Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: a single-centre, phase 2 study

Abstract

Background The combination of chemotherapy with a tyrosine kinase inhibitor (TKI) is effective in the treatment of Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Ponatinib is a more potent BCR-ABL1 inhibitor and selectively suppresses the resistant T315I clones. We examined the efficacy and safety of combining chemotherapy with ponatinib for patients with Ph+ ALL in this ongoing Phase II prospective trial. Methods Adult patients with newly diagnosed Ph+ ALL and good performance and organ status received 8 cycles of hyper-CVAD alternating with high dose methotrexate/cytarabine every 21 days. Ponatinib was given at 45 mg daily for the first 14 days of cycle 1 then continuously for the subsequent cycles. Patients in complete remission (CR) received maintenance with ponatinib 45 mg daily with vincristine/prednisone monthly for 2 years followed by ponatinib indefinitely. The primary endpoint for this study was the improvement of median event-free survival from 24 to 36 months. The trial was registered on clinicaltrials.gov with the identifier NCT01424982. Results Thirty-seven patients with a median age of 51 years were treated. The overall complete cytogenetic response, major molecular response, and complete molecular response rates were 32/32 (100%), 35/37 (95%), and 29/37 (78%), respectively. By multiparameter flow cytometry, 35 patients (95%) had no detectable minimal residual disease after a median of 3 weeks of therapy. Grade ≥ 3 toxicity included infections during induction (20 patients), increased liver functional tests (14 patients), thrombotic events (3 patients), myocardial infarction (3 patients), hypertension (6 patients), skin rash (8 patients), and pancreatitis (6 patients). Two potentially related deaths from myocardial infarction were observed. Nine patients underwent allogeneic stem cell transplantation. With a median follow up of 26 months, 29 patients (78%) remain alive and in CR. The 2-year event-free and overall survival rates are 81% and 80%, respectively. Conclusion The first results of this ongoing trial indicate that the combination of chemotherapy with ponatinib is highly effective in achieving early sustained remissions in patients with newly diagnosed Ph+ ALL. New strategies, including dosing titration of ponatinib and optimized control of vascular risk factors may further improve outcomes. ARIAD Pharmaceuticals Inc. provided free drug and financial support from the ARIAD Investigator Sponsored Trial program.

A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study

“…We continue, therefore, to support a strategy that allows a CHR to be obtained in virtually all patients, including the elderly, based on this chemotherapy-free approach. Furthermore, our study confirms the importance of MRD, the negativity of which should be a major objective in this disease: a higher rate of MRD negativity is likely to be achieved with the inclusion of 2 nd -and, more likely, 3 rd -generation TKI such as ponatinib, which have been proven to have a greater debulking effect, 9,14,16,55 and might possibly be more active in patients with the BCR-ABL p210 form, given the lower MRD clearance observed in this subgroup of patients. As far as ponatinib is concerned, a recent study from the MDACC 55 on 37 patients has indeed shown that its use as upfront therapy, combined with chemotherapy, is able to induce extremely promising results with 2-year event-free survival (EFS) and OS of 81% and 80%, respectively, although 6 toxic deaths were recorded.…”

“…As far as ponatinib is concerned, a recent study from the MDACC 55 on 37 patients has indeed shown that its use as upfront therapy, combined with chemotherapy, is able to induce extremely promising results with 2-year event-free survival (EFS) and OS of 81% and 80%, respectively, although 6 toxic deaths were recorded. 55 Other strategies, based on the use of monoclonal antibodies or other immunologic approaches, need to be tested with the goal of offering an overall chemotherapy-free approach that might eradicate/control residual leukemic clones. This is particularly challenging for the elderly/less fit patients, particularly as the prevalence of Ph + ALL cases increases with age.…”

Overall survival with ponatinib versus allogeneic stem cell transplantation in Philadelphia chromosome‐positive leukemias with the T315I mutation

“…This is an important limitation of our indirect comparison, because treatment paradigms may have changed over time. For instance, recently, ponatinib in combination with chemotherapies demonstrated a significant improvement in 24‐month event‐free OS (up to 81% in patients with Ph+ ALL) 14. Longer follow‐up also may help us understand differences in OS between the intervention groups 15.…”

Impact of complete molecular response on survival in patients with Philadelphia chromosome–positive acute lymphoblastic leukemia

“…[11][12][13] The TKI was continued indefinitely as maintenance therapy. CR was achieved in 196 patients (97%), of whom 122 had MRD assessment for BCR-ABL1 by quantitative polymerase chain reaction at both CR and 3 months, as previously described.…”