A Nationwide Observational Study of the Israeli Experience with Ponatinib Outside Clinical Trials in Chronic Myeloid Leukemia

Ponatinib is an oral tyrosine kinase inhibitor (TKI) that has been designed to be effective also in patients who harbor the TKI-refractory threonine to isoleucine mutation at position 315 (T315I). In December 2014 the drug was granted an accelerated approval by the FDA, based on the promising results from the phase II PACE (Ponatinib Ph ALL and CML evaluation) trial. In this trial, 56% of previously treated patients who had resistance to or unacceptable side effects from dasatinib or nilotinib achieved a major cytogenetic response, including 70% of patients with the T315I mutation. Albeit the PACE trial convincingly demonstrated the efficacy of ponatinib, the wide use of the drug has been limited due to safety matters and in particular arterial thrombotic complications, reported in up to 17% of patients. Currently, there is very little real-life information regarding the use of ponatinib outside of clinical trials. The purpose of this study is to characterize patients with chronic myeloid leukemia (CML) who received ponatinib and to assess the effectiveness and safety profile of ponatinib outside of clinical trials.

Between 4.2011 and 7.2015 (51 months) 24 patients with CML received ponatinib in 7 medical centers in Israel. We reviewed the medical records of these patients and asked their physicians to rank the quality of life of their patients on a 1 to 5 scale.

Prior to ponatinib therapy, patients were treated for a median of 55 months (range: 1 to 215) with 1 to 3 different TKIs (median: 3). In addition 13 patients received at least one course of chemotherapy or interferon and 2 underwent allogeneic bone marrow transplantation.

Screening for mutations at the DNA binding domain was performed at least once during the pre-ponatinib follow-up time in most patients (67%, N=16). Mutations were detected in 11 patients (69%) and the T315I mutation was detected in 8 of those.

The median age when starting ponatinib was 44 years (rang: 23 to 79). Most patients had advanced disease and their disease was classified as either accelerated (21%, N=5) or blast crisis (41%, N=10) when they started ponatinib. Based on the medical history, 48% were at-risk to develop vascular complications either because of prior cerebrovascular event or myocardial infarction (18%) or because of vascular risk factors (30%). Baseline ECG and cardiac ECHO studies were available in 11 patients. Only two had signs of prior MI in ECG and none had significant structural or functional pathology.

At time of analysis the median duration of follow up was 6 months (range <1 to 34 months), 4 patients died and 14 were still receiving ponatinib. Patients discontinued the treatment either because of major cardiovascular events (N=3), severe pancytopenia (N=1), planned bone-marrow transplantation (N=1) or because they were lost to follow-up (N=1). Seventeen patients were available for response assessment at time of analysis and the overall response rate was 77% (N=13). Five of six patients at chronic phase achieved either complete or major molecular response. Eight patients at accelerated phase or at blast crisis (8/11, 72%) achieved either hematological (5/11, 45%) or molecular response (3/11, 27%). Two of those, with hematological response, underwent allogeneic bone marrow transplantation. The median subjective scoring of ponatinib contribution to the quality of life of patients was 2.4 (range 1 to 5). Physicians that gave low scoring mentioned severe weakness, myalgia and cytopenias as a major concern.

Conclusions: In real- life setting ponatinib is generally used as a last resort. In our cohort, it was almost exclusively given to patients who experienced failure to previous TKIs. The only exceptions were 2 patients who received ponatinib for suboptimal molecular response and achieved MMR when switched to ponatinib. Only one third of patients tolerated the recommended dose of 45mg. Yet, response rate was still relatively high, suggesting that a daily dose of 30mg might be appropriate.

With only 6 months of follow-up we documented 3 cardiovascular events (12%) that prompted discontinuation of the drug and only one patient had a significant prior vascular risk.

The high response rate and overall contribution to quality of life in patients with very few alternatives, who already experienced failure of other TKIs, support the use of this treatment for patients with advanced disease.