Session: Late-Breaking Abstracts Session
Hematology Disease Topics & Pathways:
adult, Research, clinical trials, Non-Biological therapies, Clinical Research, Chemotherapy, Therapies, immunology, Adverse Events, Biological Processes, Human, Study Population
Patients and Methods: Eligible adults (age 18+) with hematologic malignancies undergoing RIC alloHCT with an 6/6 matched related (N=128), 8/8 matched unrelated (N=288), or 7/8 single mismatch (N=15) peripheral blood stem cell donor, satisfactory organ function, and adequate performance status were randomized 1:1 to receive PTCy/Tac/MMF (N=214) or Tac/MTX (N=217), stratified by transplant center and Disease Risk Index (DRI). The primary endpoint of the study was GVHD/relapse or progression-free survival (GRFS), a time-to-event outcome defined as grade III-IV acute GVHD, chronic GVHD requiring systemic immune suppression, disease relapse or progression, or death by any cause. The primary hypothesis was that PTCy/Tac/MMF has a ≥15% higher GRFS at 1 year than Tac/MTX in the intent-to-treat population. Secondary endpoints included the incidence/severity of acute and chronic GVHD, engraftment/chimerism, relapse/progression, infections, and survival.
Results: The 2 study arms were well balanced by patient sex, age, Karnofsky performance status, disease risk, comorbidities, donor match, conditioning regimen, and post-transplant maintenance therapy (Figure panel A). In the multivariate Cox regression model of the primary endpoint, the PTCy treatment group had a significantly lower hazard of GRFS than Tac/MTX (hazard ratio 0.641, 95% confidence interval [CI] 0.492 to 0.835, p=0.001). The adjusted 1-year GRFS rate was 52.7% (95% CI: 45.8%, 59.2%) for the PTCy arm and 34.9% (95% CI: 28.6%, 41.3%) for the control arm, Figure panel B). The lower proportion of GRFS events in the PTCy arm was due to a reduction in both acute and chronic GVHD. The Day 100 grade III-IV acute GVHD was 6.3% vs 14.7% (p=0.001), and chronic GVHD rate at 1 year was 21.9% vs 35.1% (p=0.005) for PTCy vs Tac/MTX, respectively. There was no difference in the relapse/progression rate at 1 year (20.8% vs 20.2%, p=0.9), or OS rate at 1 year post transplant (76.8% vs 72.6% , p=0.3), in PTCy vs Tac/MTX. The cumulative incidence of engraftment was lower for PTCy for neutrophils ≥ 500/mm3 by day +28 (90.3% vs 93.4%, p=0.03), platelets ≥ 50,000/mm3 by day +100 (79.5% vs 83.7%, p<0.001), and lymphocytes ≥ 1000/mm3 by 1 year (47.1% vs 63.2%, p<0.001). Grade 3 infection rates were similar between the arms (12.2% for PTCy vs 13.3%, p=0.8) but grade 2 infections were greater for PTCy (33.7% vs 23.5%, p=0.002). There was no difference in CMV reactivation between the treatment arms (7.3% for PTCy vs 7.1%, p=0.8). There was no significant difference in proportion of chimerism at day +100 (>95% donor in 68.6% for PTCy vs 67.8%, p=0.2) or secondary graft failure between the arms (2.9% for PTCy vs 0.9%, p=0.2).
Conclusions: BMT CTN 1703 met its primary endpoint, demonstrating a higher 1-year GRFS with PTCy/Tac/MMF compared to Tac/MTX owing to significant improvements in GVHD risk without increased risk of relapse or death. PTCy/Tac/MMF, which has become standard of care for mismatched transplants, should also become the standard of care for GVHD prophylaxis from closely-matched donors receiving reduced intensity conditioning.
Disclosures: Holtan: Incyte: Research Funding; Vitrac Therapeutics: Research Funding; CSL Behring: Other: Clinical trial adjudication. Hamadani: Genmab: Consultancy; Kite: Consultancy; Medical University of Wisconsin: Current Employment; Incyte Corporation: Consultancy; MorphoSys: Consultancy; SeaGen: Consultancy; Gamida Cell: Consultancy; Novartis: Consultancy; Legend Biotech: Consultancy; Kadmon: Consultancy; ADC Therapeutics: Consultancy, Research Funding, Speakers Bureau; Omeros: Consultancy; Abbvie: Consultancy; Takeda: Research Funding; Spectrum Pharmaceuticals: Research Funding; Astellas Pharma: Research Funding; Sanofi Genzyme: Speakers Bureau; AstraZeneca: Speakers Bureau; BioGene: Speakers Bureau. Runaas: Servier: Honoraria. Elmariah: Bristol Myers Squibb: Research Funding. Larkin: Gilead: Membership on an entity's Board of Directors or advisory committees; ASCO: Consultancy. Shaffer: Miltenyi Biotec: Research Funding; Gamida Cell: Consultancy; Hansa Biopharma: Consultancy. Solh: Partner Therapeutics: Research Funding; ADC Therapeutics: Research Funding. Alousi: Genetech: Consultancy; Sanofi / Kadmon: Honoraria; Mallinkrodt: Honoraria; Prolacta: Consultancy; Incyte: Honoraria, Research Funding. Perales: Celgene: Honoraria; Astellas: Honoraria; Sellas Life Sciences: Consultancy; AbbVie: Honoraria; Novartis: Honoraria; Nektar Therapeutics: Consultancy, Honoraria; Merck: Consultancy; Omeros: Consultancy; Bellicum: Honoraria; Karyopharm: Honoraria; Miltenyi Biotec: Consultancy, Honoraria; Orca Bio: Consultancy; Vor Biopharma: Honoraria; VectivBio AG: Honoraria; DSMB: Other; Cidara Therapeutics: Consultancy; Servier: Consultancy; MorphoSys: Consultancy, Honoraria; Takeda: Honoraria; Medigene: Consultancy; Kite, a Gilead Company: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria. Kean: Mammoth Biosciences: Current equity holder in private company, Current holder of stock options in a privately-held company; Bluebird Bio: Research Funding; Vertex: Consultancy; Magenta: Research Funding; Bristol Myers Squibb: Patents & Royalties: clinical trial, Research Funding; Novartis: Research Funding; EMD-Serono: Research Funding; HiFiBio: Consultancy. Efebera: GSK: Honoraria; Takeda: Honoraria; Pfizer: Honoraria; Janssen: Honoraria, Speakers Bureau; Sanofi: Honoraria; BMS: Research Funding. Kitko: Horizon Therapeutics: Consultancy. Reshef: Atara Biotherapeutics: Consultancy, Research Funding; Novartis: Honoraria; Synthekine: Consultancy; Gilead: Consultancy, Honoraria, Other: Travel Support, Research Funding; Incyte: Research Funding; Bayer: Consultancy; MidaTech: Consultancy; TScan: Consultancy; Regeneron: Consultancy; Jasper: Consultancy; Capstan Therapeutics: Consultancy; BMS: Honoraria; University Of Pennsylvania: Other: Data Safety Monitoring Board; Takeda: Research Funding; J&J: Research Funding; Precision Biosciences: Research Funding; Pharmacyclics: Research Funding; Shire: Research Funding; Immatics: Research Funding.