Long-Term Follow-Up after Frontline Therapy with the Hyper-CVAD and Imatinib Mesylate Regimen in Adults with Philadelphia (Ph) Positive Acute Lymphocytic Leukemia (ALL).
Authors: Thomas Deborah A. , Kantarjian Hagop M. , Ravandi Farhad , Faderl Stefan , Garcia-Manero Guillermo , Wierda William , Ferrajoli Alessandra , Verstovsek Srdan , Jones Dan , Letvak Laurie , Champlin Richard , Cortes Jorge , O’Brien Susan 
Published: November 2019

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. There was no impact on survival since remissions were brief with median CR duration of 16 mos [Kantarjian, JCO18:547, 2000; Cancer101:2788, 2004]. CR rate of imatinib in relapsed/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 for Ph-ALL was designed in 2001. Imatinib 400 mg was given days 1–14 of each course, followed by 12 months of continuous imatinib with monthly VCR and prednisone interrupted by 2 intensifications with hyper-CVAD and imatinib. Allogeneic stem cell transplant (SCT) was performed in first CR as feasible. Early results of 20 patients (pts) were encouraging and demonstrated feasibility [Thomas, Blood 103:4396, 2004]. Imatinib was then increased to 600 mg days 1–14 of course 1, continuously with courses 2–8, escalated to 800 mg during maintenance therapy (extended to 24 mos) then imatinib indefinitely. The study has completed accrual. Fifty-four pts with imatinib-naïve de novo or minimally treated Ph-ALL received therapy from April 2001 to September 2006. 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 years (range, 17–84); 52% were male. Seven pts (13%) had CNS disease at presentation. Of 45 evaluable pts 42 (93%) achieved CR (1 CRp, 1 partial response, 1 died early from sepsis). Median days to response was 21. Molecular response rate (negative by nested PCR) was 52%. Allogeneic SCT was performed in 16 pts within a median of 5 mos from start of therapy (range, 1–13), and did not appear to improve survival (2-yr rates 63% vs 56% without SCT). After median follow-up of 4 years (range, 10–74 mos), eleven relapses (22%) were observed. Eight de novo pts relapsed at 8, 8, 10, 11, 11, 15, 16 and 42 mos from start of therapy (2 after SCT without imatinib maintenance); 2 CR at start at 16 and 19 months, and 1 primary refractory pt at 12 mos. Two pts changed therapy for persistent molecular disease or intolerance and relapsed at 6 and 10 mos. Relapse was preceeded by positive multiparameter flow cytometry with minimal increments in levels of quantitative RT-PCR for bcr-abl in a few cases. Non T315I ABL kinase domain (KD) mutations were identified at relapse in 3 of 8 pts tested. Deaths included 12 pts in CR (5 infections, 4 complications of allogeneic SCT, 1 pancreatitis, 1 intracranial hemorrhage, 1 unknown). The hyper-CVAD and imatinib regimen continues to demonstrate favorable 3-yr disease-free and overall survival rates for the de novo group compared with hyper-CVAD alone (66% vs 14% and 55% vs 15%, respectively, p<0.001). Development of ABL KD mutations was noted at disease recurrence in a few cases. Incorporation of the newer tyrosine kinase inhibitors into combination with therapy with hyper-CVAD is underway.