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Acute Myelogenous Leukemia (AML)
(Acute Myelocytic Leukemia; Acute Myeloid Leukemia)
In acute myelogenous leukemia (AML), malignant transformation and uncontrolled proliferation of an abnormally differentiated, long-lived myeloid progenitor cell results in high circulating numbers of immature blood forms and replacement of normal marrow by malignant cells. Symptoms include fatigue, pallor, easy bruising and bleeding, fever, and infection; symptoms of extramedullary leukemic infiltration are present in only about 5% of patients (often as skin manifestations). Examination of peripheral blood smear and bone marrow is diagnostic. Treatment includes induction chemotherapy to achieve remission and postremission chemotherapy (with or without stem cell transplantation) to avoid relapse.
The incidence of acute myelogenous leukemia increases with age; it is the more common acute leukemia in adults, with a median age of onset of 50 yr. AML may occur as a secondary cancer after chemotherapy or radiation therapy for a different type of cancer. Secondary AML is difficult to treat with chemotherapy alone.
AML has a number of subtypes that are distinguished from each other by morphology, immunophenotype, and cytochemistry. Five classes are described, based on predominant cell type, including
Acute promyelocytic leukemia (APL) is a particularly important subtype, representing 10 to 15% of all cases of AML, striking a younger age group (median age 31 yr) and particular ethnicity (Hispanics), in which the patient commonly presents with a coagulation disorder.
Remission induction rates range from 50 to 85%. Long-term disease-free survival occurs in 20 to 40% of patients and increases to 40 to 50% in younger patients treated with intensive chemotherapy or stem cell transplantation.
Prognostic factors help determine treatment protocol and intensity; patients with strongly negative prognostic features are usually given more intense forms of therapy because the potential benefits are thought to justify the increased treatment toxicity.
The leukemia cell karyotype is an important prognostic factor. The specific chromosomal rearrangements of the different forms of AML affect the outcome. Three clinical groups have been identified: favorable, intermediate, and poor. Patients who have the cytogenetic findings of t(8;21), t(15;17), and inv(16) typically have a favorable response to therapy, durable remission, and improved survival. Patients with a normal karyotype have an intermediate prognosis, and patients with a poor prognosis are those with a deletion of chromosome 5 or 7, trisomy 8, or a karyotype with > 3 abnormalities.
Molecular genetic abnormalities are becoming more important in refining prognosis and therapy in AML. The large fraction of patients with cytogenetically normal blasts can now be further characterized. Patients with mutations in nucleophosmin (NPM1) or in CEBPA have a more favorable prognosis. Mutations in Flt3 kinase, on the other hand, have a poorer prognosis (including patients also having an otherwise favorable NPM1 mutation). Other negative factors include increasing age, a preceding myelodysplastic phase, secondary leukemia, high WBC count, and absence of Auer rods. Except in APL, the FAB or WHO classification alone does not predict response.
Initial therapy attempts to induce remission and differs most from ALL in that AML responds to fewer drugs. The basic induction regimen includes cytarabine by continuous IV infusion or high doses for 5 to 7 days; daunorubicin or idarubicin is given IV for 3 days during this time. Some regimens include 6-thioguanine, etoposide, vincristine, and prednisone, but their contribution is unclear. Treatment usually results in significant myelosuppression, with infection or bleeding. There is significant latency before marrow recovery. During this time, meticulous preventive and supportive care is vital.
In APL and some other cases of AML, disseminated intravascular coagulation (DIC) may be present when leukemia is diagnosed and may worsen as leukemic cell lysis releases procoagulant. In APL with the translocation t(15;17), all-trans retinoic acid (tretinoin) corrects the DIC in 2 to 5 days; combined with daunorubicin or idarubicin, this regimen can induce remission in 80 to 90% of patients and bring about long-term survival in 65 to 70%. Arsenic trioxide is also very active in APL. Tretinoin and arsenic trioxide without conventional cytotoxic chemotherapy have been successful in APL, and this approach is undergoing further study in clinical trials. Molecular testing for mutations that might be targeted (eg, IDH, Flt3) is becoming standard at diagnosis.
After remission, many regimens involve a phase of intensification with the same drugs used for induction or with other drugs. High-dose cytarabine regimens may lengthen remission duration, particularly when given for consolidation in patients < 60 yr. CNS prophylaxis usually is not given to adult patients because with better systemic disease control, CNS leukemia is a less frequent complication. In AML patients who have completed consolidation, maintenance therapy has no demonstrated role.
Patients who have not responded to treatment and younger patients who are in remission but who are at high risk of relapse (generally identified by high-risk molecular or chromosomal abnormalities) may be given high-dose chemotherapy and stem cell transplantation. Extramedullary sites are infrequently involved in isolated relapse. When relapse occurs, additional chemotherapy for patients unable to undergo stem cell transplantation is less effective and often poorly tolerated. Another course of chemotherapy is most effective in younger patients and in patients whose initial remission lasted > 1 yr.
AML is the most common acute leukemia in adults.
There are a number of subtypes, typically involving very immature myeloid cells.
Chromosomal and molecular genetic abnormalities are common and have implications for prognosis and treatment.
Chemotherapy often prolongs survival.
Stem cell transplantation may help patients who do not respond to treatment and younger patients.
Drug NameSelect Trade
thioguanineNo US brand name
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