Search

Abstract: A role for gut bacteria in the pathogenesis of graft-versus-host disease (GVHD) has been firmly established; however, the role of Candida spp, which form part of the mycobiome, remains unknown. In a homogenous group of patients who underwent allogeneic stem cell transplantation (SCT), we found a significant impact of Candida colonization on the occurrence of acute GVHD. Patients colonized with Candida spp developed significantly more grade II-IV acute GVHD compared with noncolonized patients (50% vs 32%; P = .03), as well as more gastrointestinal (GI)-GVHD (33% vs 19%; P = .05). Colonization with Candida spp was more frequent in patients bearing the loss-of-function polymorphism Y238X, which results in dectin-1 dysfunction, compared with patients with the wild-type allele (73% vs 31%; P = .002). There was no direct effect of dectin-1 dysfunction on acute GVHD, although it did influence the occurrence of GVHD indirectly through Candida colonization. The exact mechanism of GVHD induction by Candida spp colonization of the mucosa is unknown, but the link might prove to be the induction of Th 17/IL-23 responses through activation of pattern recognition receptors by fungal motifs, including β-d-glucan and mannans. These data indicate a role for the mycobiome in the pathogenesis of GVHD and suggest that altering the mycobiome by antifungal drugs can help ameliorate GI-GVHD. In addition, given that the genetic constitution of patients affects susceptibility to both Candida colonization and GVHD, whether identifying gene polymorphisms will facilitate personalized treatment of SCT recipients remains to be determined. [Copyright &y& Elsevier]

Allogeneic hematopoietic cell transplantation (HCT) offers the possibility of curative therapy for patients with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myelogenous leukemia (AML). However, post-HCT relapse remains a major problem, particularly in patients with high-risk cytogenetics and in patients who cannot tolerate consolidation chemotherapy (eg, due to previous toxicity). We assessed the toxicity and efficacy of 10-day decitabine (Dec), fludarabine (Flu), and 2 Gy total body irradiation (TBI) as a new conditioning regimen for allogeneic HCT in patients with MDS, CMML, or AML. Thirty patients were enrolled, including 11 with MDS, 2 with CMML, and 17 with AML. Patients received 20 mg/m 2 /day Dec on days -11 to -2, 30 mg/m 2 /day Flu on days -4 to -2, and 2 Gy TBI on day -1, followed by infusion of a donor stem cell graft on day 0. Postgrafting immunosuppression consisted of cyclosporin A and mycophenolate mofetil. At a median follow-up of 443 days, the overall survival was 53%, relapse incidence was 27%, and nonrelapse mortality was 27%. The incidence of severe acute (grade III/IV) graft-versus-host disease (GVHD) was 27%, and that of (predominantly mild) chronic GVHD was 60%. Immunomonitoring studies revealed that specific CD8 + T cell responses against epigenetically silenced tumor-associated antigens (TAAs), including cancer-testis antigens (MAGE-A1/A2/A3 and PRAME) and RHAMM, occurred more frequently in patients who had received Dec/Flu/TBI conditioning (8 of 11 patients) compared with a control group of patients who had received only Flu/TBI conditioning (2 of 9 patients). In summary, Dec/Flu/TBI conditioning proved feasible and effective and enhanced the induction of TAA-reactive CD8 + T cell responses in vivo, which may contribute to disease control post-transplantation. [ABSTRACT FROM AUTHOR]