PS1186 CURRENT DOSE RECOMMENDATIONS FOR PONATINIB IN CHRONIC MYELOID LEUKEMIA PATIENTS CAN DIMINISH ADVERSE EVENTS WHILE MAINTAINING EFFICACY
Authors: Garcia‐Gutierrez V. , Hernandez‐Boluda J.C. , Moiraghi B. , Sacha E.S. Tomasz , Pavlovsky C. , Grzybowska‐Izydorczyk O. , Correa J. , Lopez R. Perez , Góra‐Tybor E.P. Joanna , Garcia A. Novo , Prendes S. Osorio , Vallansot R. , Payer A. Ramirez , Wasilewska E. , Villaespesa M. Piris , Genovard C. Boque , Encinas M. Perez , Velasco A. Jimenez , Sanchez‐Guijo F. , Collada M.A. Romo , Casares M.T. Gomez , Pascual G. Orti , Duran M.S. , Portero A. , Mata M.I. , Noya M.S. , Caballero G. , Garcia N. , de Castro D. Robles , Ramirez M.J. , Magan A. Senin , Lakhwani S. , Dominguez J.M. Alonso , Montero M.I. , Chulvi M.J. Lis , Ciepłuch H. , Steegman J.L. 
Published: June 2019

Background:

Ponatinib has been established as an optimal salvage treatment option in chronic myeloid leukemia (CML) patients. Serious adverse events, mainly cardiovascular (CVS) events, have been related to ponatinib use at the standard dose (45 mg/day). Clinical trials are currently evaluating different dose schemes in order to answer whether dose modifications could diminish side effects while maintaining responses.

Aims:

To evaluate the efficacy and safety of ponatinib treatment in the real life‐setting.

Methods:

We have performed an International observational retrospective study collecting information from CML patients treated with ponatinib between 2014 and 2018. The indication of ponatinib, as well as its dose schedule, was made according to the criterion of the attending physician. Molecular biology tests were performed according to ELN guidelines and BCR‐ABL/ABL ratios were expressed as % IS in all centers. Treatment responses were calculated with the patients at risk at each specific time points. For progression free survival (PFS) calculation, progression was defined as transformation to the advances phases. For the event free survival (EFS), the events were treatment discontinuation due to any reason, progression or death. Data collection followed the local regulations for observational studies.

Results:

73 CML patients treated with ponatinib according to clinical practice in Spain, Poland, and Argentina, were included in the study. Patients had received a median of 2.8 TKIs prior to ponatinib treatment, with a median time of 43 months from CML diagnosis to ponatinib start. Median age at diagnosis was 58 years and Sokal prognostic risk score was low, intermediate, high, and unknown in 28%, 21%, 31%, and 20% of the patients. Patients were treated while in chronic phase (84%), accelerated phase (10%), and blast crisis (6%). In total, 61% of the patients had cardiovascular risk factors at the time of starting ponatinib, 5 patients had suffered previous thrombosis, and 4 patients had a pathological ankle‐brachial index. BCR‐ABL mutations were present in 33 patients (23 of them harbored the T315I mutation). Ponatinib starting dose was 45 mg, 30 mg, and 15 mg in 60%, 20%, and 20% of the patients, respectively. Drug dosage was diminished in 21/45 (46%) of the patients who started on 45 mg/day and in 4/14 (28%) patients who started on 30 mg/day. In contrast, 50% (7/14) of the patients who started on ponatinib 15 mg/day increased dose during follow up. Rates of Complete hematological responses, complete cytogenetic responses, and major molecular responses by 12 months (table 1) were 100%, 52%, and 45% respectively. Overall, 56% of patients improved previous response, 32% maintained the same degree of response, whereas 12% lost the baseline responses. With a median follow‐up of 24 months, 35 patients (48%) discontinued treatment due to toxicity (38%), stem cell transplantation (21%), death (17%) or lack of efficacy (24%). Most frequent toxicities leading to treatment discontinuations were severe cardiovascular events, hepatotoxicity, and myelotoxicity (table 2). Severe cardiovascular events were seen in 10 patients (9%). The majority of patients (70%) experiencing cardiovascular events had more than 2 CVS risk factors before ponatinib start. EFS, PFS, and overall survival was 46%, 69% and 83% at 21 months.

Summary/Conclusion:

The present study demonstrates that the use of ponatinib in daily clinical practice under a dose limiting strategy in responding patients appears to be safe and preserves its clinical efficacy.

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