Phase 1/2 study of high-dose palifermin for GVHD prophylaxis in patients undergoing HLA-matched unrelated donor HCT
Abstract
Abstract Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic cell transplantation (HCT). Palifermin, a recombinant N-truncated keratinocyte growth factor (KGF), protects epithelial tissues, including the thymus and gut. Although high-dose KGF prevents GVHD in preclinical models, lower doses of palifermin were ineffective in humans. We conducted a phase 1/2 trial evaluating high-dose palifermin for preventing severe chronic GVHD (CGVHD) in matched unrelated donor T-cell replete peripheral blood HCT after reduced-intensity conditioning (RIC). Using a 3+3 design, we determined the recommended phase 2 dose (RP2D), followed by an expansion phase. Palifermin (180-720 μg/kg) was given on day −7 before HCT. All 31 patients received fludarabine/cyclophosphamide RIC with tacrolimus, methotrexate, and sirolimus for GVHD prophylaxis. Palifermin was well tolerated, with self-limiting rash and pancreatic enzyme elevations as notable grade 3/4 adverse events. The RP2D was 720 μg/kg. Remarkably, no patients at this dose developed grade 2 to 4 acute GVHD (AGVHD [0/19]), although severe CGVHD rates (primary end point) remained unchanged compared to historical controls. Posttransplant lymphocyte phenotyping suggests palifermin modulates regulatory and naïve CD4+ T-cell numbers. These findings indicate that high-dose palifermin with RIC is safe and may prevent AGVHD, although it did not affect CGVHD rates in this study. This trial was registered at www.ClinicalTrials.gov as #NCT02356159.
Article Details
Authors (18)
Eduard Schulz
6Medical University of Graz, Division of Hematology, Graz, Austria
Lauren M. Curtis
3Mount Auburn Hematology Associates, Cambridge, MA
Noa G. Holtzman
1Immune Deficiency Cellular Therapy Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
Seth M. Steinberg
Kaska Wloka
6Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
Alen Ostojic
2AstraZeneca, Barcelona, Spain
Alain Mina
Najla El Jurdi
3CIBMTR® (Center for International Blood and Marrow Transplant Research), Medical College of Wisconsin, Milwaukee, United States
Filip Pirsl
18Division of Blood and Marrow Transplantation, Children’s National Hospital, George Washington University School of Medicine and Health Sciences, Washington, DC
Ashley Carpenter
3National Cancer Institute, Immune Deficiency – Cellular Therapy Program, Bethesda, United States
Mahshid Golagha
7Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
Arlene Sirajuddin
8Department of Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD
Theo Heller
Brian C. Shaffer
1Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY
Frances T. Hakim
11Experimental Transplantation and Immunotherapy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
Jeffrey S. Rubin
12Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Institutes of Health, Bethesda, MD
Ronald E. Gress
11Experimental Transplantation and Immunotherapy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
Steven Z. Pavletic
1Immune Deficiency Cellular Therapy Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD