PB1923 PONATINIB LONG-TERM FOLLOW-UP OF EFFICACY AND SAFETY IN CP-CML PATIENTS IN REAL WORLD SETTINGS IN FRANCE: THE POST-PACE STUDY

Abstract

Background: Ponatinib (PON) is a third generation tyrosine kinase inhibitor (TKI) used in adults with chronic myeloid leukaemia (CML) or Ph+ acute lymphoblastic leukaemia who are resistant or intolerant to prior TKIs or those harbouring the BCR-ABL1T315I mutant. The efficacy and safety profiles of PON were established in an extensive clinical program. The final 5-yr follow-up results of the PACE pivotal study were recently published and confirmed the durable and clinically meaningful responses obtained with PON in a heavily pre-treated chronic phase (CP)-CML population. Indeed, by the end of PACE in 2016, 33% of CP-CML patients were still on PON and continued to durably benefit from the treatment. Aims: Provide a prolonged safety and efficacy evaluation in real-world settings in national observational study. Methods: The POST-PACE study was performed on CP-CML patients still receiving PON by the end of PACE in France (8 centres). Clinical data on PON use were obtained, retrospectively from the end of PACE and prospectively until it reached 2-yr follow-up or treatment discontinuation. Data cut-off for this interim analysis was February 11, 2019. Results: A total of 16 CP-CML patients were included: 6 with molecular response (MR) (3 MMR, 2 MR4, 1 MR5), 2 with major cytogenetic response (MCyR) and 8 with complete hematologic response (CHR) at PACE end. Median age was 59.5 (30.0-83.0) and 63% were male. Regarding treatment history, most patients had previously received at least 2 (81%) or 3 (63%) approved TKIs before PON initiation. At the start of POST-PACE, the median duration in PACE was 4.8 years (4.4-5.1). The median daily dose for all patients was 15 mg/d (7.5-45.0), with 4 patients receiving 15 mg/d, 5 patients receiving 30 mg/d and 1 patient receiving 45 mg/d. The other 6 patients were receiving either 15 mg every other day (n = 4), 15 mg 4 times or 3 times a week (n = 1), or alternating 30 mg and 15 mg every other day (n = 1). Subsequently, in the POST-PACE study, the median PON additional treatment duration was 24.1 months (10.8-29.8) and the median daily dose of PON was increased to 18.8 mg (5.0-37.5). A sustained at least MMR was observed for 5 patients and achieved for 1 more; 3 patients were in MCyR and the others sustained CHR. Only one MMR loss was reported during POST-PACE following a dose decrease from 30 mg/d to 15 mg/d in a patient with MMR by the end of PACE. Overall, the median PON treatment duration across PACE and POST-PACE studies was 82.4 months (range, 68.7-88.8). Moreover, overall survival was 100% at data cut-off as no death was recorded. Regarding safety, 44 adverse events (AE) were reported including 8 vascular occlusive events (VOE) related to PON in 7 patients: 1 arterial lower limb disorder, 2 hypertensions, 2 subclavian artery stenoses (1 bilateral), 1 gut ischemia, and 1 arterial stenosis and 1 thrombosis occurring in the same patient. VOE were mostly managed by dose adaptation or treatment discontinuation (1 patient). Among AEs, 6 occurring in 4/16 (25%) patients were considered as serious, including 5 VOE: the arterial stenosis, the thrombosis, the gut ischemia (at 7.5 mg/d) and the 2 subclavian artery stenosis (at 15 mg/d and 45 mg/d). Summary/Conclusion: In summary, this first interim analysis of POST-PACE indicates that PON yields durable responses over an extended period of almost 7 years and that dose management adapted to each patient is warranted to maintain efficacy while controlling tolerability in heavily pre-treated CP-CML patients.