Hematopoietic stem cell transplantation for multiple sclerosis: is it a clinical reality?

Abstract

Hematopoietic stem cell transplantation (HSCT) is a treatment paradigm that has long been utilized for cancers of the blood and bone marrow but has gained some traction as a treatment paradigm for multiple sclerosis (MS). Success in the treatment of patients with this approach has been reported primarily when strict inclusion criteria are imposed that have eventuated a more precise understanding of MS pathophysiology, thereby governing trial design. Moreover, enhancing the yield and purity of hematopoietic stem cells during isolation along with the utility of appropriate conditioning agents has provided a clearer foundation for clinical translation studies. To support this approach, preclinical data derived from animal models of MS, experimental autoimmune encephalomyelitis, have provided clear identification of multipotent stem cells that can reconstitute the immune system to override the autoimmune attack of the central nervous system. In this review, we will discuss the rationale of HSCT to treat MS by providing the benefits and complications of the clinically relevant protocols, the varying graft types, and conditioning regimens. However, we emphasize that future trials based on HSCT should be focused on specific therapeutic strategies to target and limit ongoing neurodegeneration and demyelination in progressive MS, in the hope that such treatment may serve a greater catchment of patient cohorts with potentially enhanced efficiency and lower toxicity. Despite these future ambitions, a proposed international multicenter, randomized clinical trial of HSCT should be governed by the best standard care of treatment, whereby MS patients are selected upon strict clinical course criteria and long-term follow-up studies of patients from international registries are imposed to advocate HSCT as a therapeutic option in the management of MS.

Advising patients seeking stem cell interventions for multiple sclerosis

“…Although haematopoietic stem cells comprise only 0.01% of nucleated cells in the marrow, they can restore all blood lineages following myeloablation 14. The key marker in clinical practice used to predict functional engraftment is the peripheral CD34-positive cell count, with a requirement for 2–3×10 6  CD34-positive cells/kg body weight 15.…”

The future of multiple sclerosis treatments

“…Hematopoietic stem cell transplantation (HSCT) has been reviewed in detail elsewhere [112][113][114][115][116]. Studies on animal models showed that strong immunosuppression followed by syngeneic bone marrow transplantation can induce long term antigen-specific tolerance [117].…”

“…The choice of the conditioning regimens (myeloablative or non-myeloablative) can impact the outcomes both in terms of efficacy and toxicity [113]. The myeloablative conditioning regimens can completely eliminate the activated immune cells before the HSCT treatment, but would expose the patients to aplasia-related complications and death [113]. The use of lymphoablative but non-myeloablative conditioning regimens would be in keeping with "the rationale of auto-HSCT […] to revive an antigen-naive immune system from the patient's HSCs" [113] whilst mitigating adverse effects such as neurotoxicity [124].…”

“…The myeloablative conditioning regimens can completely eliminate the activated immune cells before the HSCT treatment, but would expose the patients to aplasia-related complications and death [113]. The use of lymphoablative but non-myeloablative conditioning regimens would be in keeping with "the rationale of auto-HSCT […] to revive an antigen-naive immune system from the patient's HSCs" [113] whilst mitigating adverse effects such as neurotoxicity [124]. Freedman recently noted that, although systematic comparison of regimens is lacking, the available data would suggest that the more intense conditioning regimens are followed by more durable responses but with more toxicity as well [121].…”

“…Different conditioning regimens following the harvesting of the stem cells were used it the studies of autologous HSCT in people with MS [123]. The choice of the conditioning regimens (myeloablative or non-myeloablative) can impact the outcomes both in terms of efficacy and toxicity [113]. The myeloablative conditioning regimens can completely eliminate the activated immune cells before the HSCT treatment, but would expose the patients to aplasia-related complications and death [113].…”