Epstein-Barr Virus and Monoclonal Gammopathy of Clinical Significance in Autologous Stem Cell Transplantation for Multiple Sclerosis

Abstract

Introduction Autologous hematopoietic stem cell transplantation (AHSCT) with anti-thymocyte globulin (ATG) conditioning as treatment of active multiple sclerosis (MS) is rapidly increasing across Europe (EBMT registry data 2017). Clinically significant Epstein-Barr virus reactivation (EBV-R) following AHSCT with ATG for severe autoimmune conditions is an underrecognized complication relative to T-cell deplete transplants performed for hematological diseases. This retrospective study reports EBV-R associated significant clinical sequelae in MS patients undergoing AHSCT with rabbit ATG. Methods Retrospective data were analyzed for 36 consecutive MS-AHSCT patients at Kings College Hospital, London. All patients routinely underwent weekly EBV DNA polymerase chain reaction monitoring and serum electrophoresis for monoclonal gammopathy (MG or M-protein). EBV-R with rising Epstein-Barr viral load, M-protein, and associated clinical sequelae were captured from clinical records. Results All patients had evidence of rising EBV DNA-emia, including 7 who were lost to long-term follow-up, with a number of them developing high EBV viral load and associated lymphoproliferative disorder (LPD). Nearly 72% (n = 18/29) developed de novo MG, some with significant neurological consequences with high M-protein and EBV-R. Six patients required anti-CD20 therapy (rituximab) with complete resolution of EBV related symptoms. Receiver operating characteristics estimated a peak EBV viremia of >500 000 DNA copies/mL correlated with high sensitivity (85.5%) and specificity (82.5%) (area under the curve: 0.87; P = .004) in predicting EBV-R related significant clinical events. Conclusion Symptomatic EBV reactivation increases risk of neurological sequelae and LPD in MS-AHSCT. We recommend regular monitoring for EBV and serum electrophoresis for MG in MS patients in the first 3 months post-AHSCT.

Autologous Hematopoietic Stem Cell Transplantation in Active Multiple Sclerosis

“…Particularly in light of the putative association of EBV in the pathogenesis of MS, 21 we speculate that in some patients the reactivation of EBV with high viral loads after AHSCT may predispose and contribute, together with other as-yet unknown susceptibility factors, to continued worsening after treatment. 11 Development of monoclonal paraprotein could be of interest as a marker of immune dysregulation after EBV reactivation, as well as its potential impact on neurologic disability after AHSCT, as also observed in our cohort, and monitoring is now recommended. 11,12 We examined NEDA, and the rates of 65% at 2 years and 53% at 4 years after AHSCT are slightly below the ranges reported in a pooled analysis of AHSCT trials, in which the proportion of individuals with NEDA was 83.4% (range 70%-92%) at 2 years after AHSCT and 67% (range 59%-70%) at 5 years.…”

“…In a subset of 85 participants, EBV DNA copy numbers in blood and paraprotein were measured regularly by standardized laboratory techniques at both sites. EBV reactivation (defined by viremia >10 DNA copies/mL consecutively, as previously described 11 ) was demonstrated in 87 of 109 (80%; 11 missing/not tested) of participants after AHSCT. Of the 87 EBV reactivation cases, 20 (23%) cases were treated with rituximab in a median of 4 courses (range 2-4).…”

Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurological diseases: updated guidelines and recommendations from the EBMT Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of EBMT and ISCT (JACIE)

“…CMV re-activation occurs at a greater rate and cases of CMV infection have been reported. EBV reactivation usually resolves spontaneously, but may need treatment with rituximab and may be associated with neurological events and de-novo paraproteinemia [109]. Immune monitoring of T-and B-cell subsets and immunoglobulin levels/electropheresis is recommended on a 3-monthly basis in the first year and then annually in order to guide infection prophylaxis and detect paraproteinaemia [110].…”

Autologous haematopoietic stem cell therapy for multiple sclerosis: a review for supportive care clinicians on behalf of the Autoimmune Diseases Working Party of the European Society for Blood and Marrow Transplantation

“…Screening for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation, similar to allogeneic haematopoietic stem cell transplantation protocols, for the first 3 months and sometimes beyond, is essential so that preemptive treatment can be instituted promptly, especially for CMV, which may be life-threatening. EBV reactivation is detected in up to 80% of MS patients with previous EBV exposure who receive ATG-conditioning regimens and may also be related to previous DMTs [44]. Symptomatic reactivation of EBV can be occasionally associated with de-novo monoclonal gammopathy and new neurological sequelea (not related to MS) as well as lymphoproliferative disorders [44].…”

“…EBV reactivation is detected in up to 80% of MS patients with previous EBV exposure who receive ATG-conditioning regimens and may also be related to previous DMTs [44]. Symptomatic reactivation of EBV can be occasionally associated with de-novo monoclonal gammopathy and new neurological sequelea (not related to MS) as well as lymphoproliferative disorders [44].…”