Effect of stem cell infusion time-of-day on acute graft-versus-host disease: a randomized clinical trial

Key PointsO_ST_ABSQuestionC_ST_ABSDoes the circadian timing of stem cell infusion influence the risk of aGVHD after allo-PBSCT? FindingsIn this randomized prospective clinical trial that included 198 patients, infusion stem cell at 12:00 pm at noon was associated with a significantly lower incidence and less severity of aGVHD compared with infusion at 6:00 pm, without influencing engraftment or relapse. MeaningScheduling stem cell infusion at an earlier time-of-day may reduce aGVHD risk after allo-PBSCT. IMPORTANCEAcute graft-versus-host disease (aGVHD) remains a major complication following allogeneic peripheral blood stem cell transplantation (allo-PBSCT), compromising patient survival and quality of life. OBJECTIVETo evaluate the effect of stem cell infusion time-of-day on aGVHD after allo-PBSCT. DESIGNA multicenter, randomized, open-label, phase 3 clinical trial was conducted from March 18, 2024, through June 11, 2025, with follow-up through December 31, 2025 (median, 462 days among survivors). SETTINGSix transplantation centers in China. PARTICIPANTSPatients aged 12 to 60 years with malignant hematologic diseases undergoing first allo-PBSCT were screened; 198 eligible patients were randomized. INTERVENTIONSPatients were randomly assigned in a 1:1 ratio to receive stem cell infusion at either 12:00 pm at noon ({+/-} 0.5 hour) or 6:00 pm ({+/-} 0.5 hour). MAIN OUTCOMES AND MEASURESThe primary end point was the cumulative incidence of grade II-IV aGVHD within 100 days after transplantation. Secondary end points included grade III-IV aGVHD, hematopoietic recovery, transplant-related mortality (TRM), relapse, and survival outcomes. RESULTSAmong 198 randomized patients (median age, 38 years; 119 [60.1%] male), grade II-IV aGVHD within 100 days occurred in 11 of 99 patients (11.1%) in the 12:00 pm group and 22 of 99 patients (23.2%) in the 6:00 pm group. The cumulative incidences of grade II-IV and III-IV aGVHD were significantly lower in the 12:00 pm group (II-IV: 11.1% [95% CI, 5.9%-18.2%] vs 23.2% [95% CI, 15.4%-32.0%], P = 0.029, hazard ratio, 2.18 [95% CI, 1.06-4.48]; III-IV: 2.0% [95% CI, 0.4%-6.5%] vs 12.2% [95% CI, 6.7%-19.5%], P = 0.006, hazard ratio, 6.25 [95% CI, 1.39-28.15]). There were no significant differences in hematopoietic recovery, TRM, or relapse between groups. The estimated probability of GVHD-free, relapse-free survival (GRFS) at 360 days favored the 12:00 pm group (66.7% [95% CI, 56.2%-75.2%] vs 56.5% [95% CI, 46.1%-65.5%]). CONCLUSIONS AND RELEVANCEStem cell infusion at 12:00 pm was associated with a lower incidence and severity of aGVHD compared with infusion at 6:00 pm, without influencing engraftment or relapse. Optimization of infusion timing may represent a simple strategy to reduce aGVHD risk. TRIAL REGISTRATIONClinicalTrials.gov Identifier: NCT06294678.