Intravenous immunoglobulin and the risk of hepatic veno-occlusive disease after bone marrow transplantation

Abstract

Recent reports using historical controls or registry cohorts suggest, respectively, either an increase in the mortality or a decrease in the incidence of hepatic veno-occlusive disease (VOD) with the administration of intravenous immunoglobulin (i.v.Ig) after bone marrow transplantation. These divergent results prompted us to conduct a retrospective analysis of two randomized clinical trials conducted at our center to determine the effect of i.v.Ig infusions on the development and severity of VOD. Patients were randomized to receive (n=318) or not to receive (n=315) i.v.Ig prophylaxis after human leukocyte antigen-identical sibling (n=414), mismatched or unrelated (n=178), or autologous or syngeneic (n=41) marrow transplantation. To determine the relationship of i.v.Ig to the development and severity of VOD, a single observer reviewed data displays created for each patient for grading VOD without knowledge of patient i.v.Ig use. In this analysis, VOD was defined as hyperbilirubinemia > or =2.0 mg/dL before day 20 and abrupt weight gain > or =2% before day 14 posttransplant in the absence of other causes of liver disease. Hepatic VOD developed in 235 (37%) of the 633 randomized patients. No evidence for VOD was found in 230 (36%) patients. The remaining 168 (27%) patients were classified as having liver disease of uncertain etiology. Hepatic VOD was judged to be severe in 63 (10%) and mild or moderate in 172 (27%) patients. The number of patients developing any VOD or severe VOD was similar between those randomized to i.v.Ig prophylaxis and untreated controls (115 vs. 120 and 32 vs. 31, respectively). Logistic regression models identified several covariates as significant (p < 0.01) factors associated with the development of severe VOD. Increased risk occurred with elevated pretransplant serum aspartate aminotransferase (odds ratio [OR] = 2.64) and earlier year of transplant (OR = 3.73); decreased risk occurred with autologous or twin donors (OR = 0.09) and acute myeloid leukemia (OR = 0.39). The development of any VOD was associated with an elevated pretransplant alkaline phosphatase (OR = 4.1), pretransplant use of vancomycin (OR = 1.6) or amphotericin (OR = 3.0), posttransplant use of cyclosporine (OR = 2.5), older patient age (OR = 1.03), and obesity (OR = 0.78). We concluded from the controlled trials of 633 patients that the administration of i.v.Ig did not influence the development or severity of VOD after bone marrow transplantation.

Hepatic Veno-Occlusive Disease following Stem Cell Transplantation: Incidence, Clinical Course, and Outcome

“…The clinical criteria used for that study were similar to those developed in the 1984 study [4], but with the stipulation that the clinical features of VOD appear within 20 days of transplantation (the modified Seattle criteria). Three additional studies from that group have reported similarly high occurrences of VOD [36,58,64]. The increased incidence noted in the more recent reports compared with the incidence of 21% in the 1984 Seattle study was attributed to increased use of intensive high-dose conditioning regimens.…”

Platelet Transfusion Containing ABO-Incompatible Plasma and Hepatic Veno-occlusive Disease after Hematopoietic Transplantation in Young Children

“…Administration of intravenous immunoglobulins is another situation where the patient is potentially exposed to allogeneic anti-A and/or anti-B Abs (24). Indeed, HVOD has been associated with intravenous immunoglobulins in several studies (25,26) but not so in another study (27). Interestingly and in accordance with our findings, results from a recent randomized double-blind placebo-controlled multicenter trial (28) suggest a deleterious dose-related effect of prophylactic intravenous immunoglobulins administration on severe HVOD occurrence after allogeneic HSCT (Pϭ0.01).…”

“…A further reduction in the risk of HVOD occurrence might be achieved by combining transfusion of ABO-compatible plasma with other approaches, such as the use of low-dose heparin (30) or ursodeoxycholic acid (31,32), while omitting prophylactic intravenous immunoglobulins administration (25,27,28).…”

Veno-occlusive disease of the liver in children with solid tumors undergoing autologous hematopoietic progenitor cell transplantation: a high incidence in patients with neuroblastoma

“…The highest incidence of VOD has been reported from the Seattle group (37-54%, with the incidence of severe VOD 10-15%). 3,15 The reasons for such a high incidence in the Seattle group's reports are multiple and may include a higher proportion of patients undergoing allogeneic and unrelated transplants, prospective follow-up for signs of disease, or possibly a lack of heparin prophylaxis. In many studies, patients undergoing ABMT had a lower incidence of VOD than those undergoing allogeneic transplantation.…”