A phase III randomized trial of intensive induction and consolidation chemotherapy ± oblimersen, a pro-apoptotic Bcl-2 antisense oligonucleotide in untreated acute myeloid leukemia patients >60 years old

7012 Background: Overexpression of Bcl-2, an inhibitor of apoptosis, may render AML cells resistant to chemotherapy and has been associated with unfavorable outcome. Genasense is a phosphorothioate 18-mer antisense oligonucleotide directed against the first 6 codons of Bcl-2. In a phase I study of older (≥60 yrs) AML patients (pts) treated with Genasense in combination with cytarabine (Ara-C) and daunorubicin (DNR) induction and with high-dose cytarabine (HiDAC) consolidation, no antisense-related toxicity was reported. Furthermore, overexpression of Bcl-2 at diagnosis and down-regulation of the Bcl-2 target after antisense treatment was shown in pts achieving complete remission (CR). Methods: A phase III trial (CALGB 10201) randomized untreated older AML pts to induction treatment with Ara-C (100 mg/m 2 /d by CIVI on days 4–10) and DNR (60 mg/m 2 /d on days 4–6) followed by consolidation therapy with HiDAC (2 g/m 2 /d on days 4–8) with (Arm A) or without (Arm B) Genasense (7 mg/m 2 /d CIVI on days 1–10 for induction and days 1–8 for consolidation). The study was powered to identify a survival advantage for pts receiving Genasense. Results: 503 pts enrolled between 12/03 and 10/06; 76 had prior MDS and 24 prior chemoradiotherapy for unrelated cancers. The arms were balanced for age, sex, race, and performance status. No differences in toxicities were observed between the 2 arms. An interim futility analysis performed at 34 months from initiation of the study showed no differences in CR rates (48% vs 52%; p=0.75) or overall survival (OS; p=0.83) between the 2 arms. Estimated OS at 1 yr was 36% for Arm A and 40% for Arm B. Similarly, there were no differences in disease-free survival from date of CR (DFS; p=0.78) or event-free survival (EFS; p=0.77). DFS and EFS rates at 1 yr were 40% and 25% for Arm A, and 43% and 7% for Arm B, respectively. Conclusions: Addition of Genasense to induction and consolidation chemotherapy failed to improve the outcome of older AML pts. Pretreatment levels and post-antisense treatment changes in Bcl-2 expression are now being measured and correlated with outcome. No significant financial relationships to disclose.