ACUTE MYELOID LEUKEMIA

INCIDENCE The incidence of acute myeloid leukemia (AML) is ~3.6 per 100,000 people per year, and the age-adjusted incidence is higher in men than in women (4.4 versus 3.0). AML incidence increases with age; it is 1.7 in individuals <65 years and 16.2 in those >65. A significant increase in AML incidence has occurred over the past 10 years.

ETIOLOGY

Heredity, radiation, chemical and other occupational exposures, and drugs have been implicated in the development of AML. No direct evidence suggests a viral etiology. Heredity Certain syndromes with somatic cell chromosome aneuploidy, e.g., Down (chromosome 21 trisomy), Klinefelter (XXY and variants), and Patau (chromosome 13 trisomy), are associated with an increased incidence of AML.

Radiation Survivors of the atomic bomb explosions in Japan had an increased incidence of myeloid leukemias that peaked 5 to 7 years after exposure. Therapeutic radiation alone seems to add little risk of AML but can increase the risk in people exposed to alkylating agents.

Chemical and Other Exposures Exposure to benzene, which is used as a solvent in the chemical, plastic, rubber, and pharmaceutical industries, is associated with an increased incidence of AML. Smoking and exposure to petroleum products, paint, embalming fluids, ethylene oxide, herbicides, and pesticides, have also been associated with an increased risk of AML. Drugs Anticancer drugs are the leading cause of treatment-associated AML. Alkylating agent– associated leukemias occur on average 4 to 6 years after exposure, and affected individuals have aberrations in chromosomes 5 and 7. Chloramphenicol, phenylbutazone, and, less commonly, chloroquine and methoxypsoralen can result in bone marrow failure that may evolve into AML.

Acute Myeloid Leukemia (AML) Classification Systems

French-American-British (FAB) Classification M0: Minimally differentiated leukemia M1: Myeloblastic leukemia without maturation M2: Myeloblastic leukemia with maturation M3: Hypergranular promyelocytic leukemia M4: Myelomonocytic leukemia M4Eo: Variant: Increase in abnormal marrow eosinophils M5: Monocytic leukemia M6: Erythroleukemia (DiGuglielmo's disease) M7: Megakaryoblastic leukemia

History Increasing fatigue or decreased exercise tolerance (anemia)   Excess bleeding or bleeding from unusual sites (DIC, thrombocytopenia)   Fevers or recurrent infections (granulocytopenia)   Headache, vision changes, nonfocal neurologic abnormalities (CNS leukemia or bleed)   Early satiety (splenomegaly)   Family history of AML (Fanconi, Bloom, or Kostmann syndromes or ataxia telangiectasia)   History of cancer (exposure to alkylating agents, radiation, topoisomerase II inhibitors)   Occupational exposures (radiation, benzene, petroleum products, paint, smoking, pesticides)

  

Physical Examination   Performance status (prognostic factor)

   Ecchymosis and oozing from IV sites (DIC, possible acute promyelocytic leukemia)   Fever and tachycardia (signs of infection)   Papilledema, retinal infiltrates, cranial nerve abnormalities (CNS leukemia)   Poor dentition, dental abscesses   Gum hypertrophy (leukemic infiltration, most common in monocytic leukemia)   Skin infiltration or nodules (leukemia infiltration, most common in monocytic leukemia)   Lymphadenopathy, splenomegaly, hepatomegaly   Back pain, lower extremity weakness [spinal granulocytic sarcoma, most likely in t(8;21) patients]

Laboratory and radiologic studies CBC with manual differential cell count   Chemistry tests (electrolytes, creatinine, BUN, calcium, phosphorus, uric acid, hepatic enzymes, bilirubin, LDH, amylase, lipase)   Clotting studies (prothrombin time, partial thromboplastin time, fibrinogen, D-dimer)   Viral serologies (CMV, HSV-1, varicella zoster)   RBC type and screen   HLA-typing of patient, siblings, and parents for potential allogeneic SCT   Bone marrow aspirate and biopsy (morphology, cytochemistry, cytogenetics, flow cytometry, molecular studies)   Cryopreservation of viable leukemia cells   Echocardiogram   PA and lateral chest radiograph

  

Symptoms Patients with AML most often present with nonspecific symptoms that begin gradually or abruptly and are the consequence of anemia, leukocytosis, leukopenia or leukocyte dysfunction, or thrombocytopenia. Nearly half have had symptoms for ≥3 months before the leukemia was diagnosed.

Physical Findings Fever, splenomegaly, hepatomegaly, lymphadenopathy, sternal tenderness, and evidence of infection and hemorrhage are often found at diagnosis. Significant gastrointestinal bleeding, intrapulmonary hemorrhage, or intracranial hemorrhage occur most often in acute promyelocytic leukemia (APL

Hematologic Findings Anemia is usually present at diagnosis and can be severe. The degree varies considerably irrespective of other hematologic findings, splenomegaly, or the duration of symptoms. The anemia is usually normochromic normocytic. The median presenting leukocyte count is about 15,000/µl. Between 25 and 40% of patients have counts <5000/µl, and 20% have counts >100,000/µl. Platelet counts <100,000/µl are found at diagnosis in ~75% of patients, and about 25% have counts <25,000/µl.

PROGNOSTIC FACTORS

Many factors influence the likelihood of entering CR, the length of CR, and the curability of AML. CR is defined after examination of both blood and bone marrow. The blood neutrophil count must be ≥1500/µl and the platelet count ≥100,000/µl.

TREATMENT Treatment of the newly diagnosed patient with AML is usually divided into two phases, induction and postremission management . The initial goal is to quickly induce CR. Once CR is obtained, further therapy must be used to prolong survival and achieve cure. The initial induction treatment and subsequent consolidation therapy are often chosen based upon the patient's age.The influence of intensifying therapy with traditional chemotherapy agents such as cytarabine and

anthracyclines in younger patients (<60 years) appears to increase the cure rate of AML.

In older patients, the benefit of intensive therapy has been more difficult to document and therefore pursuit of novel therapies as consolidation for these patients has recently been actively pursued.

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Induction Chemotherapy The most commonly used CR induction regimens (for patients other than those with APL) consist of combination chemotherapy with cytarabine (cytosine arabinoside) and an anthracycline. Cytarabine is a cell cycle S-phase-specific antimetabolite that becomes phosphorylated intracellularly to an active triphosphate form that interferes with DNA synthesis. Anthracyclines are DNA intercalaters. Their primary mode of action is thought to be inhibition of topoisomerase II, leading to DNA breaks.

Cytarabine is usually administered as a continuous intravenous infusion at 100 to 200 mg/m2 per day for 7 days. Anthracycline therapy generally consists of daunorubicin, 45 to 60 mg/m2, intravenously on days 1, 2, and 3 (the 7 and 3 regimen). Treatment with idarubicin at 12 or 13 mg/m2 per day for 3 days in conjunction with cytarabine by 7-day continuous infusion is at least as effective and may be superior to daunorubicin in younger patients. The addition of etoposide does not increase the CR rate but may improve the CR duration.

After induction chemotherapy, the bone marrow is examined to determine if the leukemia has been eliminated. If >5% blasts exist with ≥20% cellularity, the patient has traditionally been retreated with cytarabine and an anthracycline in doses similar to those given initially, but for 5 and 2 days, respectively. Our recommendation, however, is to change therapy in this setting. Patients who fail to attain CR after two induction courses should immediately proceed to an allogeneic stem cell transplant (SCT) if an appropriate donor exists.

Treatment of Promyelocytic Leukemia Tretinoin is an oral drug that induces the differentiation of leukemic cells bearing the t(15;17); it is not effective in other forms of AML. APL is responsive to cytarabine and daunorubicin, but about 10% of patients treated with these drugs die from DIC induced by the release of granule components by dying tumor cells.

Postremission Therapy

Induction of a durable first CR is critical to long-term disease-free survival in AML. However, without further therapy virtually all patients experience relapse. Once relapse has occurred, AML is generally curable only by SCT

ALL
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Treatement: Induction
Vincristine Prednisolone L-asparaginase Daunorubicin Methotrexate

Maintenance
Prednisolone Vincristine Mercaptopurine Methotrexate