A Phase 2 Trial of Ponatinib in Philadelphia Chromosome-Positive Leukemias
abstract
This abstract is available on the publisher's site.
Access this abstract nowBackground: 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.
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Additional Info
A Phase 2 Trial of Ponatinib in Philadelphia Chromosome-Positive Leukemias
N. Engl. J. Med 2013 Nov 01;[EPub Ahead of Print], JE Cortes, DW Kim, J Pinilla-Ibarz, P le Coutre, R Paquette, C Chuah, FE Nicolini, JF Apperley, HJ Khoury, M Talpaz, J Dipersio, DJ Deangelo, E Abruzzese, D Rea, M Baccarani, MC Müller, C Gambacorti-Passerini, S Wong, S Lustgarten, VM Rivera, T Clackson, CD Turner, FG Haluska, F Guilhot, MW Deininger, A Hochhaus, T Hughes, JM Goldman, NP Shah, H KantarjianFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Ponatinib is a potent tyrosine-kinase inhibitor with activity against BCR-ABL, including certain mutated forms, such as the T315I mutation. Although recent trials have indicated activity against CML and Philadelphia chromosome–positive ALL, serious vascular complications have emerged. Arterial thrombosis occurred in 11% of patients, with serious events such as stroke, fatal myocardial infarction, and peripheral thrombosis in 8% of patients. This led the FDA to request that the manufacturer suspend marketing and sales of ponatinib. When a potentially promising pharmacologic agent causes serious side-effects, the situation warrants careful analysis to determine if it is a fundamental property of the drug or something that can be avoided by a modification of the structure or by co-administering another agent that counters the vascular complications.
In terms of the etiology of the arterial thrombosis, one would clearly like more data on the nature of the vascular events in the patients treated thus far: platelet function, status of the coagulation/anticoagulant systems, circulating microparticles and tissue factor, as well as general pathologic findings at the site of the vascular pathology. One can expect this data will be forthcoming in the near future.
In considering the pathogenesis of arterial thrombosis in such a situation, several broad categories of vascular dysfunction come to mind. Vascular thrombosis in the arterial system often has strong involvement of platelets and could involve exposure/activation of the procoagulant trigger tissue factor. Although intact vasculature is largely devoid of tissue factor, the latter forms a protective cocoon around the vessel (with an increasing gradient from the quiescent endothelium, where its levels are lowest, to the adventitia, where its levels are high), thereby preventing extravascular bleeding.
Abnormal vasculature, as at the site of an atheroma in the expanded intima (neointima), is relatively rich in tissue factor and can be prone to rupture, triggering local thrombosis, which can be occlusive. Thus, one might suspect that ponatinib directly, or indirectly, has an impact on exposure of procoagulants, such as tissue factor, in an abnormal vessel to circulating blood (coagulation factors and platelets), thereby causing a local prothrombotic stimulus resulting in clinically significant thrombosis. According to this view, ponatinib could activate proteases, such as collagenases, in the vessel wall that predispose to vessel wall-rupture and plaque thrombosis.
Alternatively or simultaneously, an effect on cell membranes from platelets or other cells could release microparticles, serving as a template for assembly of procoagulant complexes (tenase and prothrombinase). An action of ponatinib on the vessel wall might also impair endogenous antithrombotic/vasoactive systems, such as the thrombomodulin/protein C/protein S pathway, fibrinolytic system, local generation of nitric oxide and/or antithrombotic prostanoids, among others.
At this point, it is too soon to speculate on the mechanism(s) involved, but armed with more clinical and pathologic data, the pathway toward understanding the mechanism should become clear.