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: 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: 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: 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: 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: ARIAD Pharmaceuticals Inc.

Copyright © 2015 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Levels of residual disease after 1 cycle of protocol therapy in CR. MRD after 1 cycle at CR by BCR-ABL1/ABL1 percentage and flow cytometry.

Figure 2

MRD status by PCR and by flow cytometry with follow-up. (A) MRD by time from therapy according to BCR-ABL1/ABL1 percentage.* The line connects the median values of the patients at the stated time points. Several patients at different time intervals had overlapping values. In 1 patient, BCR-ABL1 was undetectable at presentation by RT-qPCR and was detected by fluorescence in situ hybridization. (B) MRD by time from therapy according to multiparameter flow cytometry. *The number of patients at start is only 29 because 3 had prior therapy and 5 had a BCR/ABL1 not performed at start or it was not quantified

Figure 2

MRD status by PCR and by flow cytometry with follow-up. (A) MRD by time from therapy according to BCR-ABL1/ABL1 percentage.* The line connects the median values of the patients at the stated time points. Several patients at different time intervals had overlapping values. In 1 patient, BCR-ABL1 was undetectable at presentation by RT-qPCR and was detected by fluorescence in situ hybridization. (B) MRD by time from therapy according to multiparameter flow cytometry. *The number of patients at start is only 29 because 3 had prior therapy and 5 had a BCR/ABL1 not performed at start or it was not quantified

Figure 3

Event-free survival and OS of the patients. (A) EFS and (B) OS. Numbers of patients at risk are indicated on the horizontal axis and in the table below the chart. Dotted lines are 95% CIs.

Figure 3

Event-free survival and OS of the patients. (A) EFS and (B) OS. Numbers of patients at risk are indicated on the horizontal axis and in the table below the chart. Dotted lines are 95% CIs.

Figure 4

Outcome with and without censoring for ASCT.