Ponatinib at a lower dose is a good option in Chronic Myeloid Leukemia (CML) patients intolerant to previous TKIS

Background: Ponatinib is a third-generation tyrosine kinase inhibitor (TKI) with proven efficacy in CML patients resistant to previous TKIs. However, some warnings emerged concerning its cardiovascular (CV) safety profile when used at the recommended starting dose of 45 mg/day. It was suggested that ponatinib may cause endothelial dysfunction through its multikinase inhibitory properties affecting targets such as vascular endothelial growth factor receptor (VEGFR) and promoting the expression of proatherogenic surface adhesion receptors. Recently, it was reported a relationship between CV adverse events (AEs) and the dose, but a reduction of the daily dose has been suggested for patients who have already achieved at least a MCyR. Indeed, very limited data have been reported in the literature so far on the use of low dose ponatinib after intolerance to previous TKIs. Aims: The primary objective was to evaluate the safety and efficacy profile (molecular response rate) of low dose ponatinib when used in the real-life setting of CML patients intolerant to previous TKIs. Methods: We evaluated 46 consecutive CML patients in the real-life setting, treated with ponatinib because of intolerance to previous TKIs, between May 2012 and December 2019 in 13 Italian hematological centers. Responses to TKIs were evaluated according to the current European LeukemiaNet recommendations. Hematological and extra-hematological toxicity was graded according to the Common Terminology Criteria for Adverse Events (CTC-AE). Results: Male:female ratio was 2:1, with a median age at ponatinib start of 64.5 years (range, 34.5 - 81.0). Among comorbidities at baseline, hypertension was present in 19 (41.3%), diabetes in 6 (13%) and dyslipidemia in 4 (8.7%) patients. All of the cases started ponatinib because of intolerance to at least one TKI, most frequently dasatinib (31 patients, 67.4%), followed by nilotinib (11, 23.9%) and bosutinib (4, 8.7%). Median time from diagnosis to ponatinib treatment was 5.0 years (range, 0.7 - 23.4). Median starting dose of ponatinib was 22.5 mg daily, administered as a second-line in 19 (41.3%), third-line in 18 (39.1%) and fourth-line in 9 (19.6%) cases. At a median follow-up from ponatinib start of 22.2 months (range, 0.4 – 93.5), 35 (76.1%) patients increase the depth of molecular response (including 8 patients with MMR and 15 with DMR), with the remaining patients maintaining the same level of molecular response already achieved before ponatinib start. Interestingly, among patients who obtained a DMR during ponatinib, treatment-free remission was successfully achieved in one case. Concerning instead the safety profile, AEs were reported in 17 (36.9%) patients, including pancreatitis in 5 (10.9%), hypertension in 4 (8.7%) and cardiovascular events in 4 (8.7%) cases [including one acute myocardial infarction (IMA) and one ischemic stroke], the latter both registered in patients with pre-existing cardiovascular risk factors and who were initially treated with ponatinib at a daily dose of 30 mg. In addition, the patient who suffered from IMA received also nilotinib as a previous treatment. Summary/Conclusion: Our data highlight the efficacy and safety of low dose ponatinib in the setting of CML patients who were intolerant to previous TKIs. A reduced incidence of specific AEs was recorded, although the efficacy has not been affected. This treatment strategy could represent a possible alternative for intolerant patients: further prospective studies are needed to assess in the long-term the benefits of dose reduction.