PF190 PLASMA LEVELS AND OUTCOMES OF PROPHYLACTIC POST-TRANSPLANT PONATINIB ADMINISTRATION IN PATIENTS WITH PHILADELPHIA CHROMOSOME-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA (PH+ALL)
Authors: S. Nanno, H. Okamura, M. Nakamae, A. Hirose, K. Matsumoto, K. Morita, Y. Nakashima, H. Koh, T. Nakane, M. Hino, H. Nakamae
Journal: HemaSphere (2019)

Background: Some retrospective studies demonstrated that the administration of first- and second-generation tyrosine kinase inhibitors (TKIs) to patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) after allogeneic hematopoietic cell transplantation (allo-HCT) led to better overall survival (OS) and progression-free survival (PFS). However, most patients become intolerant, making it difficult to continue treatment. Experimental data show that third-generation TKI ponatinib is effective against various BCR-ABL1 mutations, including T315I, at plasma levels of 21.3 ng/mL. In addition, a recent study demonstrated that a reduced dose of ponatinib might result in a lower incidence of cardiovascular adverse events (AEs). However, few studies have examined ponatinib maintenance after allo-HCT to prevent relapse. We herein investigate the efficacy and safety of maintenance with low-dose ponatinib after allo-HCT to prevent relapse and evaluated plasma concentration of ponatinib. Aims: The purpose of this study was to examine whether ponatinib maintenance after allo-HCT was tolerable and contributed to superior OS and PFS. Methods: We retrospectively analyzed data of consecutive patients with Ph+ALL who underwent allo-HCT at our institution between January 2008 and December 2018. The initial ponatinib dose was 15 mg daily; thereafter, it was at the physicians' discretion. Plasma trough levels of ponatinib were measured using liquid chromatography tandem mass spectrometry on and after day 8 following the first administration. We compared outcomes between patients who did or did not receive ponatinib maintenance using 1:2 nearest neighbor propensity matching based on factors such as age, number of transplants, and minimal residual disease (MRD). Results: A total of 31 patients aged 19–65 years (median, 46) were included. Of them, 29 achieved complete remission and 24 had a negative MRD status before allo-HCT, while 10 had prior history of BCR-ABL1 mutations including T315I (n = 7). Seven patients received ponatinib maintenance for a median of 48 days (range, 36–124) after allo-HCT. The median follow-up times for all patients and for those on ponatinib maintenance were 553 (range, 34–3,836) days and 240 (69–405) days, respectively. Two-year OS and PFS in the ponatinib maintenance group tended to be better than those in the non-ponatinib group after propensity matching (n = 21) as shown in Figure 1 (100% vs. 62.5%, P = 0.206; 100% vs. 55.1%, P = 0.120, respectively). In the ponatinib group, median plasma concentration during 15 mg daily administration of ponatinib was 15.6 ng/mL (range, 4.8–23.3). The plasma level exceeded 21.3 ng/mL in only one patient and was below 10 ng/mL in two patients. The initial ponatinib dose was continued in six patients and changed to 30 mg in one patient. Although grades 3–4 non-hematologic AEs occurred in three patients, all were reversible. No cardiovascular AEs occurred during follow-up. One patient developed acute skin graft-versus-host disease shortly after ponatinib administration. In the ponatinib group, 93.5% of intended doses were administered. We found no relationship between plasma ponatinib concentrations and AEs or drug interruption.Summary/Conclusion: Our results suggest that prophylactic post-transplant ponatinib administration in patients with Ph+ALL is relatively safe and effective. It would be worthwhile to prospectively evaluate ponatinib maintenance efficacy after allo-HCT in a large patient cohort.