Session: 722. Allogeneic Transplantation: Acute and Chronic GVHD and Immune Reconstitution: Poster I
Hematology Disease Topics & Pathways:
Research, Translational Research
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<0.0001) and 3g/day flat-dosing (20.2±16.3 μg*hr/mL, p<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.
Disclosures: Srivastava: Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Regeneron: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Spark: Consultancy; Biomarin: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Octapharma: Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Abraham: Roche: Other: Travel Grant, Research Funding; Novo Nordisk: Honoraria, Other: Travel Grant, Research Funding.