Daily Practice Experience in Ponatinib Treatment of Chronic Myeloid Leukemia (CML) Patients Resistant to Other Tyrosin Kynase Inhibitors (TKIs) in Argentina
Authors: Varela Ana Inés , Penalba Romina Laura , Enrico Alicia , Catalan Marta , Ventriglia Maria Veronica , Freitas Maria Josefina , Pavlovsky Carolina , Garbiero Susana , Beccasese Martin , Bengio Raquel Maria Nelida , Abramovich Catalina , Pavlovsky Miguel A , Moiraghi Elena Beatriz 
Published: November 2019

Abstract
INTRODUCTION: Ponatinib is a potent TKI indicated in T315I mutated CML and not mutated CML resistant to other drugs. Deep responses were reported in PACE trial in patients who had failed all other TKIs in chronic and advanced phase CML with acceptable toxicity profile. Ponatinib use is authorized in United States and Europe but compassionate use allows access in Argentina with no previous reports of local results.
OBJECTIVE: To analyze a cohort of CML resistant patients treated with ponatinib: clinical characteristics, outcome and adverse events.
MATERIALS AND METHDOS: Retrospective, multicentric, observational, descriptive study.
Data was collected from charts review of patients with resistant CML treated with ponatinib at 8 different centers. Mutational status was reported. Frequency of Complete Hematologic Response (CHR), Complete Cytogenetic Response (CCgR) and Major Molecular Response (MMR) at 3, 6 and 12 months, adverse events and death were analyzed.
RESULTS
Twenty three patients were included with median follow-up from CML diagnosis 119 months (m) (IQR: 12-215) and 6 m (IQR: 2-21) from ponatinib first dose. Median age at CML diagnosis was 41 year-old (5-61). At the moment of ponatinib first dose 74% (17/23) patients were in chronic phase (CP), 13% (3/23) in accelerated phase and (AP) and 13% (3/23) in blast crisis (BC). Ponatinib was indicated as second line treatment in 4% (1/23), third line treatment in 9% (2/23), fourth line 83% (19/23) and fifth line 4% (1/23). Mutations were detected in 83% (19/23) patients with presence of T315I mutation in 44% (10/23). Median time from mutation detection to ponatinib start was 6 m (1-12). Ponatinib dose was 45 mg/d in 48% (11/23) and 55% (6/11) of these patients required dose reduction, 52% (12/23) received 30mg/d. Treatment have been discontinued in 8% (2/23) due to safety reasons. All patients in CP with evaluable response achieved CHR with median time to CHR of 1m, 27% (3/11) achieved CCgR, and 18% (2/11) obtained MMR by 3 m y 6 m, and 37% (3/8) by 12 m. Of patients in AP/BC 83% (5/6) achieved no molecular response and only 1patient have received ponatinib associated with standard chemotherapy, obtained MR4.5 and underwent unrelated bone marrow transplantation and is alive --- months after BC T315I mutated CML.
Disease progression occurred in 6% (1/17). Death occurred in 4/23 (17%) all advanced phase at start of ponatinib.
Adverse events are reported in table 1:Table 1.ADVERSE EVENTINCIDENCETOXICITY GRADEHematologic21% (5/23)1-2- 3Dermatologic13% (3/23)1-2-3Hypertension9% (2/23)2- 3Mialgia4% (1/23)3Palpitations4% (1/23)2Hipertriglyceridemia4% (1/23)4Hepatotoxicity4% (1/23)2Disnea4% (1/23)3Arterial Thrombosis4% (1/23)4Grade 4 toxicities occurred in 2 patients receiving 30 mg/d. Arterial thrombosis was the cause of death of one patient and cardiac toxicity mandated drug interruption in another.
CONCLUSION:
This is the first report of ponatinib use in daily practice in Argentina.Response rates are lower than those reported in the literature. Drug was safe with low discontinuation rates although severe cardiac toxicity occurred as reported. Time to first dose in Argentina may be a relevant factor to explain the lower rates of response in patients who have failed other ITKs.

Disclosures
Varela: Bristol Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Enrico:Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Pavlovsky:Novartis: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau. Bengio:Bristol Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Pavlovsky:Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Moiraghi:Bristol Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau.