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

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• 作者：Dr Elias Jabbour ; MD^a ; ^{ejabbour@mdanderson.org" class="auth_mail" title="E-mail the corresponding author} ; Prof Hagop Kantarjian ; MD^a ; Prof Farhad Ravandi ; MD^a ; Prof Deborah Thomas ; MD^a ; Prof Xuelin Huang ; PhD^b ; Prof Stefan Faderl ; MD^a ; Prof Naveen Pemmaraju ; MD^a ; Naval Daver ; MD^a ; Prof Guillermo Garcia-Manero ; MD^a ; Koji Sasaki ; MD^a ; Prof Jorge Cortes ; MD^a ; Rebecca Garris^a ; C Cameron Yin ; MD^c ; Joseph D Khoury ; MD^c ; Prof Jeffrey Jorgensen ; MD^b ; Prof Zeev Estrov ; MD^a ; Zachary Bohannan ; MA^a ; Marina Konopleva ; MD^a ; Tapan Kadia ; MD^a ; Nitin Jain ; MD^a ; Courtney DiNardo ; MD^a ; Prof William Wierda ; MD^a ; Vicky Jeanis ; RN^a ; Prof Susan O'Brien ; MD^a
• 刊名：The Lancet Oncology
• 出版年：2015
• 出版时间：November 2015
• 年：2015
• 卷：16
• 期：15
• 页码：1547-1555
• 全文大小：451 K

文摘

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.

Methods

a150">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.

Findings

a160">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.

Interpretation

a170">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.

Funding

a180">ARIAD Pharmaceuticals Inc.