A phase 2 trial of GVHD prophylaxis with PTCy, sirolimus, and MMF after peripheral blood haploidentical transplantation

Abstract

The introduction of posttransplant cyclophosphamide (PTCy) made performing allogeneic hematopoietic cell transplantation (HCT) from HLA haplotype-incompatible donors possible. In a setting of PTCy and tacrolimus/mycophenolate mofetil (MMF) as a graft-versus-host disease (GVHD) prophylaxis, a peripheral blood (PB) graft source as compared with bone marrow reduces the relapse rate but increases acute GVHD (aGVHD) and chronic GVHD (cGVHD). This phase 2 trial assessed sirolimus and MMF efficacy following PTCy as a GVHD prophylaxis after PB haploidentical HCT (haplo-HCT). With 32 evaluable patients (≥18 years) enrolled, this study had 90% power to demonstrate a reduction in 100-day grade II-IV aGVHD to 20% from the historical benchmark of 40% after haplo-HCT using PTCy/tacrolimus/MMF. At a median follow-up of 16.1 months, the primary end point of the trial was met with a day-100 grade II-IV aGVHD cumulative incidence of 18.8% (95% confidence interval [CI], 7.5% to 34.0%). There were no graft-failure events and the 1-year probability of National Institutes of Health (NIH) moderate/severe cGVHD was 18.8% (95% CI, 7.4% to 34.0%), nonrelapse mortality was 18.8% (95% CI, 7.4% to 34.0%), relapse was 22.2% (95% CI, 9.6% to 38.2%), disease-free survival was 59.0% (95% CI, 44.1% to 79.0%), GVHD-free relapse-free survival was 49.6% (95% CI, 34.9% to 70.5%), and overall survival was 71.7% (95% CI, 57.7% to 89.2%) for the entire cohort. These data demonstrate that GVHD prophylaxis with sirolimus/MMF following PTCy effectively prevents grade II-IV aGVHD after PB haplo-HCT, warranting prospective comparison of sirolimus vs tacrolimus in combination with MMF following PTCy as GVHD prophylaxis after PB HCT. This trial was registered at www.clinicaltrials.gov as #NCT03018223.

Conflict of interest statement

Conflict-of-interest disclosure: N.B. reports a consulting or advisory role with Kiadis Pharma and Magenta Therapeutics, and stock options from Pfizer. T.N. receives research support to the institution from Novartis and Karyopharm. A.L. serves on the scientific advisory board for EUSA Pharma and has stock options from Pfizer. M.L.D. reports research funding from Celgene, Novartis, and Atara; other financial support from Novartis, Precision Biosciences, Celyad, Bellicum, and GlaxoSmithKline; and stock options from Precision Biosciences, Adaptive Biotechnologies, and Anixa Biosciences. M.D.J. reports a consultancy/advisory role for Kite/Gilead, Novartis, Takeda, and Bristol Myers Squibb (BMS). M.A.K.-D. reports consultancy for Pharmacyclics and Daiichi Sankyo. H.F. discloses honoraria from Pfizer and Sanofi and speakers’ bureau membership with Sanofi. M.A. reports honoraria from Janssen, Amgen, and Celgene; consulting or advisory role fees for Celgene and BMS; speakers’ bureau participation for Janssen and Amgen; and research funding from BMS. F.L.L. has a scientific advisory role with Kite, a Gilead Company, Novartis, Celgene/BMS, GammaDelta Therapeutics, Wugen, Amgen, Calibr, and Allogene; is a consultant with grant options for Cellular Biomedicine Group, Inc; and receives research support from Kite, a Gilead Company. The remaining authors declare no competing financial interests.

© 2021 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Probability of neutrophil and platelet engraftment after HCT.

Figure 2.

Cumulative incidences. Cumulative incidences of grade II-IV and grade III-IV acute GVHD (A), moderate/severe chronic GVHD (B), probability of GRFS (C), and discontinuation of total immunosuppression (D) after HCT.

Figure 3.

Probabilities. Probabilities of NRM (A), relapse (B), DFS (C), and OS (D) after HCT.

Figure 4.

Infection density by posttransplant time periods.

Figure 5.

Immune reconstitution after HCT. Reconstitution of absolute lymphocyte count (A), total CD3+ T cells (B), total CD8+ T cells (C), total CD4+ T cells (D), Tregs (E), total NK cells (F), and total B cells (G) after HCT. The boxes show the interquartile range of absolute cell count (per μL) for each immune cell type. The bold horizontal lines inside of the boxes and the corresponding numbers on the bottom indicate the median absolute cell count (per μL). The whiskers represent 1.5× the height of the box (or minimum/maximum values if there is no value in that range). The circles indicate the outliers. *P < .05, compared with the pre-HCT cell count.