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.).

Figure 1. Structure and Activity of Ponatinib

In Panel A, ponatinib (shown as blue and yellow spacefilling spheres) displays an optimal fit to the binding cavity of ABL-T315I (indicated by a mesh pattern). In Panel B, the triple bond (yellow) is a unique structural feature of ponatinib (blue) that allows it to evade the mutant gatekeeper residue I315 (red space-filling spheres). In Panel C, the concentration of ponatinib (as the geometric mean) is shown during a 24-hour period in patients on day 29 after administration at 0 hours. Dose groups and the number of patients who could be evaluated in each group were as follows: 2 mg, 2 patients; 4 mg, 6 patients; 8 mg, 6 patients; 15 mg, 8 patients; 30 mg, 9 patients; 45 mg, 21 patients; and 60 mg, 9 patients. The dashed line indicates the concentration that was found to completely suppress the emergence of BCR-ABL mutations in preclinical analyses. In Panel D, the pharmacodynamic activity of ponatinib, on the basis of CRKL phosphorylation (pCRKL), a surrogate marker for BCR-ABL inhibition, is shown according to dose for 43 Ph-positive patients who could be evaluated. Shown are reductions from baseline of at least 50%, 25% to less than 50%, or less than 25% at trough time points (before the administration of ponatinib). (Details are provided in Appendix E in the Supplementary Appendix, available with the full text of this article at NEJM.org.) In Panel E, the dose-related molecular response is shown for two representative patients with chronic-phase CML with the T315I mutation who were undergoing dose escalation, with changes in BCR-ABL transcripts, shown as the ratio of BCR-ABL to ABL (as expressed as a percentage on the International Scale) over time. The dashed line indicates the threshold for achieving a major molecular response (MMR). The blue line indicates the ponatinib dose at each time point. In the left panel, the first patient had a molecular response 4 (≤0.01% transcript ratio [International Scale] in peripheral blood) during the study. In the right panel, the second patient had a partial cytogenetic response.