Outcome with the Hyper-CVAD and Imatinib Mesylate Regimen as Frontline Therapy for Adult Philadelphia (Ph) Positive Acute Lymphocytic Leukemia (ALL).

Although complete remission (CR) rates with the hyper-CVAD regimen (fractionated cyclophosphamide, vincristine VCR, doxorubicin, dexamethasone alternating with high dose methotrexate, ara-C) in de novo adult Ph-ALL were 90% or better; remissions were brief with median CR duration of 16 months (mos) Kantarjian et al, JCO18:547, 2000; Kantarjian et al, Cancer101:2788, 2004. Single agent activity of imatinib in relapsed or refractory Ph-ALL or chronic myelogenous leukemia in lymphoid blast phase was 20% with rapid disease recurrence. A phase II trial of hyper-CVAD and imatinib was conducted in newly diagnosed Ph-ALL. Imatinib was initially given 400 mg days 1–14 of each of the 8 courses, followed by 12 mos of imatinib, VCR and prednisone maintenance interrupted by hyper-CVAD and imatinib intensifications mos 6 9 pts were in CR. Median age was 51 years (range, 17–84); 52% were male. Five pts had CNS disease (10%). Of 43 evaluable pts with active disease at start (1 too early), 39 (91%) achieved CR (1 failed to meet platelet criteria for CR, 1 achieved partial response, 1 died early from sepsis). Multiparameter flow cytometry and quantitative RT-PCR for bcr-abl were monitored. Molecular response rate (negative nested PCR) without SCT was 58% in 33 evaluable pts. Fifteen pts underwent allogeneic SCT within a median of 5 months from start of therapy (range, 1–12); 3-yr survival rates were similar with or without SCT (60% vs 56%, p=0.8). After a median follow-up of 3 years (range, 1–60 mos), 7 relapses (14%) were observed. Five de novo pts relapsed at 8, 8, 11, 15 and 42 mos from start of therapy (2 after SCT without imatinib maintenance); 1 CR at start relapsed at 16 mos, and 1 primary refractory pt at 12 mos. Two other pts changed therapy either for persistent disease or intolerance and later relapsed at 6 and 10 mos. ABL mutation was identified at relapse in 1 (Q252H after SCT without imatinib) of 5 pts tested. Deaths in CR occurred in 12 pts (5 related to infections, 4 related to complications of allogeneic SCT, 1 pancreatitis, 1 intracranial hemorrhage, 1 unknown). Three-year remission and disease-free survival rates are favorable compared with hyper-CVAD alone (de novo group, 83% vs 24% and 55% vs 14%, respectively, p<0.001). Exploration of the newer tyrosine kinase inhibitors in combination with hyper-CVAD is planned.