Safety and efficacy of autologous hematopoietic stem‐cell transplantation following natalizumab discontinuation in aggressive multiple sclerosis

Abstract

Background and purpose Natalizumab (NTZ) is a highly effective treatment for relapsing‐remitting multiple sclerosis (MS), but its withdrawal is often followed by disease reactivation or rebound, even if other disease‐modifying treatments (DMTs) are administered. In this study, for the first time, the safety and efficacy of autologous hematopoietic stem‐cell transplantation (aHSCT) performed following NTZ discontinuation were retrospectively compared with conventional DMTs. Methods Patients with relapsing‐remitting MS treated with NTZ who discontinued the drug after at least six administrations and with at least 6 months of follow‐up were included. Patients underwent aHSCT after a minimum of 6 months following NTZ withdrawal, receiving meanwhile cyclophosphamide or corticosteroids, or other DMTs approved for MS (control group) after an adequate wash‐out period. Both hematological and neurological follow‐up were assessed according to standard policies. Results A total of 52 patients were included, 11 who received aHSCT and 41 who received DMTs. Baseline clinical and demographic characteristics were similar between the two groups. No fatality or life‐threatening complications, including progressive multifocal leukoencephalopathy, were observed. At 3 years following NTZ discontinuation, no evidence of disease activity was reported in 54.5% of the patients in the aHSCT group compared with 11.5% of those in the DMT group (P = 0.0212). Disease reactivation in the patients with aHSCT was observed only during wash‐out/bridging therapy and 100% of the cases were free from disease activity after aHSCT. Conclusions These data suggest that an aggressive therapy should be established after NTZ with the shortest possible wash‐out period. aHSCT after 6 months from NTZ withdrawal appears to be safe.

The TCR Repertoire Reconstitution in Multiple Sclerosis: Comparing One-Shot and Continuous Immunosuppressive Therapies

“…This observation in CD8 naive cells of NTZ patients, along with a significantly lower number of shared CDR3s with published databases (Figure 7) and the decreased number of clones and S-E mean value at t24 (Figure 1C), may be linked to a mild impact of NTZ on VLA-4 expression on the surface of naive cells compared to memory subpopulations, as previously documented (51), with the consequence of an increased thymic retention of this cell population (52). It would be worthwhile to investigate how long this effect lasts after NTZ interruption and if it may be, in part, the culprit of the higher incidence of infection-related adverse events observed in patients that shifted treatment, for example, from NTZ to AHSCT (53). Furthermore, the higher TCR sequence similarity in AHSCT patients compared to NTZ (Figure 6) may depend on the fact that AHSCT patients underwent the same posttransplant protocol, remaining at least 1 month in a sterile chamber, sharing the same nutritional restrictions and the same antimicrobial therapies.…”

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)

“…Prior to mobilisation, DMTs and other immunomodulatory drugs should be discontinued as early as possible, which may help minimise risks and inhibitory effects on successful mobilisation. 'Wash-out' periods, commonly used in neurological practice for switching between DMTs, aim to reduce the risks of PML and other infections [89]. There is no consensus to support duration of wash-out periods.…”

Autologous hematopoietic stem cell transplantation for multiple sclerosis: A current perspective

“…Furthermore, if there will be a lag of three or more months before starting AHSCT, then some form of effective “bridging” is required to prevent rebound disease activity. 42…”