High Rates of Severe aGVHD with Tacrolimus and Mycophenolate Mofetil in a Large Cohort of Related and Unrelated Allogeneic Transplant Patients
Authors: Al-Kadhimi Zaid , Gul Zartash , Chen Wei , Smith Daryn , Deol Abhinav , Abidi Muneer H. , Ayash Lois , Lum Lawrence G , Ratanatharathorn Voravit , Uberti Joseph P. 
Published: October 2019

Abstract
Abstract 1951
Both acute and chronic graft-versus-host disease (GVHD) are a major cause of morbidity and mortality in patients (pts) undergoing allogeniec hematopoietic stem cell transplantation (allo-HCT). Tacrolimus and mycophenolate mofetil (Tac-MMF) have shown encouraging results as GVHD prophylaxis in few prospective phase II trials with reduced intensity preparative regimens. Perkins et al. in a randomized phase II trial with myeloablative preparative regimen reported 11 and 26% incidence of grade III-IV aGVHD in related and unrelated donor transplants respectively.

Methods
We retrospectively evaluated clinical outcomes in a cohort of 414 consecutive pts who underwent related or unrelated allo-HCT with Tac-MMF for GVHD prophylaxis. Consecutive pts were transplanted with myeloablative or low intensity preparative regimens between January 2005 and June 2011 at Karmanos Cancer Center. Study end points were: Overall survival (OS), progression free survival (PFS) (Kaplan Meir), cumulative incidence (CI) of acute and chronic GVHD, relapse, CMV infection and non-relapse mortality (NRM).

Results
Pt characteristics are summarized in Table 1. There were 211 pts who underwent allo-HCT from a related donor (RD) and 203 patients who had allo-HCT from an unrelated donor (UD). Sixty three pts (31%) of the UD were 7/8 HLA matched. Median follow up of all patients was 60 months with 95% confidence interval (95%CI) 54.4 – 64.7 months.
The CI of aGVHD for grades II-IV was 47.4% (95%CI 40.5–54.0), 55.2% (95%CI 48.0–61.7) in RD and UD groups respectively. The CI of aGVHD grades III-IV was 22.3% (95%CI 16.9–28.1), 36.5% (95%CI 29.9–43.1) in RD and UD groups respectively (Gray's test p-value 0.0007). The CI of cGVHD at 60 months was 56.2% (95%CI 48.7–63.1), 66.3% (95%CI 58.8–72.7) in RD and UD groups respectively (Gray's test p-value 0.015). The CI of severe cGVHD (NIH grade3) at 60 months was 28.1% (95%CI 22.2–34.3), 26.1% (95%CI 20.3–32.3) in RD and UD groups respectively. The CI of bronchiolitis obliterans at 60 months was 14.0% (95%CI 9.7 –19.1), 11.6% (95%CI 7.6–16.6) in RD and UD groups respectively (NS). The CI of CMV reactivation at 60 months was 27.2% (95%CI 21.3–33.4), 23.2% (95%CI 17.6–29.2) in RD and UD groups respectively (NS). NRM at 60 months was 32.5% (95%CI 25.9–39.2), 46.5% (95%CI 39.3–53.4) in RD and UD groups respectively (Gray's test p-value 0.001). The CI of relapse was 22.4% (95%CI 16.7–28.5) for UD and 28.8% (95%CI 22.6–35.2) for RD. One year survival was 61% (95%CI 55–68), 55% (95%CI 48–62) in RD and UD groups respectively. One year PFS was 55% (95%CI 48–62), 48% (95%CI 41–55) in RD and UD groups respectively. Five year OS was 43% (95%CI 35–51), 34% (95% CI 27–41) in RD and UD groups respectively. Causes of death for the RD group (n=115) were as follows: GVHD 49%, relapse 42%, sepsis 3%, multi-organ failure (MOF) 3%, Diffuse alveolar hemorrhage 2%, and secondary malignancy 3%. As for the UD group (n=133) causes of death were: GVHD 57%, relapse 29%, sepsis 7%, MOF 4%, graft failure 2%, and secondary malignancy 1%. Uni-variate and multi-variate analysis is being performed to evaluate disease risk, donor status, and regimen intensity as predictors of GVHD and survival.

Conclusion:
The use of Tac-MMF for GVHD prophylaxis was associated with higher than previously reported incidence of severe aGVHD both in RD and UD allo-HCT. Furthermore, we observed a higher incidence of severe aGVHD, cGVHD and NRM in the UD group compared to RD. GVHD was the leading cause of mortality in both groups.

Disclosures:
No relevant conflicts of interest to declare.