Page 173 - Haematologica-April 2018

Stem Cell Trasplantation
Tocilizumab, tacrolimus and methotrexate for the prevention of acute graft-versus-host disease: low incidence of lower gastrointestinal tract disease
William R. Drobyski,1 Aniko Szabo,2 Fenlu Zhu,1 Carolyn Keever-Taylor,1
Kyle M. Hebert,3 Renee Dunn,3 Sharon Yim,1 Bryon Johnson,1 Anita D’Souza,1 Mary Eapen,1 Timothy S. Fenske,1 Parameswaran Hari,1 Mehdi Hamadani,1 Mary M. Horowitz,1 J. Douglas Rizzo,1 Wael Saber,1 Nirav Shah,1
Bronwen Shaw1 and Marcelo Pasquini1
1The Department of Medicine; 2The Division of Biostatistics, Institute for Health and Society and 3The Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI, USA
ABSTRACT
We conducted a phase 2 study in which patients undergoing allo- geneic hematopoietic stem cell transplantation received tocilizumab in addition to standard immune suppression with tacrolimus and methotrexate for graft-versus-host disease prophylaxis. Thirty-five patients were enrolled between January 2015 and June 2016. The median age of the cohort was 66 (range: 22-76). All patients received busulfan-based conditioning, and were transplanted with human leuko- cyte antigen-matched related or matched unrelated bone marrow or peripheral stem cell grafts. The cumulative incidences of grades II-IV and III-IV acute graft-versus-host disease were 14% (95% CI 5-30) and 3% (95% CI 0-11) at day 100, and 17% (95% CI 7-31) and 6% (95% CI 1- 16) at day 180, respectively. Notably, there were no cases of graft-versus- host disease of the lower gastrointestinal tract within the first 100 days. A comparison to 130 matched controls who only received tacrolimus and methotrexate demonstrated a lower cumulative incidence of grades II-IV acute graft-versus-host disease (17% versus 45%, P=0.003) and a sig- nificant increase in grades II-IV acute graft-versus-host disease-free sur- vival at six months (69% versus 42%, P=0.001) with tocilizumab, tacrolimus and methotrexate, which was the primary endpoint of the study. Immune reconstitution was preserved in patients treated with tocilizumab, tacrolimus and methotrexate, as T-cell and B-cell subsets recovered to near normal levels by 6-12 months post-transplantation. We conclude that tocilizumab has promising activity in preventing acute graft-versus-host disease, particularly in the lower gastrointestinal tract, and warrants examination in a randomized setting. clinicaltrials.gov Identifier:02206035
Introduction
Graft-versus-host disease (GvHD) is the major complication arising from allo- geneic hematopoietic stem cell transplantation (HSCT). GvHD is characterized by the overproduction of proinflammatory cytokines that induce target organ damage directly, or indirectly by activating other effector cell populations.1-3 Interleukin 6 (IL-6) has emerged as an inflammatory cytokine that plays a pivotal role in the pathophysiology of GvHD and has become a potential therapeutic target.4-6 Preclinical studies have demonstrated that IL-6 levels are increased early during GvHD and are present in all target tissues.7 Moreover, blockade of the IL-6 signaling pathway using an antibody that binds to the IL-6 receptor has been shown to reduce the severity of GvHD and prolong survival in pre-clinical murine models.7,8 In particular, IL-6 appears to have an important pathophysiological role in promot- ing inflammation in the gastrointestinal (GI) tract,7 which is a major cause of mor- bidity and mortality during GvHD.
Ferrata Storti Foundation
Haematologica 2018 Volume 103(4):717-727
Correspondence:
wdrobysk@mcw.edu
Received: October 26, 2017. Accepted: January 18, 2018. Pre-published: January 19, 2018.
doi:10.3324/haematol.2017.183434
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/4/717
©2018 Ferrata Storti Foundation
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