CD56bright natural killer regulatory cells in filgrastim primed donor blood or marrow products regulate chronic graft-versus-host disease: the Canadian Blood and Marrow Transplant Group randomized 0601 study results
Amina Kariminia,
Sabine Ivison,
Bernard Ng,
Jacob Rozmus,
Susanna Sung,
Avani Varshney,
Mahmoud Aljurf,
Sylvie Lachance,
Irwin Walker,
Cindy Toze,
Jeff Lipton,
Stephanie J. Lee,
Jeff Szer,
Richard Doocey,
Ian Lewis,
Clayton Smith,
Naeem Chaudhri,
Megan K. Levings,
Raewyn Broady,
Gerald Devins,
David Szwajcer,
Ronan Foley,
Sara Mostafavi,
Steven Pavletic,
Donna A. Wall,
Stephan Couban,
Tony Panzarella,
Kirk R. Schultz
Affiliations
Amina Kariminia
Michael Cuccione Childhood Cancer research Program, BC Children’s Hospital, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
Sabine Ivison
Michael Cuccione Childhood Cancer research Program, BC Children’s Hospital, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
Bernard Ng
Department of Statistics, University of British Columbia, Centre for Molecular Medicine and Therapeutics, Vancouver, BC, Canada
Jacob Rozmus
Michael Cuccione Childhood Cancer research Program, BC Children’s Hospital, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
Susanna Sung
Michael Cuccione Childhood Cancer research Program, BC Children’s Hospital, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
Avani Varshney
Michael Cuccione Childhood Cancer research Program, BC Children’s Hospital, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
Mahmoud Aljurf
King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia
Sylvie Lachance
Hôpital Maisonneuve-Rosemont, Université de Montréal, QC, Canada
Irwin Walker
Hamilton Health Sciences Centre and McMaster University, Hamilton, ON, Canada
Cindy Toze
Leukemia/Bone Marrow Transplant Program of BC, Vancouver General Hospital, British Columbia Cancer Agency and the University of British Columbia, Vancouver, BC, Canada
Jeff Lipton
Princess Margaret Cancer Centre University of Toronto, ON, Canada
Stephanie J. Lee
Fred Hutchinson Cancer Research Centre, Seattle, WA, USA
Jeff Szer
Royal Melbourne Hospital and University of Melbourne, Australia
Richard Doocey
Auckland City and Starship Children’s Hospital, Auckland, New Zealand
Ian Lewis
Institute of Medical and Veterinary Sciences, Adelaide, Australia
Clayton Smith
General Hematology, Blood Cancers and Bone Marrow Transplant Program, University of Colorado Hospital, Aurora, CO, USA
Naeem Chaudhri
King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia
Megan K. Levings
BC Children’s Hospital Research Institute and Department of Surgery, University of British Columbia, Vancouver, BC, Canada
Raewyn Broady
Leukemia/Bone Marrow Transplant Program of BC, Vancouver General Hospital, British Columbia Cancer Agency and the University of British Columbia, Vancouver, BC, Canada
Gerald Devins
Princess Margaret Cancer Centre University of Toronto, ON, Canada
David Szwajcer
CancerCare Manitoba, Winnipeg, MB, Canada
Ronan Foley
Hamilton Health Sciences Centre and McMaster University, Hamilton, ON, Canada
Sara Mostafavi
Department of Statistics, University of British Columbia, Centre for Molecular Medicine and Therapeutics, Vancouver, BC, Canada
Steven Pavletic
Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
Donna A. Wall
The Hospital for Sick Children and University of Toronto, ON, Canada
Stephan Couban
Nova Scotia Health Authority and Dalhousie University, Halifax, NS, Canada
Tony Panzarella
Princess Margaret Cancer Centre University of Toronto, ON, Canada
Kirk R. Schultz
Michael Cuccione Childhood Cancer research Program, BC Children’s Hospital, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
Randomized trials have conclusively shown higher rates of chronic graft-versus-host disease with filgrastim-stimulated apheresis peripheral blood as a donor source than unstimulated bone marrow. The Canadian Blood and Marrow Transplant Group conducted a phase 3 study of adults who received either filgrastim-stimulated apheresis peripheral blood or filgrastim-stimulated bone marrow from human leukocyte antigen-identical sibling donors. Because all donors received the identical filgrastim dosing schedule, this study allowed for a controlled evaluation of the impact of stem cell source on development of chronic graft-versus-host disease. One hundred and twenty-one evaluable filgrastim-stimulated apheresis peripheral blood and filgrastim-stimulated bone marrow patient donor products were immunologically characterized by flow cytometry and tested for their association with acute and chronic graft-versus-host disease within 2 years of transplantation. The immune populations evaluated included, regulatory T cells, central memory and effector T cells, interferon γ positive producing T cells, invariate natural killer T cells, regulatory natural killer cells, dendritic cell populations, macrophages, and activated B cells and memory B cells. When both filgrastim-stimulated apheresis peripheral blood and filgrastim-stimulated bone marrow were grouped together, a higher chronic graft-versus-host disease frequency was associated with lower proportions of CD56bright natural killer regulatory cells and interferon γ-producing T helper cells in the donor product. Lower CD56bright natural killer regulatory cells displayed differential impacts on the development of extensive chronic graft-versus-host disease between filgrastim-stimulated apheresis peripheral blood and filgrastim-stimulated bone marrow. In summary, while controlling for the potential impact of filgrastim on marrow, our studies demonstrated that CD56bright natural killer regulatory cells had a much stronger impact on filgrastim-stimulated apheresis peripheral blood than on filgrastim-stimulated bone marrow. This supports the conclusion that a lower proportion of CD56bright natural killer regulatory cells results in the high rate of chronic graft-versus-host disease seen in filgrastim-stimulated apheresis peripheral blood. clinicaltrials.gov Identifier: 00438958.
