Lower Mycophenolic Acid Exposure in Patients Undergoing Haploidentical Stem Cell Transplantation with Post-Transplant Cyclophosphamide/ Cyclosporine a-Based GvHD Prophylaxis - Need for Dose Intensification
Authors: Pai Aswin Anand , Panetta John C , Bijukumar Nayanthara , Renji Rachel Mariam , A Manoj , Jayaraman Agila , Karumathil Sujith , Korula Anu , Selvarajan Sushil , Srivastava Alok , Abraham Aby , Mathews Vikram , George Biju , Kulkarni Uday , Balasubramanian Poonkuzhali 
Published: December 2024

Post-transplant Cyclophosphamide (PTCy) based Graft versus Host disease (GvHD) prophylaxis has improved the success of Haploidentical transplantation (HaploHCT) in recent years. Along with PtCy, Mycophenolate Mofetil (MMF) is used concomitantly with calcineurin inhibitors (Cyclosporine A (CsA) or Tacrolimus (Tac)) interchangeably. Due to the unavailability of IV Tac at our center, we use PTCy/MMF/CsA based-GvHD prophylaxis for HaploHCT. In our previous pilot MMF Pharmacokinetic (PK) study (Pai et al. Blood, 2022), we observed low MPA (Mycophenolic acid) systemic exposure in all patients, possibly due to potential drug-drug interaction (DDI) with concomitant CsA administration. In the present study, we evaluated the PK and pharmacogenetics (PG) of MMF in a larger cohort, and we attempted to recommend the optimal MMF dosing for HaploHCT in patients receiving PTCy/MMF/CsA based-GvHD prophylaxis.

Ninety patients with various underlying diagnoses who underwent HaploHCT between October 2021 and March 2024 were enrolled. All patients received uniform GvHD prophylaxis comprising Cy (I.V. 50 mg/kg/day x 2 days (day +3 to day +4) and i.v. CsA (2.5mg/kg, Q12H) with oral MMF (15 mg/kg/dose Q8H) from day +5 post-HCT. Plasma was separated from the peripheral blood collected at pre-determined time points at day+8 post HCT. Plasma MPA levels were measured using a validated HPLC-UV method, and MPA systemic exposure and clearance were calculated using nonlinear mixed effects modeling via Monolix (version 2023R2). MPA exposure was compared with HaploHCT outcomes using GraphPad Prism8. For PG analysis, we screened for genetic variants using the Infinium Global Screening Array (Illumina, CA, USA), and the effect of genetic variants on MPA PK was then compared.

MPA levels were available for all ninety patients. In concordance with our previous findings, we observed low systemic MPA exposure in all patients [Median AUC: 8.7 (1.0 - 27.3) μg*hr/mL) less than the lower limit of the suggested therapeutic range of 30 μg*hr/mL. None of the covariates explained the large variability in MPA PK. We also did not observe any significant association between genetic variants in MPA metabolic pathway-related genes and MPA exposure. The lack of pharmacogenetic associations may be attributed to DDI with CsA, which may mask the effects of any genetic variation on MPA PK.

Of 90 patients, seven (8%) died before engraftment. Twenty-nine (32.2%) experienced acute GvHD (Grade I/II-16, III/IV - 13 patients), and at a mean follow-up of 12.3 ± 9.9 months, there were thirty-six deaths (40%). There was no difference in the MPA exposure amongst patients with or without GVHD. No associations were observed with clinical outcomes, including neutrophil engraftment, transplant-related mortality, or survival.

We then attempted simulation studies using the current patient data set to identify optimum MMF dosing using different dosing strategies (2g/day TID, 3g/day TID, 500mg/m2 TID, and 750mg/m2 TID). We observed that patients achieved higher MPA exposure when oral MMF is dosed with 750mg/m2 twice daily (15.2±7.1 μg*hr/mL, p&lt;0.0001) and 3g/day flat-dosing (20.2±16.3 μg*hr/mL, p&lt;0.0001) compared to actual dosing (9.3±4.1 μg*hr/mL).

Our study suggests that dose intensification is recommended for MMF when used concomitantly with CsA for HaploHCT to achieve therapeutic exposure. Pharmacogenomic associations were not observed with MPA exposure due to the DDI phenomenon with CsA. Simulation studies demonstrated the need for a higher MMF dosage. However, prospective trials with drug monitoring are warranted to address the safety concerns, including toxicities.