Affiliation:
1. Department of Hematology Hyogo Medical University Hospital Hyogo Japan
2. Pediatric Stem Cell Transplantation, Boston Children's Hospital/Dana‐Farber Cancer Institute Boston Massachusetts USA
3. Department of Experimental and Clinical Pharmacology University of Minnesota College of Pharmacy Minneapolis Minnesota USA
4. Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts Kyoto Japan
Abstract
AbstractHematopoietic cell transplantation (HCT) for hematologic malignancies with non‐remission disease and/or prior post‐transplant relapse have poor relapse‐free survival. We previously demonstrated the efficacy of haploidentical reduced‐intensity HCT regimen with glucocorticoid‐based graft‐versus‐host disease (GVHD) prophylaxis. We recently showed a possible association between rabbit antithymocyte globulin (rATG) exposure and acute GVHD (aGVHD) risk, leading to hypothesize that optimization of rATG exposure may further improve this regimen. We retrospectively examined the exposure–response association of rATG and key clinical outcomes post haploidentical HCT. We subsequently developed an individualized rATG dosing that optimizes rATG exposure using a previously developed population pharmacokinetic model. Of the 103 patients analyzed, the median age was 47 years (range: 17–70) and majority had a non‐remission disease prior to HCT (88%). rATG concentration on day 0 of HCT (Cday_0) was the strongest predictor of Grade 2–4 aGVHD through day +100. Patients with Cday_0 ≥ 20 μg/mL had an approximately 3‐fold lower risk of Grade 2–4 aGVHD (hazard ratio [HR]: 0.32, 95% confidence interval [CI]: 0.16, 0.62) and Grade 3–4 aGVHD (HR: 0.33, 95% CI: 0.16, 0.68) as well as an approximately 2‐fold lower risk of overall mortality (HR: 0.47, 95% CI: 0.28, 0.77) and relapse (HR: 0.50, 95% CI: 0.26, 0.94). In conclusion, this reduced‐intensity haploidentical HCT regimen with exposure‐optimized rATG may provide a promising option to patients undergoing high‐risk HCT for hematologic malignancy. The developed rATG dosing warrant prospective validation.
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