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P1264: A PREDEFINED STRATEGY AIMED TO REDUCE ANTIBIOTIC EXPOSURE OF SCT RECIPIENTS PRESERVES DIVERSITY AND COMPOSITION OF INTESTINAL MICROBIOTA AND REDUCES THE INCIDENCE OF ACUTE-GVHD WITHOUT SIDE EFFECTS

HemaSphere(2023)

Instituto de Biomedicina de Sevilla | University hospital Virgen del Rocío. | Hospital Universitario Virgen del Rocío | Hospital Universitario Marqués de Valdecilla – IDIVAL. | Hospital Universitario de Salamanca | Hospital Clínico Universitario-INCLIVA. | Hospital General Universitario Gregorio Marañón | Centro de Investigación Biomédica en Red | University Hospital Virgen del Rocío. | University Hospital Virgen Macarena | Complutense University of Madrid

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Abstract
Topic: 22. Stem cell transplantation - Clinical Background: intestinal microbiota (iMB) composition and alfa-diversity may influence incidence and severity of aGvHD after allo-SCT; antibiotherapy (anti-B) damages iMB reducing its diversity. Aims: to investigate the effect of two (centers driven) predefined antibiotic strategies (Optimized vs Standard) on:1) iMB alfa-diversity/composition. 2a) aGvHD incidence, 2b) Infectious mortality, 2c) Overall Survival (OS). Methods: Prospective, multicenter, comparative, observational, first-in-class study (clinicaltrials.gov NCT037271113) real life anti-B management in SCT. Inclusion: ≥18 year-old recipients of SCT. Exclusion: previous auto-SCT. Optimization Strategy (2 centers):1) No anti-B prophylaxis, 2) Febrile neutropenia management:2a. scalation/de-scalation of empiric anti-B, 2b. Switch to narrower-spectrum if clinical stabilization, 2c. No broadening anti-B spectrum in persistent fever if clinical stability, 2d. Withdrawal of combined anti-B in 72h when clinically indicated. 2e. Anti-B withdrawal regardless neutrophils count and expected neutropenia length when the following criteria are met: i. afebrile ≥72h, ii. Resolution of signs, symptoms, and complementary tests ≥72h, iii. Normal vital constants ≥72h. 3) anti-B simplification based on etiology and in vitro susceptibility. 4) 7-days etiological treatment for primary non-complicated bacteriemia if good evolution. Standard Strategy (3 centers):1) Anti-B prophylaxis. 2) No compulsory use of optimization strategies. Two years follow up in 4 pre-scheduled visits, clinical data prospectively collected (secure electronic Registry). Fecal iMB alfa-diversity and composition were analyzed pre-Conditioning, at day0, d+7, d+28 (±2d) by 16S ribosomal gene sequencing (Illumina MiSeq platform), bioinformatics analysis of Amplicon Sequence Variants (ASVs) and statistical analysis as appropriate (Jimenez-Jorge S. et al, BMJ Open 2020). Local Ethical Committees approval and IC obtained. Results: 209 patients: 104 in Optimization Arm (OA), 105 in Standard Arm (SA). Patient´s features were similar in both arms except for more URD (8/8 and 7/8), more rapa/tacro or MTX-based immune-prophylaxis and bone marrow grafts in OA while more haplo-donors and PTCy in SA. Mean of days receiving anti-B between day-7 and d+21:10 (5-22) in OA vs 32 (26-46) in SA (p<0,001). iMB alfa-diversity was superior in OA vs. SA in every time-point (p<2.2e-16) fig 1. Cumulative incidence of d+100 aGVHD (mortality as competitive risk): 36.1% in OA vs 55.3% in SA; p=0.009 (peripheral blood transplant ad hoc analysis: OA: 38.4% vs SA: 56.1%; p=0.02, fig 2). Day+100 mortality (fig 1) and two-year infectious mortality were equal in both arms. Two-year OS: 46,3% in OA vs 20,7% in SA (p=ns). Increased alfa-diversity (p<0.0001) and relative abundance of Blautia (p=0.003) correlated with lower risk of aGvHD. Bi-variate analysis identified factors included in a multivariate model showing that factors influencing risk of aGvHD were: mieloablative conditioning (HR 1,56; 95%CI 1.03-2,38; p=0.03), Simpson alfa-diversity <0.90 (HR 1,65; 95%CI 1.08-2.51; p=0.02) and OA (HR 0,59; CI95% 0.36-0,98; p=0.04); type of aGvHD-prophylaxis or donor type did not reach statistical significance. Summary/Conclusion: a predefined strategy aimed to reduce exposure of SCT recipients to antibiotics preserves alfa-diversity and composition of fecal iMB and reduces the incidence of aGvHD without increasing infectious or overall mortality nor decreasing long-term overall survival. The peri-transplant burden of antibiotherapy should be taken into account in aGvHD clinical trials.Keywords: Allogeneic hematopoietic stem cell transplant, Graft-versus-host disease (GVHD)
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要点】:本研究提出了一种预先定义的策略,旨在减少造血干细胞移植(SCT)受者抗生素暴露,以保护肠道微生物群多样性及组成,降低急性移植物抗宿主病(aGVHD)的发生率,同时不增加感染或总体的死亡率。

方法】:采用前瞻性、多中心、比较性、观察性研究,对两种预先定义的抗生素策略(优化策略与标准策略)进行比较。

实验】:研究包括209名患者,其中104名采用优化策略(OA),105名采用标准策略(SA)。通过16S核糖体基因测序(Illumina MiSeq平台)分析粪便肠道微生物群α多样性和组成,随访两年,收集临床数据。结果显示,优化策略组患者在抗生素使用天数、肠道微生物群α多样性及aGVHD发生率上均优于标准策略组。