Impact of Acute and Chronic Graft-Versus-Host Disease (GVHD) on Non-Relapse Mortality and Survival Following Haploidentical Donor Transplantation.

The alloimmune response giving rise to the potent graft-versus-malignancy effect of allogeneic transplant can also be associated with morbidity and mortality from GVHD. The relative risk/benefit of having acute and/or chronic GVHD in the context of haploidentical donor transplantation (HIDT) has not been definitively studied. To this end, we studied the effects of acute and chronic GVHD following HIDT and post-transplant cyclophosphamide (PTCy), utilizing both landmark analysis (LA) and time-dependent multivariable analysis (MVA), in 335 consecutive HIDT recipients transplanted between 2005 and 2021. Recipient characteristics included a median age of 50 (19.80) years, 57% male, HCT-CI≥50%, diagnoses of acute leukemia[201], MDS/CML[62], lymphoma/CLL[72]. PBSC was the graft source in 81%, and regimen intensity was myeloablative in 49%. Median follow-up was 65 (23, 207) months. Landmarks were defined as Day +40 for acute GVHD and one-year for chronic GVHD. In this analysis, development of grade III-IV acute GVHD was associated with significantly inferior 3-yr transplant outcomes compared to recipients with grade 0-1 acute GVHD (OS and DFS 38% and 36% vs. 63% and 55%, p=0.008 and p=0.010, respectively), whereas development of grade II acute GVHD was associated with improved OS and DFS (80% and 75% respectively). Compared to patients with grade III-IV acute GVHD, those with grade II acute GVHD had significantly lower NRM (5% vs. 23%, p=0.020) and relapse (20% vs. 42%, p=0.033). Development of moderate-to-severe chronic GVHD resulted in significantly higher NRM risk (15% vs. 4%, p=0.010), but had no impact on relapse, DFS or OS. The impact of grade III-IV acute GVHD and moderate-to-severe chronic GVHD was further evaluated in Cox MVA, whereby GVHD events were treated as time-dependent covariates. After controlling for other significant variables (e.g. patient and donor age, disease risk index, year of transplant), both grade III-IV acute and moderate-to-severe chronic GVHD were associated with significantly higher NRM (HR 3.38, 95% CI 1.73-6.64, p<0.001 and HR3.35, 95% CI 1.72-6.53, p<0.001 respectively). By contrast, only grade III-IV acute GVHD predicted worse OS (HR 1.80, 95% CI 1.17-2.75, p=0.007) and DFS (HR 1.55, 95% CI 1.02-2.32, p=0.041). Contrary to the positive effect of grade II acute GVHD on survival in landmark analysis, no such association was found in MVA for any transplant outcome. In summary, both grade III-IV acute GVHD and moderate-to-severe chronic GVHD were associated with higher NRM after PTCy-based HIDT in both landmark analysis and time-dependent MVA. In addition, grade III-IV acute GVHD predicted inferior survival. Methods of early identification of such patients in order to augment GVHD prophylaxis are clearly needed.