Impact of Systemic Antibiotics Use on Outcomes after Allogeneic Hematopoietic Stem Cell Transplantation

Introduction: Post-transplant complications lead to significant morbidity and mortality in the management of patients undergoing allogeneic hematopoietic stem cell transplant (allo-HCT). Broad-spectrum systemic antimicrobials and better prophylaxis strategies have reduced infection-related morbidity and mortality in allo-HCT patients. However, broad-spectrum antibiotic use disrupts the microbiome and immunome, which may result in poor post-transplant outcomes. We aimed to evaluate the impact of systemic antibiotics on allo-HCT outcomes.

Methods: A retrospective multicenter analysis was conducted, including allo-HCT patients in the publicly available Center for International Blood and Marrow Transplant (CIBMTR) registry from 2013 to 2018 using P5646 data by Ramathan et al. Chi-square and t-tests were used to compare categorical and continuous baseline demographics. Multivariate Cox regression analyses were used to calculate hazard ratios (HR) with 95% confidence intervals (CI) for overall survival (OS), disease-free survival (DFS), relapse, non-relapse mortality (NRM), acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD), engraftment, and infection-related mortality between the two groups. Statistical analysis was conducted using R version 4.16, with statistical significance defined as p <0.05.

Results: Among 7524 allo-HCT patients, 5779 were administered broad-spectrum systemic antibiotics (SA) while 1745 were not given systemic antibiotics (NSA). The median age was 58.58 years (range: 2.03-82.67) in the SA group and 56.18 years (range: 2.00 - 77.86) in the NSA group, and 58% were men in both groups. Ethnicities were Caucasian (76%), Hispanic (8%), African American (6%), and others (10%). The primary disorders included acute myeloid leukemia (47%), myelodysplastic syndrome (35%), and acute lymphoblastic leukemia (18%). Myeloablative conditioning was used in 53% of patients. Donor types were matched unrelated (49.5%), matched related (34%), and cord blood (16%). Graft sources were bone marrow (15%), peripheral blood stem cells (68%), and cord blood (16%). GVHD prophylaxis regimens included Tacrolimus and Cyclosporine-based (77%), post-transplant Cyclophosphamide-based (9%), Ex vivo T-cell depletion or CD34 selection (3%), and others (11%). In the multivariate regression analyses, systemic antibiotics independently predicted poor OS (55% SA vs 57% NSA; HR 1.13, 95% CI 1.01-1.22, p=0.026). Higher incidence of NRM (19% SA vs 15% NSA; HR 1.32, 95% CI 1.12-1.55, p=0.001), grade 2-4 aGVHD (41% SA vs 34% NSA; HR 1.24, 95% CI 1.12-1.38, p<0.001), and cGVHD (40% SA vs 39% NSA; HR 1.12, 95% CI 1.01-1.24, p=0.040) were observed with SA use. The two groups had no significant difference in DFS, relapse, infection-related mortality, and engraftment rates. The outcomes analyses were adjusted for the significant predictors identified in the univariate analyses.

Conclusion: Systemic antibiotics use in allo-HCT patients is associated with higher morbidity and mortality. Judicious use and de-escalation of systemic antibiotics when safe may help to improve post-transplant outcomes. Future research exploring microbiome restoration could result in better post-transplant outcomes.

Hamadani:Byondis: Consultancy; Omeros: Consultancy; Myeloid Therapeutics: Speakers Bureau; Forte Biosciences: Consultancy; Sanofi Genzyme: Speakers Bureau; AstraZeneca: Speakers Bureau; Autolus: Consultancy; BeiGene: Speakers Bureau; DMC, Inc: Speakers Bureau; CRISPR: Speakers Bureau; BMS: Consultancy; Spectrum Pharmaceuticals: Research Funding; ADC Therapeutics: Consultancy, Research Funding, Speakers Bureau; CRISPR: Consultancy; Genmab: Consultancy; Astellas Pharma: Research Funding; Takeda: Research Funding; Allovir: Consultancy; Caribou: Consultancy; Genentech: Speakers Bureau; Kite Pharma: Consultancy, Speakers Bureau; AbbVie: Consultancy. McGuirk:Autolus: Consultancy; Kite: Consultancy; Envision: Consultancy; Allo Vir: Consultancy; CRISPR therapeutics: Consultancy; Sana technologies: Consultancy; Caribou bio: Consultancy; BMS: Consultancy; Novartis: Consultancy; NEKTAR therapeutics: Consultancy; Legend biotech: Consultancy. Mushtaq:Iovance Biotherapeutics: Research Funding.