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.)

Overall survival with ponatinib versus allogeneic stem cell transplantation in Philadelphia chromosome‐positive leukemias with the T315I mutation

“…A threonine‐to‐isoleucine substitution at position 315 (T315I mutation), the gatekeeper residue of the Abelson murine leukemia viral oncogene homolog (ABL) kinase domain, is identified in approximately 20% of patients with resistant or relapsed CML3, 4 and confers resistance to most TKIs indicated for CML treatment, such as imatinib, dasatinib, bosutinib, and nilotinib 5. Ponatinib is approved in the United States and the European Union for adult patients with refractory CML or Ph+ ALL and those with the BCR‐ABL T315I mutation, and is now the only effective TKI for treating CML or Ph+ ALL in T315I‐positive patients 3, 4, 6. Recently, it was demonstrated that omacetaxine mepesuccinate, a first‐in‐class cephalotaxine, also has inhibitory activity in TKI‐resistant CML stem cells and provides a benefit to patients who have T315I‐positive chronic phase (CP)‐CML as a single agent or in combination with a TKI 7.…”

“…Allo‐SCT has been considered standard therapy for CML over many decades. However, ponatinib may present an alternative to allo‐SCT in T315I‐positive patients 6. No prospective trial has compared outcomes of T315I‐positive patients who received with ponatinib relative to those who underwent allo‐SCT.…”

“…Data were pooled from the Ponatinib Ph+ ALL and CML Evaluation (PACE) trial6 and the EBMT registry10 to conduct an indirect comparison of ponatinib versus allo‐SCT. PACE is a multicenter, international, open‐label, single‐arm, phase 2 trial among patients with CML and Ph+ ALL who are resistant to or intolerant of dasatinib or nilotinib or who have the T315I mutation.…”

Chronic myeloid leukemia: Second‐line drugs of choice

“…Ponatinib is a potent multikinase inhibitor with activity against wildtype BCR-ABL as well as against the T315I mutation [16,75] which constitutes the best "niche" for ponatinib use. Approval for ponatinib was based on results of a phase II trial in heavily pretreated patients that demonstrated CCyR in 40% of patients who were resistant to nilotinib and/or dasatinib and in 66% of patients with the T315I mutation [16].…”

“…Approval for ponatinib was based on results of a phase II trial in heavily pretreated patients that demonstrated CCyR in 40% of patients who were resistant to nilotinib and/or dasatinib and in 66% of patients with the T315I mutation [16]. A safety review by the FDA found a 27% rate of arterial and venous thrombosis in ponatinib-treated patients, which led to temporary market withdrawal of ponatinib and a later restriction of the indication [75].…”