Study Determines Optimal Chemotherapy Regimen for Younger Patients With AML
In a study (Medical Research Council AML 15 Trial) reported in Journal of Clinical Oncology, Alan K. Burnett, MD, of Cardiff University School of Medicine and colleagues compared induction with daunorubicin/cytarabine, daunorubicin/cytarabine plus etoposide, and fludarabine/cytarabine/granulocyte colony-stimulating factor (Neupogen) (FLAG) plus idarubicin, and consolidation with amsacrine/cytarabine/etoposide followed by mitoxantrone/cytarabine vs high-dose cytarabine in younger patients with acute myeloid leukemia (AML). The results suggest that FLAG plus idarubicin induction and high-dose cytarabine consolidation may be the most beneficial regimen in patients with favorable- or intermediate-risk disease.
The trial population consisted of 3,106 patients with AML with a median age of 49 years, including 87 children (who received daunorubicin/cytarabine plus etoposide after closure of the FLAG plus idarubicin arm) and 424 patients (14%) who were older than 60 years. Patients were randomly assigned to two courses of induction therapy with daunorubicin/cytarabine (n = 994) vs daunorubicin/cytarabine plus etoposide (n = 989) and daunorubicin/cytarabine plus etoposide (n = 633) vs FLAG plus idarubicin (n = 635). Among patients achieving remission, 1,440 were then randomly assigned to two courses of amsacrine/cytarabine/etoposide followed by mitoxantrone/cytarabine (n = 718) or high-dose cytarabine (n = 722) at 1.5 g/m2 (n = 329) or 3 g/m2 (n = 393, including 65 children). Finally, 227 patients (younger than 45 years) were randomly assigned to a fifth course of cytarabine (n = 112) or not (n = 115).
Induction Comparisons
The complete remission rate was nonsignificantly better with daunorubicin/cytarabine plus etoposide vs daunorubicin/cytarabine (82% vs 78%, hazard ratio [HR] = 1.24, P = .06); complete remission with incomplete peripheral count recovery rates were 4% and 6%, giving an overall complete marrow response of 86% vs 84%. Complete remission or complete remission with incomplete peripheral count recovery after course 1 was achieved in 70% of daunorubicin/cytarabine plus etoposide patients (81% of patients achieving remission) and 63% of daunorubicin/cytarabine patients (75% of remissions) (P = .002). There were no significant differences in induction deaths or 30- or 60-day mortality.
There were no significant differences between daunorubicin/cytarabine plus etoposide and FLAG plus idarubicin in rates of complete remission (81% vs 84%), complete remission with incomplete peripheral count recovery (4% vs 2%), or overall marrow response (85% vs 86%), but more FLAG plus idarubicin recipients (77%, 90% of all remissions) achieved complete remission or complete remission with incomplete peripheral count recovery with one course than did daunorubicin/cytarabine plus etoposide recipients (67%, 78% of remissions) (P < .001). There were no differences in rates of induction death or 30- and 60-day mortality.
Daunorubicin/cytarabine plus etoposide and daunorubicin/cytarabine were associated with equivalent relapse risk, death in remission, relapse-free survival, and overall survival. FLAG plus idarubicin was associated with significantly reduced relapse rate at 8 years (38% vs 55%, P < .001) but increased risk of death in remission (17% vs 11%, P = .02). Relapse-free survival at 8 years was better with FLAG plus idarubicin (45% vs 34%, HR = 0.82, P = .01), but there was no overall survival benefit (44% vs 37%, HR = 0.92, P = .2).
Consolidation Comparisons
Randomization to consolidation occurred at a median of 77 days from diagnosis. There were no significant differences between amsacrine/cytarabine/etoposide followed by mitoxantrone/cytarabine and high-dose cytarabine groups in cumulative incidence of relapse, cumulative incidence of death in complete remission, relapse-free survival, or overall survival. When analyzed by cytogenetic risk group, there were no differences in cumulative incidence of relapse, cumulative incidence of death in complete remission, relapse-free survival, or overall survival in favorable-risk or intermediate-risk subgroups, but 8-year overall survival in the amsacrine/cytarabine/etoposide followed by mitoxantrone/cytarabine group was significantly better in patients with adverse-risk cytogenetics (39% vs 0%, P = .0004, P = .003 for interaction).
Amsacrine/cytarabine/etoposide followed by mitoxantrone/cytarabine was associated with more toxicity and myelosuppression, particularly after the second course, during which slower neutrophil (31 vs 23 days, P = .001) and platelet recovery (50 vs 31 days, P = .001) required significantly more blood product and antibiotic support and resulted in more hospitalizations.
In the cytarabine dose comparison, there was a trend for higher relapse risk in the lower-dose subgroup, but no difference in overall survival. There were modest differences in hematologic toxicity between the two subgroups, but significantly more care and hospitalization was required in the higher-dose subgroup. Cytarabine as a fifth course of treatment provided no advantage overall or for any subgroup compared with no fifth course of treatment.
Among 54 patients who received two induction courses of FLAG plus idarubicin and no consolidation, 8-year overall survival did not differ significantly from that in patients receiving all four courses of daunorubicin/cytarabine plus etoposide or daunorubicin/cytarabine induction and consolidation (57% vs 54%, P = .5). Among 101 patients who received two courses of daunorubicin/cytarabine plus etoposide or daunorubicin/cytarabine induction and no consolidation, survival was significantly worse compared with those who also received consolidation (35% vs 54%, P < .001).
Survival in the 230 FLAG plus idarubicin patients who received four courses of induction and consolidation was significantly better than that in 979 daunorubicin/cytarabine plus etoposide or daunorubicin/cytarabine patients who received four courses of induction and consolidation (70% vs 54%, P < .001). The benefit persisted after adjustment for age, white blood cell count, cytogenetics, and secondary disease (P = .002).
Patients with favorable- or intermediate-risk disease who received two courses of FLAG plus idarubicin induction and two courses of high-dose cytarabine consolidation had an 8-year survival rate of 72% (95% for favorable risk and 63% for intermediate risk). Censoring of transplant recipients at time of transplant yielded overall survival rates of 100% and 77% for favorable- and intermediate-risk groups. As stated by the investigators, “This suggests that this is the optimal treatment plan that emerges from this study.”
The investigators concluded: “[FLAG plus idarubicin] is an effective remission induction treatment, with a high complete remission rate after course 1 and reduced relapse. Consolidation with [amsacrine/cytarabine/etoposide followed by mitoxantrone/cytarabine] is similar overall to high-dose cytarabine, but superior in high-risk patients. Cytarabine at 1.5 g/m2 is equivalent to a 3 g/m2 dose. A fifth course is unnecessary. In patients receiving [FLAG plus idarubicin] (two courses) and cytarabine (two courses), 8-year survival was 63% for patients with intermediate-risk and 95% for those with favorable-risk disease.”
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