Higher Mycophenolic Acid (MPA) Trough Levels Result in Lower Day 100 Severe Acute Graft-Versus-Host Disease (aGVHD) without Increased Toxicity in Double-Unit Cord Blood Transplantation (CBT) Recipients

 

 

Background: Mycophenolate mofetil (MMF) is frequently combined with cyclosporine-A (CSA) as immunosuppression in CBT. Drug monitoring of MPA, the active MMF metabolite, is advisable based on variable MMF pharmacokinetics and the association of low unbound MPA AUCs with increased aGVHD. This is highly relevant in CBT as aGVHD is a leading cause of mortality. However, a limited pharmacokinetic parameter such as MPA troughs is ideal. Additionally, the toxicity associated with MPA troughs is not established and is of concern in CBT due to the theoretical risk of myelosuppression from high levels. Methods: We evaluated the association between serial (weeks 1-6) total MPA trough levels and outcomes in double-unit CBT recipients transplanted 8/2009-11/2012. Intravenous CSA/MMF commenced on day -3. Trough levels were dichotomized into <2 mcg/mL and ≥2 mcg/mL for the toxicity analysis (engraftment, gastro-intestinal toxicity as measured by TPN duration and CMV infection) at each time point. For the efficacy (aGVHD prevention) analysis, mean week 1 and 2 trough levels were split at <0.5 vs ≥0.5 mcg/mL. Results: Eighty-three patients (median age 44 years, range 1-71) had weekly MPA levels for 6 weeks after CBT. Sixty-nine (83%) received myeloablative (MA) conditioning and 45 (54%) were CMV seropositive. Median trough levels ranged 0.6-1.3 mcg/mL. Trough levels increased over time (p=0.03).  Myeloablative (MA) had lower MPA troughs than non-myeloablative recipients (p=0.02). Younger age (0-15 years old) was associated with lower trough levels (p=0.002). By time-dependent Cox regression analysis, there was no association between troughs and toxicity, and MA recipients with high troughs ≥2 mcg/mL had enhanced platelet recovery (p=0.005). In a competing risk 2-week landmark analysis, there were no differences grade II-IV aGVHD incidences (61% vs 57%, p=0.52) according to troughs. However, patients with a low MPA trough early post-CBT had nearly triple the incidence of grade III-IV aGVHD (27.8% vs 9.5%, p=0.06, Figure). Conclusions: Higher total MPA troughs are safe and may protect against severe aGVHD. The platelet benefit could be explained by the lower severe aGVHD incidence. Prospective investigation of MPA troughs, and ultimately intervention based on drug monitoring in CBT recipients is warranted.