Superiority of Post-Transplant Cyclophosphamide-Based Graft Versus Host Disease (GvHD) Prophylaxis in Patients 70 Years and Older: A BMT CTN 1703 Post-Hoc Analysis

Introduction

Allogeneic hematopoietic cell transplant (HCT) in adults ≥70 years is increasing with improved donor availability, newer disease therapies, and increasingly preserved fitness. Registry studies indicate that these older patients represent a frailer transplant population overall, with a historical 1-year non-relapse mortality (NRM) at around 25%.

BMT CTN 1703 enrolled adult patients undergoing allogeneic HCT with a matched related donor, or 7-8/8 HLA-matched unrelated donor and reduced intensity conditioning (Bolanos-Meade NEJM, 2023). Patients were randomized 1:1 to post-transplant cyclophosphamide, tacrolimus, and mycophenolate (PTCy/Tac/MMF) or tacrolimus and methotrexate (Tac/MTX) and the primary endpoint was 1-year GVHD/relapse or progression-free survival (GRFS). Overall, a superior 1-year GRFS rate was seen with PTCy/Tac/MMF, however NRM and overall survival (OS) did not differ between treatment arms. We report here, a post hoc analysis of patients ≥70 years randomized on the BMT CTN 1703 protocol.

Methods

Patients ≥70 years randomized on BMT CTN 1703 (PTCy=43, Tac/MTX=53; N=96) were included. The primary endpoint of this post-hoc analysis was 1y-GRFS. Secondary endpoints included infections, engraftment, incidence/severity of acute and chronic GVHD, relapse/progression, adverse events, NRM, and OS in these patients.

Results

Baseline characteristics were balanced between the two treatment arms. Median age at transplant between patients treated with PTCy/Tac/MMF and Tac/MTX was 72 years (70.1-78.6y) and 73 years (70.1-77.4) respectively. In similar order 88% and 85% underwent HCT with HLA matched unrelated donor, and 46% and 40% received Flu/Mel conditioning, which was the most common conditioning regimen. Multivariate Cox model of GRFS revealed that the PTCy/Tac/MMF maintained superiority over Tac/MTX with a significantly lower hazard of GRFS (0.341, 95% CI 0.184-0.633, p<0.001). The adjusted 1-year GRFS rate was 63.1% (95%CI, 47.9%,74.9%) for PTCy and 29.9% (95%CI, 19.2,41.3%) for Tac/MTX. With PTCy/Tac/MMF or Tac/MTX, rates of grade III-IV acute GVHD at Day 100 were 0% and 9.9% (p=0.175), and rates of chronic GVHD requiring immunosuppression were 18.3% and 24.4% (p=0.089). The cumulative incidence of neutrophil recovery (>500mm3) by day 28 was similar between arms (92.8% vs 92.8%, p=0.85). From a toxicity standpoint, with PTCy/Tac/MMF or Tac/MTX, rates of grade 3 infections at 6 months were 4.6% and 11.8%, rates of Grade 3-5 cardiac events were 30.2% and 34%, and rates of Grade 3-5 renal events were 14.0% and 15.1%; none were significantly different. Together, 1-year NRM was significantly lower in PTCy/Tac/MMF treated patients at 4.6% compared to 20.0% with Tac/MTX (p=0.038). Finally, incidence of relapse/progression at 1-year was 19.5% in patients receiving PTCy/Tac/MMF and 25.7% with Tac/MTX (p=0.232). Overall, there was a significant overall survival benefit with PTCy at 1 year post transplant at 90.6% in PTCy/Tac/MMF treated patients compared to 61.8% with Tac/MTX (p=0.003).

Conclusions

This post-hoc analysis of transplant recipients ≥70 years confirms that even in this older, frailer sub-population, PTCy/Tac/MMF is standard of care in patients for GVHD prophylaxis following HLA-matched RIC HCT. The PTCy arm of BMT CTN 1703 showed superior GRFS, lower NRM, and increased OS in in septuagenarians, in whom the apprehension concerning excess toxicity has been greatest.

Abedin:AbbVie, Daichii Sankyo, Servier: Consultancy, Honoraria; Actinium Pharmaceutical, AltruBio, Incyte: Research Funding. Al Malki:Tr1X: Consultancy; Tscan: Consultancy; Stemline therapeutics: Research Funding; CareDx: Consultancy; Incyte: Research Funding; NexImmune: Consultancy, Research Funding. Elmariah:BMS: Research Funding; Shoreline Biosciences: Consultancy. Gooptu:Syndax: Consultancy, Other: Travel expenses. Shaffer:Hansa Biopharma: Consultancy. Solh:GlaxoSmithKline: Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau; Sanofi: Consultancy. Perales:Bristol-Myers Squibb: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria, Research Funding; Vor Biopharma: Consultancy; AbbVie: Honoraria; VectivBio AG: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Syncopation: Consultancy; OrcaBio: Consultancy, Current holder of stock options in a privately-held company; Cidara Therapeutics: Other: DSMB member; Sellas: Other: DSMB member; Nektar Therapeutics: Consultancy, Honoraria, Research Funding; Omeros: Consultancy, Current equity holder in publicly-traded company; Sanofi: Consultancy; Incyte: Consultancy, Honoraria, Research Funding; Adicet: Consultancy; Celgene: Consultancy, Honoraria; Allovir: Consultancy; Allogene: Consultancy, Research Funding; Caribou Biosciences: Consultancy; Astellas: Honoraria; Karyopharm: Honoraria; MorphoSys: Honoraria; Takeda: Honoraria; Medigene: Other: DSMB member; Servier: Other: DSMB member. Efebera:Takeda, Janssen, Akcea Therapeutics, Alnylum: Speakers Bureau; Oncopeptides, Sanofi, Janssen Oncology, Pfizer: Consultancy; Takeda, Oncopeptides, Alnylam, Sanofi, GlaxoSmithKline, ORCA Therapeutics, Bristol Myers Squibb/Celgene, Pharmacyclics through Alliance and AFT: Research Funding. Reshef:Orca Bio: Consultancy; Autolus: Consultancy; Sanofi: Research Funding; Atara Biotherapeutics: Research Funding; J&J: Research Funding; Immatics: Research Funding; Quell Biotherapeutics: Consultancy; Takeda: Research Funding; Gilead Sciences: Consultancy, Research Funding; Cabaletta: Research Funding; TCR2: Research Funding; Abbvie: Research Funding; Synthekine: Research Funding; TScan: Consultancy, Research Funding; CareDx: Research Funding; Bayer: Consultancy; Sana Biotechnology: Consultancy; BMS: Research Funding; Incyte: Consultancy, Research Funding; Genentech: Research Funding; Allogene: Consultancy; Precision Biosciences: Research Funding. Clark:Abbvie Inc: Research Funding; Caribou: Consultancy, Research Funding; GPCR Therapeutics, Inc.: Research Funding; IMMPACT Bio: Research Funding; Janssen: Research Funding; Kite: Research Funding; medac Gesellschaft für klinische Spezialpräparate: Research Funding. Horowitz:CSL Behring: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Astellas: Research Funding; Medac: Research Funding; Sanofi: Research Funding; Gamida Cell: Research Funding; Xenikos: Research Funding; Sobi: Research Funding; Janssen: Research Funding; Bristol-Myers Squibb: Research Funding. Hamadani:CRISPR: Consultancy; Forte Biosciences: Consultancy; Kite Pharma: Consultancy, Speakers Bureau; Spectrum Pharmaceuticals: Research Funding; AbbVie: Consultancy; Sanofi Genzyme: Speakers Bureau; Genmab: Consultancy; Astellas Pharma: Research Funding; AstraZeneca: Speakers Bureau; ADC Therapeutics: Consultancy, Research Funding, Speakers Bureau; Omeros: Consultancy; BMS: Consultancy; Autolus: Consultancy; Caribou: Consultancy; Allovir: Consultancy; BeiGene: Speakers Bureau; Byondis: Consultancy; CRISPR: Speakers Bureau; DMC, Inc: Speakers Bureau; Genentech: Speakers Bureau; Myeloid Therapeutics: Speakers Bureau; Takeda: Research Funding.