title: In vivo DPP-4 inhibition to enhance engraftment of single-unit cord blood transplants in adults with hematological malignancies.
abstract: Delayed engraftment is a significant limitation of umbilical cord blood (UCB) transplantation due to low stem cell numbers. Inhibition of dipeptidyl peptidase (DPP)-4 enhanced engraftment in murine transplants. We evaluated the feasibility of systemic DPP-4 inhibition using sitagliptin to enhance engraftment of single-unit UCB grafts in adults with hematological malignancies. Twenty-four patients (21-58 years) received myeloablative conditioning, followed by sitagliptin 600 mg orally days -1 to +2, and single UCB grafts day 0. Seventeen receiving red cell-depleted (RCD) grafts, matched at 4 (n=10) or 5 (n=7) of 6 human leucocyte antigen (HLA) loci with median nucleated cell dose 3.6 (2.5-5.2)×10(7)/kg, engrafted at median of 21 (range, 13-50) days with cumulative incidence of 94% (95% confidence interval, 84%-100%) at 50 days. Plasma DDP-4 activity was reduced to 23%±7% within 2 h. Area under DPP-4 activity-time curve (AUCA) correlated with engraftment; 9 of 11 with AUCA <6,000 activity·h engrafted within ≤21 days, while all 6 with higher AUCA engrafted later (P=0.002). Seven patients receiving red cell replete grafts had 10-fold lower colony forming units after thawing compared with RCD grafts, with poor engraftment. Systemic DPP-4 inhibition was well tolerated and may enhance engraftment. Optimizing sitagliptin dosing to achieve more sustained DPP-4 inhibition may further improve outcome.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. ssfarag@iupui.edu
authors.forename: Sherif S
authors.initials: SS
authors.lastname: Farag
authors.forename: Shivani
authors.initials: S
authors.lastname: Srivastava
authors.forename: Steven
authors.initials: S
authors.lastname: Messina-Graham
authors.forename: Jennifer
authors.initials: J
authors.lastname: Schwartz
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Robertson
authors.forename: Rafat
authors.initials: R
authors.lastname: Abonour
authors.forename: Kenneth
authors.initials: K
authors.lastname: Cornetta
authors.forename: Lisa
authors.initials: L
authors.lastname: Wood
authors.forename: Angie
authors.initials: A
authors.lastname: Secrest
authors.forename: R Matthew
authors.initials: RM
authors.lastname: Strother
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
authors.forename: Hal E
authors.initials: HE
authors.lastname: Broxmeyer
mesh_terms: D000328:Adult; D036101:Cord Blood Stem Cell Transplantation; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use; D005260:Female; D005312:Fetal Blood; D019337:Hematologic Neoplasms / Q000628:therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011719:Pyrazines / Q000627:therapeutic use; D000068900:Sitagliptin Phosphate; D019172:Transplantation Conditioning; D014230:Triazoles / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D011719:Pyrazines; D014230:Triazoles; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000068900:Sitagliptin Phosphate