Phase II study of combination of hyperCVAD with ponatinib in frontline therapy of patients (pts) with Philadelphia chromosome (Ph) positive acute lymphoblastic leukemia (ALL).

Abstract

7024 Background: Combination of chemotherapy with TKIs was evaluated and appears to be effective in Ph+-ALL. Ponatinib is a more potent inhibitor and suppresses the T315I clones, a common cause of relapse in pts with Ph+- ALL. Clinical trials of ponatinib have demonstrated its high activity and limited toxicity in pts with Ph+-leukemia failing 2-3 TKIs and in those with a T315I mutation. Combinations of chemotherapy regimens and ponatinib may be associated with better response rates and higher likelihood of eradication of MRD. Methods: In this phase II trial, pts with newly diagnosed Ph+ ALL receive ponatinib 45 mg po QD for the first 14 days of cycle 1 then continuously for the subsequent 7 cycles. Pts in CR receive maintenance with ponatinib 45 mg po QD and vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. MRD monitoring is conducted. Results: To date 20 pts with untreated Ph+ ALL have received a median of 6 cycles; 5 pts are receiving maintenance in CR. Median age is 49 years. Median WBC at diagnosis was 2.45 x 109/L. All pts were in CR after 1 cycle. 15 of the 17 pts (88%) known to be Ph+ by cytogenetic analysis at baseline achieved CCyR after 1 cycle; 1 had mCyR only and 1 had no cytogenetic analysis at CR, both of them achieved CCyR after cycles 2; 3 had a diploid karyotype at the start. To date, 17 pts (85%) have achieved MMR, of whom 11 (55%) have achieved CMR at a median of 10 weeks from initiation of treatment. MRD assessment by flow cytometry is negative in 18 (90%) pts at a median of 3 weeks. Median time to neutrophil and platelet recovery for cycle 1 was 18 and 22 days, and 16 and 22 days for subsequent cycles, respectively. Grade ≥3 toxicity included increase of LFT’s/hyperbilirubinemia in 8 pts, thrombosis in 3, skin rash in 2, pancreatitis in 1, and pericardial effusion in 1. With a median follow up of 6 months, 19 pts are alive and in CR; 1 pt died in CR from an unrelated cardiac event. 1 pt has undergone an allogeneic transplant. The 1-year PFS and OS rates were 100% and 95%, respectively. Conclusions: The combination of hyperCVAD with ponatinib is safe and highly effective in achieving molecular remissions in pts with Ph+ ALL. Clinical trial information: NCT01424982.