Mycophenolate Mofetil (MMF) [900 MG/M2 Q8H] in Combination with Tacrolimus Is Effective to Prevent Acute and Chronic GVH in Pediatric Allogeneic Stem Cell Transplant (AlloSCT) Recipients

Background: MMF is hepatically metabolized to mycophenolic acid (MPA) glucuronide and reconverted to an active MPA by colonic bacteria (Shaw et al, Clin Biochem 2001). MPA area under the curve and steady state concentration (Css) predict acute rejection in solid organ transplant. MMF at 900 mg/m² q6h results in (MPA) Css concentrations between 4.73 (±2.22) to 6.54 (±3.55) mcg/mL in pediatric recipients post-AlloSCT (Bhatia/Militano/Cairo, BBMT 2010).

Objective: To determine safety/efficacy of MMF at 900 mg/m²/dose q8h in combination with tacrolimus in pediatric AlloSCT recipients.

Methods: GVHD prophylaxis included tacrolimus 0.03-0.04 mg/kg/day IVCI on Day -1 or 1^st day of conditioning (target range 10-20 ng/mL) and MMF 900 mg/m² (max 1.5 g/dose) IV/PO q8h starting on Day +1. MPA trough concentrations were obtained if toxicity or acute GVHD (aGVHD) was suspected. AGVHD, chronic GVHD (cGVHD) and overall survival (OS) were determined by Kaplan-Meier method.

Results: 15 pts: mean age 9.1 yrs (range 0.8-17.2); M:F 13:2; 7 pts non-malignant & 8 with malignant disease; donor source: 4 related BM, 5 MUD, 5 UCB, 1 haploSCT; conditioning: 8 myeloablative and 7 reduced intensity. Median time to myeloid and platelet engraftment was 17 and 29 days, respectively. Probability of Grade II-IV aGVHD and limited + extensive cGVHD was 35.3% (CI₉₅:5.7-68.5) and 0%, respectively. Probability of 1-year OS was 78.7% (CI₉₅: 38.0-94.2). Four pts had MPA trough levels prior to day +30 (mean trough 1.22 mcg/mL; range <0.5–2). Eight pts had 15 MPA trough concentrations reported Day +30 to Day +100 (mean trough 4.2 mcg/mL; range < 0.5–7.9). Four of 8 (50%) patients had MPA trough levels above the recommended maximum of 3.5 mcg/mL during Day +30 to +100 post-transplant period.

Conclusion: MMF at 900 mg/m² q8h in combination with tacrolimus appears effective for prevention of aGVHD and cGVHD in the pediatric AlloSCT recipients. MMF dosing and pharmacokinetics in the later post-SCT period (Day +30 to Day +100) deserve further attention due to increased potential for high MPA trough concentrations. The potential difference in MPA trough concentration between early (<Day +30) or late post-SCT period, could be due to improved mucosal healing following conditioning that leads to improved drug absorption and enterohepatic recirculation. Based on these results, we recommend MMF dose reduction and monitoring MPA trough concentrations in the late post-AlloSCT period to avoid potential toxicity.