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Clinical Trial
. 2012 Nov 29;367(22):2075-88.
doi: 10.1056/NEJMoa1205127.

Ponatinib in refractory Philadelphia chromosome-positive leukemias

Jorge E Cortes  1 , Hagop Kantarjian, Neil P Shah, Dale Bixby, Michael J Mauro, Ian Flinn, Thomas O'Hare, Simin Hu, Narayana I Narasimhan, Victor M Rivera, Tim Clackson, Christopher D Turner, Frank G Haluska, Brian J Druker, Michael W N Deininger, Moshe Talpaz
Affiliations
Clinical Trial

Ponatinib in refractory Philadelphia chromosome-positive leukemias

Jorge E Cortes et al. N Engl J Med. .

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 VSports手机版. 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 V体育安卓版. Median follow-up was 56 weeks (range, 2 to 140). .

Results: Dose-limiting toxic effects included elevated lipase or amylase levels and pancreatitis V体育ios版. 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 VSports最新版本. (Funded by Ariad Pharmaceuticals and others; ClinicalTrials. gov number, NCT00660920. ). .

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Figure 1
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.
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References

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    1. Faderl S, Garcia-Manero G, Thomas DA, Kantarjian HM. Philadelphia chromosome-positive acute lymphoblastic leukemia — current concepts and future perspectives. Rev Clin Exp Hematol. 2002;6:142–60. - PubMed
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