia (APL).
Perform human leukocyte antigen (HLA) or DNA typing in patients who are potential candidates for allogeneic transplantation.
In patients with signs or symptoms suggesting central nervous system (CNS) involvement, computed tomography (CT) or magnetic resonance imaging (MRI) should be performed. Lumbar puncture is indicated in those patients if no CNS mass or lesion is detected on CT or MRI.[25]
Chest radiographs help assess for pneumonia and signs of cardiac disease in individuals with AML.
Evaluation of myocardial function is needed once the diagnosis of AML is confirmed because many of the chemotherapeutic agents used in treatment are cardiotoxic. Echocardiography or multiple gated acquisition (MUGA) scanning is particularly important for patients who have a history or symptoms of heart disease or risk factors for iatrogenic cardiotoxicity (ie, exposure to cardiotoxic drugs or thoracic radiotherapy).[25] All patients should have a baseline electrocardiogram before starting treatment for AML.
A complete blood count (CBC) with differential demonstrates anemia and thrombocytopenia to varying degrees. Patients with AML can have high, normal, or low white blood cell (WBC) counts.
The most common abnormality is disseminated intravascular coagulation (DIC), which results in an elevated prothrombin time, a decreasing fibrinogen level, and the presence of fibrin split products. Acute promyelocytic leukemia (APL), also known as M3, is the most common subtype of AML associated with DIC. Patients with acute monocytic leukemia also have a high incidence of clinically significant DIC.
Review of the peripheral blood smear confirms the findings from the CBC count. Circulating blasts are usually seen. Schistocytes are occasionally seen if DIC is present.
Most patients with AML have an elevated lactate dehydrogenase (LDH) level and, frequently, an elevated uric acid level. Elevation of those test results indicates possible tumor lysis syndrome, which should be treated expeditiously. Liver function tests and blood urea nitrogen (BUN)/creatinine tests are necessary before the initiation of therapy.
Appropriate cultures should be obtained in patients with fever, or with signs of infection even in the absence of fever.
Flow cytometry (immunophenotyping) can be used to help distinguish AML from acute lymphocytic leukemia (ALL) and further classify the subtype of AML (see the table below). The immunophenotype correlates with prognosis in some instances.
Table 1. Common Antigens for Immunophenotyping of AML Cells
 View Table | See Table |
Cytogenetic studies performed on bone marrow provide important prognostic information. Guidelines from an international expert panel, on behalf of the European LeukemiaNet (ELN), recommend risk stratification for patients with AML on the basis of genetic abnormalities. The ENL identifies three levels of risk: favorable, intermediate, and adverse.[26]
Genetic abnormalities that convey favorable risk are as follows:
Genetic abnormalities that convey intermediate risk are as follows:
Genetic abnormalities that convey adverse risk are as follows:
Note that neither mutated RUNX or mutated ASXL1 should be used as an adverse prognostic marker if it occurs together with favorable-risk AML subtypes.[26]
Cytogenetic studies are also useful for confirming a diagnosis of APL, which bears the t(15;17) chromosome abnormality and is treated differently. See Table 2, below.
Table 2. Cytogenetic Abnormalities in APL
View Table | See Table |
Fluorescence in situ hybridization (FISH) studies can be used to get an overview of cytogenetic abnormalities more quickly than can be done with traditional cytogenetic studies. However, FISH does not replace cytogenetics.
Although it has been known for some time that patients with multiple cytogenetic abnormalities have a poor prognosis, Breems et al demonstrated that a monosomal karyotype (defined as two or more distinct autosomal monosomies or one single autosomal monosomy in the presence of structural abnormalities) confers a particularly poor prognosis.[27] Several other groups have since confirmed this finding.[28, 29]
Several molecular abnormalities that are not detected with routine cytogenetics have been shown to have prognostic importance in patients with AML. The bone marrow should be evaluated at least with the commercially available tests. Patients with APL should have their marrow evaluated for the PML/RARa genetic rearrangement. When possible, the bone marrow should be evaluated for Fms-like tyrosine kinase 3 (FLT3) and nucleophosmin (NPM1) mutations.
FLT3 is the most commonly mutated gene in cases of AML and is constitutively activated in one third of AML cases.[30] Internal tandem duplications (ITDs) in the juxtamembrane domain of FLT3 exist in 25% of AML cases. In other cases, mutations exist in the activation loop of FLT3. Most studies demonstrate that patients with AML and FLT3-ITDs have a poor prognosis. Analysis of FLT3 is commercially available.
Mutations in NPM1 are associated with increased response to chemotherapy in patients with a normal karyotype.[31] In a study by Thiede et al of FLT3 and NPM1 in 1485 patients with AML, analysis of the clinical impact in 4 groups (NPM1 and FLT3-ITD single mutants, double mutants, and wild-type [wt] for both) revealed that patients having only an NPM1 mutation (without a FLT3 -ITD) had a significantly better overall and disease-free survival and a lower cumulative incidence of relapse.[32] Analysis of NPM1 is commercially available.
Mutations in CEBPA are detected in 15% of patients with normal cytogenetics findings. Biallelic mutations are associated with a longer remission duration and longer overall survival.[33] ERG overexpression is an adverse predictor in cytogenetically normal AML.
A study by the Cancer and Leukemia Group B (CALGB) found that high BAALC expression was associated with FLT3-ITD, wild-type NPM1, mutated CEBPA, MLL-PTD, absent FLT3-TKD and high ERG expression. In a multivariate analysis, high BAALC expression independently predicted lower complete remission rates when ERG expression and age were adjusted for and shorter survival when FLT3-ITD, NPM1, CEBPA and WBC count were adjusted for.[34]
The clinical impact of MLL partial tandem duplication (MLL-PTD) was evaluated in 238 adults aged 18 to 59 years with cytogenetically normal de novo AML who were treated by CALGB. Of the patients with MLL-PTD, 92% achieved complete remission, compared with 83% of patients without MLL-PTD.
Ley et al identified a somatic mutation in DNMT3A, encoding a DNA methyltransferase, in the cells of a patient with AML and a normal karyotype.[35] The authors sequenced the exons of DNMT3A in 280 additional patients with de novo AML to define recurring mutations. A total of 62 of 281 patients (22.1%) had mutations in DNMT3A that were predicted to affect translation. These mutations were highly enriched in the group of patients with an intermediate-risk cytogenetic profile but were absent in all 79 patients with a favorable-risk cytogenetic profile. The median overall survival (OS) of patients with DNMT3A mutations was significantly shorter than that of patients without such mutations (12.3 vs. 41.1 mo, respectively; P< 0.001).
Schwind et al measured miR-181a expression in pretreatment marrows in 187 adults (< 60 y) with CN-AML. Higher miR-181a expression was associated with a higher complete remission (CR) rate (P =0.04), longer OS (P =0.01) and a trend for longer disease-free survival (P =0.09). The impact of miR-181a was most striking in poor molecular risk patients with FLT3-ITD and/or NPM1 wild-type, where higher miR-181a expression was associated with a higher CR rate (P =0.009) and longer disease-free survival (P< 0.001) and OS (P< 0.001). In multivariable analyses, higher miR-181a expression was significantly associated with better outcome, both in the whole patient cohort and in patients with FLT3-ITD and/or NPM1 wild-type. These results were also validated in an independent set of older (≥60 y) patients with CN-AML.[36]
Gene expression profiling is a research tool that allows a comprehensive classification of AML based on the expression pattern of thousands of genes.[37] Marcucci used next-generation sequencing analysis of methylated DNA to identify differentially methylated regions associated with prognosis in older patients with AML. Seven genes were associated with prognosis: CD34, RHOC, SCRN1, F2RL1, FAM92A1, MIR155HG, and VWA8. The fewer the genes with high expression, the better the prognosis.[38]
Several groups have demonstrated that mutations in IDH1 and IDH2 have an adverse effects on prognosis in AML. Next-generation sequencing can detect these abnormalities and can identify patients who are candidates for therapies targeting these mutations.[39]
Chest radiographs help assess for pneumonia and signs of cardiac disease in individuals with AML.
Multiple gated acquisition (MUGA) scanning is needed once the diagnosis of AML is confirmed, because many chemotherapeutic agents used in treatment are cardiotoxic.
Electrocardiography should be performed before treatment of AML.
The traditional French–American–British (FAB) classification of AML is as follows:
The newer WHO classification is as follows[1] :
See also Acute Myeloid Leukemia Staging.
Treatment options for acute myeloid leukemia (AML) comprise a variety of chemotherapy regimens, biologic agents, and stem cell transplantation.[40, 41] Treatment recommendations include general recommendations, which take into account patient age and performance status, as well as recommendations for relapsed or refractory disease and acute promyelocytic leukemia (APL). See also Acute Myeloid Leukemia Treatment Protocols. Go to Oncology Decision Point for expert commentary on AML treatment decisions and related guidelines.
Current standard chemotherapy regimens cure only a minority of patients with AML. As a result, all patients should be evaluated for entry into well-designed clinical trials. If a clinical trial is not available, the patient can be treated with standard therapy. For consolidation chemotherapy or for the management of toxic effects of chemotherapy, readmission is required.
When receiving chemotherapy, patients should avoid exposure to crowds and people with contagious illnesses, especially children with viral infections. Any patient with neutropenic fever or infection should immediately be treated with broad-spectrum antibiotics. (See Antimicrobial Agents in Neutropenic Cancer Patients and Neutropenic Fever Empiric Therapy .)
Appropriate transfusion support must be provided to patients with AML. This includes transfusion of platelets and clotting factors (fresh frozen plasma [FFP], cryoprecipitate) as guided by the patient’s blood test results and bleeding history. Blood products must be irradiated to prevent transfusion-associated graft versus host disease (GVHD).
Patients with AML are best treated at a center whose staff has significant experience in the treatment of leukemia. Patients should be transferred to an appropriate (generally tertiary care) hospital if they are admitted to hospitals without appropriate blood product support, leukapheresis capabilities, or physicians and nurses familiar with the treatment of leukemia patients.
Various acceptable induction regimens are available. The most common approach, "3 and 7," consists of 3 days of a 15- to 30-minute infusion of an anthracycline (idarubicin or daunorubicin) or anthracenedione (mitoxantrone), combined with 100-200 mg/m2 of cytarabine (arabinosylcytosine; ara-C) as a 24-hour infusion daily for 7 days. Traditional dosages have been as follows:
These regimens require adequate cardiac, hepatic, and renal function. On these regimens, approximately 50% of patients achieve remission with one course. Another 10-15% of patients enter remission after a second course of therapy.
Improved outcomes have been reported with induction regimens using a higher dose of daunorubicin (90 mg/m2/d for 3 d compared with 45 mg/m2/d). In a study by Fernandez et al in 657 patients younger than 60 years with untreated AML, the complete remission rate with high-dose daunorubicin was 70.6%, versus 57.3% with conventional-dose daunorubicin, and overall survival was a median of 23.7 versus 15.7 months, respectively.[42]
In a similar study in 813 patients 60 years of age or older by Lowenberg et al, the complete remission rate was 64% in the escalated-dose group compared with 54% in conventional-dose group. In both groups, daunorubicin was administered over 3 hours on days 1-3. Cytarabine was given in a dose of 200 mg/m2/d as a continuous infusion for 7 days, followed by a second cycle at a dose of 1000 mg/m2/12 h for 6 days.[43]
No significant difference was seen between the groups in terms of hematologic toxic effects, 30-day mortality, or other significant adverse events. Although survival endpoints did not differ between the two groups overall, in patients aged 60-65 years the complete remission rate, event-free survival, and overall survival were superior in the escalated-dose group.[43]
A study comparing daunorubicin 90 mg/m2 versus 60 mg/m2 for AML induction found no difference in complete remission rate (73% versus 75%) or in 2-year overall survival (59% versus 60%).[44]
A study by Liu et al in 74 patients older than 60 years with newly diagnosed non-M3 AML reported a significantly higher complete remission rate with reduced-intensity idarubicin plus cytarabine than with daunorubicin plus cytarabine (70.4% vs 40%, P = 0.028). The difference was especially marked in patients with white blood cell (WBC) counts >10 × 109/L (P = 0.042) and ECOG (Eastern Cooperative Oncology Group) score < 2 (P = 0.021). However, the overall survival of the entire population was poor, with a median survival of 10 months.[45]
Alternatively, high-dose cytarabine combined with idarubicin, daunorubicin, or mitoxantrone can be used as induction therapy in younger patients. The use of high-dose cytarabine outside the setting of a clinical trial is considered controversial. However, 2 studies demonstrated improved disease-free survival rates in younger patients who received high-dose cytarabine during induction.
A study of dosing regimens for cytarabine induction therapy determined that lower doses produce maximal antileukemic effects for all response end points.[46] Thus, high-dose cytarabine results in excessive toxic effects with no therapeutic advantage.
Midostaurin
Midostaurin (Rydapt), an orally administered multitargeted kinase inhibitor, was approved by the US Food & Drug Administration (FDA) in April 2017 for adults with newly diagnosed AML that is FLT3 mutation positive. The FLT3 mutation is observed in approximately 30-35% of patients with AML.
Midostaurin is used in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy. Midostaurin and its major active metabolites inhibit the activity of wild-type FLT3, FLT3 mutant kinases (ITD and TKD), KIT (wild type and D816V mutant), PDGFR-alpha/beta, VEGFR2, and members of the serine/threonine kinase protein kinase C (PKC) family.
Approval of midostaurin was based on the CALGB 10603 (RATIFY) study, conducted in 717 adults younger than 60 years with newly-diagnosed FLT3-mutated AML. Patients who received midostaurin plus standard induction and consolidation chemotherapy had significantly longer overall survival than patients who received standard treatment plus placebo (hazard ratio [HR] for death, 0.78; one-sided P=0.009), as well as longer event-free survival (HR for event or death, 0.78; one-sided P=0.002).[47]
Cladribine
Purine analogs increase intracellular uptake of cytarabine by accumulation of cytarabine triphosphate (ara-CTP) in leukemia blasts. A preliminary trial by the Polish Adult Leukemia Group demonstrated a significantly increased complete remission rate when cladribine was added to cytarabine and daunorubicin.[48]
In a larger trial, 652 patients with AML, aged 17 to 60 years, were randomized to receive daunorubicin and cytarabine (DA), DA plus cladribine, or DA plus fludarabine. Complete remission was higher with DA plus cladribine compared with DA (67.5% versus 56%, respectively, P=0.01). The improvement was due to a reduction in resistant disease. Overall survival was also improved with DA plus cladribine versus DA (45% versus 33% at 3 years, respectively, P=0.02). There was no benefit to the addition of fludarabine to DA except in the subset of patients with adverse karyotype.[49]
Most patients younger than 60 years should be evaluated for allogeneic stem cell transplantation (HCT). Exceptions include patients with favorable cytogenetic and molecular markers and those with significant comorbidities. Other options for post-remission therapy include further chemotherapy and, rarely, autologous HCT.
Mayer et al conducted a randomized study of three different doses of cytarabine in patients with AML who achieved remission after standard 3 and 7 induction chemotherapy.[50] Patients received four courses of cytarabine at one of the following dosages:
The probability of remaining in continuous complete remission after 4 years in patients aged 60 years or younger was 24% in the 100-mg group, 29% in the 400-mg group, and 44% in the 3-g group. The outcome in older patients did not differ. On the basis of this study, high-dose cytarabine for four cycles is a standard option for consolidation therapy in younger patients.[50]
Patients with good-risk AML (ie, t[8;21] or inversion of chromosome 16[inv16]) have a good prognosis after consolidation with standard high-dose cytarabine (see above) for four consolidation cycles.
A study by Li et al of consolidation therapy in 45 patients with t(8;21) AML found that relapse-free survival (RFS) and overall survival (OS) were significantly higher with four courses of fludarabine plus cytarabine, compared with four courses of high-dose cytarabine, especially in patients without c-kit mutations. At 36 months, RFS for patients without c-kit mutations was 100% in those who received fludarabine plus cytarabine, compared with 57.8% in those who received high-dose cytarabine (P = 0.005); OS was 100% and 51.4%, respectively (P = 0.004).[51]
Alternatively, autologous HCT can be given after (typically) one or two cycles of consolidation therapy. Allogeneic HCT should be reserved for patients who relapse. Other patients who are considered low risk for relapse and in whom a non-transplant approach could be considered include those with isolated NPM1 or biallelic CEBPA mutations
Most other patients have less than a 50% chance of cure with consolidation chemotherapy and should thus be considered for allogeneic HCT. Newer techniques for patients without sibling or unrelated donors (cord blood and haploidentical transplants) have increased the percentage of patients who have an appropriate donor and are thus eligible for such an approach.
Hematopoietic stem cell transplantation in younger patients
The American Society for Blood and Marrow Transplantation (ASBMT) considers that in patients with AML who are under age 55, allogeneic HCT offers no survival advantage for those with low-risk cytogenetics who are in first clinical remission, but does offer a survival advantage versus chemotherapy for those with high-risk cytogenetics.[52]
In patients younger than 60 years, National Comprehensive Cancer Network (NCCN) guidelines recommend matched sibling or alternate donor HCT as an option in the following situations[25] :
Before referral for allogeneic HCT, a suitable donor must be identified. Ideally, this is a fully HLA-matched sibling; however, many patients do not have such a donor. In those patients, alternatives include transplantation using a matched unrelated donor or using cord blood. Newer studies are examining the possibility of transplanting across HLA barriers (ie, with haploidentical-related donors) via intensive conditioning regimens and high doses of infused CD34+ donor cells.
In September 2017, the FDA approved gemtuzumab ozogamicin (Mylotarg) for the treatment of adults with newly diagnosed AML whose tumors express the CD33 antigen (CD33-positive AML). The FDA also approved gemtuzumab ozogamicin for the treatment of relapsed or refractory CD33-positive AML in patients aged 2 years and older.[53]
Gemtuzumab ozogamicin originally received accelerated approval in May 2000 as a stand-alone treatment for relapsed CD33-positive AML in older patients, but was voluntarily withdrawn from the market after subsequent confirmatory trials failed to verify clinical benefit. The September 2017 approval includes a lower recommended dose, a different treatment schedule, and a new patient population.[53]
The approval is based on data from several trials, including the ALFA-0701 and AML-19 trials. The multicenter, open-label phase III ALFA-0701 trial randomized 271 patients with newly-diagnosed AML to daunorubicin and cytarabine alone or combined with gemtuzumab ozogamicin. Gemtuzumab at 3 mg/m2 was administered on days 1, 4, and 7 during induction and day 1 of each of the 2 consolidation chemotherapy courses. The primary endpoint was event-free survival (EFS) with a secondary endpoint of overall survival (OS). Gemtuzumab ozogamicin was associated with a statistically significant improvement in EFS of 7.8 months. However, the drug was not associated with a significant improvement in OS.[54]
In the open-label phase III study AML-19, elderly patients who could not tolerate other AML treatments were randomized to gemtuzumab ozogamicin (n=118) or best supportive care (n=119). Gemtuzumab ozogamicin was initially administered at 6 mg/m2 on day 1 and 3 mg/m2 on day 8. Patients without evidence of disease progression then received the drug at 2 mg/m2 on day 1 every 4 weeks. Patients received a single course of gemtuzumab ozogamicin. The trial measured how many patients achieved a complete remission. Following treatment with gemtuzumab ozogamicin, 26% of patients achieved a complete remission that lasted a median 11.6 months.[55]
NCCN guidelines also recommend the following targeted therapies for patients who are not candidates for intensive remission induction therapy or who decline intensive therapy[25] :
Overall, the results of treatment of AML in elderly patients (particularly those older than 75 years) remain unsatisfactory. In a Cancer and Leukemia Group B (CALGB) study, patients older than 60 years had a complete remission rate of 47% after standard therapy. There were 31% aplastic deaths, and only 9% of patients were alive at 4 years. It should be noted that patients with antecedent hematologic disorders were excluded; accordingly, these results overestimate the benefit of chemotherapy in elderly patients.
Many patients are never referred for treatment, because of serious comorbid medical conditions and the knowledge that the treatment results are poor in this group of patients. For example, an analysis by Menzin et al of Medicare claims for treatment of AML found that only 30% of patients received chemotherapy (44% of patients aged 65-74 y, 24% of patients aged 75-84 y, and only 6% of patients 85 y or older).[56]
Despite the low rate of chemotherapy use in these patients, approximately 90% of them were hospitalized, and the patients spent approximately one third of their remaining days in the hospital. Therefore, novel treatments need to be developed for this patient population.[56]
There is evidence that patients who are treated have longer survival than those who are not treated. In the study by Menzin et al, the median survival was 6.1 months for patients who received chemotherapy versus 1.7 months for those who did not.[56]
Similarly, Lowenberg et al reported a median survival of 21 weeks for elderly patients randomized to therapy compared with 11 weeks for patients randomized to a “watch and wait” approach.[57] In a Medical Research Council study, the median survival was significantly improved for patients who received low dose ara-C as opposed to hydroxyurea.
In November 2018, the FDA approved glasdegib, a hedgehog pathway inhibitor, for newly diagnosed AML. It is indicated in adults aged 75 years or older, or adults who have comorbidities that preclude use of intensive induction chemotherapy in combination with low-dose cytarabine. Approval was based on the ongoing phase 2 BRIGHT 1003 study that evaluated glasdegib combined with low-dose cytarabine or cytarabine alone. Median OS was 8.8 months for patients treated with glasdegib plus cytarabine compared with 4.9 months for cytarabine alone. This difference represented a nearly 50% reduction in the risk of death for patients treated with glasdegib plus cytarabine.[58]
Similarly, venetoclax gained accelerated approval for AML in November 2018 for treatment of newly diagnosed AML in adults aged 75 years or older, or adults who have comorbidities that preclude use of intensive induction chemotherapy. It is used in combination with azacytidine or decitabine or low-dose cytarabine. Venetoclax is a selective inhibitor of the B-cell lymphoma 2 (Bcl-2) regulator protein. BCL-2 overexpression has been demonstrated in AML cells, where it mediates tumor cell survival and has been associated with resistance to chemotherapeutics.
The accelerated approval of venetoclax was based on data from the phase 1b M14-358 and phase 1-2 M14-387 dose escalation and expansion studies. In the M14-358 study, complete remission was 37% (N=25/67) in the venetoclax plus azacitidine group and 54% (N=7/13) in the venetoclax plus decitabine group.[59] In the M14-387 study, the complete remission rate was 21% (N=13/61) for patients receiving venetoclax plus low-dose cytarabine.[60]
The hypomethylating agents azacytidine and decitabine are the therapies most commonly prescribed for elderly patients with AML. Although response rates are low, these drugs are well tolerated and can result in prolonged remissions in some patients. Additionally, hypomethylators are active in AML subtypes that typically respond poorly to standard chemotherapy, including those with complex cytogenetics and TP53 mutations.[61] In a study of azacytidine treatment in 149 previously untreated AML patients (median age, 74 years) who were considered ineligible for intensive chemotherapy, 2-year OS was 51% in responders to azacytidine and 10% in non-responders (P < 0.0001).[62]
A randomized, open-label, phase III trial in 488 patients age ≥65 years with newly diagnosed AML with > 30% bone marrow blasts reported a 1-year survival rate of 46.5% with azacitidine versus 34.2% with conventional care regimens.[63] In a study of azacitidine treatment in 130 AML patients older than 50 years (median age, 67 years) who had experienced relapse or induction failure with intensive chemotherapy, the overall response rate was 17% (complete response [CR], 10%, CR with incomplete platelet or neutrophil count recovery [CRi], 7%).[64]
A systematic review and meta-analysis by He at al of nine published studies that enrolled 718 elderly AML patients concluded that decitabine is an effective and well-tolerated therapeutic alternative with acceptable side effects in this patient population.[65] Pooled estimates (and 95% confidence index) were as follows:
A meta-analysis by Bian et al of 38 studies (3298 AML patients) in elderly patients with AML compared decitabine with several traditional chemotherapy regimens, including intensive therapy and low-dose cytarabine and found that the response rate to decitabine was better than those observed with other treatments, albeit with similar rates of infection and early death. Decitabine combined with other regimens achieved a CR rate of 46% and an OR rate of 75%.[66]
A retrospective single-institution study by Talati et al of survival outcomes in 980 elderly (≥70 years) AML concluded that hypomethylating agents (ie, azacytidine, decitabine) provided a significant survival benefit, compared with high-intensity, low-intensity, or supportive care.[67] Median OS rates were as follows:
Some older patients do reasonably well with standard therapy. In an analysis of 998 older patients treated at MD Anderson Cancer Center, the following factors were associated with an adverse outcome:[68]
Patients with none of those risk factors had a complete remission rate of 72%, 8-week mortality of 10%, and median 2-year survival of 35%, whereas patients with 3 or more risk factors had a complete remission rate of 24%, an 8-week mortality of 57%, and a median 2-year survival of only 3%.[68] Thus, some low-risk elderly patients can benefit from standard intensive chemotherapy.
A study in elderly patients with newly diagnosed AML compared conventional-dose daunorubicin (45 mg/m2/d for 3 d) with high-dose daunorubicin (90 mg/m2/d for 3 d).[43] These regimens were administered with cytarabine 200 mg/m2/d for 7 days for the first cycle. A second cycle of cytarabine alone (1000 mg/m2/d for 6 d) was also administered. Complete remission occurred in 64% in the high-dose daunorubicin group compared with 54% in the conventional-dose group[43] ; remission after the first cycle was 52% in the high-dose daunorubicin group compared with 35% in the conventional-dose group.
Older patients with AML with myelodysplasia-related changes are eligible for liposomal cytarabine and daunorubicin (Vyxeos). In the registration study, which also included patients with therapy-related AML, 309 patients aged 60-75 years received the liposomal combination product or cytarabine and daunorubicin given separately, in the 3+7 regimen. The CR or CRi rate was 47.7% for the combination, compared with 33.3% for 3+7. OS at 12 and 24 months for the fixed-dose combination was 41.5% and 31.1%, respectively, compared with OS of 27.6% and 12.3% with 3+7.[69]
In May 2019, the FDA expanded use of ivosidenib for AML to include newly-diagnosed IDH1-mutated AML in adults aged 75 years or older, or adults who have comorbidities that preclude use of intensive induction chemotherapy. Approval was based on an open-label, single-arm, multicenter clinical trial (AG120-C-001, NCT02074839) that included 28 adult patients with newly-diagnosed AML with an IDH1 mutation. Efficacy was based on the rate of complete remission (CR) or complete remission with partial hematologic recovery (CRh), the duration of CR+CRh, and the conversion rate from transfusion dependence to transfusion independence. Twelve (42.9%) of the 28 achieved CR+CRh (95% CI: 24.5, 62.8), and 7 (41.2%) of the 17 transfusion-dependent patients achieved transfusion independence lasting at least 8 weeks.[70]
Other therapies are being studied in older patients who are not candidates for intensive chemotherapy.[71] As part of the National Cancer Research Institute Acute Myeloid Leukemia 14 Trial, 217 patients who were deemed unfit for intensive chemotherapy were randomized to receive low-dose cytarabine (20 mg twice daily for 10 d) or hydroxyurea with or without all-trans retinoic acid (ATRA). Low-dose cytarabine produced a better remission rate (18% vs 1%; P = 0.00006) and better OS (odds ratio, 0.60; P = 0.0009). OS was 80 weeks for patients achieving CR verus 10 weeks for patients with no remission.[72]
Clofarabine is a purine analogue that is approved by the FDA for the treatment of relapsed pediatric acute lymphocytic leukemia (ALL). A study of clofarabine and cytarabine in newly diagnosed patients with AML who were 50 years or older yielded a complete response rate of 52% and a CRi rate of 8%. Induction deaths occurred in 7% of patients.[73]
No standard consolidation therapy exists for patients older than 60 years. Options include a clinical trial, high-dose ara-C in select patients, or repeat courses of standard-dose anthracycline and cytarabine (2 and 5; ie, 2 d of anthracycline and 5 d of cytarabine). Select patients can be considered for autologous stem cell transplantation or nonmyeloablative allogeneic transplantation.
Hematopoietic stem cell transplantation
Although allogeneic HCT is a potentially curative treatment option for patients with AML, the risk of death increases with age. Fit elderly patients are candidates for reduced-intensity conditioning and nonmyeloablative transplants.[74, 75, 76, 77] Reduced-intensity and nonmyeloablative regimens feature the use of the purine analog fludarabine and lower doses of alkylating agents or total body irradiation (TBI). Nonmyeloablative regimens may cause only minimal cytopenias that do not require stem cell support, whereas reduced-intensity regimens do require stem cell support.[78]
A study in 190 patients age 60-70 years with AML in first remission reported lower risk of relapse and longer leukemia-free survival with reduced-intensity allogeneic HCT than with induction and postremission chemotherapy using CALGB protocols. At 3 years, risk of relapse was 32% vs 81%, respectively (P < 0.001) and leukemia-free survival was 32% vs 15% (P = 0.001); however, nonrelapse mortality was higher with transplantation (36% vs 4% at 3 years; P < 0.001).[79]
For patients 60 years of age or older who have residual disease after standard-dose cytarabine, the National Comprehensive Cancer Network (NCCN) recommends reduced-intensity HCT as an option. Reduced-intensity HCT is also an option for post-remission therapy in patients with a complete response to intensive therapy. Allogeneic HCT, preferably in a clinical trial, can be considered in patients with induction failure after previous intensive therapy.[25]
Patients who develop AML as a complication of conventional chemoradiotherapy for a primary malignancy have traditionally had a poor prognosis, with a median survival of only 6 months. Allogeneic HCT has generally been recommended because these cases respond poorly to traditional chemotherapy.[80]
In August 2017, the FDA approved a fixed-dose combination of cytarabine and daunorubicin liposomal (CPX-351; Vyxeos) for newly diagnosed therapy-related AML and AML with myelodysplasia-related changes. Approval was based on a phase III trial in 309 patients aged 60-75 years that evaluated the efficacy and safety of the combination product with cytarabine and daunorubicin given separately in the 3+7 regimen (daunorubicin, 60 mg/m2 on days 1, 2, and 3; cytarabine, 100 mg/m2/day x 7 days;).[69]
The CR or CRi rate was 47.7% for the combination compared with 33.3% for 3+7. For CR alone, the rates were 37.3% for the combination and 25.6% percent for 3+7. OS at 12 and 24 months for the fixed-dose combination was 41.5% and 31.1%, respectively, compared with 3+7 OS of 27.6% and 12.3%.[69]
In an exploratory analysis of the phase III study for those with secondary untreated AML, 34 of the 52 patients (65%) in the fixed-dose combination arm who proceeded to transplant remained alive after a median follow-up of 521 days. In the 3+7 arm, after 442 days of follow-up, 13 of 39 patients remained alive (33%).[69]
The principal role for CPX-351 appears to be in patients with a history of myelodysplastic syndrome who were never treated with a hypomethylating agent (eg, azacitidine, decitabine). In these patients, the combination may not only improve outcome but increase eligibility for transplantation. Adverse effects of CPX-351 are the same as with the standard 3+7 regimen, so for unfit/elderly patients, hypomethylating agents remain the preferred therapy.[81]
APL is a special subtype of AML. It differs from other subtypes of AML in that patients are, on average, younger (median age 40 y) and most often present with pancytopenia rather than with elevated white blood cell (WBC) counts. In fact, WBC counts higher than 5000 cells/µL at presentation are associated with a poor prognosis.
APL is also the subtype of AML that is most commonly associated with coagulopathy due to disseminated intravascular coagulation (DIC) and fibrinolysis. Therefore, aggressive supportive care is an important component of the treatment of APL. Platelets should be transfused to maintain a platelet count of at least 30,000/µL (preferably 50,000/µL). Administer cryoprecipitate to patients whose fibrinogen level is less than 100 mg/dL.
There are two histologic subtypes of APL: hypergranular and hypogranular. In both cases the bone marrow contains atypical promyelocytes that have bilobed nuclei. In the hypergranular variant the cells contain large dense cytoplasmic granules, sheets of fine granules, and/or varying numbers of Auer rods. In the hypogranular variant granules are nearly absent and the cytoplasm has a pale appearance.
Although the initial diagnosis of APL is based on morphology, the diagnosis is confirmed on the basis of cytogenetic and molecular studies. Do not delay treatment pending the results of confirmatory tests.
In more than 95% of cases of APL, cytogenetic testing reveals t(15;17)(q21;q11). Molecular studies reveal the PML/RARa rearrangement. Patients with either t(15;17) or the PML/RARa rearrangement respond well to all-trans-retinoic acid (ATRA) and chemotherapy.
A small percentage of patients have other cytogenetic abnormalities, including t(11;17)(q23;q11), t(11;17)(q13;q11), t(5;17)(q31;q11), or t(17;17). Patients with t(11;17)(q23;q11) are resistant to ATRA. Older studies using standard chemotherapy regimens without ATRA showed that approximately 70% of patients achieved complete response and 30% were disease free at 5 years. Induction failures were due to deaths resulting from hemorrhage caused by DIC, with few actual resistant cases.[82, 83, 84]
In the 1980s, reports from China, France, and the United States demonstrated that most patients with APL could enter remission with ATRA as the single agent. Unfortunately, in the absence of further therapy, these remissions were short-lived.
In addition, a new toxicity, the retinoic acid syndrome, was discovered.[85] The retinoic acid syndrome results from differentiation of leukemic promyelocytic cells into mature polynuclear cells and is characterized by fever, weight gain, pleural and pericardial effusions, and respiratory distress. The syndrome occurs in approximately 25% of patients, and, in the past, was fatal in 9%. Subsequently, the early addition of chemotherapy (idarubicin and cytarabine) resulted in a reduction of deaths caused by retinoic acid syndrome.
In a US Intergroup study, 346 patients with previously untreated APL received either ATRA or daunorubicin plus cytarabine as induction therapy[86] . Patients in remission then received a second cycle of the same therapy as their induction, followed by one cycle of high-dose cytarabine plus daunorubicin. Patients then underwent a second randomization to either ATRA maintenance or observation. In this study ATRA as either induction or maintenance improved disease-free and overall survival compared with chemotherapy (3 year overall survival 67% for ATRA versus 55% for chemotherapy (P=0.003). Using this approach, as many as 70% of these patients are long-term survivors.[87]
European groups proposed that cytarabine was not necessary in induction therapy for newly diagnosed patients.[88] The GIMEMA AIDA regimen (ie, ATRA 45 mg/m2 daily combined with idarubicin 12 mg/m2 on days 2, 4, 6, and 8 until remission) yielded remissions in 95% of patients.
However, a randomized study from France questioned this approach.[88] Newly diagnosed APL patients younger than 60 years with a WBC count of less than 10,000/µL were randomly assigned to receive either ATRA combined with and followed by three courses of daunorubicin plus cytarabine and a 2-year maintenance regimen (cytarabine group) or the same treatment but without cytarabine (no-cytarabine group).
Patients older than 60 years and patients with an initial WBC count of greater than 10,000/μL were not randomly assigned but received risk-adapted treatment, witha higher dose of cytarabine and central nervous system (CNS) prophylaxis in patients with WBC counts greater than 10,000/μL. Overall, 328 (96.5%) of 340 patients achieved complete remission.
In the cytarabine and the no-cytarabine groups, the complete remission rates were 99% for the ara-C arm and 94% for the no-cytarabine arm, the 2-year cumulative incidence of relapse (CIR) rates were 4.7% in those who received cytarabine and 15.9% in those who did not receive cytarabine, the event-free survival rates were 93.3% in the cytarabine group and 77.2% in the no-cytarabine group, and survival rates were 97.9% in patients who received cytarabine and 89.6% in those who received no cytarabine.
In patients younger than 60 years with WBC counts more than 10,000/μL, the complete response rate was 97.3%, 2-year cumulative incidence of relapse (CIR) was 2.9%, event-free survival was 89%, and the survival rate was 91.9%.
After studies from China demonstrated that arsenic trioxide was highly active against APL cells in vitro,[89] clinical trials demonstrated that arsenic trioxide resulted in high response rates in patients with relapsed disease.[90, 91] Arsenic trioxide was then moved into the frontline setting, first in combination with standard chemotherapy and then without chemotherapy.
A North American Intergroup study compared the addition of two cycles of consolidation therapy with arsenic trioxide followed by two cycles of chemotherapy with cytarabine and daunorubicin to consolidation with two cycles of cytarabine and daunorubicin chemotherapy without arsenic trioxide.[92] Event-free survival, the primary endpoint, was 77% at 3 years in the arsenic trioxide arm (median not reached) compared with 59% at 3 years in the standard arm (median, 63 mo).
Overall, 84% of adults were alive at last follow-up. Overall survival was 86% at 3 years in the arsenic trioxide arm compared with 77% at 3 years in the standard arm (medians not reached). Maintenance therapy with ATRA, 6-mercaptopurine (6-MP), and methotrexate was effective in preventing relapses compared with no maintenance therapy; however, the optimal schedule of this therapy is not yet determined.
More recent trials have studied regimens utilizing ATRA plus arsenic trioxide without chemotherapy. Lo-Coco et al conducted a phase III randomized trial of ATRA plus chemotherapy verus ATRA plus arsenic trioxide in patients with APL classified as low-to-intermediate risk (WBC ≤10 x 109/L). Complete remission was achieved in 100% of patients in the ATRA-arsenic group and 95% of the ATRA-chemotherapy group. Two-year event-free survival rates were 97% for ATRA-arsenic and 86% for ATRA-chemotherapy group. Overall survival was better with ATRA-arsenic trioxide, largely due to a reduction in cytopenic deaths. Longer follow-up is needed to determine if long term cure rates will be the same.[93]
Current guidlines for treatment are as follows[25] :
Patients with relapsed AML have an extremely poor prognosis. Most patients should be referred for investigational therapies. Young patients who have not previously undergone transplantation should be referred for such therapy.
Estey et al reported that the chances of obtaining a second remission with chemotherapy correlate strongly with the duration of the first remission.[94] Patients with an initial complete response (CR) duration of longer than 2 years had a 73% complete response rate with initial salvage therapy. Patients with an initial complete response duration of 1-2 years had a complete response rate of 47% with initial salvage therapy.
Patients with an initial complete response duration of less than 1 year or with no initial complete response had a 14% complete response rate with initial salvage therapy. Patients with an initial complete response duration of less than 1 year (or no initial complete response) who had no response to first-salvage therapy and received a second or subsequent salvage therapy had a response rate of 0%. These data underscore the need to develop new treatment options for these patients.
Response to third-line therapy is even worse. Giles et al studied 594 patients with AML undergoing second salvage therapy from 1980 to 2004.[95] The patient median age was 50 years. Salvage therapy included allogeneic stem cell transplantation (SCT), standard-dose cytosine arabinoside (ara-C) combinations, high-dose ara-C combinations, non–ara-C combinations, and phase I-II single agents. Overall, 76 patients (13%) achieved CR. The median CR duration was 7 months. The median survival was 1.5 months, and the 1-year survival rate was 8%. A multivariate analysis identified the following 6 independent adverse prognostic factors:
Owing to the poor outcome with salvage therapy, it is important to refer patients for well-designed clinical trials whenever possible. For patients who are unable to participate in a clinical trial, but are able to tolerate aggressive therapy, options include the following[25] :
For patients who require less aggressive therapy, possible regimens include hypomethylating agents (5-azacytidine or decitabine) or low-dose cytarabine.
Targeted therapeutic options for AML include the following[25] :
In November 2018, the FDA approved gilteritinib (Xospata), an orally administered multiple tyrosine kinase inhibitor, for treatment of adults with relapsed or refractory AML that has an FLT3 mutation. Gilteritinib inhibits multiple receptor tyrosine kinases, including FMS-like tyrosine kinase 3 (FLT3). It inhibits FLT3 receptor signaling and proliferation in cells exogenously expressing FLT3. Gilteritinib also induces apoptosis in leukemic cells expressing FLT3-ITD.
Approval of gilteritinib was based on interim analysis of the ADMIRAL clinical trial, a phase 3 open-label, multicenter, randomized study comparing gilteritinib with salvage chemotherapy. Salvage chemotherapy consisted of low-dose cytarabine or azacitidine, MEC (mitoxantrone, etoposide, and intermediate-dose cytarabine), or FLAG-IDA (fludarabine, cytarabine, G-CSF, and idarubicin).[97]
Final results of ADMIRAL demonstrated significant superiority of gilteritinib over salvage chemotherapy. Patients randomized to gilteritinib had significantly longer overall survival (9.3 months, versus 5.6 months with salvage chemotherapy; hazard ratio [HR] for death = 0.637; P=0.0007), as well as 1-year survival (37.1% versus 16.7%, respectively).[98, 99]
In August 2017, enasidenib—an oral, selective inhibitor of mutant-IDH2 enzymes—was approved by the FDA for treatment of relapsed/refractory IDH2-mutated AML. The approval was based on data from a phase I/II dose-escalation and expansion study (AG221-C-001) in which enasidenib proved safe and well tolerated, and induced hematologic responses. Median overall survival (OS) with enasidenib was 9.3 months. In those achieving a CR, the median OS was 19.7 months and in the non-CR responders the median OS was 13.8 months. In those without a response, the median OS was 7 months.96 A second IDH inhibitor, ivosidenib, was approved for IDH2-mutated AML in 2018.[100]
In September 2017, the FDA approved gemtuzumab ozogamicin (Mylotarg) for the treatment of patients aged 2 years and older with relapsed or refractory AML whose tumors express the CD33 antigen (CD33-positive AML).[53] The dosage for these patients is 3 mg/m2 on days 1, 4 and 7. Differences in CD33 expression (with lower levels seen in cases with adverse karyotype and core-binding factor AML, and higher expression seen in AML with mutations in FLT3, MLL or NPM1) and CD33 splicing polymorphisms are factors influencing response rates[101]
Chimeric antigen receptor (CAR) T-cell therapy is being studied for use in AML that relapses after allogeneic HCT. More than 20 clinical trials of CAR T-cell therapy in patients with AML are currently in progress. In most of those trials, the target antigens are CLL-1, CD33, or CD123.[102]
Patients with AML have a deficiency in the ability to produce normal blood cells and, therefore, need replacement therapy. The addition of chemotherapy temporarily worsens this deficiency. All blood products should be irradiated to prevent transfusion-related graft versus host disease, which is almost invariably fatal.
Packed red blood cells are given when the hemoglobin concentration is lower than 7-8 g/dL or at a higher level if the patient has significant cardiovascular or respiratory compromise.
Platelets should be transfused if the platelet count is lower than 10,000-20,000/µL. Patients with pulmonary or GI hemorrhage should receive platelet transfusions to maintain a value greater than 50,000/µL. Patients with CNS hemorrhage should be transfused until they achieve a platelet count of 100,000/µL. Patients with APL should have their platelet count maintained above 50,000/µL, at least until evidence of DIC has resolved.
Fresh frozen plasma (FFP) should be given to patients with a significantly prolonged prothrombin time, and cryoprecipitate should be given if the fibrinogen level is less than 100 g/dL.
Intravenous (IV) antibiotics should be given to all febrile patients. At a minimum, antibiotics should include broad-spectrum coverage, such as that provided by a third-generation cephalosporin with or without vancomycin. In addition to this minimum, additional antibiotics should be given to treat specific documented or suspected infections.
Patients with persistent fever should be evaluated for an alternate source of infection. Persistent fever can be due to fungal infections, viral infections (including cytomegalovirus [CMV]), Clostridium difficile, and resistant bacteria such as vancomycin-resistant enterococcus, bacteria with extended spectrum beta-lactamases, and carbapenem-resistant Enterobacteriaceae. Evaluation of persistent fever should include CT scans of the chest, abdomen, pelvis and sinuses, fungal markers (aspergillus antigen and Fungitell), and other tests depending on the symptoms of the patient. Empiric antifungal therapies include the following:
Prophylactic antibiotics are usually used in nonfebrile patients undergoing intensive chemotherapy. Both the National Comprehensive Cancer Network (NCCN) and Infectious Diseases Society of America (IDSA) guidelines strongly recommend antifungal prophylaxis in this group of patients. The following combination regimen is commonly used for prophylaxis:
In a randomized trial of posaconazole versus either fluconazole or itraconazole (selected on the basis of local practice) in patients with AML and myelodysplastic syndrome undergoing intensive chemotherapy, posaconazole proved more effective at preventing invasive fungal infections, including invasive asperglilosis. In addition, all-cause mortality at day 100 was significantly lower in patients who received posaconazole. However, serious adverse events possibly or probably related to treatment occurred more frequently in the posaconazole group.[103]
Once patients receiving oral antibiotic prophylaxis become febrile, the regimen is changed to IV agents, as indicated above.
Allopurinol 300 mg should be given 1-3 times a day during induction therapy until the clearance of blasts and resolution of hyperuricemia. For patients who cannot tolerate oral medications, IV drugs such as rasburicase are an option. Rasburicase should be administered to patients at high risk of severe tumor lysis, including those with very high white blood counts, very high lactate dehydrogenase [LDH] levels, and/or baseline renal insufficiency.
Several randomized studies have been performed that attempted to determine the effect of growth factors on induction therapy.
In an early Japanese study, patients with poor-risk acute leukemia randomly received either granulocyte olony-stimulating factor (G-CSF) derived from Escherichia coli or no drug. Patients in the G-CSF group had a faster neutrophil recovery (20 d) than those receiving no drug (28 d), fewer febrile days (3 vs 7 d, respectively), and fewer documented infections.[104] No significant difference in response rate or remission duration was observed between the 2 groups.
In a French study of G-CSF, the duration of neutropenia was shorter in the G-CSF arm (21 d) than in the placebo arm (27 d), and the complete response rate was higher in those who received G-CSF (70%) than in those who received placebo (47%); however, the overall survival rate was unaffected.[105]
In a Southwestern Oncology Group (SWOG) study, a decrease was observed in the time to neutrophil recovery and days with fever in those who received G-CSF; however, no difference in complete remission rate and overall survival rate was observed for patients receiving G-CSF versus no drug.[106]
Other groups have studied the effect of granulocyte macrophage colony-stimulating factor (GM-CSF) on induction therapy.
In an Eastern Cooperative Oncology Group (ECOG) study of yeast-derived GM-CSF in elderly patients with AML, no significant increase in induction chemotherapy response rate was observed; however, a significant decrease in the death rate from pneumonia and fungal infection was observed.[107] Neutrophil recovery rate was increased in the GM-CSF group (14 d vs 21 d, respectively), and overall survival was significantly improved (323 d vs 145 d, respectively).[107]
In a CALGB study of GM-CSF derived from E coli, no difference was observed in induction chemotherapy response rates between the GM-CSF group and the placebo group.[108] The risk of severe infection and resistant leukemia was similar in the 2 groups. However, in an EORTC study using GM-CSF derived from E coli, patients who randomly received GM-CSF after induction had a significantly lower complete rate (48%) than those who did not receive GM-CSF (77%).[109]
These data suggest that G-CSF and yeast-derived GM-CSF accelerate neutrophil recovery and decrease the risk of infection in patients who are undergoing induction therapy.[109] For this reason, most clinicians use either of these growth factors in patients who are at high risk for complications from infection.
Placement of a central venous catheter (eg, triple lumen, Broviac, Hickman) is necessary. Caution should be used in patients with severe DIC (APL); nevertheless, proper access is needed to administer the needed blood products in a timely fashion.
Patients with AML should follow a neutropenic diet (ie, no fresh fruits or vegetables). All foods should be cooked. Meats should be cooked completely (ie, well done).
Patients should limit their activity to what is tolerable. They should refrain from strenuous activities (eg, lifting, exercise).
Patients should come to the office for monitoring of disease status and chemotherapy effects. Guidelines from the National Comprehensive Cancer Network (NCCN) recommend that after completion of consolidation therapy for AML, patients should undergo surveillance with a complete blood cell count every 1–3 months for 2 years, then every 3–6 months up to 5 years. The NCCN recommends a bone marrow aspirate and biopsy only if a peripheral smear is abnormal or cytopenias develop.[25]
Guidelines on the initial diagnostic workup of acute leukemia (AL) have been issued by the College of American Pathologists and the American Society of Hematology (CAP/ASH).[110]
Guidelines for the management of acute myeloid leukemia (AML) have been issued by the following organizations:
CAP/ASH guidelines on the initial diagnostic workup of AL include the following recommendations[110] :
Both the NCCN and ESMO guidelines recommend including the following tests in the diagnostic workup for AML[25, 111] :
ESMO guidelines include the following additional tests to the diagnostic workup for all patients[111] :
Although not specifically mentioned in the NCCN guidelines, sperm preservation and pregnancy testing are standard practice in the United States.
The NCCN further recommends the following tests if neurologic symptoms are present[25] :
Many commonly used induction regimens contain an anthracycline or anthracenedione. Therefore, assessment of cardiac risk factors and assessment of myocardial function (by echocardiogram or multigated acquisition [MUGA] scan) are a standard part of the diagnostic workup.[25, 111]
The risk pattern in AML is determined not only by cytogenetic abnormalities (eg, chromosomal translocations, deletions, or duplications) but also by molecular mutations that lead to over- or under-expressions of proteins.[25] See Table 3, below.
Table 3 AML Cytogenetic Risk Factors – National Comprehensive Cancer Network
View Table | See Table |
The ESMO risk classifications vary slightly from those of the NCCN.[111] See Table 4, below.
Table 4 AML Cytogenetic Risk Factors – European Society of Medical Oncology
View Table | See Table |
According to both guidelines, the finding of a translocation between chromosomes 15 and 17, or t(15;17), is associated with a diagnosis of acute promyelocytic leukemia (APL), an AML subtype that is treated and monitored differently than other subtypes.[25, 111]
Both the NCCN and the ESMO guidelines are in agreement with the following general recommendations for treatment[25, 111] :
The NCCN guidelines give more detailed recommendations based on patient characteristics such as age, presence of comorbid conditions affecting performance status, and preexisting myelodysplasia. For patients with Among the recommendations is that patients with poor performance status, significant comorbities, and/or advanced age (ie, some patients ≥ 60 years old and most patients ≥ 70 years old) should receive low-intensity therapy or supportive care if a clinical trial is not available.
The NCCN guidelines recommend that all patients receive supportive care that includes the following[25] :
For individuals receiving treatment for APL, the supportive care recommendations also include the following:
The NCCN recommends that the following not be used in APL patients:
Medications used for the treatment of acute myeloid leukemia (AML) cause severe bone marrow depression. Only physicians specifically trained in their use should use these agents. In addition, access to appropriate supportive care (ie, blood banking) is required.
Clinical Context: Azacitidine is a pyrimidine nucleoside analog of cytidine. It interferes with nucleic acid metabolism. It exerts antineoplastic effects by DNA hypomethylation and direct cytotoxicity on abnormal hematopoietic bone marrow cells. Hypomethylation may restore normal function to genes critical for cell differentiation and proliferation. Nonproliferative cells are largely insensitive to azacitidine. It is indicated to treat myelodysplastic syndromes (MDSs) and is FDA approved for all 5 MDS subtypes.
Clinical Context: Cytarabine is an antimetabolite specific for cells in the S-phase of the cell cycle. It acts through inhibition of DNA polymerase and cytosine incorporation into DNA and RNA.
Clinical Context: Daunorubicin is a topoisomerase-II inhibitor. It inhibits DNA and RNA synthesis by intercalating between DNA base pairs.
Clinical Context: Idarubicin is a topoisomerase-II inhibitor. It inhibits cell proliferation by inhibiting DNA and RNA polymerase.
Clinical Context: Mitoxantrone inhibits cell proliferation by intercalating DNA. It inhibits topoisomerase II.
Clinical Context: Arsenic trioxide is used in patients with relapsed acute promyelocytic leukemia (APL). Its mechanism of action is not completely understood. Arsenic trioxide causes morphologic changes and DNA fragmentation that are characteristic of apoptosis in NB4 human promyelocytic leukemia cells in vitro. Arsenic trioxide also causes damage or degradation of the fusion protein PML-RAR alpha.
Clinical Context: Fludarabine contains fludarabine phosphate, a fluorinated nucleotide analog of the antiviral agent vidarabine, 9-b-D-arabinofuranosyladenine (ara-A), that enters the cell and is phosphorylated to form the active metabolite 2-fluoro-ara-ATP, which inhibits DNA synthesis. It is also incorporated into RNA, causing inhibition of RNA and protein synthesis; however, its primary effect may result from activation of apoptosis. It is also relatively resistant to deamination by adenosine deaminase.
The dosage may be decreased or delayed based on evidence of hematologic or nonhematologic toxicity. Physicians should consider delaying or discontinuing the drug if neurotoxicity occurs. The optimal duration of treatment is not clearly established. It is recommended that 3 additional cycles of fludarabine be administered following the achievement of maximal response, and then the drug should be discontinued.
Clinical Context: Cyclophosphamide is a cyclic polypeptide that suppresses some humoral activity. It is chemically related to nitrogen mustards and is activated in the liver to its active metabolite, 4-hydroxycyclophosphamide, which alkylates the target sites in susceptible cells in an all-or-none type of reaction. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with the growth of normal and neoplastic cells.
It is biotransformed by cytochrome P450 system to hydroxylated intermediates that break down to active phosphoramide mustard and acrolein. The interaction of phosphoramide mustard with DNA is considered cytotoxic.
When cyclophosphamide is used in autoimmune diseases, the mechanism of action is thought to involve immunosuppression due to destruction of immune cells via DNA cross-linking.
In high doses, it affects B cells by inhibiting clonal expansion and suppression of the production of immunoglobulins. With long-term, low-dose therapy, it affects T-cell functions.
Clinical Context: Cladribine is a synthetic antineoplastic agent for continuous IV infusion. The enzyme deoxycytidine kinase phosphorylates this compound into an active 5+-triphosphate derivative, which, in turn, brakes DNA strands and inhibits DNA synthesis. It disrupts cell metabolism, causing death to resting and dividing cells.
Clinical Context: Decitabine is a hypomethylating agent believed to exert antineoplastic effects by incorporating into DNA and inhibiting methyltransferase, resulting in hypomethylation. Hypomethylation in neoplastic cells may restore normal function to genes critical for cellular control of differentiation and proliferation. It is indicated for myelodysplastic syndromes (MDSs), including previously treated and untreated, de novo, and secondary MDSs of all French-American-British (FAB) subtypes (ie, refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, chronic myelomonocytic leukemia) and International Prognostic Scoring System (IPSS) groups intermediate-1 risk, intermediate-2 risk, and high risk.
Clinical Context: Fixed-dose combination of liposomal bound cytarabine and daunorubicin that delivers the 2 medications in a 5:1 molar ratio. The combination has been shown to have synergistic effects at killing leukemia cells in vitro and in murine models. It is indicated for newly diagnosed therapy-related AML (t-AML) and AML with myelodysplasia-related changes (AML-MRC).
Clinical Context: Gemtuzumab ozogamicin binds to CD33 antigen, an antigen expressed on the surface of leukemic blasts in more than 80% of AML patients. Binding of the anti-CD33 antibody portion of gemtuzumab with the CD33 antigen results in the formation of a complex that is internalized. Upon internalization, the calicheamicin derivative is released inside the lysosomes of the myeloid cell. The released calicheamicin derivative binds to DNA in the minor groove resulting in DNA double strand breaks and cell death.
Antineoplastic agents are used for induction or consolidation therapy. These agents inhibit cell growth and differentiation. They include cytarabine, daunorubicin, idarubicin, and mitoxantrone.
Clinical Context: Midostaurin and its major active metabolites inhibit FLT3 receptor signaling and cell proliferation, and it induced apoptosis in leukemic cells expressing ITD and TKD mutant FLT3 receptors or overexpressing wild type FLT3 and PDGF receptors. It is indicated in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy, for adults with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive, as detected by an FDA-approved test.
Clinical Context: Gilteritinib inhibits multiple receptor tyrosine kinases, including FMS-like tyrosine kinase 3 (FLT3). It inhibits FLT3 receptor signaling and proliferation in cells exogenously expressing FLT3. It is indicated for adults with AML with a FLT3 mutation who have relapsed or are refractory.
Tyrosine kinase inhibitors that target FLT3 mutations have been approved by the FDA to treat AML.[47, 97]
Clinical Context: Inhibits the SMO receptor, a transmembrane protein involved in Hh signal transduction, thereby disrupting the Hh pathway. It is indicated for newly diagnosed AML in adults aged 75 years or older, or adults who have comorbidities that preclude use of intensive induction chemotherapy in combination with low-dose cytarabine.
Smoothen (SMO) inhibition of Hedgehog (Hh) signaling impacts tumor biology by disrupting the regulation of cancer stem cell survival. This may inhibit development of drug resistance and prevent relapse.
Clinical Context: Selective inhibitor of the B-cell lymphoma 2 (Bcl-2) regulator protein, an antiapoptotic protein. Venetoclax helps restore the process of apoptosis by binding directly to Bcl-2 protein. It is indicated for newly diagnosed AML in adults aged 75 years or older, or adults who have comorbidities that preclude use of intensive induction chemotherapy. It is used in combination with azacytidine, or decitabine, or low-dose cytarabine.
Overexpression of Bcl-2 has been demonstrated in AML cells, where it mediates tumor cell survival and has been associated with resistance to chemotherapeutic agents.
Clinical Context: Enasidenib is a small molecule inhibitor of IDH-2 enzyme. Enasidenib targets mutant IDH2 variants (ie, R140Q, R172S, and R172K) at ~40-fold lower concentrations than the wild-type enzyme in vitro. It is indicated for adults with relapsed or refractory IDH2-mutated AML.
Clinical Context: IDH1 inhibitor; inhibits selected IDH1 R132 mutants at much lower concentrations than wild-type IDH1 in vitro. In blood samples from patients with AML with mutated IDH1, ivosidenib decreased 2-HG levels ex vivo, reduced blast counts, and increased percentages of mature myeloid cells. It is indicated for patients with susceptible IDH1 mutations who have relapsed or refractory AML. It is also indicated for newly-diagnosed IDH1-mutated AML in patients aged 75 y or older, or patients who have comorbidities that preclude use of intensive induction chemotherapy.
Clinical trials of inhibitors of isocitrate dehydrogenase (IDH) demonstrated decreased 2-hydroxyglutarate (2-HG) levels and induced myeloid differentiation in vitro and in vivo in mouse xenograft models of IDH mutated AML.
Marker Lineage CD13 Myeloid CD33 Myeloid CD34 Early precursor HLA-DR Positive in most AML, negative in APL CD11b Mature monocytes CD14 Monocytes CD41 Platelet glycoprotein IIb/IIIa complex CD42a Platelet glycoprotein IX CD42b Platelet glycoprotein Ib CD61 Platelet glycoprotein IIIa Glycophorin A Erythroid TdT Usually indicates acute lymphocytic leukemia, however, may be positive in M0 or M1 CD11c Myeloid CD117 (c-kit) Myeloid/stem cell
Translocation Genes Involved All-Trans-Retinoic Acid Response t(15;17)(q21;q11) PML/RARa Yes t(11;17)(q23;q11) PLZF/RARa No t(11;17)(q13;q11) NuMA/RARa Yes t(5;17)(q31;q11) NPM/RARa Yes t(17;17) stat5b/RARa Unknown
Risk Group Cytogenetic Abnormality Better Risk inv(16), t(16;16), t(8;21), t(15;17) Intermediate Risk Normal cytogenetics, +8 alone, t(9;11); other chromosomal abnormalities Poor Risk Complex (≥3 clonal chromosomal abnormalities)
Monosomal karyotype
-5, 5q-, -7, 7q-, 11q23 other than t(9;11), inv(3), t(3;3), t(6;9), t(9;22)
Risk Group Cytogenetic Abnormality Favorable inv(16), t(8;21), t(15;17) Biallelic CEBPα
mutation with normal cytogenetics
Normal karyotype with NPM mutation and no FLT3 ITDIntermediate Risk Normal cytogenetics and no adverse molecular features, FLT3 ITD with normal karyotype Adverse Risk Complex karyotype abnormalities (≥3 clonal chromosomal abnormalities)
Monosomal karyotype