Published: April 2014
Acute myeloid leukemia (AML), also known as acute nonlymphocytic leukemia, represents a group of clonal hematopoietic stem cell disorders in which both a block in differentiation and unchecked proliferation result in the accumulation of myeloblasts at the expense of normal hematopoietic precursors. It is the most common acute leukemia in adults.
There are a number of risk factors for the development of AML.
Chromosomal instability in several autosomal dominant conditions can lead to AML, including Fanconi's anemia, ataxia-telangiectasia, neurofibromatosis, and Bloom's syndrome. Germline mutations in the AML-1 gene are known to be associated with an increased risk of the development of AML. Additionally, congenital disorders, including infantile X-linked agammaglobulinemia and Down's syndrome, have also been associated with an increased incidence of AML.
Ionizing radiation and organic solvents such as benzene and other petroleum products have been associated with a higher risk of developing AML. Both ras mutations and polymorphisms resulting in the inactivation of nicotinamide adenine dinucleotide phosphate (NADPH) and reduced NADPH-quinone oxidoreductase have been found in patients with these exposures. Increased incidence of leukemia is proportional to the cumulative dose of radiation. Doses less than 100 cGy are not typically associated with leukemia.
Therapy-related AML typically develops after alkylating agent-induced damage at a median of 5 to 7 years after therapy for the primary malignancy. It is usually associated with an antecedent myelodysplastic disorder. DNA topoisomerase II agents may also produce gene rearrangements leading to AML, with a short latency period of 12 to 18 months following treatment. The latency between exposure to radiation therapy for other cancers and AML development is similar to that of alkylating agents.
Secondary AML can develop in patients with various hematologic disorders, such as aplastic anemia, paroxysmal nocturnal hemoglobinuria, and severe congenital neutropenia. Other inherited hematologic conditions have also been implicated, such as Bloom's syndrome and Fanconi's anemia. Myelodysplastic and myeloproliferative syndromes, present for at least 3 months, can also progress to AML.
The incidence rate of AML increases with age. In the United States, the median age of patients with AML is 67 years. The age-adjusted population incidence is 12.2 per 100,000 for people older than 65 years, compared with 1.3 per 100,000 for those younger than 65 years. Similarly, chromosomal abnormalities occur with greater frequency among this older population of patients.
In AML, the normal process of hematopoietic cell differentiation is interrupted in those cells committed to the myeloid lineage. Some reports have supported the concept of a single transformed hematopoietic stem cell, whereas others have contended that transformation can occur at any point from stem cell to lineage-committed progenitor cell. This transformation can occur either as a de novo event, or in association with previous therapy, and in most cases likely results from multiple genetic events.
Several molecular and genetic lesions have been identified in AML, leading to advances in defining its pathogenesis. The most familiar of these is the t(15;17) translocation, resulting in AML with abnormal promyelocytes, known as acute promyelocytic leukemia (APL). Translocation of these chromosomes results in the fusion of the PML gene on chromosome 15, with the retinoic acid receptor gene alpha (RARA) on chromosome 17, giving rise to a fusion product (PML/RARA) that prevents differentiation to mature granulocytes. This block in differentiation can be overcome with all-trans retinoic acid (ATRA), a vitamin A derivative. The DNA-binding subunit core-binding factor β (CBF β) produces a transcription factor that regulates numerous hematopoietic-specific genes. The genetic translocations t(8;21), inv(16), and t(16;16) have all been associated with this transcription factor. AML patients with these genetic disorders have a better prognosis. Six percent to 8% of patients with AML have structural alterations of 11q23, leading to the MLL rearrangement. The MLL gene rearrangement, also known as mixed lineage leukemia, may lead to AML composed of both myeloid and lymphoid cells. The MLL gene rearrangement portends a worse outcome in patients with AML.
AML often manifests with clinical sequelae attributable to pancytopenia. The deficient production of red blood cells can lead to patient complaints of weakness, fatigue, or dyspnea on exertion. Pallor is a common finding on physical examination. Infection can result from insufficient numbers of white cells or impaired white blood cell function. Collections of leukemic cells, seen in leukemia cutis, granulocytic sarcomas, or chloromas, can also occur. These collections represent extramedullary sites of disease and often involve cutaneous and visceral tissues. In some cases, hyperleukocytosis can lead to ocular, cardiac, pulmonary, or cerebral dysfunction. Low numbers of platelets can lead to petechiae, gingival bleeding, ecchymosis, epistaxis, or menorrhagia. APL is a distinct entity of AML that often manifests with hemorrhagic complications, including disseminated intravascular coagulation. Palpable lymphadenopathy and hepatosplenomegaly are rare findings in AML. It is typical for patients to complain of flu-like symptoms for 4 to 6 weeks before the diagnosis.
In some patients, the diagnosis of AML can constitute a medical emergency, making prompt referral to a medical hematologist or oncologist a requisite. Hyperleukocytosis, leukostasis, or both can cause impairment of blood flow, most often resulting in central nervous system (CNS) or pulmonary symptoms. Rapid lowering of the white blood cell count can be achieved with the institution of chemotherapy, leukapheresis, or low-dose radiation. CNS leukemia, although less common in AML, can manifest with patient complaints of headache, lethargy, or cranial nerve signs. For these patients, intrathecal chemotherapy or cranial radiation are treatment options. Additionally, metabolic abnormalities, including tumor lysis syndrome, can occur spontaneously because of high tumor burden or as a result of cytotoxic chemotherapy. AML should always be considered a medical emergency in younger (age <60 years) adults, in whom each day of delay in instituting definitive chemotherapy may compromise survival.
The diagnosis of AML requires the identification of 20% or more leukemic blasts in the bone marrow. Further analysis then must separate AML from acute lymphoblastic leukemia by showing evidence for commitment to the myeloid lineage. Immunohistochemical staining for myeloperoxidase is the best method for determining which cells are committed to the myeloid lineage (Figure 1). The leukemic clone giving rise to AML can occur at any point in the differentiation of the myeloid cell, creating heterogeneity among patients. Flow cytometry and cytogenetics are then used to differentiate the various AML subtypes.
The subtypes of AML were previously described as M0 through M7 by the French-American-British (FAB) system (Box 1). In 1997, however, the World Health Organization (WHO) reclassified AML into four categories (Box 1) in an attempt to predict the prognosis and biologic properties of AML subcategories more accurately and to enhance the clinical relevance of the system. This new classification reflected those entities with similar biologic and clinical features. It also takes into account the morphologic, genetic, and immunophenotypic features of the disease entities. The four categories include AML with recurrent genetic abnormalities, AML with myelodysplasia-related changes, therapy-related AML, and AML not otherwise specified, which roughly correlates with the FAB classification (Figures 2 and 3). The WHO classification system differs from the FAB system in that the previous blast cell threshold of 30% for the diagnosis of AML has been reduced to 20%, and patients with recurring cytogenetic abnormalities are now classified as having AML regardless of blast percentage.
|M0: Myeloblastic without maturation|
|M1: Myeloblastic with minimal maturation|
|M2: Myeloblastic with maturation|
|M3: Promyelocytic; M3v: Promyelocytic ("microgranular")|
|M4: Myelomonocytic; M4 Eo: Myeloblastic with abnormal eosinophils (Eo)|
|M5: Monocytic: poorly (M5a) or well differentiated (M5b)|
|World Health Organization Classification|
|Acute myeloid leukemia with recurrent genetic abnormalities|
|Acute myeloid leukemia with myelodysplasia-related changes|
|Therapy-related myeloid neoplasms|
|Acute myeloid leukemia, not otherwise specified|
Adapted with permission from the American Society of Hematology (Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009; 114:937–951); permission conveyed through Copyright Clearance Center, Inc.
Box 2 presents the laboratory and imaging studies needed to diagnose and ultimately treat patients with AML accurately. Baseline evaluation involves routine blood work, including a complete blood count with differential, comprehensive metabolic profile, and coagulation studies. A bone marrow aspiration and biopsy should be evaluated by cytochemistry, immunophenotyping, flow cytometry, and cytogenetics; this is necessary for determining diagnosis and prognosis. Additional studies, including chest radiography and echocardiography are needed to determine a patient's ability to receive potentially cardiotoxic chemotherapy. A lumbar puncture may be needed if CNS symptoms are identified. Human leukocyte antigen (HLA) typing is needed if bone marrow transplantation is being considered, and it should be performed prior to myeloablation.
|Complete blood cell count with differential|
|Determination of the following:|
|Partial thromboplastin time, activated partial thromboplastin time, fibrinogen, D dimer|
|Bone marrow biopsy with cytochemistry, immunophenotyping, flow cytometry, cytogenetics|
|Lumbar puncture in symptomatic patients|
|Human leukocyte antigen typing of patient and siblings|
|Herpes simplex and cytomegalovirus serology|
The British Medical Research Council (MRC) AML 10 trial and a Cancer and Leukemia Group B (CALGB) trial found that patients could then be categorized prognostically based on their pretreatment cytogenetics. Patients could be separated into distinct cytogenetic categories based on response to induction treatment, relapse risk, and overall survival: favorable, intermediate (I and II), and adverse cytogenetic groups (Box 3). Typically, patients with favorable-risk cytogenetics have abnormalities of the AML1-CBFβ DNA subunit. This subunit is composed of two proteins, AML1 (also known as CBF 2α, CBF2α) which heterodimerizes with another protein, CBFβ, to form a transcription factor necessary for normal hematopoiesis. Adverse cytogenetics include complex (three or more) abnormalities, deletion of 5q, abnormal 3q, and deletion of chromosome 7. Thus, it is crucial to test for cytogenetics and, when applicable, to use fluorescence in situ hybridization, because these may help dictate therapy. More recently, gene expression profiling has been shown to improve the molecular classification and prediction of outcome in patients with AML. More recently, molecular profiling has become standard among patients with "normal" cytogenetics, to further distinguish good from poor prognostic groups within these patients. These include assessment for the nucleophosmin1 (NPM1) mutation, considered good risk; FMS-like tyrosine kinase-3 (FLT3) mutations, considered poor-risk; and the CCAAT/enhancer-binding protein-alpha (CEBPα) mutation, considered good-risk. A number of other mutations, including ASXL1, TET2, IDH1/2, DNMT3A, have also been associated with prognosis, though at the time of this writing, have not been incorporated into standard clinical practice.
|Balanced structural rearrangements|
|Balanced structural rearrangements|
|Cytogenetics abnormalities not classified as favorable or adverse|
|Balanced structural rearrangements|
|Unbalanced structural rearrangement|
Data from Döhner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010; 115:453–474.
Therapy for AML includes remission induction followed by postremission chemotherapy for most patients. For some, this is followed by hematopoietic stem cell transplantation (HSCT) (see later). Treatment recommendations for AML vary, taking into account patient age, cytogenetics, and prognostic factors. The recommendations are often divided into those for patients younger than 60 and those 60 years and older (Table 1).
|Induction chemotherapy||7 + 3||7 + 3|
|Postremission chemotherapy||HiDAC||5 or 5 + 2|
|Complete response rates (%)||60-85||40-55|
|Treatment-related mortality (%)||5-10||20-30|
|5-year disease-free survival (%)||30||5-10|
HiDAC, high-dose cytarabine (1,000-3,000 mg/m2 IV over 1-3 hours every 12 hours for 6 to 12 doses); 7 + 3, 7 days of cytarabine at 100 mg/m2 plus 3 days of an anthracycline or anthracenedione (most commonly idarubicin, 12 mg/m2, mitoxantrone, 12 mg/m2, or daunorubicin, 45 mg/m2); 5 or 5 + 2, 5 days of cytarabine at 100 mg/m2 alone or combined with 2 days of an anthracycline or anthracenedione.
The goal of induction chemotherapy is to reduce the number of leukemic cells, as well as to return proper function to the bone marrow. The 7 + 3 regimen of cytarabine (100 mg/m2 for 7 days plus an anthracycline or anthracenedione [most often daunorubicin, 45 mg/m2 in older adults, 90mg/m2 in younger adults, but other options include idarubicin or mitoxantrone 12 mg/m2] for 3 days) is the most common induction regimen. Potential toxicities of induction therapy include: tumor lysis syndrome, cardiac abnormalities (electrocardiographic changes, arrhythmias, or congestive heart failure), tissue necrosis (anthracycline chemotherapy is considered a vesicant), pancytopenia, nausea and vomiting, alopecia, and death, among others. Commonly, a bone marrow biopsy will be repeated 2 weeks following the initiation of therapy, to assess marrow aplasia. If residual leukemia is detected, patients are treated with another chemotherapy course, termed reinduction.
Postremission chemotherapy then aims to eradicate any residual disease in an attempt at cure. Postremission chemotherapy includes high-dose cytarabine (ara-c; HiDAC) for patients younger than 60 years, in whom a survival advantage has been demonstrated with this therapy, particularly in patients with good-risk, core binding factor cytogenetic abnormalities. In patients younger than 60 years, HiDAC yields a 4-year disease-free survival rate of 44%, but carries with it a 5% treatment-related mortality. In contrast, HiDAC failed to improve the outcome of patients older than 60 years (15% disease-free survival at 4 years). The HiDAC regimen is 1,000 to 3,000 mg/m2 IV over 1 to 3 hours every 12 hours for 6 to 12 doses. High doses of cytarabine can be associated with cerebellar, ophthalmologic, and gastrointestinal toxicity, particularly in patients over the age of 60 years.
The treatment of older AML patients is controversial. Older adults often cannot tolerate the toxicities of intensive remission induction chemotherapy. With the typical treatment plans, the treatment-related mortality is between 15% and 30%. Other less intensive regimens that may be used are oral agents (such as hydroxyurea), "low dose cytarabine" (20 mg/m2 subcutaneous injection twice daily for 10 days), or one of the hypomethylating agents (azacitidine or decitabine). These are associated with less of a myelosuppressive effect, lower treatment-related mortality, and less time spent in the hospital.
Allogeneic bone marrow transplantation is an additional option for postremission therapy in adults with AML. For some patients younger than 60 years with poor-risk disease features (such as adverse cytogenetics) and for whom an HLA-matched sibling or matched unrelated donor is available, allogeneic stem cell transplantation should follow induction chemotherapy. This procedure is not without risk; it has an associated 20% to 25% treatment-related mortality rate. Furthermore, the majority of studies fail to reveal any survival advantage for allogeneic transplantation in good risk cytogenetics. Those patients with unfavorable cytogenetics have a high-risk for relapse with chemotherapy alone and may receive maximum benefit from allogeneic transplantation following remission induction chemotherapy. There is no role for maintenance therapy in AML.
In summary, recommendations for HSCT in AML rely heavily on risk-stratified cytogenetics (Box 3). In patients with good-risk cytogenetics, induction followed by postremission chemotherapy has shown outcomes superior to those of HSCT, with lower treatment-related mortality. There is minimal role for autologous HSCT for those patients who relapse. For those with intermediate-risk cytogenetics, age is often a determining factor, because the risk of treatment-related mortality increases with age. For these patients, treatment options include allogeneic transplantation for those with sibling donors and postremission chemotherapy, without clear benefit for one approach compared with the other. For those with poor-risk cytogenetics, allogeneic transplantation with a sibling or matched unrelated donor can be anticipated immediately following induction chemotherapy.
Of note, gemtuzumab ozogamicin (Mylotarg) was approved by the U.S. Food and Drug Administration for use in refractory AML. Gemtuzumab ozogamicin, an anti-CD33 immunotoxin conjugate, was shown to have a 30% response rate (complete response plus partial response) in older AML patients in first relapse, with their first remission having lasted 6 months or longer. However, this drug was withdrawn from the United States market in October 2010 due to excessive adverse events without clear support of initial benefits seen. This medication is only available under investigation protocol. New agents in studies now are nucleoside analogs (cladribine, clofarabine) and hypomethylating agents (azacitadine and decitabine).
The treatment of APL differs from the recommendations for AML. Instead, ATRA (45 mg/m2/day divided into two doses), which promotes differentiation of leukemic promyelocytes into mature cells, has been shown to improve disease-free survival and overall survival compared with chemotherapy alone. ATRA, along with an anthracycline and cytarabine, is currently the standard up-front therapy for patients with APL. A significant complication of APL treatment is APL differentiation syndrome. This is a cardiopulmonary syndrome, characterized by fever, respiratory distress, pulmonary changes (interstitial infiltrates, pleural effusion), pericardial effusion, hypotension, and acute renal failure. The mechanism behind this is the rapid differentiation of blasts into neutrophils. Differentiation syndrome occurs 25% of the time when ATRA is used alone, but is decreased to less than 10% when ATRA is used concurrently with chemotherapy. There are no clear factors linked to differentiation syndrome. Corticosteroids are the mainstay course of treatment. APL is also linked with coagulopathy complications of disseminated intravascular coagulopation and increased fibrinolysis. Patients need to be monitored very carefully and treated immediately. Despite these potential complications, the complete remission rate of APL is quite high, ranging from 70% to 95%. Arsenic trioxide has now been incorporated into the immediate post-remission setting based on the results of a randomized U.S. Intergroup study in which patients receiving this agent had improved disease-free survival. APL is the only AML subtype in which maintenance therapy (ATRA) is standard.
Over the past few decades, success in the treatment of AML has improved only modestly for patients younger than 60 years. In 1966, the median survival of adult patients with AML was 40 days. Today, AML patients younger than 60 years have complete response rates of 70% to 80% after induction chemotherapy. Overall survival, however, remains at only about 50% for those who go into a complete remission, or 30% to 40% overall. In 1998, the MRC AML 10 trial found that patients could be separated into three prognostic groups—favorable, intermediate, and adverse—defined by pretreatment cytogenetics. Overall survival at 5 years was found to be 65%, 41%, and 14%, respectively. If a patient undergoes an allogeneic HSCT while in first remission, the complete response rate ranges from 45% to 65%, although patient selection influences these outcomes.
Most relapses occur within 2 years of diagnosis, and the prognosis of relapsed disease is quite poor. In relapsed AML, complete response after allogeneic HSCT is 35% or lower. These patients should be considered for investigation trials. The prognosis for older patients remains quite poor. In the MRC AML 8 trial, the remission rate was 70% for patients younger than 50 years, 52% for those 60 to 69 years old, but only 26% for those older than 70 years. One theory for such disparity is that neutropenia after chemotherapy lasts longer and is less well tolerated in older adults than in younger patients. Another possible answer is the finding that hematopoietic cells of older patients are derived from a leukemic clone at diagnosis, in contrast to normal stem cells in younger counterparts. It is clear that older adults have worse cytogenetics, and more expression of genes encoding for drug efflux pumps, which compromises chemotherapy efficacy. The use of granulocyte-monocyte colony-stimulating factors or granulocyte colony stimulating factors reduce the period of neutropenia and the duration of hospitalization by approximately two days; unfortunately, this has not translated into improved overall survival or a decrease in infectious complications. Therefore, their use is not indicated.