The combination of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) with ponatinib appears to be safe and effective in achieving long-term remission in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL), according to study results published in The Lancet Haematology.
In a long-term phase 2 trial, 76 patients (median age, 47 years) with previously untreated Philadelphia chromosome-positive ALL received 8 cycles of 21 days of treatment. Treatment alternated between hyper-CVAD and a combination of high-dose methotrexate and cytarabine. In addition, patients received 45 mg ponatinib, a third generation BCR-ABL1 inhibitor, orally for the first 2 weeks of cycle 1 and continuously for subsequent cycles.
Patients who achieved complete remission received maintenance ponatinib indefinitely (30 mg or 15 mg daily). They also received vincristine (2 mg intravenously on day 1) and prednisone (200 mg orally on days 1-5) monthly for 24 months.
Ponatinib plus hyper-CVAD was found to result in sustained responses, with 83% of patients achieving a complete molecular response. The 3-year overall survival was 76%; overall survival was not affected by whether patients had received an allogeneic stem cell transplantation. Event-free survival at 3 years after treatment was 70%. Infections, increased transaminases, increased bilirubin, pancreatitis, hypertension, bleeding, and skin rash were the most common grade 3 or 4 adverse events reported.
The authors concluded that this regimen may represent a new standard of care as first-line therapy for this patient population, but further studies are warranted to investigate the optimal dose titration of ponatinib and the potential use of this agent with new monoclonal antibodies to further improve patient outcomes.
1. Jabbour E, Short NJ, Ravandi F, et al. Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: long-term follow-up of a single-centre, phase 2 study [published online December 1, 2018]. Lancet Haematol. doi: 10.1016/S2352-3026(18)30176-5