Journal Article

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

Kantarjian, Hagop, Estrov, Zeev, DiNardo, Courtney, O'Brien, Susan, Jain, Nitin, Wierda, William, Huang, Xuelin, Sasaki, Koji, Ravandi, Farhad, Thomas, Deborah, Garcia-Manero, Guillermo, Bohannan, Zachary, Jeanis, Vicky, Konopleva, Marina, Daver, Naval, Khoury, Joseph D, Garris, Rebecca, Jabbour, Elias, Cortes, Jorge, Jorgensen, Jeffrey, Faderl, Stefan, Kadia, Tapan, Yin, C Cameron, Pemmaraju, Naveen

2015

Overview

Combination of chemotherapy with a tyrosine-kinase inhibitor is effective in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia. Ponatinib is a more potent BCR-ABL1 inhibitor than all other tyrosine-kinase inhibitors and selectively suppresses the resistant T315I clones. We examined the activity and safety of combining chemotherapy with ponatinib for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia in this continuing phase 2 trial. In this single-centre, phase 2, single-arm trial, adult patients with previously untreated Philadelphia chromosome-positive acute lymphoblastic leukaemia were sequentially enrolled. Patients who had received fewer than two courses of previous chemotherapy with or without tyrosine-kinase inhibitors were also eligible. Patients had to be aged 18 years or older, have an Eastern Cooperative Oncology Group performance status of 2 or less, have normal cardiac function (defined by ejection fraction above 50%), and have adequate organ function (serum bilirubin ≤3·0 mg/dL and serum creatinine ≤3·0 mg/dL, unless higher concentrations were believed to be due to a tumour). Patients received eight cycles of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) alternating with high-dose methotrexate and cytarabine every 21 days. Ponatinib 45 mg was given daily for the first 14 days of cycle 1 then continuously for the subsequent cycles. Patients in complete remission received maintenance with ponatinib 45 mg daily with vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. The primary endpoint for this study was event-free survival. The trial is registered at ClinicalTrials.gov, number NCT01424982. 37 patients were enrolled and treated from Nov 1, 2011, to Sept 1, 2013. 2-year event-free survival rate was 81% (95% CI 64–90). Grade 3 or more toxic effects included infections during induction (20 [54%] patients), increased aspartate aminotransferase and alanine aminotransferase concentration (14 [38%] patients), thrombotic events (three [8%]), myocardial infarction (three [8%]), hypertension (six [16%]), skin rash (eight [22%]), and pancreatitis (six [16%] patients). Two patients died from from myocardial infarction potentially related to treatment; another patient also died from myocardial infarction related to sepsis. Two further patients died, one from bleeding and another from infection, both deemed unrelated to treatment. The first results of this ongoing trial indicate that the combination of chemotherapy with ponatinib is effective in achieving early sustained remissions in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia. New strategies, including dosing titration of ponatinib and optimised control of vascular risk factors, might further improve outcomes. ARIAD Pharmaceuticals Inc.

• Publisher: Elsevier Ltd,Elsevier Limited
• Subject: Adult / Aged / Antineoplastic Agents - administration & dosage / Antineoplastic Combined Chemotherapy Protocols - administration & dosage / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Bone marrow / Cardiovascular disease / Chemotherapy / Chromosomes / Colleges & universities / Cyclophosphamide - administration & dosage / Cytogenetics / Dexamethasone - administration & dosage / Disease-Free Survival / Doxorubicin - administration & dosage / Fees & charges / Female / Flow cytometry / Heart attacks / Hematology, Oncology, and Palliative Medicine / Humans / Hypertension / Imidazoles - administration & dosage / Kinases / Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy / Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics / Male / Middle Aged / Mutation / Philadelphia Chromosome / Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy / Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics / Pyridazines - administration & dosage / Vincristine - administration & dosage