In this issue of Blood Advances, Politikos et al1 address the question of whether the administration of tocilizumab in addition to standard graft-versus-host disease (GVHD) prophylaxis with cyclosporine and mycophenolate mofetil could decrease the incidence of grades 2 to 4 acute GVHD in patients receiving double umbilical cord blood transplantation for the treatment of hematologic malignancies.
Preclinical studies conducted more than a decade ago demonstrated that antibody blockade of the interleukin-6 (IL-6)/IL-6 receptor (IL-6R) signaling pathway using an anti–IL-6R antibody could reduce the severity of GVHD and improve overall survival.2,3 Mechanistically, the proinflammatory effects of IL-6 were observed to be attributable to diminished regulatory T-cell reconstitution,2 direct cytopathic effects on intestinal epithelium,3 and dendritic cell induction of alloreactive T-cell expansion and inflammatory cytokine production.4 These results served as the preclinical foundation for subsequent phase 2 clinical studies in which tocilizumab was administered in conjunction with standard immune suppression consisting of a calcineurin inhibitor and methotrexate for GVHD prevention. These clinical trials revealed that tocilizumab could be safely administered to patients and was associated with a decreased incidence of acute GVHD compared with historical control or demographically matched patient populations.5,6 However, a subsequent phase 3 trial failed to demonstrate a significant reduction in the severity of grades 2 to 4 acute GVHD,7 although the authors posited that the trial may have been underpowered given that the rate of acute GVHD in the placebo control group was lower than initially expected and the effect size in GVHD-free survival was only 10% to 20%.
In this study, Politikos et al have performed the first phase 2 trial in which prophylactic tocilizumab was administered to patients who had received umbilical cord blood, as opposed to bone marrow or peripheral blood, as a stem cell source. Their trial also differed from previous studies5,6 in that standard immune suppression consisted of cyclosporine and mycophenolate mofetil as opposed to a calcineurin inhibitor and methotrexate. The authors enrolled 45 patients who were compared with a demographically matched control population who received only standard immune suppression. Results of this study revealed that there was no difference in grades 2 to 4 acute GVHD, which was the primary end point of the trial, nor was there any difference in secondary end points of transplant-related mortality, relapse, or overall survival. Patients who were treated with tocilizumab had a significant delay in neutrophil engraftment compared with the control population (ie, 25.5 vs 22 days), which has also been observed in adult patients,7 but there was no difference in graft failure, which was quite low in both cohorts.
Although the trial did not meet the primary end point, there were several secondary end points that were of interest in this study. The first pertained to pre-engraftment syndrome (PES), which is a well-recognized complication of double-unit cord blood transplantation and is characterized by the overproduction of inflammatory cytokines. Thus, this syndrome has features that are also characteristic of acute GVHD. In fact, PES has been associated with acute GVHD,8 although not all reports have confirmed this finding.9 In this study, the authors observed that there was a statistically significant decrease in the incidence and severity of PES compared with historical controls, suggesting that tocilizumab attenuated inflammatory cytokine production after transplantation, although this was not directly measured.
In addition, Politikos et al note that patients who received tocilizumab had an altered microbiome in which the commonly observed pattern of enterococcal domination that occurs in allogeneic hematopoietic stem cell transplant (HSCT) patients was markedly reduced. Although not prima facie evidence of causality, it is of interest that these results align with a previous publication that reported on a cohort of adult patients who underwent myeloablative HSCT and received adjunctive tocilizumab as GVHD prophylaxis.10 This report also notes a reduction in enterococcal domination and preservation of alpha diversity compared with a demographically matched historical control population. Furthermore, in both studies, there was a commensurate low incidence of lower tract gastrointestinal (GI) GVHD, suggesting that a potential beneficial effect of tocilizumab may be to attenuate GVHD-induced inflammation within the GI tract leading to an attendant reduction in opportunistic, potentially pathogenic organisms. Further studies with contemporaneous control populations will be required to validate these findings and determine whether a cytokine blockade strategy targeting the IL-6/IL-6R signaling pathway is able to preserve microbial diversity.
In summary, the administration of tocilizumab as adjunctive GVHD prophylaxis failed to reduce the incidence of grades 2 to 4 acute GVHD in recipients of double-unit cord blood grafts compared with a historical control population. A trend in the reduction of GI GVHD accompanied by decreased enterococcal abundance raises the question as to whether the administration of tocilizumab for GVHD prevention has a potential more targeted role in attenuating inflammation within the GI tract.
Conflict-of-interest disclosure: W.R.D. declares no competing financial interests.
