Systemic complement activation influences outcomes after allogeneic hematopoietic cell transplantation: A prospective French multicenter trial

Abstract

Complement activation has shown a role in murine models of graft‐versus‐host disease (GVHD) and in endothelial complications after allogeneic hematopoietic cell transplantation (allo‐HSCT). However, its impact on post‐transplant outcomes has not been so far fully elucidated. Here, we conducted a prospective multicentric trial (NCT01520623) performing serial measurements of complement proteins, regulators, and CH50 activity for 12 weeks after allo‐HSCT in 85 patients receiving a myeloablative conditioning (MAC) regimen for various hematological malignancies. Twenty‐six out of 85 patients showed an “activated” complement profile through the classical/lectin pathway, defined as a post‐transplant decline of C3/C4 and CH50 activity. Time‐dependent Cox regression models demonstrated that complement activation within the first weeks after allo‐HSCT was associated with increased non‐relapse mortality (hazard ratio [HR]: 3.69, 95% confident interval [CI]: 1.55–8.78, p = .003) and poorer overall survival (HR: 2.72, 95% CI: 1.37–5.39, p = .004) due to increased incidence of grade II–IV acute GVHD and in particular gastrointestinal (GI) GVHD (HR: 36.8, 95% CI: 12.4–109.1, p < .001), higher incidences of thrombotic microangiopathy (HR: 8.58, 95% CI: 2.16–34.08, p = .0022), capillary leak syndrome (HR: 7.36, 95% CI: 2.51–21.66, p = .00028), post‐engraftment bacterial infections (HR: 2.37, 95% CI: 1.22–4.63, p = .0108), and EBV reactivation (HR: 3.33, 95% CI: 1.31–8.45, p = .0112). Through specific immune staining, we showed the correlation of deposition of C1q, C3d, C4d, and of C5b9 components on endothelial cells in GI GVHD lesions with the histological grade of GVHD. Altogether these findings define the epidemiology and the clinical impact of complement classical/lectin pathway activation after MAC regimens and provide a rational for the use of complement inhibitory therapeutics in a post‐allo‐HSCT setting.

The function of the complement system remains fully intact throughout the course of allogeneic stem cell transplantation

“…Both PA and PB showed a marked increase in CRP and IL-6 as compared to patients with uneventful course. These results indicate that systemic complement activation is involved in the pathogenesis of different complications leading to severe morbidity during HSCT, which is in accordance with a previous study ( 19 ). Recent results indicate that complement inhibition is beneficial in pediatric TA-TMA ( 18 ) indicating that complement may play a role in developing HSCT-related complications.…”

“…Therapeutic inhibition targeted at complement component C5, preventing C5a and C5b-9 formation, seems promising as reported in a large pediatric cohort with TA-TMA ( 18 ). Furthermore, a multi-center study has previously indicated a correlation between complement activation and outcome after HSCT ( 19 ). In this study we aimed to investigate the innate immune profile, including neutrophil and platelet activation, the cytokine network, and, in particular, the function and activation of complement in HSCT.…”