Invasive Fungal Disease in Allogeneic Hematopoietic Stem Cell Transplant Recipients Is an Important Risk Factor Not Only for Acute Graft-Versus-Host Disease but Also for Chronic Graft-Versus-Host Disease

Introduction: Infections and graft-versus-host disease (GVHD) are the leading causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). And their close relationship is gaining more and more attentions in recent years. Although it has been demonstrated that invasive fungal disease (IFD) is associated with an increased risk of acute GVHD, the link between IFD and chronic GVHD is rarely reported. This large retrospective study was performed to assess the relationship between IFD and GVHD, especially chronic GVHD.

Methods: A total of 684 patients with hematologic malignancies who underwent allo-HSCT at Nanfang Hospital between January 2011 and December 2015 were enrolled in the retrospective study. We defined IFD according to the European Organization for Research and Treatment of Cancer and Mycoses Study Group (EORTC/MSG) revised definitions of 2008 (De Pauw B et. al. Clin Infect Dis 2008) and included proven and probable cases for analysis. Cases of possible IFD were also included if initial antifungal treatments were considered effective, otherwise possible cases were excluded. Acute GVHD was graded from 0 to IV and chronic GVHD was defined as no, limited or extensive chronic GVHD according to standard criteria (Przepiorka D et. al. Bone Marrow Transplant 1995; Sullivan KM et. al. Semin Hematol 1991). Cumulative incidence of acute GVHD, chronic GVHD, non-relapse mortality (NRM) and overall survival (OS) were estimated by the Kaplan-Meier and comparison was done by a log- rank test. Risk factors associated with chronic GVHD after allo-HSCT were identified in a multivariable Cox regression model.

Results: Within 1 year post-transplantation, 191 patients developed IFD (42 proven, 98 probable and 51 possible), including 39 patients with a history of IFD pre-transplantation. Of the 39 patients, 32 patients had stable IFD and 7 patients had active IFD at the time of their transplantation. The 1-year cumulative incidence of IFD was 25.3% ±1.7%. The cumulative incidence of grades II to IV acute GVHD at 100 days was 47.8% ± 4.4% in IFD group and 25.8% ±2.0% in non-IFD group, respectively (P < .001). The 2-year cumulative incidence of chronic GVHD and extensive chronic GVHD were significantly higher in patients with IFD compared to those without IFD (66.6% ± 5.0% versus 41.5% ± 2.4%, P < .001; 31.6% ± 4.8% versus 9.4% ± 1.4%, P < .001). Besides, patients with IFD also had higher 5-year NRM and lower 5-year OS compared to patients without IFD (29.2 ± 3.6% versus 10.9% ± 1.6%, P < .001 and 53.6 ± 3.8% versus 69.3% ± 2.2%, P < .001). Multivariate analyses showed that IFD was a significant risk factor for chronic GVHD, independent of other risk factors (hazard ratio [HR], 1.502; 95% confidence interval [CI], 1.127-2.001; P=0.005).

Conclusions: The occurrence of IFD confers a high risk for acute GVHD and chronic GVHD development. This may provide new insights that allo-HSCT patients might benefit most from early and prolonged antifungal prophylaxis and immediate antifungal therapy.