Less Acute Graft-Versus-Host Disease with Higher Mycophenolate Dose in Double Umbilical Cord Blood Transplant Recipients

Mycophenolate mofetil (MMF) is commonly used in reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) for graft-versus-host disease (GVHD) prophylaxis and to facilitate engraftment. We previously reported that higher level of mycophenolic acid can be achieved with MMF administered at 3 g/day MMF as compared to 2g/day dose in patients (pts) with RIC transplantation. Thus, we retrospectively compared clinical outcomes of pts with hematological malignancies undergoing myloablative (MA, n=147) and RIC (n=265) double umbilical cord blood HCT (dUCBT) who received MMF 2g (n=139) vs. 3g (n=273) daily. In multiple regression analysis after adjusting for conditioning regimen (NMA RR 1.98, 95%CI, 1.59-2.47;p<0.01), HLA disparity (HLA-match 6/6 RR 1.84, 95%CI, 1.21-2.82; p<0.01; 5/6 RR 1.05; 95%CI 0.83-1.33, p=0.67; ref 4/6) and infused CD34 dose (≥ 3.5 x10⁷/kg RR 1.63, 95%CI 1.27-2.09, p<0.01; ref <3.5x10⁷/kg), MMF dosing was not an independent predictor of neutrophil engraftment (MMF 3 g RR 0.83, 95% CI 0.66-1.05; p=0.12; ref MMF 2g). However, after adjustment for gender (female RR 0.72, 95%CI 0.54-0.94; p=0.02) and conditioning (NMA RR 0.72, 95%CI 0.55-0.95; p=0.02), MMF 3 g/day led to 42% reduction in grade II-IV acute GVHD rate (RR=0.58, 95%CI 0.45-0.76; p<0.01).  Higher MMF dose was not protective for chronic GVHD (RR 0.73, 95% CI 0.48-1.11; p=0.15). The effect of MMF dosing on the risk of infections was evaluated by cumulative density function that accounts for multiple infectious events in an individual pt. When we studied the effect of MMF dose on frequency of bacterial, fungal and viral infections using specific post-transplant time intervals (Figure), MMF 2g/day resulted in significantly higher density of bacterial infections (8.37 vs. 6.07 per 1000 pt days, p<0.01) and total infectious events requiring therapy (14.38 vs. 12.00 per 1000 pt day, p=0.03) between post-transplant days 46-180, the period when pts with GVHD are on systemic immunosuppression. The most frequent bacterial infections were staphylococcus (n= 129), enterococcus (n=56), clostridium difficile (n=42), pseudomonas (n=18), mycobacterium (n=9), and others (n=54). In contrast, MMF dose had no impact on specific infection types at post-transplant days 0-45 and days 181-365. Additionally, MMF dose was not an independent predictor of treatment related mortality at 6 months (RR 1.38, 95%CI 0.91-2.10, p=0.13), or 2-year post-transplant disease relapse (RR 1.08, 95%CI 0.74-1.59, p=0.69), disease free survival (RR 1.17, 95%CI 0.89-1.53, p=0.26), or overall survival (RR 1.27, 95%CI 0.94-1.72, p=0.12). Infection related mortality rate was similar between two groups (14% MMF 2g vs. 16% MMF 3g, p=0.55). Our data indicates that MMF 3g/day dosing reduces the risk of acute GVHD without increasing the risk of infectious complications and it should be used for GVHD prophylaxis following dUCBT.