ATLANTA — Ponatinib treatment is associated with significant molecular response rates among patients intolerant to dasatinib and nilotinib or who have dasatimib- and nilotinib-resistant chronic myeloid leukemia (CML), according to an analysis of data from the open-label multinational phase 2 PACE clinical trial. The analysis was presented during the 54th American Society of Hematology Annual Meeting and Exposition.

“Ponatinib led to early, deep, and durable molecular responses in this heavily pretreated population,” reported Andreas Hochhaus, MD, of the Department of Hematology and Oncology, Universitätsklinikum (University Hospital) Jena, in Jena, Germany. Ponatinib is an oral pan-BCR-ABL tyrosine kinase inhibitor active against native and mutated BCR-ABL, including the uniformly refractory T315I mutant. Dr. Hochhaus and colleagues assessed molecular responses to ponatinib (45mg once daily) among 449 patients with CML or Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia (Ph+ ALL) who were resistant or intolerant to dasatinib or nilotinib or who had the T315I BCR-ABL mutation.

The trial is ongoing; the reported analysis was based on data collected by July 28, 2012. Median patient age was 59 years (range, 18 to 94 years). Median time from diagnosis to initiation of ponatinib therapy was 6 years (range, 0.3 to 28 years).BCR-ABL mutations were detected in 55% of all patients at baseline. Among the overall study population, the most common mutations confirmed at study entry were T315I (29%), F317L (8%), E255K (4%), F359V (4%), and G250E (3%).

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At a median follow-up of 15 months, the cumulative MMR rate for the total CP-CML population was 34%. In the 256 patients with CP-CML who had received prior dasatinib or nilotinib, a 10-fold higher MMR rate was achieved with ponatinib (33%) than that reported with the most recent dasatinib- or nilotinib-containing regimen (3%). Molecular responses were deep, Dr. Hochhaus noted, with 15% of CP-CML and 5% of AP-CML achieving a response.Responses were observed against all mutations detected in at least 2 patients at baseline; CP-CML patients with the most common non-T315I mutations responded to ponatinib.

MMR was durable; at 6 and 12 months, 84% and 81% of patients with CP-CML, respectively, were estimated to remain in MMR. The median duration of MMR in CP-CML has not been reached (range, <1 to >20 months).

Ponatinib was generally well tolerated. The most common treatment-emergent adverse events (≥20% of patients) were thrombocytopenia, rash, abdominal pain, headache, dry skin, constipation, fatigue, pyrexia, nausea, arthralgia, neutropenia, hypertension, and anemia, all primarily grade 1 or 2 in severity.