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Ponatinib in refractory Philadelphia chromosome-positive leukemias.

ABSTRACT: 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.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).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.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.).

SUBMITTER: Cortes JE

PROVIDER: S-EPMC3777383 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Ponatinib in refractory Philadelphia chromosome-positive leukemias.

Cortes Jorge E JE Kantarjian Hagop H Shah Neil P NP Bixby Dale D Mauro Michael J MJ Flinn Ian I O'Hare Thomas T Hu Simin S Narasimhan Narayana I NI Rivera Victor M VM Clackson Tim T Turner Christopher D CD Haluska Frank G FG Druker Brian J BJ Deininger Michael W N MW Talpaz Moshe M

The New England journal of medicine 20121101 22

<h4>Background</h4>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.<h4>Methods</h4>In this phase 1 dose-escala ...[more]

PMID: 23190221

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Project description:BackgroundPonatinib 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).MethodsWe 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.ResultsAmong 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.ConclusionsPonatinib had significant antileukemic activity across categories of disease stage and mutation status. (Funded by Ariad Pharmaceuticals and others; PACE ClinicalTrials.gov number, NCT01207440 .).

Project description:Promising results have been shown with the combination of ponatinib and chemotherapy in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). The PONALFIL (Ponatinib With Chemotherapy for Young Adults Ph Positive Acute Lymphoblastic Leukemia) trial combined ponatinib (30 mg/d) with standard induction and consolidation chemotherapy followed by allogeneic hematopoietic stem cell transplant (alloHSCT) in newly diagnosed Ph+ ALL patients aged 18 to 60 years. Ponatinib was only given pre-emptively after alloHSCT. Primary end points were hematologic and molecular response before alloHSCT and event-free survival (EFS), including molecular relapse as event. Thirty patients (median age, 49 years; range, 19-59 years) entered the trial. All exhibited hematologic response, and alloHSCT was performed in 26 patients (20 in complete molecular response and 6 in major molecular response). Only 1 patient died (of graft-versus-host disease), and 5 patients exhibited molecular relapse after alloHSCT. No tyrosine kinase inhibitor was given after HSCT in 18 of 26 patients. Twenty-nine patients are alive (median follow-up, 2.1 years; range, 0.2-4.0 years), with 3-year EFS and overall survival (OS) of 70% (95% confidence interval, 51-89) and 96% (95% confidence interval, 89-100), respectively. Comparison of the PONALFIL and the ALLPh08 (Chemotherapy and Imatinib in Young Adults With Acute Lymphoblastic Leukemia Ph [BCR-ABL] Positive; same schedule, using imatinib as the tyrosine kinase inhibitor) trials by propensity score showed significant improvement in OS for patients in PONALFIL (3-year OS, 96% vs 53%; P = .002). The most frequent grade 3 to 4 adverse events were hematologic (42%), infectious (17%), and hepatic (22%), with only one vascular occlusive event. The combination of chemotherapy with ponatinib followed by alloHSCT is well tolerated, with encouraging EFS in adults with newly diagnosed Ph+ ALL. Cross-trial comparison suggests improvement vs imatinib (clinicaltrials.gov identifier #NCT02776605).

Project description:Vascular and cardiac safety during tyrosine kinase inhibitor (TKI) therapy is an emerging issue. We evaluated vascular/cardiac toxicities associated with long-term bosutinib treatment for Philadelphia chromosome-positive (Ph+) leukemia based on treatment-emergent adverse events (TEAEs) and changes in QTc intervals and ejection fraction in two studies: a phase 1/2 study of second-/third-/fourth-line bosutinib for Ph+ leukemia resistant/intolerant to prior TKIs (N = 570) and a phase 3 study of first-line bosutinib (n = 248) versus imatinib (n = 251) in chronic phase chronic myeloid leukemia. Follow-up time was ≥48 months (both studies). Incidences of vascular/cardiac TEAEs in bosutinib-treated patients were 7%/10% overall with similar incidences observed with first-line bosutinib (5%/8%) and imatinib (4%/6%). Few patients had grade ≥3 vascular/cardiac events (4%/4%) and no individual TEAE occurred in >2% of bosutinib patients. Exposure-adjusted vascular/cardiac TEAE rates (patients with events/patient-year) were low for second-line or later bosutinib (0.037/0.050) and not significantly different between first-line bosutinib (0.015/0.024) and imatinib (0.011/0.017; P ≥ 0.267). Vascular/cardiac events were managed mainly with concomitant medications (39%/44%), bosutinib treatment interruptions (18%/21%), or dose reductions (4%/8%); discontinuations due to these events were rare (0.7%/1.0%). Based on logistic regression modelling, performance status >0 and history of vascular or cardiac disorders were prognostic of vascular/cardiac events in relapsed/refractory patients; hyperlipidemia/hypercholesterolemia and older age were prognostic of cardiac events. In newly diagnosed patients, older age was prognostic of vascular/cardiac events; history of diabetes was prognostic of vascular events. Incidences of vascular and cardiac events were low with bosutinib in the first-line and relapsed/refractory settings following long-term treatment in patients with Ph+ leukemia. Am. J. Hematol. 91:606-616, 2016. © 2016 Wiley Periodicals, Inc.

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Ponatinib in refractory Philadelphia chromosome-positive leukemias.

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Ponatinib in refractory Philadelphia chromosome-positive leukemias.

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