Autologous hematopoietic stem cell transplantation in multiple sclerosis: a global approval and availability review

Abstract

Multiple sclerosis (MS) is a chronic, autoimmune, demyelinating disorder of the central nervous system. With a prevalence of ~100 per 100,000 population in Europe, it is one of the most common and severe neurologic disorders of young adults [1]. The majority (80–90%) of patients present initially with a relapsing-remitting (RRMS) and later secondary progressive (SPMS) course, while a minority present with a primary progressive course (PPMS) [2]. Disability accumulation over the years has enormous consequences and causes significant impairment of quality of life and ability to work. In the last two decades, efficient therapies that drastically reduce relapses and alter the course of the disease with significant impact on prognosis have been developed and approved [3, 4], however, progression of disability is often not prevented. A novel concept, the status of no evidence of disease activity (NEDA or NEDA3, characterized by absence of relapses, new MRI lesions, and disability accrual), has therefore emerged as a metric of therapeutic efficacy [5], with the goal to achieve a sustained, prolonged, and perhaps permanent NEDA status. In addition, employing an induction treatment strategy (as opposed to an escalation strategy) to block disease activity as early and completely as possible is increasingly discussed [6]. Despite great reduction and in many cases elimination of relapses and MRI activity with newer approved therapies, 2-year-pooled NEDA is maximally 48% [7]. Moreover, a minority of patients with aggressive MS remains clinically and/or radiologically active despite use of approved highefficacy treatments and shows rapid disability accrual. Similarly, in a subset of patients transitioning from RRMS to SPMS, the progression cannot be halted with current high-efficacy treatments. It is in meticulously selected cases of aggressive, high-efficacy treatment-refractory RRMS or early PP and SPMS with an inflammatory component that autologous hematopoietic stem cell transplantation (aHSCT) has emerged over the last two decades as a treatment option [8]. Although aHSCT is intensive and until 2000 had shown significant mortality [9], it is increasingly safe with mortality reported to the European Blood and Marrow Transplantation Society from 2012 to 2016 of 0.2% in MS [7] and, importantly, it is presently the most effective immunotherapy with 2-year pooled NEDA ranging from 70 to 92%, in comparison to 32–48% with ocrelizumab, natalizumab, alemtuzumab, or cladribine [7–9]. Several studies from different countries across several continents have demonstrated the high efficacy of aHSCT (reviewed in [10]). Furthermore, the use of aHSCT is currently rapidly increasing [8], and the main premise, establishment of a new adaptive immune system, particularly of CD4+ T cells, has been demonstrated [11]. Based on (a) the growing evidence of high efficacy, (b) the fact that aHSCT is safe, well established, and approved for several indications including another autoimmune disease, systemic sclerosis, (c) the fact that phase III clinical trials of aHSCT compared to best available therapy are difficult to perform due to the high cost and lack of support from commercial, private, and government entities, but also due to recruitment difficulties as aHSCT is indicated in a small number of patients with MS, (d) a clear desire of patients with aggressive disease to have access to aHSCT, (e) the fact that many patients with MS are willing to travel to countries where aHSCT is offered widely, and (f) socioeconomic considerations that aHSCT as a one-time treatment will reduce overall disease cost long term, we * P. Stathopoulos [email protected]