Addition of 5-Azacitidine to Standard Induction Therapy Is Feasible In Older Patients with Acute Myeloid Leukemia: The AML-AZA Trial of the SAL Study Group

Standard chemotherapy is curative only in a minority of older patients with AML and chemotherapy efficacy in this patient group has not improved in the last decade. Epigenetic alterations such as aberrant promoter DNA methylation occur frequently in AML patients and might provide novel targets for therapy improvement. The demethylating agent azacitidine is effective as a single agent in AML and MDS but does not lead to long term remissions. In the dose-finding part of the AML-AZA study, we analyzed the feasibility of two different doses of azacitidine added to standard 7+3 induction therapy in older patients (≥61 years) with AML.

Two cohorts with 6 patients each were treated with azacitidine either 37.5 or 75 mg/sqm for 5 days, followed by standard induction chemotherapy 7+3 (cytarabine 100 mg/sqm on days 6–12 and daunorubicin 45 mg/sqm on days 8–10). In patients without blast clearance on day 15, a second cycle of the same induction regime (azacitidine +7+3) was administered. Patients who achieved a complete remission received two cycles of consolidation therapy consisting of 5 days of azacitidine (same dose as for induction therapy) followed by intermediate-dose cytarabine (1g/sqm q12h days 6, 8 and 10).

Overall, 2 out of 6 patients at the 37.5 mg/sqm dose level and 4 out of 6 patients at the 75 mg/sqm level achieved a complete remission after induction therapy. Character and number of adverse events were similar to reported data from elderly AML patients treated with intensive chemotherapy. Among the 12 patients, the following 4 serious adverse events occurred: a severe hemolysis (most likely induced by fluorchinolone antibiotics) which resolved, a fatal apoplectic stroke and a fatal hepatorenal syndrome four days after the end of 7+3 chemotherapy at the 37.5 mg/sqm level, and a fatal pneumonia before 7+3 therapy could be initiated at the 75 mg/sqm level. The median duration of grade 4 leukopenia (CTCAE) was 26 days and the median duration of grade 4 thrombopenia was 22 days. Two patients went on for allogenic stem cell transplantation and were censored for survival analysis at the time of transplantation. Median event free survival was not reached after a median follow up of 5.5 months, and median overall survival was 8.1 months after a median follow up of 7 months.

Our data indicate that the combination of azacitidine with standard induction therapy is feasible in older patients with AML with a similar tolerability of 37.5 mg/sqm and 75 mg/sqm. As a result, 75 mg/sqm azacitidine was selected as the investigational arm of the currently recruiting randomized phase II study comparing standard chemotherapy in AML with versus without azacitidine (AML-AZA). The study is registered at clinicaltrials.gov (NCT00915252).

Off Label Use: use of Azacitidine, a hypomethylating agent, in adjunct to classic chemotherapy in elderly patients with AML. Koschmieder: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees.