Consolidation Chemotherapy for Adults With AML in First Remission: Is There a Best Choice?

The treatment of patients younger than 60 years with acute myeloid leukemia (AML) is divided into two phases: remission induction and postremission therapy. Newly diagnosed patients receive socalled induction chemotherapy, with a goal of lowering the presumed 10 AML cells present at diagnosis to a level at which AML cells are undetectable by morphological analysis in the blood, bone marrow, and elsewhere, to the 10 cells believed to be present at the time of complete remission. Options for postremission therapy include highly myelosuppressive chemotherapy for three to four cycles, high-dose chemotherapy with autologous stem-cell transplantation (autotransplant), or allogeneic stem-cell transplantation (allo SCT). A potential third phase of therapy, maintenance therapy with low-dose chemotherapy, beneficial in acute lymphoblastic leukemia, is rarely used in AML. The rationale for induction followed by consolidation, as opposed to repetitive chemotherapy cycles as in the curative treatment for lymphoma, is that aggressive induction therapy is required to rapidly restore hematopoeisis in a patient who may be ill, infected, and/or bleeding. The problem of residual undetected cells at the time of remission and the requirement for postremission therapy was recognized 30 years ago. Some patients could be cured by chemotherapy, autotransplant, or allo SCT, the latter being associated with considerable morbidity and mortality but with a relatively low rate of leukemia relapse. The debate concerning the choice among postinduction options continues today but has been informed to a greater degree over time by cytogenetic and molecular-based predictors of who will respond well to chemotherapy approaches and who will require allo SCT. Modern postremission chemotherapy in AML has largely been based on the results of the Cancer and Leukemia Group B (CALGB) 8525 trial, in which adults of all ages were enrolled at diagnosis, given standard induction chemotherapy with 3 days of daunorubicin and 7 days of cytarabine (and a second cycle if needed), and randomly allocated at remission to four cycles of ara-C at various doses (100 mg/m over 24 hours per day for 5 days, 400 mg/m over 24 hours per day for 5 days, or 3 gm/m over 3 hours every 12 hours given on days 1, 3, and 5 [high-dose ara-C]). At the conclusion of these four courses, all patients were to receive lower doses of chemotherapy consisting of four cycles of 1 day of daunorubicin and 5 days of subcutaneous cytarabine. Patients younger than 60 years who were randomly allocated to the high-dose ara-C arm experienced a superior event-free and overall survival compared with those allocated to lower doses of ara-C. Subsequent analysis of this work demonstrated that the benefit of high-dose ara-C was seen mainly in those patients with so-called favorable chromosomal abnormalities at diagnosis (translocations involving the core binding factor [CBF] transcriptional apparatus, inv16 and t(8;21)), and/or in those with RAS mutations. High-dose ara-C given in the “CALGB style” was widely adopted as the standard of care for patients younger than 60 who undergo nontransplant approaches in AML in first complete remission and became the treatment of choice for those with favorable chromosomal abnormalities. The outcomes with high-dose ara-C–based consolidation chemotherapy are far from satisfactory. First, this is a toxic and expensive regimen with a low but appreciable rate of treatment-related mortality. Second, even among the most favorable group (patients with a CBF chromosomal abnormality) only about two thirds are cured; patients with less favorable disease biology are rarely cured. So-called risk adapted therapy is considered the ideal approach: patients with a favorable chromosome profile should receive high-dose ara-C, and those with clearly adverse biology should be allocated to an allogeneic transplant if there is an available donor. Most recent data suggest that it is reasonable to consider patients with intermediate-risk cytogenetics (mainly those with normal karyotype) for a sibling or matched unrelated donor allo SCT, except those with NPM1 mutation and without an FLT3 length mutation (and the smaller group of patients with CEBP bi-allelic mutation) who seemed to be responsive enough to chemotherapy such that stem-cell transplantation would not be advisable in first remission. The role of autologous transplantation is less clear, but its effect is probably roughly equivalent to several cycles of high-dose ara-C–based therapy. There have been several efforts to improve on high-dose ara-C postremission therapy. The CALGB itself dropped the fourth cycle of high-dose ara-C as well as four cycles of daunorubicin/cytarabine given at the end of the intensive consolidation and have replaced all high-dose ara-C cycles with an autologous transplant–based approach for non-CBF patients, but there seems little improvement in the overall outcome as a result of this change. Is the high-dose ara-C based postremission therapy beneficial just because it is myelo-intense, or is something particularly useful about high-dose ara-C itself? Could high-dose ara-C be given during induction, or would high-dose ara-C be useful only in consolidation? The trials that attempted to answer these questions included CALGB 9222, in which patients in remission received either three cycles of high-dose ara-C or three cycles of a so-called noncross-resistant regimen: the first was high-dose ara-C, the second was cyclophosphamide JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 17 JUNE 1