Sitagliptin Improves Engraftment and Platelet Recovery After Single Unit, Very Low Cell Dose Cord Blood Transplantation

Abstract 2963

Cord blood transplantation (CBT) is an emerging treatment for many hematologic diseases. However, the low cell dose of most banked cord blood units precludes the safe use of single unit CBT for many adults. We developed a dog model of unrelated CBT to evaluate approaches to overcome the poor engraftment associated with low cell dose cord blood. The results of initial studies with double unit CBT in the dog model were previously reported.

Nine dogs were conditioned with 9.2 Gy total body irradiation. A single unit of low cell dose (median, 0.7×10⁷total nucleated cells/kg), major histocompatibility complex (MHC)-matched unrelated dog umbilical cord blood was infused on day 0. Post-grafting immunosuppression was cyclosporine from day -3 to +98 and mycophenolate mofetil from day 0 to +84. Among the 5 control recipients, there was poor neutrophil and platelet engraftment, 2 dogs had secondary graft rejection and only 1 dog had platelet engraftment (day +68). All 5 control recipients were euthanized due to severe infectious complications on days 11, 54, 70, 74 and 105, despite intensive supportive care including transfusions and prompt intervention with broad-spectrum antibiotics.

Next, based on studies showing inhibition of CD26/dipeptidyl-peptidase-IV (DPP4) blocks inactivation of the chemokine CXCL-12 (SDF-1a), improving homing of hematopoietic stem/progenitor cells, we asked if pharmacologic inhibition of DPP4 with sitagliptin at the time of CBT improved the engraftment of a single low cell dose MHC-matched unit. Sitagliptin is clinically approved to lower post-prandial hyperglycemia in patients with Type II diabetes mellitus since DPP4 inhibition reduces proteolysis of glucagon like peptide-1.

In 4 dogs sitagliptin was administered orally 10 mg/kg twice daily from day -3 to day +6. These dogs were otherwise treated identically to the control group. There were no adverse effects from sitagliptin treatment. Serum from treated dogs showed >90% inhibition of DPP4 activity. All 4 sitagliptin treated dogs engrafted with donor neutrophils (median, day +21) and platelets (median, day +48). There was no late graft rejection or secondary thrombocytopenia. None of the dogs developed GVHD. One dog was euthanized on day +66 due to seizures; necropsy showed viral encephalitis. The remaining 3 dogs remain alive and well with stable engraftment and prompt immune reconstitution. Even though a very limited number of dogs were studied, the survival benefit of sitagliptin treatment was significant, p =0.047 (log-rank test). Donor chimerism was increased and platelet recovery was significantly improved in sitagliptin recipients compared to single unit controls. The median number of blood/platelet transfusions given to sitagliptin vs. control recipients for supportive care was 9 vs. 17, respectively, p = 0.03.

The results suggest that DPP4 inhibition with sitagliptin is effective in improving engraftment and survival after low cell dose CBT. Our findings are novel and can be readily translated to clinical trials. If a simple treatment with a well tolerated oral drug could make a significant difference in neutrophil and platelet recovery after human CBT, this would be a substantial therapeutic advance. Our data support further clinical trials of sitagliptin with CBT to improve engraftment.