Intensifying induction therapy in acute myeloid leukemia: has a new standard of care emerged?

I term survival without an apparent effect on the initial response rate. However, reports of improved disease-free surNDUCTION THERAPY for acute myeloid leukemia (AML) has been fairly standardized over the past two decades, with major controversies addressing the optimal vival attributable to intensified induction therapy need to be cautiously interpreted. Such benefit may be impossible to postremission therapy. Nevertheless, whereas the most common induction therapy for AML consists of 3 days of an determine without regard to the choice of postremission therapy, much like the difficulty in evaluating the results of anthracycline, usually daunorubicin, and 7 days of cytarabine (3 / 7), many trials have been conducted in an attempt consolidation therapy without considering the type of induction. Finally, any strategy to intensify induction may lead to to improve this standard by introducing a more intensive combination with potential to improve the complete remismore profound myelosuppression and the potential for toxicity needs to be carefully considered. Such an approach may sion rate, remission duration, or the number of patients cured. Modern therapy with AML begun some 30 years ago with be associated with more severe treatment-related morbidity and mortality or, alternatively, toxicity may be less if fewer the introduction of cytosine arabinoside and daunorubicin. With either of these single agents, 30% to 40% of adults patients require more than one course of induction therapy. Several studies have explored the benefits of amsaattained a complete response and a small proportion of these crine, aclarubicin, mitoxantrone, and idarubicin. patients were long-term survivors. Significant further imSeveral well-conducted randomized trials showed that idaruprovement occurred with the introduction of combination bicin, aclarubicin, and amsacrine may be superior to chemotherapy for AML induction. For much of the past two daunorubicin in younger adults. Furthermore, a randomized decades, induction therapy has consisted of daunorubicin, study suggested that mitoxantrone is at least as effective cytarabine, and 6-thioguanine (DAT). Most investigators as daunorubicin. However, these agents have been compared now have eliminated 6-thioguanine from the standard inducwith daunorubicin at a dose of 45 mg/m. Notwithstanding tion regimen because its inclusion was not shown to improve theoretical advantages to the use of idarubicin, it is not overall results. Although there is no single established clear that any observed improvement represents an inherent induction regimen, the most widely used combination for biologic advantage of a particular drug rather than biologic treatment of newly diagnosed AML has been daunorubicin dose equivalence. There are no data to suggest that a higher (the first available anthracycline) at a dose of 45 mg/m dose of daunorubicin is more effective, because a prospective intravenously for 3 days and cytarabine at a dose of 100 mg/ comparison of daunorubicin 45 mg/m versus 60 mg/m or m intravenously by continuous infusion for 7 days. This higher has not been conducted. However, studies by the is the standard against which most new regimens are tested. Southwest Oncology Group (SWOG) have reported a subWith this regimen, between 50% and 75% of adult patients stantially better complete response rate with daunorubicin at with AML achieve complete remission, but 25% to 40% a dose of 70 mg/m 32 compared with 45 mg/m. Although of patients require more than one course of induction to this was not a randomized comparison, these were sequential achieve complete remission. A randomized study by the studies by the same cooperative group in which only the Cancer and Leukemia Group B (CALGB) established that dose of daunorubicin varied. Randomized data comparing reducing the dose of daunorubicin to 30 mg/m resulted in a lower response rate, particularly in adults less than 60 years of age. From the University of Rochester Medical Center, Rochester, NY; Increasing the intensity of induction has generated considRambam Medical Center, Technion, Haifa, Israel; and the Northerable recent interest and such a strategy may be effective western University Medical Center, Chicago, IL. in at least two ways. First, because achieving complete reSubmitted May 13, 1997; accepted June 27, 1997. mission is considered a sine qua non for prolonged diseaseAddress reprint requests to Jacob M. Rowe, MD, University of free survival, it is likely that any combination that alters the Rochester Medical Center, 601 Elmwood Ave, Rochester, NY 14642. complete remission rate will affect the long-term outcome. q 1997 by The American Society of Hematology. 0006-4971/97/9006-0040$3.00/0 Second, intensified induction therapy may affect the long-