Sirolimus Results in Similar Outcomes to Tacrolimus for Gvhd Prophylaxis after Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplant Cyclophosphamide

Abstract

Background Graft-versus-host disease (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCy), tacrolimus (TAC) and mycophenolate mofetil (MMF) for allogeneic haploidentical (haplo) donor hematopoietic cell transplantation (HCT) has proven safe and effective. Many centers replace TAC with sirolimus (SIR) as this drug preserves regulatory T cells and may have a preferable side effect profile with less risk of kidney injury and thrombotic microangiopathy. A recent phase II single arm study reported comparable rates of grade II-IV acute GVHD with the use of SIR after haplo HCT (Bejanyan, Blood Adv. 2021). Methods We performed a retrospective cohort study comparing haplo HCT outcomes with SIR vs. TAC in combination with PTCy/MMF. All consecutive patients receiving haplo donor T cell replete peripheral blood stem cell graft HCT for hematologic malignancy at the Moffitt Cancer Center or the City of Hope Cancer Center between 2015-2020 were included. Associations with HCT related survival outcomes were assessed using Cox proportional hazard survival models. Fine and Gray regression models were used to assess associations of transplant related endpoints with competing risks. Kaplan Meier curves and cumulative incidence function curves were also plotted using the IBM SPSS analytic software version 28. Results A total of 423 patients met the inclusion criteria of which 84 (20%) received SIR and 339 (80%) received TAC. The SIR group had a higher proportion of patients >60 years (58% vs. 34%, p=<0.01), and the groups were also unbalanced in terms of diagnosis type, conditioning regimen, and cytomegalovirus serostatus (Table 1). Median follow-up was 30 months (range: 2-88 months). Neutrophil engraftment at day 30 was lower with SIR than TAC (89% vs. 95%, p=0.04), while platelet engraftment at day 60 was not significantly different (77% in SIR vs. 84% in TAC; p=0.14). For SIR and TAC, we found no significant differences in the rates of grade II-IV acute GVHD (45% vs. 47%, p=0.6), grade III-IV acute GVHD (20% vs. 15%, p=1.0) or chronic GVHD (48% vs. 55%, p=0.80). The probability of non-relapse mortality (NRM) was similar between SIR vs. TAC groups both at day 100 (19% vs. 11%, p=0.16) and at 1 year (29% vs. 28%, p=0.98) after HCT. Similarly, we observed no significant differences between the SIR and TAC groups in 2-year probabilities of relapse (23% vs. 25%, p=1.0), disease free survival (DFS; 55% vs. 55%, p=1.0) or overall survival (OS; 64% vs. 63%, p=0.99). In multivariate analysis (MVA) (Table 2), TAC was associated with faster neutrophil engraftment (OR=3.33, CI 1.20-9.26, p=0.02), but GVHD prophylaxis type had no significant impact on platelet engraftment, acute or chronic GVHD, relapse, NRM, DFS, or OS after haplo HCT. Conclusions Our study suggests that SIR is a comparable alternative to TAC in combination with PTCy/MMF for GVHD prophylaxis, resulting in overall similar clinical outcomes after peripheral blood haplo HCT. Rather than a uniform approach, the choice of TAC vs. SIR may be determined based on the side effect profile of these medications with consideration of patient medical comorbidities at HCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal