Takuto Takahashi1,2, Rachael Pearson3, Qing Cao4, Aileen Scheibner3, Kinjal Sanghavi3, Daniel Weisdorf5, Claudio Brunstein5, John Rogosheske6, Veronika Bachanova5, Erica D Warlick5, Anthony Wiseman7,8, Pamala A Jacobson3. 1. Division of Pediatric Hematology/Oncology/Blood and Marrow Transplant, University of Minnesota, Minneapolis, MN, USA. takah033@umn.edu. 2. Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota College of Pharmacy, Minneapolis, MN, USA. takah033@umn.edu. 3. Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota College of Pharmacy, Minneapolis, MN, USA. 4. Biostatistics Core, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA. 5. Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA. 6. Department of Pharmacy, Fairview MHealth, Minneapolis, MN, USA. 7. University of Minnesota Medical School, Minneapolis, MN, USA. 8. Essentia Health, Hematology and Oncology, Duluth, MN, USA.
Abstract
PURPOSE: Genetic variants may influence the pharmacokinetics and pharmacodynamics (PKPD) of cyclophosphamide (CY). CY plays a critical role in conditioning chemotherapy for hematopoietic cell transplantation (HCT), but its use is limited by toxicity. We explored the effect of genetic variants, potentially affecting PKPD of CY, and outcomes after HCT. METHODS: This observational pharmacogenomic study included 85 adults with hematologic malignancies who received reduced intensity conditioning with CY, fludarabine, and total body irradiation. We collected recipient DNA prior to HCT and evaluated 97 candidate variants in 66 genes and 3 metabolism phenotypes potentially involved in PKPD pathways of CY. In multivariable analysis we investigated the association between the genotypes and four clinical outcomes: Day 180 non-relapse mortality (NRM) and day 180 overall survival (OS), acute graft-versus-host-disease (aGVHD) grades 2-4, and engraftment. p values were not adjusted for multiple testing. RESULTS: The median recipient age was 63 years (range 21-75). Acute myeloid leukemia was the most common diagnosis (34%; n = 29). In multivariable analysis adjusted for exposure to phosphoramide mustard, the final active metabolite of CY, we identified 6 variants in 6 genes associated with at least one of the clinical outcomes. An ABCC4 variant (rs9561778) was associated with poor Day 180 NRM (p < 0.01), MUTYH variant (rs3219484) with higher Day 180 NRM and aGVHD (both p < 0.01), and SYNE1 variant (rs4331993) with better Day 180 OS and engraftment (both p ≤ 0.01). CONCLUSION: The present study suggests that genetic variants influencing the PKPD of CY may help identify patients at risk for inferior outcomes after HCT using CY-based reduced-intensity conditioning.
PURPOSE: Genetic variants may influence the pharmacokinetics and pharmacodynamics (PKPD) of cyclophosphamide (CY). CY plays a critical role in conditioning chemotherapy for hematopoietic cell transplantation (HCT), but its use is limited by toxicity. We explored the effect of genetic variants, potentially affecting PKPD of CY, and outcomes after HCT. METHODS: This observational pharmacogenomic study included 85 adults with hematologic malignancies who received reduced intensity conditioning with CY, fludarabine, and total body irradiation. We collected recipient DNA prior to HCT and evaluated 97 candidate variants in 66 genes and 3 metabolism phenotypes potentially involved in PKPD pathways of CY. In multivariable analysis we investigated the association between the genotypes and four clinical outcomes: Day 180 non-relapse mortality (NRM) and day 180 overall survival (OS), acute graft-versus-host-disease (aGVHD) grades 2-4, and engraftment. p values were not adjusted for multiple testing. RESULTS: The median recipient age was 63 years (range 21-75). Acute myeloid leukemia was the most common diagnosis (34%; n = 29). In multivariable analysis adjusted for exposure to phosphoramide mustard, the final active metabolite of CY, we identified 6 variants in 6 genes associated with at least one of the clinical outcomes. An ABCC4 variant (rs9561778) was associated with poor Day 180 NRM (p < 0.01), MUTYH variant (rs3219484) with higher Day 180 NRM and aGVHD (both p < 0.01), and SYNE1 variant (rs4331993) with better Day 180 OS and engraftment (both p ≤ 0.01). CONCLUSION: The present study suggests that genetic variants influencing the PKPD of CY may help identify patients at risk for inferior outcomes after HCT using CY-based reduced-intensity conditioning.