In vivo DPP-4 inhibition to enhance engraftment of single-unit cord blood transplants in adults with hematological malignancies

Sherif Farag, Shivani Srivastava, Steven Messina-Graham, Jennifer Schwartz, Michael Robertson, Rafat Abonour, Kenneth Cornetta, Lisa Wood, Angie Secrest, R. Matthew Strother, David R. Jones, Hal Broxmeyer

Research output: Contribution to journalArticle

63 Citations (Scopus)

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)×107/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.

Original languageEnglish
Pages (from-to)1007-1015
Number of pages9
JournalStem Cells and Development
Volume22
Issue number7
DOIs
StatePublished - Apr 1 2013

Fingerprint

Dipeptidyl Peptidase 4
Hematologic Neoplasms
Fetal Blood
Transplants
Stem Cells
HLA Antigens
Cell Count
Transplantation
Confidence Intervals
Incidence
Sitagliptin Phosphate

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Hematology

Cite this

In vivo DPP-4 inhibition to enhance engraftment of single-unit cord blood transplants in adults with hematological malignancies. / Farag, Sherif; Srivastava, Shivani; Messina-Graham, Steven; Schwartz, Jennifer; Robertson, Michael; Abonour, Rafat; Cornetta, Kenneth; Wood, Lisa; Secrest, Angie; Strother, R. Matthew; Jones, David R.; Broxmeyer, Hal.

In: Stem Cells and Development, Vol. 22, No. 7, 01.04.2013, p. 1007-1015.

Research output: Contribution to journalArticle

Farag, Sherif ; Srivastava, Shivani ; Messina-Graham, Steven ; Schwartz, Jennifer ; Robertson, Michael ; Abonour, Rafat ; Cornetta, Kenneth ; Wood, Lisa ; Secrest, Angie ; Strother, R. Matthew ; Jones, David R. ; Broxmeyer, Hal. / In vivo DPP-4 inhibition to enhance engraftment of single-unit cord blood transplants in adults with hematological malignancies. In: Stem Cells and Development. 2013 ; Vol. 22, No. 7. pp. 1007-1015.
@article{56ac3f75113a421893a05f9588862891,
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)×107/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.",
author = "Sherif Farag and Shivani Srivastava and Steven Messina-Graham and Jennifer Schwartz and Michael Robertson and Rafat Abonour and Kenneth Cornetta and Lisa Wood and Angie Secrest and Strother, {R. Matthew} and Jones, {David R.} and Hal Broxmeyer",
year = "2013",
month = "4",
day = "1",
doi = "10.1089/scd.2012.0636",
language = "English",
volume = "22",
pages = "1007--1015",
journal = "Stem Cells and Development",
issn = "1547-3287",
publisher = "Mary Ann Liebert Inc.",
number = "7",

}

TY - JOUR

T1 - In vivo DPP-4 inhibition to enhance engraftment of single-unit cord blood transplants in adults with hematological malignancies

AU - Farag, Sherif

AU - Srivastava, Shivani

AU - Messina-Graham, Steven

AU - Schwartz, Jennifer

AU - Robertson, Michael

AU - Abonour, Rafat

AU - Cornetta, Kenneth

AU - Wood, Lisa

AU - Secrest, Angie

AU - Strother, R. Matthew

AU - Jones, David R.

AU - Broxmeyer, Hal

PY - 2013/4/1

Y1 - 2013/4/1

N2 - 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)×107/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.

AB - 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)×107/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.

UR - http://www.scopus.com/inward/record.url?scp=84875956072&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84875956072&partnerID=8YFLogxK

U2 - 10.1089/scd.2012.0636

DO - 10.1089/scd.2012.0636

M3 - Article

VL - 22

SP - 1007

EP - 1015

JO - Stem Cells and Development

JF - Stem Cells and Development

SN - 1547-3287

IS - 7

ER -