Mitigation of gastrointestinal graft versus host disease with tocilizumab prophylaxis is accompanied by preservation of microbial diversity and attenuation of enterococcal domination

Abstract

A common feature in the gastrointestinal (GI) tract during allogeneic hematopoietic stem cell transplantation is the loss of microbial diversity and emergence of opportunistic pathogens that can adversely impact survival. Consequently, preventing transplant-associated dysbiosis is an emerging strategy for optimizing treatment outcomes. In this study, we examined the effect of an extended tocilizumab administration schedule in addition to tacrolimus/methotrexate (Tac/MTX) as graft versus host disease (GVHD) prophylaxis on microbial composition in the GI tract along with overall transplant outcomes. Twenty-nine patients received busulfan-based myeloablative conditioning and were transplanted with HLA-matched related or unrelated peripheral blood stem cell grafts. The primary end point of the trial was GVHD-free relapse-free survival (GRFS) at 12 months. The cumulative incidences of grades 2-4 and 3-4 acute GVHD were 10.5% and 7% at day 180, respectively. There was one case of GVHD of the lower GI tract within the first 12 months. Non-relapse mortality and relapse-free survival were 3.4% and 86.2% at one year, respectively. GRFS was 38% at one year which was significantly higher than the pre-specified historical control rate of 20% (p=0.02) and therefore met the primary end point of the trial. Fecal samples from this patient population were sequenced and computationally analyzed centrally along with a demographically matched control cohort that received only Tac/MTX for GVHD prophylaxis. This comparative analysis revealed significantly less loss of α-diversity and reduced emergence of pathogenic organisms such as enterococcus in tocilizumab-treated recipients, demonstrating that loss of microbial diversity and enterococcal domination is attenuated in these patients. (Clinicaltrial.gov Identifier: NCT03699631).