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Originally published as JCO Early Release 10.1200/JCO.2009.22.0897 on March 23 2009 © 2009 American Society of Clinical Oncology.
Prophylactic Intravenous Immunoglobulin Does Not Have a Role in Hematopoietic Stem-Cell Transplantation: Is the Evidence Clear?Hematology and Stem Cell Transplantation Section, Division of Hematology/ Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN To the Editor: In their recently published meta-analysis of prophylactic intravenous immunoglobulin (IVIG) in allogeneic stem-cell transplantation (alloSCT), Raanani et al1 concluded that IVIG does not have a role in SCT. There are several issues in the meta-analysis that raise concern. The analysis included 30 trials, most of which were published before the year 2000, when the majority of patients received a matched related-donor bone marrow transplant (26 of 30 trials) after a myeloablative conditioning regimen. Unfortunately, in most of the studies that analyzed outcome after prophylactic IVIG, patients were not randomly assigned on the basis of initial serum immunoglobulin G (IgG) level. In their meta-analysis, Raanani et al1 used a fixed-effect model. However, with the heterogeneity of the various studies, we wonder whether similar results would have been obtained using a random-effect model. Raanani et al should have verified their results using a random-effect model. The reasons for heterogeneity should also have included immunosuppressive regimens, patient age, and length of follow-up. Raanani et al1 included three studies of alloSCT to investigate the risk of veno-occlusive disease (VOD) after prophylactic IVIG. The first study, by Ustun et al,2 published in abstract form, included only seven patients in the IVIG group (receiving 500 mg/kg weekly), one of whom developed VOD; none of the seven patients in the control group developed VOD. In the second study, by Poynton et al,3 none of the 29 patients in the IVIG group developed VOD; one of 34 patients in the control group did. In the third study comparing IVIG with placebo, Cordonnier et al4 concluded that the use of IVIG did not influence the development of VOD (of 50, 53, 49, and 48 patients randomly assigned to receive 0, 50, 250, and 500 mg/kg of IVIG weekly, only three, seven, seven, and eight patients developed any grade of VOD, respectively; P > .2). However, only higher doses of IVIG were associated with grade 3 VOD (none of 50 patients receiving placebo weekly developed grade 3 VOD, and none of 53 patients receiving 50 mg/kg, two of 49 patients receiving 250 mg/kg, and five of 48 patients receiving 500 mg/kg of IVIG weekly developed grade 3 VOD; P = .014). In current practice, most transplantation centers are giving a selected group of patients who are unlikely to experience an increased risk of VOD (ie, patients with hypogammaglobulinemia) a lower weekly dose of prophylactic IVIG (6 to 12 g). At our center, when prophylactic IVIG has been used for hypogammaglobulinemia after transplantation involving a matched unrelated donor or cord blood transplantation (CBT) in patients with recurrent infection (especially viral infections after CBT), we have not observed an increased risk of VOD (unpublished data). Moreover, in current practice, IVIG is not normally initiated in the first week after SCT; however, this was routinely done in most of the studies included in the meta-analysis by Raanani et al. In addition, the timing of the administration of IVIG therapy with relation to the conditioning regimen may be important. In almost all the studies, prophylaxis was initiated either during the conditioning regimen or immediately after transplantation. The risk of VOD related to IVIG use was highest in patients receiving IVIG at a dose of 500 mg/kg weekly (approximately 35 to 40 g weekly), with administration of IVIG beginning as early as within 1 week of SCT.4 Other factors, such as fluid overload resulting from excess hydration during and immediately after the conditioning regimen, may have also contributed to the risk of VOD. With the increasing use of unrelated- and mismatched-donor SCT and CBT—as well as older patients undergoing alloSCT after reduced-intensity conditioning regimens (ie, more immunosuppressive regimens with frequent use of anti–T-cell antibody)—in the last decade,5 a certain group of patients who can benefit from prophylactic IVIG use has been identified. The Centers for Disease Control recommend administering IVIG every 1 to 2 weeks in patients whose IgG level is < 400 mg/dL to maintain a serum IgG concentration of > 400 to 500 mg/dL (level of recommendation, BII).6 With this standard practice, it would be difficult today to conduct a prospective, randomized study of the use of prophylactic IVIG in patients with hypogammaglobulinemia after unrelated- and mismatched-donor alloSCT and CBT. It may be possible to perform more analyses of retrospective data; however, it remains unclear if these would be relevant. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. ACKNOWLEDGMENT We thank Angela Woods for manuscript preparation. REFERENCES
1. 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. 2. Ustun C, Ozcan M, Beksac M, et al: Clinical effects of intravenous immune globulin (IVIG) treatment in patients with allogeneic peripheral stem cell transplantation. Blood 92:355b; 1998. 3. Poynton CH, Jackson S, Fegan C, et al: Use of IgM enriched intravenous immunoglobulin (Pentaglobin) in bone marrow transplantation. Bone Marrow Transplant 9:451–457, 1992.[Medline] 4. 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. 5. Barrett AJ, Savani BN: Stem cell transplantation with reduced-intensity conditioning regimens: A review of ten years experience with new transplant concepts and new therapeutic agents. Leukemia 20:1661–1672, 2006.[CrossRef][Medline] 6. 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]
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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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