Published September 1, 2005
Suzanne Department of
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DefinitionPrevalencePathophysiologySigns
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Acute myeloid 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.1 It is the most common leukemia in adults. |
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EPIDEMIOLOGY |
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Risk factors for the development of AML include the following: Genetic Predisposition
Environmental
Exposure Prior
Therapy Prior
Bone Marrow Disorders Age |
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| 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 literature
supports the concept of a single transformed hematopoietic stem cell, whereas
others contend 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 and called 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 AML1-CBFβ produces a transcription factor that regulates numerous hematopoietic-specific genes.11 The genetic translocations t(8;21), inv(16), and t(16;16) have all been associated with this transcription factor.12 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, leads to AML composed of both myeloid and lymphoid cells. The MLL gene rearrangement portends a worse outcome among patients with AML. |
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| AML
often presents 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 as well as 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 presents 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 diagnosis.
In some patients, the diagnosis of AML can constitute a medical emergency, making prompt referral to a medical hematologist/oncologist a requisite. Hyperleukocytosis and/or leukostasis 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, leukopheresis, or low-dose cranial radiation. Central nervous system leukemia, though less common in AML, can present 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 either spontaneously due to high tumor burden or as a result of cytotoxic chemotherapy. |
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| The
diagnosis of AML requires the identification of greater than 20% leukemic
blasts in the bone marrow (see below). 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. 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 2001, however, the World Health Organization (WHO) reclassified AML into four categories (Table 1), in an attempt to more accurately predict the prognosis and biologic properties of AML subcategories and enhance the clinical relevance of the system.13 This new classification reflected those entities with similar biological and clinical features.14 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. The WHO classification system differs from the FAB system in that the previous blast cell threshold of 30% for diagnosis of AML has been reduced to 20%, and patients with recurring cytogenetic abnormalities are now classified as having AML regardless of blast percentage.13 The British Medical Research Council (MRC) AML 10 trial15 and a Cancer and Leukemia Group B (CALGB) trial16 found that patients could then be categorized prognostically based on their pretreatment cytogenetics. Patients could be separated into three categories based upon response to induction treatment, relapse risk, and overall survival: favorable, intermediate, and adverse cytogenetic groups.15 Typically, patients with favorable-risk cytogenetics have abnormalities of the AML1/CBFß DNA-subunit. This subunit is composed of two proteins, AML1 (also known as core binding factor 2-alpha, CBF2-alpha) which heterodimerizes with another protein, core binding factor ß (CBFß), to form a transcription factor necessary for normal hematopoiesis. Adverse cytogenetics include complex (>3) 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), as these may help to dictate therapy. More recently, gene-expression profiling has been shown to improve the molecular classification and prediction of outcome in patients with AML.17 Table 2 details the laboratory and imaging studies needed to accurately diagnose and ultimately to treat patients with AML. Baseline evaluation involves routine bloodwork 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 both diagnosis as well as prognosis. Additional studies, including a chest x-ray, and an echocardiogram are needed to determine a patient's ability to undergo chemotherapy. A lumbar pucture may be needed if CNS symptoms are identified. HLA typing and viral serologies are needed if bone marrow transplant is necessary. |
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Therapy for AML includes remission induction followed by post-remission chemotherapy for most patients. For some, this is followed by hematopoietic stem-cell transplantation (see below). 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 years and those older than 60 (Table 3).
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 at 45-60mg/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 evaluated patients treated with granulocyte-monocyte colony-stimulating factor for priming of the bone marrow prior to induction chemotherapy.18 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/oncologist as soon as possible for prompt initiation of induction chemotherapy. Post-remission chemotherapy then aims to eradicate any residual disease in an attempt at cure. Post-remission chemotherapy includes high-dose cytarabine (HiDAC) for patients under age 60, while either a 5 or a 5 + 2 regimen of cytarabine plus an anthracycline or anthracenedione is preferred for patients over age 60. HiDAC has proven to be quite efficacious in young patients with good or intermediate prognosis. In patients under age 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 60.16 HiDAC has shown particular efficacy in patients with the core binding factor (CBF) DNA-subunit abnormalities. HiDAC is composed of 1000-3000mg/m2 IV over 1-3 hours every 12 hours for 8-12 doses. Allogeneic or autologous bone marrow transplantation is an additional option for post-remission therapy in adults with AML. For some patients under age 60 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 transplant are options.19 Two novel therapies, arsenic trioxide and gemtuzumab ozogamicin, have recently been approved by the US 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 + partial response) in AML patients in first relapse with their first remission having lasted 6 months or longer.1 Studies are ongoing to determine if 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.21 In elderly 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.22 Although not yet approved by the FDA, early studies have demonstrated a 20% to 32% complete response rate among patients with a poor prognosis.23,24 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 4). In patients with good-risk cytogenetics, induction followed by post-remission chemotherapy has shown response rates similar to those of HSCT, with lower treatment-related mortality. There is a role for autologous HSCT for these patients who relapse. For those with intermediate-risk cytogenetics, age is often a determining factor, as the risk of treatment-related mortality increases with age. For these patients, treatment options include allogeneic transplantation among those with sibling donors, autologous HSCT, and post-remission chemotherapy. For those with poor-risk cytogenetics, allogeneic transplant with a sibling or a matched-unrelated donor can be anticipated immediately following induction chemotherapy. 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 both disease-free survival and overall survival compared with chemotherapy alone.25 ATRA, along with an anthracycline, is currently the standard of care for patients with APL. |
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Over the past few
decades, success in the treatment of AML has improved only modestly for
patients under the age of 60. In 1966, the median survival of adult patients
with AML was 40 days.26 Today, AML patients
under the age of 60 have complete response rates of 70% to 80% after induction
chemotherapy.16 Overall survival, however,
remains at only about 50% for those who go into a complete response, or
30% overall.27 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.15 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.28 In relapsed
AML, however, complete response after allogeneic HSCT is 35% or less.29 |
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