Phenotype-Specific Associations between Graft‑Versus‑Host Disease and Post‑Transplant Outcomes.

Disease relapse remains the leading cause of failure following allogeneic hematopoietic cell transplantation (HCT). As novel prophylactic strategies increasingly aim to universally eliminate all forms of graft‑versus‑host disease (GVHD), how these approaches may inadvertently sacrifice graft‑versus‑leukemia activity in the post‑transplant cyclophosphamide (PTCy) era is unclear. To evaluate the associations between time‑updated GVHD phenotypes and clinical outcomes, including relapse, non‑relapse mortality (NRM), and overall survival (OS), in patients undergoing PTCy‑based haploidentical or mismatched unrelated donor (MMUD) HCT. This was a retrospective cohort study using the Center for International Blood and Marrow Transplant Research registry. Participants included 7055 patients with hematologic malignancies who received a first haploidentical or MMUD HCT with PTCy from 2013 to 2021. Associations with relapse, NRM, and OS were evaluated using multi‑state time‑dependent Cox proportional hazards models and a multi‑state random survival forest (MS‑RSF). Time‑updated acute and chronic GVHD phenotypes included isolated Grade II acute GVHD (aGVHD), Grade III to IV aGVHD, mild chronic GVHD (cGVHD), and immunosuppressive therapy-requiring (IST‑requiring) cGVHD. IST‑requiring cGVHD without antecedent aGVHD was associated with a lower modeled relapse hazard compared with remaining GVHD‑free (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.62 to 0.89; false discovery rate-adjusted P [q] = 0.006) and lower overall mortality (HR, 0.62; 95% CI, 0.53 to 0.73; q < 0.001). In contrast, Grade III to IV aGVHD was associated with significantly higher modeled NRM (HR, 3.15; 95% CI, 2.57 to 3.84; q < 0.001). Mild cGVHD and isolated Grade II aGVHD showed intermediate patterns without consistent associations. These associations were directionally consistent across multiple analytic approaches, including standard time‑dependent Cox regression, dynamic and fixed landmark analyses, and MS‑RSF. In this large PTCy‑treated mismatched donor cohort, IST‑requiring cGVHD was the GVHD phenotype most consistently associated with lower relapse incidence, whereas severe aGVHD was associated with higher NRM. These findings highlight heterogeneity in GVHD phenotypes and suggest that strategies distinguishing toxic aGVHD from chronic alloreactivity patterns may better balance morbidity and long‑term disease control. Given that relapse remains the predominant cause of post‑transplant mortality, approaches aiming to universally eliminate all GVHD warrant careful reconsideration.