Real-Life Experience with Ponatinib in Chronic Myeloid Leukemia (CML): A Multicenter Observational Study

Ponatinib is a multi-targeted pan-BCR-ABL1 tyrosine-kinase inhibitor (TKI) and the only approved TKI capable of inhibiting BCR-ABL1 with the T315I kinase domain mutation. In December 2012, based on the PACE trial, ponatinib was granted an accelerated approval for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) and for chronic myeloid leukemia (CML) resistant or intolerant to other TKIs. At least 4 clinical trials tested ponatinib in newly diagnosed or previously treated CML patients and showed that the drug is effective. Nevertheless, the wide use of ponatinib has been limited because of vascular complications, reported in up to 17% of patients. Currently there is very little information on how this drug is used outside of clinical trials.

Between April 2011 and August 2016, 37 CML patients in 9 medical centers in Israel received ponatinib. Similar to patients enrolled in the PACE trial, all patients received at least 1 other TKI prior to ponatinib. 21 patients (57%) were in chronic phase, 6 patients (16%) were in accelerated phase and 10 patients (27%) were in blast crisis. Nine patients (24%) harbored the T315I mutation. Remarkably, in our centers ponatinib was given primarily to young patients with a resistant disease. While the median age of patients in the PACE trial was 60 years, the median age in our cohort was only 43 years (range 9 to 82). Furthermore, only 1 patient received the drug because of unacceptable side effects compared to 12% of patients who entered the PACE trial. Full medical history was available for 33 out of the 37 patients. Based on the medical history, 12 out of these 33 patients (36%) were at increased risk for vascular complications, either because of prior cerebrovascular event or myocardial infarction (3/33) or because of vascular risk factors (9/33).

In our cohort, 22 patients started treatment with ponatinib 45 mg daily but only 16 patients remained on this dose throughout treatment. The remaining patients received either 30mg/day (N=10, 27%) or 15mg/day (N=11, 30%). The median follow-up duration with ponatinib treatment was 14 months (range: 1 to 51) and 19 patients (51%) were still receiving ponatinib at the time of last follow up. Response assessment during treatment with ponatinib was available in 32 patients (86%). In the remaining, the follow up duration was too short. The ORR was 88%. Twenty-one patients (57%) achieved complete cytogenetic response, 16 patients (43%) experienced at least MMR or deeper responses, 4 of those in accelerated or blastic phase. In 3 patients, ponatinib was given only for a limited period as a bridge towards allogeneic BMT. In the remining, 15 out of 34 patients (44%), either discontinued treatment (N = 13) or died during treatment (N = 2). Patients discontinued ponatinib because of disease progression (N=6), severe cytopenia (N=3), vascular events (N=2), pancreatitis (N=1) and because the drug was not available any more (N=1). One patient was lost to follow-up. The median survival of patients since the start of ponatinib treatment was 36 months (range: 18 to 54).

Conclusions: The fear of vascular complications, the temporary withdrawal of the drug from the market shortly after it was approved and the availability of alternative treatments in most patients, all led to the use of ponatinib as a niche drug that is reserved to a unique population of exceptionally young CML patients with or without the T315I mutation. Even then, a short term treatment with ponatinib, as a bridge towards transplant and/or treatment with ponatinib in lower doses were commonly used. In these patients, most of which were resistant to previous treatments, the drug was very effective and response was observed by most. Yet, serious adverse effects led to drug discontinuation by many of our patients and 2 of them died of vascular complications.