Preliminary data from the phase 2 PACE (Ponatinib Ph+ALL and CML Evaluation) trial show that ponatinib (Ariad Pharmaceuticals) can overcome the difficult-to-treat T315I mutation in patients with chronic myeloid leukemia (CML). Currently, patients with this genetic mutation have no effective treatment options.
In PACE, the tyrosine kinase inhibitor (TKI) ponatinib achieved a 47% major cytogenetic response (MCyR). For patients with the T315I mutation, ponatinib induced a 65% MCyR. This drug was specifically designed to overcome the T315I mutation.
“Ponatinib has the potential to become a promising new treatment option for patients with multi-refractory/relapsed CML,” said PACE lead investigator Jorge E. Cortes, MD, of the University of Texas M.D. Anderson Cancer Center, Houston.
This open-label study enrolled 499 patients with CML or with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) who had previously been treated with nilotinib or dasatinib, but their disease was resistant or intolerant to those drugs, or they had the T315I mutation.
Patients were stratified into 1 of 6 groups, according to disease, disease phase, and mutation status. All patients were treated with the same dose and schedule. The primary end points were MCyR for chronic-phase (CP)-CML, and major histologic response for accelerated-phase (AP)-CML, blast-phase (BP)-CML, or Ph+ALL.
After a median follow-up of 5 months, Dr Cortes reported high levels of response being observed in all patient types. Patients with AP-CML achieved a major histologic response of 74%, and MCyRs ranging up to 53%. For patients with the most severe prognosis, the BP-CML and Ph+ALL cohorts, both groups achieved a major histologic response of 37%, and MCyRs of 34% and 37%, respectively.
A major molecular response rate of 33% was reported in patients with the T315I mutation and those with CP-CML/T315I.
Treatment-related adverse events were generally mild; the most common serious events were thrombocytopenia and neutropenia.
“Extremely exciting,” said Tim Brümmendorf, MD, of the University Hospital, Aachen, Germany, in response to the ponatinib data. “It is the most promising approach to target the most problematic mutation that we currently see—the T315I mutation. This mutation confers absolute resistance to all TKIs that we currently have approved in clinical use. So, from what I have seen, it [ponatinib] looks extremely promising.”