(ChemotherapyAdvisor) – Ponatinib has substantial activity in treatment-refractory patients with acute lymphomblastic leukemia (ALL) or chronic myeloid leukemia (CML), according to a multinational team of researchers. The conclusion is based on abstract entitled “PACE: A Pivotal Phase 2 Trial of Ponatinib in Patients with CML and PH all Resistant or Intolerant to Dasatinib OR Nilotinib, or with the T315I Mutation,” which was presented at the 17th Congress of the European Hematological Association in Amsterdam, The Netherlands.

Ponatinib is a potent, oral, pan-BCR-ABL inhibitor active against the native enzyme and all tested resistant mutants, including the uniformly resistant T315I mutation, noted lead author Jorge Eduardo Cortes, MD, of The University of Texas M.D. Anderson Cancer Center, Houston, TX. In this trial, known as PACE (Ponatinib Ph+ALL and CML Evaluation), patients with refractory CML (CP, AP, or BP) or Ph+ALL resistant or intolerant (R/I) to dasatinib or nilotinib or with T315I received 45mg ponatinib (orally, once daily). The trial is ongoing, but preliminary results based on a median follow-up of 6.6 months, were reported.

Of the 444 eligible patients, diagnoses were: 271 CP-CML (R/I=207; T315I=64); 79 AP-CML (R/I=60; T315I=19); 94 BP/ALL (R/I=48; T315I=46). Prior tyrosine kinase inhibitors (TKIs) included imatinib (96%), dasatinib (85%), nilotinib (66%), bosutinib (7%); 94% failed >2 prior TKIs, 59% failed >3 prior TKIs. A total of 83% had a history of resistance to dasatinib or nilotinib; 12% were purely intolerant. In CP, best response to most recent dasatinib or nilotinib was a major cytogentic response of 25%. Frequent mutations confirmed at entry included 29% T315I, 8% F317L, 4% E255K, 4 % F359V, and 3% G250E. Despite a 64% continuation rate, the most frequent reasons for discontinuation were progression (12%) and AE (10%); the most common drug‑related AEs were thrombocytopenia (33%), rash (33%), and dry skin (26%).

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The investigators concluded that “ponatinib has substantial activity in heavily pretreated patients and those with refractory T315I; response rates continue to improve with longer follow-up.”