Outcome with the Hyper-CVAD and Imatinib Mesylate Regimen as Frontline Therapy for Adult Philadelphia (Ph) Positive Acute Lymphocytic Leukemia (ALL).
Authors: Thomas Deborah A. , Kantarjian Hagop M. , Cortes Jorge , Faderl Stefan , Giles Francis , Garcia-Manero Guillermo , Wierda William , Ferrajoli Alessandra , Ravandi-Kashani Farhad , Verstovsek Srdan , Andreeff Michael , Letvak Laurie A. , Jones Dan , Champlin Richard , O’Brien Susan 
Published: October 2019

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 & 13. Allogeneic stem cell transplant (SCT) was performed in first CR if feasible. Preliminary results of the first 20 patients (pts) treated were encouraging [Thomas et al, Blood103:4396, 2004]. To exploit dose-response relationships, imatinib was increased to 600 mg days 1–14 of course 1, then daily with courses 2–8. Maintenance was extended to 24 mos followed by imatinib indefinitely. To date, 52 pts with imatinib-naïve de novo or minimally treated Ph-ALL received therapy from April 2001–July 2006. Forty-four pts had active disease, either untreated (n=37) or refractory (n=6) to 1 induction course; 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.