Outcome after frontline therapy with the hyper-CVAD and imatinib mesylate regimen for adults with de novo or minimally treated Philadelphia (Ph) positive acute lymphoblastic leukemia (ALL)

Abstract

7019 Background: Historically, complete remission (CR) rates with hyper-CVAD in de novo adult Ph-ALL were 90% or better; disease recurrence remained problematic. The selective ABL tyrosine kinase inhibitor (TKI) imatinib was thus incorporated into hyper-CVAD for de novo or minimally treated Ph-ALL. Methods: The final regimen included imatinib 600 mg days 1–14 of induction, 600 mg continuously with courses 2–8, 800 mg during 2 yrs of maintenance therapy interrupted by intensifications, followed by imatinib indefinitely. Allogeneic stem cell transplant (SCT) was performed in first CR as feasible. The study accrued from April 2001 to September 2006. Fifty-four pts with imatinib-naive de novo or minimally treated Ph-ALL were treated: 6 were refractory to 1 induction course and 9 were in CR at start. Median age was 51 yrs (17–84); 52% were male, and 13% had CNS disease. Results: 42 of 45 pts (93%) with active disease achieved CR (1 CRp, 1 PR, 1 early death). All 6 refractory pts achieved CR. Molecular CR rate (MCR, confirmed by nested PCR) was 52% overall. Outcome was similar for achievement MCR vs no MCR (prior to SCT) with 3-yr disease-free (DFS) and overall survival (OS) rates of 80% vs 60% and 62% vs 50%, respectively (p=NS). Sixteen pts (33%) underwent allogeneic SCT in first CR a median of 5 mos from start of therapy (1–13). In the de novo group, 14 pts with median age 37 yrs had SCT whereas 33 pts with median age 53 yrs did not. 2-yr OS rates were 70% vs 58%, respectively (p=0.09), with 4 deaths in CR (2 infection, 2 GVHD) after SCT versus 10 deaths in CR (7 infection, 1 pancreatitis, 1 CNS hemorrhage, 1 unknown) after chemotherapy. With median follow-up of 4 yrs (13–74 mos), 22% pts relapsed within median of 15 mos (8–42), including 2 after SCT without imatinib maintenance. In the de novo group, 3 of 8 evaluable relapses had non-T315I ABL kinase domain mutations. The addition of imatinib improved outcome compared with hyper-CVAD alone (irrespective of SCT); overall 3-yr DFS and OS rates were 62% vs 14% and 55% vs 15%, respectively, p<0.001. Conclusions: Incorporation of second generation TKIs into the hyper-CVAD regimen may further improve on the favorable imatinib experience. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis