Acute Myelogenous Leukemia
Acute myelogenous leukemia (AML), also known as acute nonlymphocytic leukemia, represents a group of clonal hematopoietic stem cell disorders in which both failure to differentiate and overproliferation into the stem cell compartment result in the accumulation of myeloblasts. It is the most common 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 immunodeficiency disorders. including infantile X-linked agammaglobulinemia and Down 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, reduced (NADPH)–quinone oxidoreductase have been found in patients with these exposures.
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.
Prior Bone Marrow Disorders
Secondary AML can develop in patients with various hematologic disorders, such as aplastic anemia 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 of AML increases with age. In the United States, the median age of patients with AML is 68 years. The age-adjusted population incidence is 17.6 per 100,000 for people older than 65 years, compared with 1.8 per 100,000 for those younger than 65 years. Similarly, chromosomal abnormalities occur with greater frequency among this older population of patients.
Hematopoiesis in normal cells involves the differentiation of a stem cell into myelocytes, lymphocytes, and megakaryocytes. In AML, this process of 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 associated with previous therapy.
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 retinoic acid receptor gene alpha on chromosome 15, with the PML gene on chromosome 17, giving rise to a fusion product 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 b (CBFb) 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.
Signs and symptoms
AML often manifests with the clinical sequelae attributable to pancytopenia. The deficient production of red 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 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 flulike 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 or pulmonary symptoms. Rapid lowering of the white blood cell count can be achieved with the institution of chemotherapy, leukapheresis, or low-dose radiation. Central nervous system 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.
The diagnosis of AML requires the identification of greater than 20% leukemic blasts in the bone marrow (see later). 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 (Fig. 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. 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 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 multilineage dysplasia, therapy-related AML and myelodysplastic syndromes, and AML not otherwise categorized, which roughly correlates with the FAB classification (Figs. 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.
|Box 1: WHO Classification of Acute Myelogenous Leukemia|
|Acute myeloid leukemia with recurrent genetic abnormalities
|Acute myeloid leukemia with multilineage dysplasia
|Acute myeloid leukemia and myelodysplastic syndromes, therapy-related
|Acute myeloid leukemia, not otherwise categorized; classify as:
AML1, acute myelogenous leukemia 1; CBFb, core-binding factor b; ETO, eight twenty-one; MDS, myelodysplastic syndromes; MYH11, myosin heavy chain, type 11; MLL, mixed lineage leukemia; MPD, myeloproliferative disease; PML, promyelocytic leukemia; RARa, retinoic acid receptor.
Adapted from Vardiman JW, Harris NL, Brunning RD: The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002;100:2292-2302.
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 three categories based on response to induction treatment, relapse risk, and overall survival—favorable, intermediate, and adverse cytogenetic groups. 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 core-binding factor 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 (FISH), 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.
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, complete metabolic profile, and coagulation studies. A bone marrow 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 undergo chemotherapy. A lumbar puncture may be needed if central nervous system (CNS) symptoms are identified. Human leukocyte antigen (HLA) typing and viral serologies are needed if bone marrow transplantation is necessary.
|Box 2: Routine Testing for Diagnosis and Treatment of AML|
|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|
|Two-dimensional echocardiography in patients with history and/or symptoms of heart-related issues|
|Lumbar puncture in symptomatic patients|
|Human leukocyte antigen typing of patient and siblings|
|Herpes simplex and cytomegalovirus serology|
Therapy for AML includes remission induction followed by postremission chemotherapy for most patients. For some, this is followed by hematopoietic stem cell transplantation (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 ).
Table 1: Treatment-Related Statistics for AML Stratified by Age
|Induction chemotherapy||7 + 3||7 + 3|
|Postremission chemotherapy||HiDAC||5 or 5 + 2|
|Complete response rates (%)||65-85||40-55|
|Treatment-related mortality (%)||5-10||20-30|
|5-year disease-free survival (%)||30||5-10|
HiDAC, high-dose cytarabine (1000-3000 mg/m2 IV over 1-3 hr every 12 hr for 6 to 12 doses); 7 + 3, 7 days of cytarabine at 100 mg/m2 + 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 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 to 60 mg/m2, but other options include idarubicin or mitoxantrone] for 3 days) is the most common induction regimen for both age groups.
A recent study by the Eastern Cooperative Oncology Group has evaluated patients treated with granulocyte-monocyte colony-stimulating factor for priming of the bone marrow before induction chemotherapy. This study revealed a statistically significant difference in complete response rates for patients in whom induction therapy was not delayed for priming. This reinforces the need to refer patients to a hematologist or oncologist as soon as possible for prompt initiation of induction chemotherapy.
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, whereas a 5 or 5 + 2 regimen of cytarabine plus an anthracycline or anthracenedione is preferred for patients older than 60 years. HiDAC has proven to be efficacious for young patients with good or intermediate prognosis. In patients younger than 60 years, HiDAC yields a 4-year disease-free survival rate of 44%, with relatively few relapses, but carries with it a 5% treatment-related mortality. In contrast, HiDAC failed to improve the outcome of patients older than 60 years. HiDAC has shown particular efficacy for patients with CBF DNA subunit abnormalities. The HiDAC regimen is 1000 to 3000 mg/m2 IV over 1 to 3 hours every 12 hours for 6 to 12 doses.
Allogeneic or autologous bone marrow transplantation is an additional option for postremission therapy in adults with AML. For some patients younger than 60 years 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. For patients without a compatible donor or for whom age precludes such treatment, additional chemotherapy or autologous stem cell transplantation are options.
Two novel therapies, arsenic trioxide and gemtuzumab ozogamicin, have recently been approved by the U.S. Food and Drug Administration (FDA) 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. Studies are ongoing to determine whether initial chemotherapy plus gemtuzumab ozogamicin has a role in previously untreated patients. Arsenic trioxide, which targets intracellular mitochondria, has shown good success in the treatment of relapsed or refractory APL. Single-agent studies with arsenic trioxide in other subtypes of AML have not proven to be as encouraging. In older patients, however, use of arsenic trioxide in combination with ascorbic acid may be a viable treatment option for patients not able to endure intensive chemotherapy.
Farnesyltransferase inhibitors are an emerging class of signal transduction inhibitors. The theorized mechanism of action involves inhibition of several cell-signaling processes. Such inhibition then leads to decreased proliferation of malignant cells. Although not yet approved by the FDA, early studies have demonstrated a 10% to 20% complete response rate among patients with a poor prognosis. Therapy is generally well tolerated. Common side effects include fatigue, nausea, vomiting, and skin rash.
Recommendations for hematopoietic stem cell transplantation (HSCT) in AML rely heavily on risk-stratified cytogenetics ( Table 2 ). In patients with good-risk cytogenetics, induction followed by postremission chemotherapy has shown response rates similar 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, autologous HSCT, and postremission chemotherapy. For those with poor-risk cytogenetics, allogeneic transplantation with a sibling or matched unrelated donor can be anticipated immediately following induction chemotherapy.
Table 2: Cytogenetic Risk Stratification for Overall Survival
|Good Risk||Intermediate Risk||Poor Risk|
|t(8;21)||Normal karyotype||Complex karyotype|
|loss of 7q||t(6;11)|
Data from Byrd J, Mrozek K, Dodge RK, et al: Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: Results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002;100:4325-4336.
The treatment of APL differs from the recommendations for AML. Instead, ATRA, 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 of care for patients with APL.
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% 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 numbers. In relapsed AML, complete response after allogeneic HSCT is 35% or lower. The prognosis for older patients remains poor, however. 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. The use of granulocyte-monocyte colony-stimulating factors reduces the period of neutropenia and the duration of hospitalization by approximately 2 days; unfortunately, this has not translated into improved overall survival or a decrease in infectious complications. Therefore, their use is not indicated.
- Acute myelogenous leukemia (AML) represents a group of clonal hematopoietic stem-cell disorders.
- The incidence of AML increases with age.
- A diagnosis of AML requires 20% or more leukemic myeloid blasts.
- Pretreatment cytogenetics are useful in determining prognosis and appropriate treatment.
- Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: Results from Cancer and Leukemia Group B (CALGB 8461). Blood. 100: 2002; 4325-4336.
- Repetitive cycles of high-dose cytarabine benefit patients with acute myeloid leukemia and inv(16)(p13q22) or t(16;16)(p13;q22): Results from CALGB 8461. J Clin Oncol. 22: 2004; 1087-1094.
- Factors affecting the outcome of allogeneic bone marrow transplantation for adult patients with refractory or relapsed acute leukaemia. Br J Haematol. 107: 1999; 409-418.
- The importance of diagnostic cytogenetics on outcome in AML: Analysis of 1,612 patients entered into the MRC AML 10 trial. Blood. 92: 1998; 2322-2333.
- Leukemias and myelodysplastic syndromes secondary to drug, radiation, and environmental exposure. Semin Oncol. 19: 1992; 47-84.
- Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med. 331: 1994; 896-903.
- Principal results of the Medical Research Council's 8th acute myeloid leukaemia trial. Lancet. 2: 1986; 1236-1241.
- A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: A trial by the Eastern Cooperative Oncology Group. Blood. 103: 2004; 479-485.
- Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. Cancer and Leukemia Group B. N Engl J Med. 332: 1995; 1671-1677.
- All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med. 337: 1997; 1021-1028.
- The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 100: 2002; 2292-2302.