Untreated acute leukemia is a uniformly fatal disease with a median survival time shorter than 3 months. Current treatment strategies provide a significant increase in survival time for most patients, some of whom may be cured. The majority of patients with acute leukemia, however, ultimately die of the disease or complications of treatment. The effective treatment of acute leukemia requires (1) differentiation of acute myeloid leukemia (AML) from acute lymphoblastic leukemia (ALL) and recognition of clinically relevant subtypes; (2) identification of patients who are more likely or less likely than average to benefit from a conventional treatment; and (3) selection of therapy that provides a reasonable likelihood of response with acceptable risk of toxic effects. The diagnosis of acute leukemia is established in most cases by a bone marrow aspirate that demonstrates at least 30% blast cells. The traditional criteria to distinguish between AML and ALL rely on morphology and cytochemical reactions. Immunologie analysis of antigen expression and analysis for numerical or structural chromosomal abnormalities of leukemia cells are routinely feasible. Karyotypic analysis is of prognostic importance and should be performed on all diagnostic specimens of bone marrow aspirate. Immunophenotypic analysis may be useful to confirm the disease classification in selected cases. The importance of the routine immunophenotypic characterization of acute leukemia, however, is controversial. The subtypes that must be recognized because of the need for specific treatment include (a) acute promyelocytic leukemia (APL), which is the M3 subtype of AML, and (b) the L3 subtype or mature B-cell ALL. Induction therapy for acute leukemia is treatment intended to achieve induction of complete remission (CR). Complete remission is defined as the absence of morphologic evidence of leukemia after recovery of the peripheral blood cell counts. Failure to achieve CR may be attrib-uted to death during chemotherapy-induced bone marrow hypoplasia or to drug resistance manifested either as failure to achieve hypoplasia or as persistent leukemia after recovery from hypoplasia. Postremission therapy is treatment administered in CR to prevent or delay relapse of the leukemia. However, the majority of patients have disease relapse. Intensification of therapy is a treatment strategy designed to overcome resistance to chemotherapy. Recent clinical trials of intensified induction or postremission therapy suggest improved outcome. However, the toxic effects of dose intensification can be substantial, limiting any potential benefit of this approach. Identification of prognostic factors may allow one to estimate the likelihood of an outcome, to determine an optimal treatment strategy. It is well established that age at the time of diagnosis, leukemia cell karyotype, and whether the leukemia is de novo or secondary are factors that influence treatment decisions. Patients with favorable. prognostic factors should probably receive conventional therapy. Patients with unfavorable prognostic factors have shown little benefit from conventional therapy. In addition, factors that indicate poor outcome with conventional therapy are also predictive of poor outcome with intensified therapy. Consequently, these patients should be considered for investigational therapeutic strategies. The bias may be to counsel them to accept the potential increased morbidity of such treatment before there is definite evidence of the possibility of improved outcome. Induction chemotherapy for younger patients with AML (less than 55 years of age) in general consists of one or more courses of cytarabine (ara-C) and an anthracycline or an anthracycline derivative. Randomized trials have failed to confirm that treatment with either etoposide or high-dose ara-C induces disease remission. Patients with secondary AML, high levels of CD34 antigen expression, or an unfavorable karyotype, however, may benefit from induction therapy with high-dose ara-C. For APL,the combination of all-trans-retinoic acid and an anthracycline during induction therapy is a reasonable therapeutic strategy.Adults withALL typically receive vincristine, prednisone, and an anthracycline; the efficacy of additional agents such as L-asparaginase and cyclophosphamide has not been unequivocally demonstrated. Patients with the L3 subtype of ALL should receive intensive chemotherapy that is completed within 6 months. The risk of toxic effects in some older patients may outweigh the potential benefit of therapy. In general, conventional induction therapy appears to be the best option for those who are treated. The relative value of conventional and myeloablative therapy during the first complete remission (CR1) is controversial and is thought to depend on characteristics of the patient. Randomized trials have not confirmed the value of allogeneic or autologous bone marrow transplantation (BMT) in CR1 for most patients withAML or ALL. Younger patients with poor prognostic factors may be candidates for BMT in CR1. Patients with ALL positive for the Philadelphia chromosome (Ph) should have allogeneic BMT in CR1. Thus the majority of patients in CR1 should receive conventional postremission therapy. For patients withAML, postremission therapy should include highdose ara-C. All of the treatment strategies proposed for ALL include consolidation therapy, which involves administration of drugs at doses and schedules that are significantly myelosuppressive, followed by maintenance therapy, which consists of prolonged moderately myelosuppressive chemotherapy administered intermittently. Approximately 75% of patients with acute leukemia who achieve CR have relapse. The likelihood of relapse is influenced by a variety of factors including age, cytogenetic findings, and initial leukocyte count. Effective treatment of relapsed acute leukemia is limited by a low CR rate, a high treatment-related mortality, and a low likelihood of prolonged disease-free survival. Multiple studies have demonstrated that the longer the duration of CR1 the greater the likelihood of response to reinduction therapy and a durable CR2. BMT appears to be the optimal treatment in second relapse or untreated first relapse. Use of partially matched, related donors or matched, unrelated donors is feasible and may be preferable to autologous BMT.
ASJC Scopus subject areas
- Cancer Research