Prophylactic Use of Intravenous Immune Globulin in the Management of Patients Undergoing Hematopoietic Stem Cell Transplantation: A Systematic Review of Literature.

Background: Intravenous immunoglobulin (IVIG) is a scarce resource derived from pooled plasma of whole blood through industrial fractionation. IVIG for the prevention of infections and Graft versus host disease (GVHD) after Hematopoietic Stem cell transplantation (HSCT) is one of only 5 licensed indications; however, its use in HSCT is contentious with multiple conflicting reports. Given this uncertainty, we sought to summarize and quantify the clinical effects of prophylactic IVIG in the context of HSCT.

Methods: We conducted a systematic review to summarize evidence from prospective randomized controlled trials (RCTs) addressing prophylactic IVIG use in patients undergoing HSCT. In particular, we included studies which addressed clinical outcomes and excluded studies that addressed only biochemical surrogates. The search strategy included MEDLINE (1966 to 4th week of July 2006), EMBASE (1980 to 4th week of July 2006) and all EBM Reviews (2ndquarter of 2006). A random effects model was used to summarize the outcome data.

Results: Twenty two RCTs representing 3346 patients were included in the review; 16 RCTs addressing patients undergoing allogeneic HSCT, 4 RCTs addressing patients undergoing either allogeneic or autologous HSCT and 1 trial in patients undergoing autologous HSCT. Nine RCTs (n=1462) compared conventional IVIG to no treatment, 8 RCTs (n=538) compared CMV specific IVIG to no treatment, 2 RCTs (n=950) compared 2 different doses of conventional IVIG while 3 RCTs (n=212) compared conventional IVIG to CMV specific IVIG/plasma. Eleven RCTs comparing IVIG to no treatment did not demonstrate an overall survival advantage (RR 1.01; 95% 0.92–1.12). IVIG did not attenuate transplant related mortality (RR 1.24; 95% 0.83–1.85), acute GVHD (RR 0.95; 95% 0.80–1.14), chronic GVHD (RR 1.19; 95% 0.85–1.67), interstitial fibrosis (RR 1.00; 95% 0.50–2.00) or relapse (RR 0.76; 95% 0.38–1.52). Although CMV infections were reduced (RR 0.80; 95% 0.66–0.96), this did not result in a reduction in CMV disease (RR 0.90; 95% 0.52–1.56). Of concern, the risk of hepatic sinusoidal obstruction syndrome (HSOS) was increased (RR 3.09; 95% 1.11–8.58). Several a priori defined sensitivity analyses were performed including comparisons of the type of IVIG, dose of IVIG, type of HSCT and the quality of studies.

Conclusions: There is no evidence to support the routine use of prophylactic IVIG in improving clinical outcomes in patients undergoing HSCT. Furthermore, no subgroups appear to benefit from IVIG use. The increased risk of HSOS merits further study. Given the lack of benefit of IVIG in patients undergoing HSCT, the labeled indications for IVIG should be reassessed.