The use of keratinocyte growth factor (KGF; palifermin) has been limited in the allogeneic peripheral blood stem cell transplant setting due its lack of effectiveness in accelerating engraftment, controlling graft-versus-host disease (GVHD), or improving early survival. In this issue of Leukemia and Lymphoma, the work of Wang and colleagues suggests that administration of KGF may be beneficial to patients receiving a cord blood stem cell transplant to improve immune reconstitution [Citation1].
The use of cord blood stem cells in allogeneic stem cell transplant has increased tremendously in the last decade because of the low incidence of GVHD and the ability to transplant individuals who do not have a human leukocyte antigen (HLA)-identical donor. However, cord blood stem cells also have significant disadvantages, including delayed hematopoietic recovery and the presence of a very immature immune system leading to delayed immune reconstitution [Citation2]. Wang and colleagues herein report that KGF significantly increases immune reconstitution in a mouse model of umbilical cord blood (UCB) transplant. Furthermore, they demonstrate that increased thymopoiesis accounts for the observed immune reconstitution, as shown by increased levels of single joint T-cell receptor rearrangement excision circles (sjTRECs) in circulation, and provide data to suggest that graft-versus-leukemia (GVL) effects are enhanced by KGF administration [Citation1].
Keratinocyte growth factor promotes epithelial recovery, and when given in the peri-transplant setting reduces the severity of radiation-induced mucositis [Citation3]. However, previous murine transplant studies showed that KGF administration also impacts immune reconstitution after allogeneic transplant. KGF-treated mice retained enhanced thymopoiesis and peripheral T-cell counts after stem cell transplant because KGF averted radiation-induced damage to the thymic epithelium [Citation4]. Surprisingly, peri-transplant administration of KGF also prevented subsequent GVHD-induced thymic damage [Citation5]. Based on these animal studies, several clinical trials of palifermin were conducted in patients undergoing an allogeneic stem cell transplant. These trials unfortunately failed to demonstrate any reduction in GVHD [Citation6,7]. Furthermore, patients who received KGF did not have an advantage over control patients in terms of controlling infection, GVHD, or long-term survival.
The unique aspect of the study by Wang et al. consists of the investigation of KGF in UCB transplant, a situation with more HLA-mismatching and more severe immune deficiency. The investigators used an elegant model whereby they avoided some of the toxicities of UCB by prophylactic infusion of platelet concentrates. This allowed them to effectively investigate the effects of KGF. They observed that administration of KGF resulted in an increased number of donor derived T, natural killer (NK)/T, and NK cells in spleens of mice undergoing UCB transplant. Furthermore, the study found that pretreatment with KGF prior to UCB stem cell transplant prevented a relapse of leukemia, suggesting enhanced GVL [Citation1].
These studies extend previous work by several other groups using non-UCB stem cells, and raise the possibility of testing KGF to enhance immune reconstitution after UCB transplant.
Potential conflict of interest:
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References
- Wang Y, Chen G, Qiao S, et al. Keratinocyte growth factor enhanced immune reconstitution in murine allogeneic umbilical cord blood cell transplant. Leuk Lymphoma 2011;52:1556–1566.
- van Besien K. Cord blood transplant: the glass is half full--can we do better? Leuk Lymphoma 2011;52:554–555.
- Spielberger R, Stiff P, Bensinger W, et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers N Engl J Med. 2004;351:2590–2598.
- Min D, Taylor PA, Panoskaltsis-Mortari A, et al. Protection from thymic epithelial cell injury by keratinocyte growth factor: a new approach to improve thymic and peripheral T-cell reconstitution after bone marrow transplantation. Blood 2002;99:4592–4600.
- Zhang Y, Hexner E, Frank D, Emerson SG. CD4+ T cells generated de novo from donor hemopoietic stem cells mediate the evolution from acute to chronic graft-versus-host disease. J Immunol 2007;179:3305–3314.
- Blazar BR, Weisdorf DJ, Defor T, et al. Phase 1/2 randomized, placebo-control trial of palifermin to prevent graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Blood 2006;108:3216–3222.
- Levine JE, Blazar BR, DeFor T, Ferrara JL, Weisdorf DJ. Long-term follow-up of a phase I/II randomized, placebo-controlled trial of palifermin to prevent graft-versus-host disease (GVHD) after related donor allogeneic hematopoietic cell transplantation (HCT). Biol Blood Marrow Transplant 2008;14:1017–1021.