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Chemotherapy plus ponatinib may improve Ph+ALL outcomes
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The combination of chemotherapy plus ponatinib yielded early sustained remissions among patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia, according to the results of a single-arm, phase 2 study.
Combining chemotherapy with a tyrosine kinase inhibitor has demonstrated efficacy among patients with Ph+ALL, according to study background.
Thus, Elias Jabbour, MD, associate professor in the department of leukemia at The University of Texas MD Anderson Cancer Center, and colleagues sought to examine the safety and efficacy of combining hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (hyper-CVAD) with ponatinib (Iclusig, Ariad Pharmaceuticals) — a more potent BCR-ABL1 inhibitor than all other TKIs — in patients with newly diagnosed Ph+ALL.
The study included data from 37 patients (median age, 51 years; range, 27-75), including those who were previously untreated, as well as those who had received fewer than two previous chemotherapy courses with or without TKIs.
Patients received eight hyper-CVAD cycles alternating with high-dose methotrexate and cytarabine every 21 days, along with 45 mg daily ponatinib during the first 14 days of the first cycle. Researchers then administered ponatinib continuously in subsequent cycles.
Patients who achieved complete remission received maintenance therapy consisting of 45 mg daily ponatinib with monthly vincristine and prednisone for 2 years, followed by ponatinib indefinitely.
EFS served as the primary endpoint.
Median follow-up was 26 months (range, 15-39).
The cohort had a 2-year EFS rate of 81% (95% CI, 64-90), and the estimated 2-year OS rate was 80% (95% CI, 63-90).
At follow-up, 78% of patients (n = 29) achieved complete remission. The other nine patients underwent allogeneic stem cell transplantation.
At time of reporting, 13 patients remained in complete remission and on maintenance therapy.
Two patients died of myocardial infarction potentially related to treatment. An additional patient died of MI related to sepsis. The researchers deemed two additional deaths — one from bleeding and one from infection — unrelated to treatment.
Infection during induction was the most frequent grade 3 or higher adverse event, occurring in 54% (n = 20) of patients. Other reported adverse events included increased aspartate aminotransferase and alanine aminotransferase concentration (38%; n = 14), skin rash (22%; n = 8), pancreatitis (16%, n = 6), hypertension (16%; n = 6), thrombotic events (8%; n = 3) and MI (8%; n = 3).
“A longer follow-up is needed to confirm these findings,” Jabbour and colleagues wrote. “New strategies, including dose titration of ponatinib, optimum control of vascular risk factors and the addition of new monoclonal antibodies, might help to further improve outcomes.”
Questions remain regarding patient suitability and appropriate treatment course, Xavier Thomas, MD, PhD, a hematologist at Lyon-Sud Hospital in France, wrote in an accompanying editorial.
“Despite these encouraging results, some issues remain,” Thomas wrote. “First, should all patients receive ponatinib or only those harboring the T3151 mutation either present at diagnosis or developing or remaining after treatment with other TKIs? … Second, do favorable results allow a decrease in the intensity of chemotherapy combined with TKIs? Although systemic therapy with cytotoxic agents that cross the blood-brain barrier remains attractive to avoid sanctuary sites not penetrable by TKIs, it has been shown with imatinib [Gleevec, Novartis] that less intensive induction chemotherapy reduces mortality without impairing efficacy. Third, the question arises as to whether minimal residual disease is a major component for a personalized treatment algorithm that might identify candidates for allogeneic stem cell transplantation.” – by Cameron Kelsall
Disclosure: Ariad Pharmaceuticals provided funding for this study. Jabbour reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures. Thomas reports no relevant financial disclosures.
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