Novel approaches for preventing acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

ABSTRACT

Introduction: Allogeneic hematopoietic stem cell transplantation (alloHSCT) offers potential curative treatment for a wide range of malignant and nonmalignant hematological disorders. However, its success may be limited by post-transplant acute graft-versus-host disease (aGVHD), a systemic syndrome in which donor’s immune cells attack healthy tissues in the immunocompromised host. aGVHD is one of the main causes of morbidity and mortality after alloHSCT. Despite standard GVHD prophylaxis regimens, aGVHD still develops in approximately 40–60% of alloHSCT recipients.

Areas covered: In this review, after a brief summary of current knowledge on the pathogenesis of aGVHD, the authors review the current combination of a calcineurin inhibitor with an antimetabolite with or without added anti-thymocyte globulin (ATG) and emerging strategies for GVHD prevention.

Expert opinion: A new understanding of the involvement of cytokines, intracellular signaling pathways, epigenetics and immunoregulatory cells in GVHD pathogenesis will lead to new standards for aGVHD prophylaxis allowing better prevention of severe aGVHD without affecting graft-versus-tumor effects.

KEYWORDS:

• Acute graft-versus-host disease
• anti-IL-6 receptor antibody
• histone deacetylase inhibitors
• demethylating agents
• JAK inhibitors
• mesenchymal stem cells
• mTOR inhibitors
• proteasome inhibitors
• regulatory T cells
• T-cell depletion

Article highlights

• Three randomized studies have demonstrated that ATG (combined with CSA and MTX) might be the new standard of care for patients transplanted with HLA-matched PBSC.

• New understanding of aGVHD pathogenesis has led to the development of new targets for aGVHD prophylaxis.

• Most promising pharmacological approaches include post-transplant Cy administration, JAKs inhibitors, HDAC inhibitors, bortezomib, hypomethylating agents, as well as IL-6 blockade.

• Most promising cellular approaches include co-transplantation of Tregs.

• Risk-stratification directed strategies for aGVHD prevention will likely help to improve aGVHD-related morbidity and mortality.

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Declaration of interests

S Servais is Postdoctoral Researcher, F Baron Senior Research Associate, and L Delens, G Ehx, G Francolet are Televie PhD students at the National Fund for Scientific Research (FNRS) Belgium. S Humblet-Baron is postdoctoral researcher at the Fonds Wetenschappelijk Onderzoek - Vlaanderen (FWO). The review was in part supported by funds from the FNRS, the Belgian Foundation against Cancer (FBC), the Anti-Cancer Center and the Leon Fredericq Foundation from the University of Liege, the Terry Fox Foundation, and Plan Cancer from the Belgian Government. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.