Outcomes of Grades II-IV Acute Graft-Versus-Host Disease Post-Allogeneic Hematopoietic Stem Cell Transplantation: How Much Progress Was Achieved?

Despite recent reduction in mortality following hematopoietic cell transplant (HCT), graft versus host disease (GVHD) remains a major causes of failure. It is unclear if advances in antiviral, antifungal and antibacterial prophylaxis/treatment, and immunosuppression, have led to better survivals following the onset of acute GVHD (aGVHD). We therefore analyzed within the CIBMTR database outcomes over time of allogeneic HCT recipients who developed grade II-IV aGVHD. The objectives were to determine the change in overall survival (OS), disease-free survival (DFS), treatment-related mortality (TRM) and to identify risk factors.

Methods: Between 1999 and 2012, 7295 patients with AML (57%), ALL (29%) or MDS (14%) received sibling (35%) or unrelated donor (65%) blood (65%) or marrow (35%) HCT (1216 for 1999-2001, 2329 for 2002-2005, 3750 for 2006-2010), and 3312 (45%) developed grades II-IV aGVHD.  Median follow-up was 141 (3-174), 96 (3-144) and 49 (3-95) months for 1999-2001, 2002-2005, and 2006-2010 periods respectively. Multivariate models were built using the Cox’s proportional hazards model. Clinical variables were tested for the affirmation of the proportional hazards assumption. Factors violating the proportional hazards assumption were adjusted through stratification. Stepwise model building procedure was used in developing models for each outcome with a threshold of 0.05 for both entry and stay in the model. Interactions between the main variable, (i.e. year of transplant) and the adjusted covariates were tested.

Results: Univariate analyses showed a decrease in the incidence of grades III-IV aGVHD: 56 % (52-60), 47 %(44-50), and 38% (36-40) for 1999-2001, 2002-2005, and 2006-2010, respectively (p= <0.001). Multivariate analyses showed that age of recipient, organ affected by aGVHD, treatment of aGVHD (steroids vs. other), disease status at transplant and KPS influenced OS; while age of recipient, organ affected by aGVHD, treatment of aGVHD (steroids vs. other), CMV serostatus matching, disease status at transplant, unrelated donor age and KPS affected OS and TRM. After adjusting for these factors, recipients of tacrolimus-based GVHD prophylaxis who developed grade II aGVHD had better OS after 2006 (HR 0.78, p=0.02), while a trend for lower TRM (HR 0.79, p=0.056) and better OS (HR 0.83, p=0.08) were observed for those with grades III-IV aGVHD.

Conclusions: Incidence of grades III-IV aGVHD has overall decreased and OS and TRM have improved over time for recipients of tacrolimus-based GVHD prophylaxis who developed grades II-IV aGVHD.