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.

Competing Interest Statement

S.C. reports institutional research funding from Janssen, Amgen, Sanofi, Syndax, BMS, and honoraria from GSK and Sanofi. S.A. receives research funding from AltruBio Inc and Actinium Pharmaceuticals, consulting for AbbVie and Amgen, and honoraria from Stemline Therapeutics. P.H. reports consulting honoraria from Bristol Myers Squibb, Janssen, Glaxo Smith Kline, Takeda, Incyte, and Kadmon. M.H. reports research support/funding from Takeda Pharmaceutical, ADC Therapeutics, Spectrum Pharmaceuticals, and Astellas Pharma, consultancy from Incyte Corporation, ADC Therapeutics, Omeros, Verastem, MorphoSys, Kite, Genmab, SeaGen, Gamida Cell, Novartis, and Legend Biotech. He also serves on the Speakers Bureau for Sanofi Genzyme, AstraZeneca, BeiGene, and ADC Therapeutics, as well as the Data Safety Monitoring Committee for Myeloid Therapeutics, Inc. N.N.S. reports participation on advisory boards and/or consultancy for Kite Pharma, TG therapeutics, Miltenyi Biotec, Lily, Epizyme, Legend, Incyte, Novartis, and Umoja and is on the speakers bureau with Incyte. He has also received research funding and honoraria from both Lily and Miltenyi Biotec and has Scientific Advisory Board membership for Tundra Therapeutics. J.J reports consulting fees from Omeros. Dr. Marcel van den Brink has received research support and stock options from Seres Therapeutics and stock options from Notch Therapeutics and Pluto Therapeutics; he has received royalties from Wolters Kluwer; has consulted, received honorarium from or participated in advisory boards for Seres Therapeutics, Vor Biopharma, WindMIL Therapeutics, Rheos Medicines, Merck & Co Inc. Magenta Therapeutics, Frazier Healthcare Partners, Nektar Therapeutics, Notch Therapeutics, Forty Seven Inc. Ceramedix, Lygenesis, Pluto Therapeutics, GlaskoSmithKline, Da Volterra, Vor Biopharma, Novartis (Spouse), Synthekine (Spouse), and Beigene (Spouse); he has IP Licensing with Seres Therapeutics and Juno Therapeutics; and holds a fiduciary role on the Foundation Board of DKMS (a nonprofit organization). MSK has institutional financial interests relative to Seres Therapeutics. J.U.P. reports research funding, intellectual property fees, and travel reimbursement from Seres Therapeutics, and consulting fees from DaVolterra, CSL Behring, and from MaaT Pharma. He serves on an Advisory board of and holds equity in Postbiotics Plus Research. He has filed intellectual property applications related to the microbiome (reference numbers #62/843 849, #62/977 908, and #15/756 845). Memorial Sloan Kettering Cancer Center (MSK) has financial interests relative to Seres Therapeutics. W.R.D. receives research funding from Sun Pharmaceuticals.

Clinical Trial

NCT03699631

Funding Statement

This research was supported by funding from K08 HL143189 (J.U.P.), and the MSKCC Cancer Center Core Grant NCI P30 CA008748 (J.U.P.). This research was also supported by the Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center; J.U.P. is a member of the Parker Institute for Cancer Immunotherapy.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The IRB of the Medical College of Wisconsin gave ethical approval for this clinical study

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

Data Availability

All data produced in the present study are available upon reasonable request to the authors

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