High-dose sitagliptin for systemic inhibition of dipeptidylpeptidase-4 to enhance engraftment of single cord umbilical cord blood transplantation

Abstract

// Sherif S. Farag 1, 4 , Robert Nelson 1, 4 , Mitchell S. Cairo 5 , Heather A. O’Leary 1, 4 , Shuhong Zhang 1 , Carol Huntley 4 , David Delgado 3 , Jennifer Schwartz 1 , Mohammad Abu Zaid 1 , Rafat Abonour 1 , Michael Robertson 1, 4 and Hal Broxmeyer 2, 4 1 Division of Hematology and Oncology, Department of Medicine, Indianapolis, Indiana, USA 2 Department of Microbiology and Immunology, Indianapolis, Indiana, USA 3 Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA 4 Indiana University Simon Cancer Center, Indianapolis, Indiana, USA 5 Children and Adolescent Cancer and Blood Diseases Center and Department of Pediatrics, New York Medical College, Valhalla, New York, USA Correspondence to: Sherif S. Farag, email: ssfarag@iupui.edu Keywords: cord blood; DPP-4; CD26; engraftment; leukemia Received: October 03, 2017      Accepted: October 30, 2017      Published: November 27, 2017 ABSTRACT Delayed engraftment remains a limitation of umbilical cord blood (UCB) transplantation. We previously showed that inhibition of dipeptidylpeptidase (DPP)-4 using sitagliptin 600 mg daily was safe with encouraging results on engraftment, but inhibition was not sustained. We evaluated the efficacy and feasibility of higher doses of sitagliptin to enhance engraftment of UCB in patients with hematological cancers. Fifteen patients, median age 41 (range, 18-59) years, received single UCB grafts matched at 4 (n=11) or 5 (n=4) of 6 HLA loci with median nucleated cell dose of 3.5 (range, 2.57-4.57) x10 7 /kg. Sitagliptin 600 mg every 12 hours was administered days -1 to +2. All patients engrafted by day 30, with 12 (80%) engrafting by day 21. The median time to neutrophil engraftment was 19 (range, 12-30) days. Plasma DPP-4 activity was better inhibited with a mean residual trough DPP-4 activity of 70%±19%. Compared to patients previously treated with 600 mg/day, sitagliptin 600 mg every 12 hours appeared to improve engraftment, supporting the hypothesis that more sustained DPP-4 inhibition is required. In-vivo inhibition of DPP-4 using high-dose sitagliptin compares favorably with other approaches to enhance UCB engraftment with greater simplicity, and may show synergy in combination with other strategies.