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Originally published as JCO Early Release 10.1200/JCO.2009.22.2158 on March 23 2009 © 2009 American Society of Clinical Oncology.
Reply to N. Reddy et alInstitute of Hematology, Davidoff Cancer Center, Petah Tikva; and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Institute of Hematology, Davidoff Cancer Center, Petah Tikva; and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Internal Medicine E, Beilinson Hospital, Petah Tikva; and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Institute of Hematology, Davidoff Cancer Center, Petah Tikva; and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel In their letter, Reddy et al1 point out several limitations of our meta-analysis.2 We appreciate the opportunity to discuss them as well as some implications for the future. We agree that the majority of the studies included in our meta-analysis2 were old, especially in view of changes in the techniques and supportive treatment for patients undergoing bone marrow transplantation or, more recently, for those receiving hematopoietic stem-cell transplants (HSCTs). However, these are the best—and only—data available to date. These data show that all-cause mortality, the one outcome that encompasses all potential benefits and detriments of intravenous immunoglobulin (IVIG), was not influenced by the use of IVIG prophylaxis (relative risk [RR], 0.99; 95% CI, 0.88 to 1.12). We undertook several sensitivity analyses of all-cause mortality using different methods—assessment at 100 days, 1 to 2 years, and longer follow-up; assessment according to type of transplant and IVIG dose; and assessment by randomization and blinding—all of which yielded similar results. As for the use of a fixed-effect versus random-effect model, we maintain that our analysis2 was conducted in the correct way for the following reasons. No significant heterogeneity in the effect of IVIG versus control was observed in the analyses for primary and other outcomes. Meta-analysis using a random-effect model addresses heterogeneity that cannot be readily explained by assuming a normal distribution of treatment effects among studies.3 Without heterogeneity, the pooled effect estimate and average treatment effects are similar. The width of the random-effect average treatment effect tends to spread more widely than do the 95% CIs of the fixed-effect pooled effect estimate. Thus, one cannot expect a nonheterogeneous, nonsignificant difference in the fixed-effect model to become significant or otherwise different in a random-effect model. Accordingly, the random-effect results for all-cause mortality in our meta-analysis included an RR of 0.98 (95% CI, 0.87 to 1.11). Reddy et al1 mention that at their center, they have not observed an increased risk for veno-occlusive disease (VOD) after prophylactic IVIG. Publication of such retrospective data might indeed be helpful. However, the current evidence, based on randomized controlled trials, shows an increased risk, without significant heterogeneity between the trials (RR, 2.73; 95% CI, 1.11 to 6.71). The Centers for Disease Control guidelines,4 developed in 2000, state that "researchers have recommended routine IVIG use to prevent bacterial infections among the approximately 20% to 25% of HSCT recipients with unrelated marrow grafts who experience severe hypogammaglobulinemia (eg, IgG < 400 mg/dL) within the first 100 days after transplant (CIII)." However, the guidelines go on to state that "in the absence of severe demonstrable hypogammaglobulinemia (eg, IgG levels < 400 mg/dL, which might be associated with recurrent sinopulmonary infections), routine monthly IVIG administration to HSCT recipients more than 90 days after HSCT is not recommended (DI)." We should be careful to note that the recommendation for no treatment is based on level I evidence, whereas that for treatment is based on expert opinion (ie, level III evidence). We appreciate that many centers still use IVIG, as described by Kruger et al.5 Our meta-analysis2 shows the lack of evidence underlying this practice, and we would be interested to see a contemporary and well-designed randomized controlled trial assessing IVIG for allogeneic transplant recipients. Thus, in designing such a study, one should consider including unrelated, haploidentical, or cord blood transplant recipients. Stratification should be based on factors known to affect overall survival rather than on a single measurement of immunoglobulin level. No dose-effect relationship was observed in the most recent large trial,6 although higher doses of IVIG were associated with VOD. Thus, low-dose IVIG should probably be assessed. Given the timing of the infectious complications targeted by IVIG and the risk for VOD, later initiation of IVIG (eg, after 7 days), as suggested by Reddy et al,1 might be considered. All-cause mortality should be assessed, as should infection, VOD, and other adverse events, using currently standardized diagnostic methods and criteria. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Reddy N, Goodman S, Savani BN: Prophylactic intravenous immunoglobulin does not have a role in hematopoietic stem-cell transplantation: Is the evidence clear? J Clin Oncol doi: 10.1200/JCO.2009.22.0897. 2. Raanani P, Gafter-Gvili A, Paul M, et al: Immunoglobulin prophylaxis in hematopoietic stem cell transplantation: Systematic review and meta-analysis. J Clin Oncol 27:770–781, 2009. 3. Higgins JPT, Greene S: Cochrane Handbook for Systematic Reviews of Interventions, Version 5.0.1: The Cochrane Collaboration. http://www.cochrane-handbook.org. 4. Centers for Disease Control and Prevention, Infectious Disease Society of America, American Society of Blood and Marrow Transplantation. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR Recomm Rep 49:1–125, CE1–7, 2000.[Medline] 5. Krüger WH, Hornung RJ, Hertenstein B, et al: Practices of infectious disease prevention and management during hematopoietic stem cell transplantation: A survey from the European group for blood and marrow transplantation. J Hematother Stem Cell Res 10:895–903, 2001.[CrossRef][Medline] 6. Cordonnier C, Chevret S, Legrand M, et al: Should immunoglobulin therapy be used in allogeneic stem-cell transplantation? A randomized, double-blind, dose effect, placebo-controlled, multicenter trial. Ann Intern Med 139:8–18, 2003.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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