Post-transplant cyclophosphamide pharmacokinetics and haploidentical hematopoietic cell transplantation outcomes: an exploratory study

Abstract

Pharmacokinetics of cyclophosphamide has been explored to optimize conditioning dosing. We hypothesized that post-transplant cyclophosphamide (PTCy) metabolite carboxy-ethyl phosphoramide mustard (CEPM) pharmacokinetics might impact haploidentical transplantation (haplo-HCT) outcomes. CEPM area under the curve (AUC_0–48) was determined by eleven sampling timepoints on day +3/+4 using LC-MS/MS. The median CEPM AUC_0–48 in a cohort of 30 patients was 14.2 (14) mg·hr/L. The incidence of severe chronic graft-versus-host disease (GVHD) (73% vs. 11%, p = 0.02), and GVHD-/relapse-free survival (GRFS) was significantly inferior in the CEPM AUC_0–48 < 14 mg·hr/L group (54 days vs. 344 days, p = 0.02). There was, however, no difference in grade III-IV acute GVHD (38% vs. 14%, p = 0.12) and overall survival (295 days vs. not reached, p = 0.2). CEPM AUC_0–48, is associated with severe chronic GVHD and GRFS post-haplo-HCT in this exploratory study. There is scope for personalizing day + 4 PTCy dose based on day + 3 CEPM AUC_0–8.

Keywords:

• PTCy
• pharmacokinetics
• CEPM
• GVHD
• haplo-HCT

Acknowledgments

We want to acknowledge the contributions of Ms. Jyotsna Kapoor to this work. As we mourn her loss to COVID-19, we would like to thank all frontline workers for putting their work above themselves to serve humanity.

Authors’ contributions

DPL and ANP conceived the study. KSK, ANP, DPL, NV analyzed the lab data. DPL, ANP, and KSK drafted the manuscript. All authors were involved in patient recruitment, clinical care of the patients, and manuscript writing. DPL, ANP, and KSK confirm full access to the data in the study and final responsibility for the manuscript.

Disclosure statement

All other authors have no conflicts of interest to disclose.

Additional information

Funding

This work was funded by the Indian Council of Medical Research [ICMR IRIS ID 2020-2997] grant to ANP and DPL.