Journal Article

Association of pharmacokinetic biomarkers with early immune recovery following HLA-haploidentical hematopoietic cell transplantation

Synold, Timothy W, Nakamura, Ryotaro, Kanakry, Christopher G, Shen, Guofang, Horne, David A, Khan, Shanzay

2025

Overview

Prophylactic immunosuppressants for graft-versus-host disease (GVHD) in allogeneic hematopoietic cell transplantation (alloHCT), including post-transplant cyclophosphamide (PTCy) and mycophenolate mofetil (MMF), exhibit complex pharmacokinetic profiles. Interindividual variations in pharmacokinetic exposure to these immunosuppressants or their metabolites may interfere with treatment outcomes. A feasibility study (n = 11) was conducted to investigate the pharmacokinetic/pharmacodynamic relationship in patients undergoing HLA-haploidentical alloHCT with standard high-dose PTCy (50 mg·kg ·day on days +3/+4) combined with MMF and tacrolimus or sirolimus. Blood samples were collected to assess the variability in pharmacokinetic biomarkers, including exposures [areas under the curve (AUCs)] to cyclophosphamide (Cy), carboxycyclophosphamide (cepm), -dechloroethyl cyclophosphamide (dccy), 4-ketocyclophosphamide (ketocy), mycophenolic acid (MPA), and mycophenolic acid glucuronide (MPAG). Serial dynamic changes in immune cell populations, including regulatory T cells (Tregs), over the first 3 post-transplant weeks were monitored. A transient reduction in the proliferation (Ki-67 ) of activated (HLA-DR ) T cells coincided with Cy treatment. The ratio of Tregs to the CD4 T-cell population increased in a time-dependent manner within the first 21 days post-transplant. We observed moderate interindividual variability across all pharmacokinetic biomarkers. Serum creatinine and blood urea nitrogen levels positively correlated with exposure to Cy and MMF metabolites, including cepm, MPA, and MPAG. Using correlation analysis, we further confirmed the negative association between pharmacokinetic (PK) biomarkers and lymphocyte count, but not Treg percentage, suggesting that careful optimization of Cy and MMF dosing may have the potential to support immune recovery, although this requires further validation in larger studies. The relationship of pharmacokinetic biomarkers to immune and clinical outcomes warrants further investigation in larger studies but holds promise for personalizing dosing of GVHD prophylaxis to improve patient outcomes after alloHCT.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Acids / Adult / Allografts / Biomarkers / Biomarkers - blood / Blood / CD4 antigen / Cell number / Cell proliferation / Chromatography / Cloning / Correlation analysis / Creatinine / Cyclophosphamide / Cyclophosphamide - administration & dosage / Cyclophosphamide - pharmacokinetics / Disease prevention / Dosage / Drug dosages / Feasibility studies / Female / Graft versus host disease / Graft vs Host Disease - immunology / Graft vs Host Disease - prevention & control / Graft-versus-host reaction / hematopoietic cell transplantation (HCT) / Hematopoietic Stem Cell Transplantation - adverse effects / Hematopoietic Stem Cell Transplantation - methods / Hematopoietic stem cells / Histocompatibility antigen HLA / HLA Antigens - genetics / HLA Antigens - immunology / Humans / immune monitoring / Immunoregulation / Immunosuppressive agents / Immunosuppressive Agents - administration & dosage / Immunosuppressive Agents - pharmacokinetics / Immunosuppressive Agents - therapeutic use / Lymphocytes T / Male / Mass spectrometry / Metabolites / Middle Aged / Mycophenolate mofetil / mycophenolate mofetil (MMF) / Mycophenolic acid / Mycophenolic Acid - administration & dosage / Mycophenolic Acid - pharmacokinetics / Patients / Pharmacodynamics / Pharmacokinetics / Plasma / post-transplant cyclophosphamide (PTCy) / Rapamycin / regulatory T cells (Tregs) / Scientific imaging / Stem cell transplantation / T-Lymphocytes, Regulatory - immunology / Tacrolimus / Tacrolimus - administration & dosage / Tacrolimus - pharmacokinetics / Toxicity / Transplantation / Transplantation, Haploidentical / Young Adult