A Multicenter Phase I/II Study of Relapse Prophylaxis with Nilotinib after Hematopoietic Cell Transplantation (HCT) for High-Risk Philadelphia Chromosome-Positive (Ph+) Leukemias

Background: In a previous study, we showed that relapse prophylaxis with imatinib (IM) is feasible early after allogeneic HCT for treatment of Ph+ leukemia [Carpenter et al, Blood 2007;109:2791]. The goal of the current study was to ask whether nilotinib (NIL) might address IM resistance (IR) or intolerance (IT) because IR leukemia might be sensitive to NIL.  Previous non-HCT trials have shown that NIL and IM have comparable hematopoietic toxicity, but the incidence of edema and gastrointestinal toxicity is less with NIL than with IM. Methods: 57 mostly adults (median age 42.5 y) with high-risk Ph+ leukemia were enrolled. Given NIL's unique QTc prolongation risks and data showing that IM can be given early after engraftment, IM was given for the first 80 days after HCT.  Treatment was then changed to NIL prophylaxis at day 81. Based on risk-benefit considerations IR cases and IT patients began NIL before day 80 but at lower dose. The primary safety endpoint defined "success" as administration of NIL at ³400 mg/day for ³85% of time from days 81-365, but 1 full year of NIL therapy was planned through Day 445. The primary efficacy endpoint defined "success" as molecular remission (CMR) at 1 yr. Results: See Figure. 1) 28/57 of patients registered in the study did not begin or continue NIL because of post-HCT eligibility exclusions: most frequently QTc>450 (n=7) or myocardial infarction (n=2), early relapse (n=8), and other exclusions because of laboratory abnormalities (n=6). 2) We confirmed our prior data that IM is tolerable early post-HCT: 28/29 tolerated treatment at a median of 100% of the intended dose (range, 48%-100%) for a median of 42 days. 3) 9/11 IR/IT cases tolerated NIL early post-HCT (data not shown). 4) 13/57 patients registered in the study or 13/40 (32.5%) who maintained eligibility at engraftment, tolerated NIL between Days 81 and 365. Another 11/40 received NIL at a median intended dose intensity of 99% for a median of 130 days before stopping prematurely because of relapse or reasons other than toxicity. 5) 19/40 subjects had 38 possibly (33), probably (4) or definitely related, grade 3/4 non-serious AEs: cytopenias (84%) and metabolic abnormalities (16%). 6) 38/40 were not in complete molecular remission (CMR) pre-HCT. 28/40 (70%: 23 ALL, 4 advanced CML) are alive at a median 4.4 yrs (range 1-5.7), with 26 in CMR. The 2 patients without CMR either did not start NIL or stopped at Day 110. 4/40 subjects died with progressive leukemia (1 isolated CNS relapse) and 8/40 died with non-relapse causes. Conclusions: Efficacy data are encouraging, but the post-HCT relapse prophylaxis approach with NIL is limited by QTc prolongation (16% of all registered patients), early relapse before prophylaxis can begin, and by miscellaneous post-HCT events that preclude NIL administration.