Ponatinib Continues March to Potential Front-line Use in CML


PACE trial results show patients with previously treated CML achieved a 47% major cytogenetic response rate (MCyR) with ponatinib.

Jorge Cortes, MD

Jorge Cortes, MD

Initial results from a phase II investigation demonstrated that, to date, patients with chronic-phase (CP) chronic myeloid leukemia (CML), who were resistant or intolerant to previous treatment with a tyrosine kinase inhibitor (TKI), achieved a 47% major cytogenetic response rate (MCyR) with the drug, ponatinib.

For patients with the difficult-to-treat T315I mutation — for which currently approved TKIs are largely ineffective — ponatinib was able to induce a 65% MCyR.

"Robust responses were observed in all patient cohorts, regardless of mutation status or disease stage,” stated study lead investigator, Jorge Cortes, MD, professor and deputy chair, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.

Ponatinib is an oral, pan-BCR ABL, 3rd-generation TKI that was rationally designed to overcome the T315I mutation.

The Ponatinib Ph+All and CML Evaluation (PACE) trial enrolled chronic patients with CML, regardless of disease phase, as well as patients with Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL), and overall were represented by 1 of 2 categories: Patients resistant or intolerant to previous TKI therapy; and patients with the T315I mutation (N=449). The primary endpoints were MCyR for CP-CML, and major histologic response (MaHR) for accelerated-phase CML (AP-CML) or Ph+ALL. Secondary endpoints looked at safety and tolerability.

All subjects enrolled in the study had previous exposure to currently available, and other investigational TKIs: 16 patients (4%) had been treated with imatinib alone, 172 patients (39%) had been treated with imatinib plus nilotinib or dasatinib, and a majority of 237 patients (53%) had been treated with at least 3 prior TKIs. “Clearly, this is a heavily pretreated population,” said Cortes. Typical responses to prior treatments ranged from 33% for MaHR and 25% for MCyR.

After a median follow-up of 5 months, high levels of responses were observed in all patient types, even in the sickest patients. Participants with AP-CML achieved MaHR of 74%, and MCyR up to 53%; blast-phase-CML, and Ph+ALL patients both achieved MaHR of 37%, and MCyR of 34%, and 37% respectively. Most notably, patients with the T351I mutation with CP-CML achieved a 33% major molecular response rate.

Few treatment-related adverse events were observed, the most common serious events being thrombocytopenia and neutropenia.

That, and so much more?

“Ponatinib has the potential to become a promising new treatment option for patients with multirefractory, relapsed CML,” concluded Cortes.Pierre Laneuville, MD, FRCPC, associate professor at the Department of Medicine and Oncology at McGill University, and the former head of Hematology for the McGill University Health Center, Montreal, sees even greater potential for ponatinib. “If you look at the IRIS study for Gleevec, they had about 20% resistance at 8 years, half of those had mutations. Well, the ponatinib is effective in almost virtually all those mutations.” The argument going forward is that if ponatinib was used up front, 10% of eventual treatment failures with currently available agents could be eliminated outright. “So, that’s potentially quite interesting, and we’ll see if the company pursues that indication. I hope they will.”

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