Overall survival with ponatinib versus allogeneic stem cell transplantation in Philadelphia chromosome‐positive leukemias with the T315I mutation

Abstract

BACKGROUNDEffective treatment options for patients with chronic myeloid leukemia (CML) or Philadelphia‐positive (Ph+) acute lymphoblastic leukemia (ALL) who have the threonine to isoleucine mutation at codon 315 (T315I) are few. The objective of this study was to compare overall survival (OS) between patients with CML and those with Ph+ ALL who received treatment with ponatinib versus allogeneic stem cell transplantation (allo‐SCT).METHODSA post hoc, retrospective, indirect comparison of OS among patients who received single‐agent ponatinib in the Ponatinib Ph+ ALL and CML Evaluation (PACE) trial with those who underwent allo‐SCT as reported to the European Bone Marrow Transplant registry, stratified by CML disease phase and Ph+ ALL, was conducted. Kaplan‐Meier survival curves and multivariate Cox proportional‐hazards models were used to compare OS between intervention groups, adjusting for time from diagnosis to intervention, age, sex, and geographic region; 24‐month and 48‐month OS rates and median OS were reported.RESULTSAfter adjustment for potential confounders, 24‐month and 48‐month OS rates were significantly higher in patients with chronic‐phase CML (CP‐CML) who received ponatinib compared with those who underwent allo‐SCT (24 months: 84% vs 60.5%, respectively; P = .004; 48 months: 72.7% vs 55.8%, respectively; P = .013), with a hazard ratio (HR) of 0.37 (95% confidence interval [CI], 0.16‐0.84; P = .017). In patients who had accelerated‐phase CML, OS rates were not significantly different between the groups (HR, 0.90; 95% CI, 0.20‐4.10; P = .889). In patients who had blast‐crisis CML and those with Ph+ ALL, ponatinib was associated with shorter OS compared with allo‐SCT (blast‐crisis CML: HR, 2.29 [95% CI, 1.08‐4.82; P = .030]; Ph+ ALL: HR, 2.77 [95% CI, 0.73‐10.56; P = .146]).CONCLUSIONSAlthough allo‐SCT remains an important treatment option for patients with T315I‐positive advanced CML and Ph+ ALL, ponatinib represents a valuable alternative for patients with T315I‐positive CP‐CML. Cancer 2017;123:2875–80. © 2017 American Cancer Society.

Ponatinib in the Treatment of Chronic Myeloid Leukemia and Philadelphia Chromosome-Positive Acute Leukemia: Recommendations of a German Expert Consensus Panel with Focus on Cardiovascular Management

“…This significantly improves the prospects for long-term survival in CML even after SCT [7]. In a retrospective comparison between the European Bone Marrow Transplant registry and the ponatinib Ph+ ALL and CML evaluation (PACE) clinical trial, ponatinib in T315I-mutant CP-CML was associated with significantly longer overall survival (OS) than alloSCT [8]. Therefore, ponatinib may be an alternative in this setting, especially in older patients unsuitable for SCT or patients without a matched donor.…”

Upfront low‐dose ponatinib (15 mg/day) for multi‐TKI resistant chronic myeloid leukemia

“…The phase‐2 “PACE” trial included 267 patients with CP‐CML who failed treatment with nilotinib or dasatinib, or harbored T315I mutation; the 5‐year update of the PACE trial was recently communicated and indicated that ponatinib dose reductions down to 15 mg/day were implemented because of AOE concerns; cumulative CCyR was reported in 54% and MMR in 40%; MMR was sustained in 74% of those achieving the milestone; AOEs were reported in 29% of patients and in 17% after dose reduction to 15 mg/day . The durability of ponatinib response in heavily pre‐treated patients with chronic phase CML was also suggested by another report that showed a 73% 4‐year survival rate in patients receiving ponatinib vs 56% for those treated with allogeneic stem cell transplant …”

“…1 The durability of ponatinib response in heavily pre-treated patients with chronic phase CML was also suggested by another report that showed a 73% 4-year survival rate in patients receiving ponatinib vs 56% for those treated with allogeneic stem cell transplant. 8 Low-dose ponatinib (15 mg/day) might be associated with a lower risk of AOE without compromising treatment efficacy. 1 Furthermore, ponatinib might be superior to other 2G-TKIs in terms of its efficacy in patients with ABL1 mutations, in addition to those carrying T315I.…”

Towards a Personalized Treatment of Patients with Chronic Myeloid Leukemia

“…The T315I mutation is sensitive to ponatinib only and the prognosis of patients carrying this mutation impressively improved since approval of ponatinib. Five-year report of phase 2 "Ponatinib Ph1 ALL and CML Evaluation" (PACE) international study indicated a 70% rate of complete cytogenetic responses, a 58% rate of MMR, and a 38% rate of MR4.5 in the T315I+ cohort and responses were sustained, thus dispelling the specter of allogeneic stem cell transplantation (ASCT) [46] [47]. Although exceptionally performed, ASCT remains a key option in case of multi-resistance or progression to AP/BC.…”