Acute GvHD Risk After Allo

by Ingrid Hein, Staff Writer, MedPage Today June 8, 2023

Certain antibiotics for treating neutropenic fever and infections following allogeneic hematopoietic cell transplantation (allo-HCT) were associated with a higher risk for acute graft-versus-host disease (GvHD) than others, a retrospective single-center study found.

In a comprehensive analysis that looked at 17 classes of antibiotics, the most consistent association for an elevated risk of acute GvHD following allo-HCT was seen with carbapenems during the 2 weeks postprocedure, with hazard ratios ranging from 2.75 (95% CI 1.77-4.28) to 7.42 (95% CI 2.78-19.76), reported researchers led by Armin Rashidi, MD, PhD, of the Fred Hutchinson Cancer Center in Seattle.

"Avoiding this class of antibiotics early after transplant seems prudent," the group wrote in JAMA Network Open.

Penicillin with a β-lactamase inhibitor during week 1 was also linked with a higher risk postprocedure, with hazard ratios ranging from 6.55 (95% CI 2.35-18.20) to 7.90 (95% CI 2.69-23.25).

The cohort study assessed acute GvHD risk among more than 2,000 adults undergoing the common blood cancer treatment. Exposure to antibiotics was examined in the 7 days before transplant and 30 days after, totaling five nonoverlapping periods of about a week each. Researchers performed three methods to analyse risk: conventional Cox proportional hazard regression, marginal structural models, and machine learning.

Overall, seven other of the most frequently used antibiotics were associated with a greater risk for acute GvHD during one of the five intervals: fluoroquinolones, third-generation or later cephalosporins, oral or IV vancomycin, trimethoprim sulfamethoxazole, penicillins, and aztreonam.

Rashidi and coauthors proposed that this increased risk might be connected to "microbiota injury" during the peritransplant period, noting that microbiota changes occur within days of exposure to antibiotics.

"Weeks 1 and 2 after allo-HCT appeared to be the highest-risk intervals, with multiple antibiotic exposure associated with greater hazard of [acute GvHD]," they wrote. "These intervals represent the pre-engraftment period, when the allogeneic graft is rapidly expanding and its immune effector cells are coming into contact with the changing gut microbiota."

Various approaches are being tested to protect the microbiota, they noted, either before antibiotic exposure (with nonselective luminal adsorbents or selective luminal antibiotic degraders) or after exposure (with prebiotics or fecal transplant).

An "unexpected finding" in the study, according to Rashidi and colleagues, was that exposure to penicillin with a β lactamase inhibitor in the week before allo-HCT was associated with a lower risk for acute GvHD, with statistical significance observed in one model (HR 0.59, 95% CI 0.37-0.94). But they said the consistent pattern and hazard ratios across the three models for both the primary endpoint (grade II-IV GvHD) and secondary endpoint (grade III-IV) "may suggest a true biological relationship."

The findings have important implications for patient care, and could pave the way for designing antimicrobial stewardship programs to maximize the benefits and minimize harms in patients undergoing allo-HCT, said Miranda So, PharmD, MPH, of the University of Toronto, writing in an accompanying editorial.

"Preserving the effectiveness of antibiotics and mitigating against antibiotic resistance remain integral to supporting patients throughout their cancer treatment," said So, adding that such "interventions for the prevention and management of neutropenic fever in patients receiving treatment for hematological malignant neoplasms is gaining momentum."

She noted that the role, selection, and timing of antibiotics is less understood during pretransplant conditioning regimens and in the early weeks following HCT.

"Antibiotics may be perceived as protective for the patient by the prescriber, especially during the pre-engraftment phase when the patient is profoundly neutropenic with severe mucositis and is susceptible to health care–associated infections," wrote So. "However, emerging data are pointing toward the potential harms."

The study from Rashidi and colleagues was performed using the Fred Hutchinson Cancer Center allo-HCT database, included a total of 2,023 adult patients undergoing a first T-replete allo-HCT from 2010 to 2021 (median age 55 years, 57% male). At least 6 months of follow-up was required for survivors.

At day 180 after transplant, 72% of the patients developed grade II-IV acute GvHD (median 29 days after HCT), with grade III-IV in 15%. Deaths at that point occurred in 14% (206 patients) and 35% (102 patients), respectively.

A limitation was that the researchers did not know the reasons for antibiotic choice, noting that these patterns can be partially dictated by epidemiological trends in multidrug-resistant organisms.

"If our results are replicated in independent cohorts, antibiotic-associated risk of [acute GvHD] could become a consideration in antibiotic stewardship programs," the researchers concluded.

Ingrid Hein is a staff writer for MedPage Today covering infectious disease. She has been a medical reporter for more than a decade. Follow

Disclosures

The study was supported by the Fred Hutchinson Cancer Center.

Rashidi reported consulting fees from Seres Therapeutics outside the work; co-authors reported several grants paid to their institutions and outside the submitted work.

So had nothing to disclose.

Primary Source

JAMA Network Open

Source Reference: Rashidi A, et al "Analysis of antibiotic exposure and development of acute graft-vs-host disease following allogeneic hematopoietic cell transplantation" JAMA Netw Open 2023; DOI: 10.1001/jamanetworkopen.2023.17188.

Secondary Source

JAMA Network Open

Source Reference: So M "Determining the optimal use of antibiotics in hematopoietic stem cell transplant recipients" JAMA Netw Open 2023; DOI: 10.1001/jamanetworkopen.2023.17101.