A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias

Abstract

Background: Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor-refractory threonine-to-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL).

Methods: We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months.

Results: Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients discontinued treatment because of an adverse event.

Conclusions: Ponatinib had significant antileukemic activity across categories of disease stage and mutation status. (Funded by Ariad Pharmaceuticals and others; PACE ClinicalTrials.gov number, NCT01207440 .).

Figure 1. Response to Ponatinib According to Type of Leukemia, Resistance to or Unacceptable Side Effects from Previous Treatment with Dasatinib or Nilotinib, and T3151 Mutation Status

Panel A shows the percentages of patients with chronic-phase CML who had a complete hematologic response, major cytogenetic response, complete cytogenetic response, or major molecular response. It was estimated that 91% (95% confidence interval [CI], 85 to 95) of the patients with a major cytogenetic response would have a sustained response of at least 12 months. Overall survival was estimated to be 94% at 12 months. Panel B shows the percentages of the patients with accelerated-phase CML who had a major hematologic response, major cytogenetic response, complete cytogenetic response, or major molecular response. It was estimated that 48% (95% CI, 32 to 63) of the patients with a major hematologic response would have a sustained response of at least 12 months. Overall survival was estimated to be 84% at 12 months. Panel C shows the percentages of patients with blast-phase CML who had a major hematologic response, major cytogenetic response, or complete cytogenetic response. It was estimated that 42% (95% CI, 19 to 63) of the patients with a major hematologic response would have a sustained response of at least 12 months. Overall survival was estimated to be 29% at 12 months (median, 7 months). Panel D shows the percentages of patients with Ph-positive ALL who had a major hematologic response, major cytogenetic response, or complete cytogenetic response. It was estimated that 8% (95% CI, 0.5 to 29) of the patients with a major hematologic response would have a sustained response of at least 12 months. Overall survival was estimated to be 40% at 12 months (median, 8 months).