Outcome after Frontline Therapy with the Hyper-CVAD and Imatinib Mesylate Regimen for Adults with De Novo or Minimally Treated Philadelphia Chromosome (Ph) Positive Acute Lymphoblastic Leukemia (ALL)

Abstract

Historically, complete remission (CR) rates with hyper-CVAD (cyclophosphamide, vincristine [VCR], doxorubicin and dexamethasone alternating with methotrexate and cytarabine) in de novo adult Ph-ALL were 90% or better; disease recurrence remained problematic. The selective ABL tyrosine kinase inhibitor (TKI) imatinib mesylate was thus incorporated into the hyper-CVAD regimen for de novo or minimally treated Ph-ALL [Thomas, Blood 103:4396, 2004]. The final regimen included imatinib 600 mg days 1–14 of induction, 600 mg continuously with courses 2–8, followed by escalation to 800 mg as tolerated during 24 mos of maintenance therapy with monthly VCR and prednisone interrupted by 2 intensifications with hyper-CVAD and imatinib, then 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. Forty-five pts had active disease, untreated (n=39) or refractory (n=6) to one induction course; 9 were in CR at start. Median age was 51 yrs (range, 17–84); 52% were male, and 13% had CNS disease at presentation. Of the 45 pts with active disease, 42 (93%) achieved CR (1 CRp, 1 partial response, 1 early death from sepsis). All 6 refractory patients achieved CR. Molecular CR rate (MCR, confirmed by nested PCR) prior to SCT was 52% overall. Sixteen pts (33%) underwent allogeneic SCT in first CR within a median of 5 mos from start of therapy (range 1–13). In the de novo group, 14 pts with median age of 37 yrs underwent allogeneic SCT in first CR whereas 33 pts with a median age of 53 years did not. The 3-yr survival (OS) rates were 66% vs 49% with or without SCT, respectively, p=0.36. The 3-yr CR duration rate was 84% for pts who achieved MCR (2 of 16 had SCT) compared to 64% for those who did not (14 of 35 had SCT), p=0.1; OS rates were similar regardless of MCR status. With a median follow-up of 52 mos (range 19–83+), 22% pts relapsed within a median of 15 mos from the start of therapy (range 8–42), including 2 after allogeneic SCT without imatinib maintenance. Detection of additional chromosome abnormalities at presentation did not influence outcome. In the de novo group, 4 of 9 evaluable relapses had ABL kinase domain mutations [E459K, Y253H, Y253F, F359V], none harbored T315I. The addition of imatinib improved outcome compared with hyper-CVAD alone (irrespective of allogeneic SCT); overall 3-yr CR duration and OS rates were 68% vs 25% and 55% vs 15%, respectively, p<0.001. Incorporation of second or later generation tyrosine kinase inhibitors into the hyper-CVAD regimen may further improve on the favorable imatinib experience. Allogeneic SCT in the TKI era needs to be reexamined in a prospective randomized trial.