Should Immunoglobulin Therapy Be Used in Allogeneic Stem-Cell Transplantation?

A Randomized, Double-Blind, Dose Effect, Placebo-Controlled, Multicenter Trial

1 July 2003 | Volume 139 Issue 1 | Pages 8-18

Background: The universal use of prophylactic immunoglobulin in stem-cell transplantation has not been supported by strong evidence of benefit. Results of most trials were reported before effective drugs for cytomegalovirus infection and disease were available, and no trial was placebo controlled.

Objective: To assess the role and the dose-effect relationship of immunoglobulin in the prophylaxis of complications after allogeneic stem-cell transplantation.

Design: Multicenter randomized, double-blind, dose effect placebo-controlled study.

Setting: 19 stem-cell transplantation centers in France.

Patients: 200 patients who had allogeneic stem-cell transplantation from HLA-identical sibling donors between 1998 and 2000.

Intervention: Immunoglobulin at doses of 50 mg/kg of body weight, 250 mg/kg, or 500 mg/kg weekly from day –7 to day 100 after transplantation or placebo.

Measurements: Cumulative incidence of infection, graft-versus-host disease, veno-occlusive disease, interstitial pneumonia, and transplantation-related mortality at 6 months; overall survival at 2 years after transplantation.

Results: Immunoglobulin had no benefit over placebo; 92% of patients in the pooled immunoglobulin group and 90% of patients in the placebo group had one or more infections (difference, 2 percentage points [95% CI, –8 to 12 percentage points]). Cumulative incidences of interstitial pneumonia, graft-versus-host disease, transplantation-related mortality, and overall survival were similar in patients receiving placebo and those receiving immunoglobulin; no dose-effect relationships were evident. Grade 3 (severe) veno-occlusive disease occurred more frequently as the immunoglobulin dose increased (P = 0.01).

Conclusions: Use of prophylactic immunoglobulin in allogeneic recipients of stem-cell transplant from HLA-identical sibling donors is not recommended.

*For investigators and participating centers for the GREFIG Study Group, see the Appendix.

Editors' Notes Context No placebo-controlled trials have evaluated potential benefits of immunoglobulin in patients undergoing hematopoietic stem-cell transplantation. Contribution This multicenter randomized, double-blind trial involved 200 recipients of HLA-matched sibling transplants. At 6 months, the benefit of prophylactic immunoglobulin (given weekly from day –7 to day 100) compared with placebo was not significant for the following outcomes: number of infections, interstitial pneumonia, graft-versus-host disease, and transplantation-related mortality. Implications Prophylactic immunoglobulin is not indicated for patients undergoing allogeneic hematopoietic stem-cell transplantation from HLA-identical siblings. –The Editors

 

Author and Article Information

From Assistance Publique-Hôpitaux de Paris, Créteil, France.

The authors dedicate this article to Claude Chastang, MD, PhD, a friend and colleague whose vision and leadership have been cornerstones in the design and development of therapeutic trials in France. He played a major role in the design of this study. His friendship will be missed.

Acknowledgment: The authors thank the physicians, pharmacists, data managers, and nurses of the participating centers and the support staff of the Délégation de la Recherche Clinique, Hôpital Saint-Louis, Paris. The authors also thank Dr. Isabel Cunningham for her critical reading of the manuscript and Dr. Per Ljungman for his useful comments.

Grant Support: By the French Ministry of Health (PHRC 96029), Assistance Publique-Hôpitaux de Paris (GERMED 1996), and the Caisse Nationale d'Assurance Maladies des Professions Indépendantes.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Catherine Cordonnier, MD, Service d'Hématologie Clinique, Hôpital Henri Mondor, 51, Av. Maréchal de Lattre de Tassigny, 94000 Créteil, France; e-mail, carlcord{at}club-internet.fr.

Current Author Addresses: Drs. Cordonnier and Rafi: Service d'Hématologie Clinique, Hôpital Henri Mondor, 51, Av. Maréchal de Lattre de Tassigny, 94000 Créteil, France.

Dr. Chevret: Département de Biostatistique et Informatique Médicale, Hôpital Saint-Louis, 1, Avenue Claude Vellefaux, 75475 Paris Cedex 10, France.

Mr. Legrand: Département d'Information Médicale, Hôpital Robert Debré, 49, Boulevard Serurier, 75019 Paris, France.

Dr. Dhédin: Service d'Hématologie, Hôpital Pitié-Salpétriêre, 47-83, Boulevard de l'hôpital, 75013 Paris, France.

Dr. Lehmann: Unité Essais Cliniques, Etablissement Pharmaceutique des Hôpitaux de Paris, 7, rue du Fer à Moulin, 75005 Paris, France.

Dr. Bassompierre: Délégation Régionale à la Recherche Clinique, Hôpital Saint-Louis Aile Hillairet, 1, Avenue Claude Vellefaux, 75475 Paris Cedex 10, France.

Dr. Glückman: Unité de Greffe de Moelle, Hôpital Saint-Louis, 1, Avenue Claude Vellefaux, 75475 Paris Cedex 10, France.

Author Contributions: Conception and design: C. Cordonnier, F. Bassompierre, E. Gluckman.

Analysis and interpretation of the data: C. Cordonnier, S. Chevret.

Drafting of the article: C. Cordonnier.

Critical revision of the article for important intellectual content: H. Rafi, B. Lehmann.

Final approval of the article: C. Cordonnier, S. Chevret, E. Gluckman.

Provision of study materials or patients: C. Cordonnier, H. Rafi, N. Dhédin, B. Lehmann.

Statistical expertise: S. Chevret.

Obtaining of funding: C. Cordonnier, F. Bassompierre, E. Gluckman.

Administrative, technical, or logistic support: M. Legrand, H. Rafi, B. Lehmann, F. Bassompierre.

Collection and assembly of data: M. Legrand.