Ponatinib and platelets a conflict in CML

In this issue of Blood, Lafiti et al address the critical question of vascular and cardiac toxicity of ponatinib, using a mouse model.¹  They elegantly show that ponatinib vascular toxicity is due to von Willebrand factor (VWF)-mediated platelet adhesion.

Ponatinib, a third-generation tyrosine kinase inhibitor (TKI), has been approved for the treatment of TKI-resistant or -intolerant chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph⁺ ALL). Although ponatinib has a powerful effect on T315I-mutated cells, cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke, have occurred in ponatinib-treated patients. In clinical trials, serious arterial thrombosis and venous thromboembolism occurred in at least 35% and 6% of ponatinib-treated patients, respectively. Heart failure, including fatal cases, occurred in 9% of ponatinib-treated patients.² 

To explore the vascular toxicity due to endothelial alterations from ponatinib, Lafiti et al used in vivo ultrasound molecular imaging and intravital microscopy. The animal models included a wild-type C57Bl/6 mouse and a hyperlipidemic mouse harboring the apoliprotein-E gene deletion (ie, ApoE^−/− mice). They compared ponatinib to dasatinib treatment in these 2 mice strains. Dasatinib was selected as a control because this TKI was known to induce very few thrombotic events. Mice were also treated with N-acetylcysteine (NAC), which reduces VWF multimer size or recombinant human ADAMTS13, a regulatory protease that cleaves ultralarge VWF. A large panel of in vivo imaging methods was employed to investigate the endothelial angiopathy. Mice were the unfortunate actors in movies performed with contrast-enhanced ultrasound molecular imaging, intravital microscopy, echocardiography, or computed tomography coronary angiography. I really encourage the readers to look at the impressive videos provided in the supplemental data. The treatment-related mortality was significantly higher in ponatinib-treated mice. As has been observed in patients, blood pressure measurements in animals acclimatized to the procedure revealed a gradual increase in both systolic and diastolic blood pressure in ponatinib-treated wild-type and ApoE^−/− mice. This supports the previous observation of the activity of ponatinib on vascular endothelial growth factor receptor-2.

In both large arteries and the peripheral microcirculation, ponatinib caused a prothrombotic angiopathy. More precisely, ponatinib increased endothelial VWF with exposure of the A1 binding domain, and platelet adhesion several fold within days of the onset of treatment. The use of a high dose of rADAMTS13 reversed aortic platelet adhesion in ponatinib-treated mice. Thus, ponatinib caused an acquired resistance to VWF. Treatment of ApoE^−/− mice with NAC, coadministered daily with ponatinib, also eliminated the VWF signal but reduced the platelet signal only by half. Of interest, there was no coronary artery occlusion or stenosis but rather wall motion abnormalities as revealed by left ventricular coronary microvascular anatomy. In the aggregate, these data provided evidence of a thrombotic microangiopathy due to ponatinib. This is consistent with postmortem findings in patients of coronary microvascular thrombosis and histologic evidence of platelets adhesion.

Ponatinib also increased surface expression of VWF on human umbilical vein endothelial cells (HUVECs) cultured in a microfluidic system, indicating that increased surface mobilization and decreased proteolytic cleavage played a role in the angiopathy. Ponatinib inhibited HUVEC tube formation, indicating a possible suppressive effect on neoangiogenesis of vascular endothelial cells.³  Using transgenic zebrafish lines, it has been shown that ponatinib inhibits cardiac survival signaling pathways, leading to cardiomyocyte apoptosis and ventricular dysfunction.⁴ 

The activity of ponatinib on coagulation has also been studied. Gene expression and pathway analysis demonstrated that ponatinib enhanced the messenger RNA expression of coagulation factors of both the contact activation (intrinsic) and the tissue factor (extrinsic) pathways. In line with this, ponatinib enhanced plasma levels of factor VII and increased cardiovascular risk through induction of a prothrombotic state.⁵ 

In the initial ARIAD brochure, it was stated that no remarkable adverse effects of ponatinib were identified in single-dose mouse and rat studies designed to assess central nervous system, renal, pulmonary, and gastrointestinal system functioning. In addition, in an in vitro study of ponatinib effects on human platelet aggregation, significant inhibition of aggregation was observed only at ponatinib concentrations ∼100 times higher than the estimated plasma C_max at the therapeutic dose. Ponatinib was extensively tested in 2 multicenter trials for drug registration. The pivotal phase 2 Ponatinib Ph⁺ ALL and CML Evaluation trial evaluated efficacy and safety of ponatinib in resistant and intolerant previously treated CML patients (N = 449 patients). Serious arterial occlusive events and serious venous thrombotic events occurred in 26% and 5% of the patients, respectively.⁶  The phase 3 EPIC trial exploring ponatinib in untreated patients with CML was discontinued due to a high occurrence of arterial events in the study. In this trial, 11 (7%) of 154 patients given ponatinib and 3 (2%) of 152 patients given imatinib had arterial occlusive events.⁷  In real life, this would mean a high percentage of patients with cardiovascular events.⁸ 

Thus, what shall we do now for our patients? Physicians should optimize control of cardiovascular risk factors and carefully select patients when ponatinib therapy is considered. Patients with the highly resistant T315I mutated clone are the most likely to benefit from treatment.⁹