Incidence, Patterns, and Outcomes of Fungal Infections in Patients with Graft Versus Host Disease Requiring Systemic Steroids Following Allogeneic Hematopoietic Cell Transplantation

BACKGROUND: Graft-versus-host disease (GVHD) and infections are leading factors contributing to non-relapse morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HSCT). Fungal infections pose a common challenge among HSCT recipients; however, the precise patterns and outcomes of fungal infections in patients with GVHD requiring systemic steroids remain uncertain. We aimed to analyze the existing data to investigate the incidence, pattern, and outcomes of fungal infections in patients with GVHD requiring systemic steroids following HSCT.

METHODS: A literature search was performed on PubMed, Cochrane Library, and ClinicalTrials.Gov databases following PRISMA guidelines. A total of 460 articles were identified and after excluding duplicate and ineligible studies, 5 studies were finalized to be included in the review. Data was extracted following the PRISMA guidelines. The inter-study variance was calculated using the Der Simonian-Laird Estimator. Pooled analyses were done using a meta-package by Schwarzer et al. in R studio version 4.4.0. Proportions with 95% confidence intervals (CI) were computed.

RESULTS:

A total of 1452 patients from 5 studies were included; 61.3% were males (n=890) and 38.7% were females (n=562) with a median age of 49.5 (0.6-73.2) years and a median follow-up period of 27.3 months ranging from 0.5 to 79.2 months. Baseline characteristics were not available for all studies. Patients had an underlying diagnosis of acute myeloid leukemia (AML, n=245), acute lymphoblastic leukemia (ALL, n=87), myelodysplastic syndrome (MDS, n=78), chronic myeloid leukemia (CML, n=239), multiple myeloma (MM, n=92), non-Hodgkin or Hodgkin lymphoma (NHL/HL, n=179), chronic lymphocytic leukemia (CLL, n=21), aplastic anemia (AA, n=17) and unknown (n=494). Transplant conditioning regimens included myeloablative (MAC, n=89) and reduced intensity/non-myeloablative (RIC/NMAC, n=197). Donor type was matched unrelated donor (MUD, n=288), matched related/sibling donor (MRD/MSD, n=415), mismatched unrelated donor (MMUD, n=16) and haploidentical (haplo, n=69). GVHD prophylaxis regimens included cyclosporine (n=116), tacrolimus or sirolimus (n=11), mycophenolate mofetil (MMF, n=125) and daclizumab (n=8). Seventy-four percent of the patients (n=1076) had acute GVHD of which 63.5% had grade I-II (n=521) and 36.5% (n=299) had grade III-IV acute GVHD. Twenty-two percent of the patients (n=320) had chronic GVHD of which 9.7% were limited (n=31) and 90.3% were extensive (n=289). Patients received azoles (n=790), amphotericin B (n=62), and echinocandins (n=9) as anti-fungal prophylaxis. The incidence of proven/probable invasive fungal infection (IFI) was 11% (n=159). Among the proven cases of IFI, 74% had aspergillosis (n=60), 14.8% had candidiasis (n=12), 11.2% (n=9) had other fungal infections. Invasive fungal infections were 15.8% in acute GVHD and 7.1% in chronic GVHD. IFI rate was lower in grade I-II acute GVHD at 7.1% than in grade III-IV acute GVHD at 13%. Similarly, the IFI rate was lower in limited chronic GVHD (3.2%) than in extensive chronic GVHD (7.6%). One study reported the cumulative incidence of IFIs as 12.2% at 100-days and 14.2% at 1-year. One study reported overall survival of IFIs patients as 77%, 69% and 43% at 1, 2 and 3 years, respectively. One study reported 100-days mortality as 55%. The pooled overall mortality rate due to IFIs was 23.6% (95% CI: 0.06-0.58, I2 =86.3%).

CONCLUSION:

Invasive fungal infections lead to significant mortality in patients with GVHD, with a higher incidence in acute GVHD as compared to chronic GVHD. Available literature is very heterogeneous, and our findings underscore the need for further research in this area.

Abhyankar:CSL Behring, Miltenyi Biotec.: Research Funding; Incyte: Consultancy. McGuirk:Autolus: Consultancy; Kite: Consultancy; Novartis: Consultancy; Envision: Consultancy; Allo Vir: Consultancy; Legend biotech: Consultancy; CRISPR therapeutics: Consultancy; Caribou bio: Consultancy; Sana technologies: Consultancy; NEKTAR therapeutics: Consultancy; BMS: Consultancy. Mushtaq:Iovance Biotherapeutics: Research Funding.