Ponatinib in Refractory Philadelphia Chromosome–Positive Leukemias

Abstract

Background Resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph-positive ALL) is frequently caused by mutations in the BCR-ABL kinase domain. Ponatinib (AP24534) is a potent oral tyrosine kinase inhibitor that blocks native and mutated BCR-ABL, including the gatekeeper mutant T315I, which is uniformly resistant to tyrosine kinase inhibitors. Methods In this phase 1 dose-escalation study, we enrolled 81 patients with resistant hematologic cancers, including 60 with CML and 5 with Ph-positive ALL. Ponatinib was administered once daily at doses ranging from 2 to 60 mg. Median follow-up was 56 weeks (range, 2 to 140). Results Dose-limiting toxic effects included elevated lipase or amylase levels and pancreatitis. Common adverse events were rash, myelosuppression, and constitutional symptoms. Among Ph-positive patients, 91% had received two or more approved tyrosine kinase inhibitors, and 51% had received all three approved tyrosine kinase inhibitors. Of 43 patients with chronic-phase CML, 98% had a complete hematologic response, 72% had a major cytogenetic response, and 44% had a major molecular response. Of 12 patients who had chronic-phase CML with the T315I mutation, 100% had a complete hematologic response and 92% had a major cytogenetic response. Of 13 patients with chronic-phase CML without detectable mutations, 100% had a complete hematologic response and 62% had a major cytogenetic response. Responses among patients with chronic-phase CML were durable. Of 22 patients with accelerated-phase or blast-phase CML or Ph-positive ALL, 36% had a major hematologic response and 32% had a major cytogenetic response. Conclusions Ponatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations. (Funded by Ariad Pharmaceuticals and others; ClinicalTrials.gov number, NCT00660920.)

Ponatinib Induces Apoptosis in Imatinib-Resistant Human Mast Cells by Dephosphorylating Mutant D816V KIT and Silencing β-Catenin Signaling

“…Considering the present findings and the approval of ponatinib by FDA for the treatment of refractory patients with chronic myelogenous leukemia (19), a clinical trial of ponatinib for systemic mastocytosis patients with D816V KIT mutation may be warranted.…”

“…Ponatinib (AP24534), a potent multitargeted kinase inhibitor (18), has been approved by the FDA for treating imatinib-resistant patients with chronic myelogenous leukemia, including those harboring the gatekeeper mutant T315I Bcr-Abl (19,20). Besides, ponatinib also manifests inhibitory activity toward PDGFR, KIT, as well as FGFR (21,22).…”

A molecular and biophysical comparison of macromolecular changes in imatinib-sensitive and imatinib-resistant K562 cells exposed to ponatinib

“…Ponatinib, one of the third-generation TKIs, is known to be effective in CML patients even bearing T315I mutation because of its capability to bind to BCR/ABL kinase. In a phase I clinical trial, it has been reported that ponatinib treatment of CML patients with T315I mutation results in hematological response in all of the patients, complete cytogenetic response (CCyR) in 75 % of the patients, and also major molecular response (MMR) in 67 % of the patients [33]. A phase II international clinical study, Ponatinib Ph+ ALL and CML Evaluation (PACE), has reported that CCyR is seen in 46 % of CML patients with T315I mutation [34].…”

Molecular analysis of the BCR-ABL1 kinase domain in chronic-phase chronic myelogenous leukemia treated with tyrosine kinase inhibitors in practice: Study by the Nagasaki CML Study Group

“…Minami Y, et al reported that monitoring gene mutations in fractionated hematopoietic stem cells and progenitors at diagnosis may help detect the T315I mutation earlier [38]. Standard methods to detect the T315I mutation and the standard management of patients with this mutation in practice need to be established [28,39,40].…”