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Defining the Benefits of Desensitization Therapy

2013; Wolters Kluwer; Volume: 95; Issue: 6 Linguagem: Inglês

10.1097/tp.0b013e3182845fe1

1534-6080

Stanley C. Jordan, Ashley Vo, Chih‐Hung Lai, Nancy L. Reinsmoen,

Drug-Induced Adverse Reactions

Recently, two articles appeared in Transplantation that seriously questioned the benefits of desensitization using intravenous immunoglobulin (IVIg) alone (1) or IVIg combined with rituximab (2). However, neither Alachkar et al. (1) nor Marfo et al. (2) referenced important counter opinions, including our published articles that addressed many of these concerns (3–8). Here, we attempt to clarify concerns raised by addressing three points: (a) the histocompatibility and antibody criteria used to select recipients for transplantation with low risk for immune complication, (b) the subsequent transplantation rates, and (c) the overall benefits of desensitization therapy. In summary, we hope this discussion helps to identify the important impediments and offers reasonable solutions to improving transplantation rates for the highly human leukocyte antigen (HLA)–sensitized (HS) patients. First, we have published the antibody level and corresponding crossmatch criteria used to select patients and the appropriate donor combinations that are at low risk for immune complications (3–6). In the Lai et al. (3) study, we clearly showed the change of antibody levels postdesensitization therapy using comprehensive single-antigen bead antibody analysis. With careful consideration for the various technical issues, we showed that all patients respond to therapy with the lowest antibodies levels being reached at 30 to 120 days posttreatment. We agree with Alachkar et al. (1) that the calculated panel reactive antibody (CPRA), as defined by the United Network for Organ Sharing calculator, which takes into account the class I and II unacceptable antigens and their corresponding allele, allele groups, and haplotype frequencies, does not show remarkable changes postdesensitization. Both the Johns Hopkins and the Cedars-Sinai programs enter those antigens expected to produce a positive complement-dependent cytotoxicity (CDC) crossmatch. For very strongly binding antibodies, especially those against common antigens, no difference would be expected. The difference between our two programs is the removal of unacceptable antigens in UNet by the Johns Hopkins program resulting in a pre-removal versus post-removal increase in the crossmatch rate per patient per month from 0.14 to 1.92 (P 90%) patients awaiting DD transplantation. These conclusions pose serious concerns regarding the future of desensitization and its ability to improve transplantation rates and lives of the 30% to 35% of patients on the DD wait list who are considered sensitized. Alachkar et al. (1) performed an open-label study of high-dose IVIg for desensitization in HS DD recipients. They found that the IVIg group had a higher transplantation rate (41% vs. 12.8%) than seen for historic HS controls, but no effect of IVIg on CPRA levels was seen. They indicated that IVIg did nothing because all patients treated would have received a compatible transplant anyway and linked improved transplantation rates to better wait-list management of these patients. The rates of transplantation for the IVIg treated and control groups are similar to those obtained in our placebo-controlled IGO2 study (11) (37% vs. 13%). However, in this and other studies, clear benefits on reduction of PRA values and more recently DSA and flow cytometry crossmatch (FCMX) values were seen (4, 5). In fact, IVIg is recommended as the therapy of choice for desensitization in a recent analysis of desensitization therapies (8). Both authors dismiss any benefit of IVIg or IVIg+rituximab on desensitization. However, our experience in more than 250 HS DD patients suggests otherwise (3–7). We also discontinued desensitization with IVIg alone in 2005 due to the increased risk of ABMR seen in clinical trials and our own center experience. In this regard, it is noted that 3 of 11 (27%) patients in the Johns Hopkins study lost their grafts after transplantation; however, no mention is made of the ABMR rates or causes for graft loss. Our experience and that of others suggest that desensitization and immune modulation with IVIg is an important modality for improving the rates and outcomes (6–8, 11) of transplantation in HS patients that cannot be achieved by good wait-list management alone. The article by Marfo et al. (2) examined the efficacy of IVIg+rituximab as a desensitization agent in HS patients awaiting DD transplantation but found no discernable effect on CPRA levels or transplantation rates. This article contrasts greatly with our previous reported data showing transplantation rates consistently at approximately 70% for those with CPRAs greater than 80% with more than 250 patients transplanted. Why should there be such discrepancies? Although the protocols are similar, the most important differences lie in patient selection (3, 5–7). We have reported extensively on the processes used to select HS patients for desensitization and transplantation. Unfortunately, these reports were not referenced. More importantly, the authors offer no explanation on what their criteria are for acceptance of DD offers in HS patients. We would consider offers from FCMX-positive and DSA-positive DDs based on antibody and FCMX strength as has been previously outlined (3, 5–7). In conclusion, management of the HS patient represents one of the greatest challenges to transplant medicine. We hope this discussion helps to clarify the important aspect of each protocol that likely explains differences in efficacy. Finally, all investigators in this field should seek to improve transplantation rates and outcomes for HS patients through development of collaborative, evidence-based approaches. Stanley C. Jordan 1 Ashley Vo1 Chih-Hung Lai2 Nancy Reinsmoen2 1 Transplant Immunotherapy Program Comprehensive Transplant Center Cedars-Sinai Medical Center Los Angeles, CA 2 HLA Laboratory Comprehensive Transplant Center Cedars-Sinai Medical Center Los Angeles, CA