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Updated views on autologous hematopoietic stem cell transplantation for treatment of MS
DOI:10.1586/14737175.2016.1158648Maria Pia Sormania* & Paolo Murarob
pages 469-470
Publishing models and article dates explained
Published online: 17 Mar 2016
Multiple sclerosis (MS) is an inflammatory, putatively autoimmune disease, estimated to affect more than 2 million people worldwide. It affects young adults, especially women. For the large majority of patients it is characterized in its early stages by inflammatory demyelination of the CNS, a phase of the disease that is called relapsing-remitting (RR). In addition, a neurodegenerative process causes irreversible loss of neurologic function, leading to the so-called primary or secondary progressive (PP or SP) MS phenotypes. Disease-modifying therapies (DMT) targeting inflammation have been shown to reduce the disease activity in patients with RRMS, by decreasing the accumulation of lesions detected by magnetic resonance imaging (MRI), the frequency of clinical relapses and, to a lesser extent, slow down the progression of disability as compared to placebo, or, more recently, to standard injectable therapies. However, there are currently no medications that can effectively treat the SPMS phase of the disease; also, some patients with RRMS have an aggressive course and do not respond to conventional DMT. It should be noted that we do not have predictive markers to identify patients who will develop aggressive MS early in the disease and that some patients may obtain long-lasting benefit from currently used drugs.
Against this scenario, immunoablative therapy followed by autologous hematopoietic stem cell transplantation (aHSCT) has been investigated for the past two decades to manage severe and treatment-refractory MS [1]. The target of this treatment is the eradication of self-reactive abnormal immune system by intense immunosuppression, followed by the infusion of autologous hematopoietic stem cells aimed at restoring the hemato-lymphopoietic system. The premise of aHSCT is that it produces an ‘immune reset’, whereby the aberrantly overactive immune system is eliminated by intense immunosuppression, and a more tolerant immunity arises, devoid of or with better control of any disease-inducing cells. Early clinical trials of high-dose immunosuppressive therapy were conducted in patients with advanced disabilities and progressive forms of MS. Many patients continued to lose neurologic function, consistent with the contribution of noninflammatory factors to progressive neurodegeneration. Almost all the studies evaluating aHSCT in MS were observational cohort studies; only one comparative phase II randomized clinical trial assessing the effect of aHSCT versus Mitoxantrone in aggressive RR or SPMS patients has been published (ASTIMS trial) [2]. Despite the lesser number of subjects enrolled (n = 21) and some methodological limitations [2], the results were positive for aHSCT, which reduced by 79% the number of new T2 lesions appearing over 4 years as compared to mitoxantrone (p = 0.00016). Patients enrolled in the ASTIMS trial were mostly progressive patients (67%).
The more recent experience with aHSCT indicates that the therapy may be more successful if instituted in the earlier inflammatory stages of MS [3–5]. Three recent studies of aHSCT in patients with RRMS have been published: the 3-year interim analysis of the high-dose immunosuppression and AutoLogous Transplantation for Multiple Sclerosis trial [3]; a single-center patient cohort enrolled and treated at Northwestern University [4] (Burt, JAMA 2015) and a 4-year follow up of the Swedish multicenter experience [5]. The HALT-MS study included 25 patients treated with aHSCT who all had RRMS and breakthrough disease activity. The Northwestern cohort included 145 patients (81% RRMS). The Swedish study included 41 patients (85% RRMS). The proportion of patients with a complete control of the diseases...
FULL ARTICLE: http://www.tandfonline.com/doi/full/...5.2016.1158648
DOI:10.1586/14737175.2016.1158648Maria Pia Sormania* & Paolo Murarob
pages 469-470
Publishing models and article dates explained
Published online: 17 Mar 2016
Multiple sclerosis (MS) is an inflammatory, putatively autoimmune disease, estimated to affect more than 2 million people worldwide. It affects young adults, especially women. For the large majority of patients it is characterized in its early stages by inflammatory demyelination of the CNS, a phase of the disease that is called relapsing-remitting (RR). In addition, a neurodegenerative process causes irreversible loss of neurologic function, leading to the so-called primary or secondary progressive (PP or SP) MS phenotypes. Disease-modifying therapies (DMT) targeting inflammation have been shown to reduce the disease activity in patients with RRMS, by decreasing the accumulation of lesions detected by magnetic resonance imaging (MRI), the frequency of clinical relapses and, to a lesser extent, slow down the progression of disability as compared to placebo, or, more recently, to standard injectable therapies. However, there are currently no medications that can effectively treat the SPMS phase of the disease; also, some patients with RRMS have an aggressive course and do not respond to conventional DMT. It should be noted that we do not have predictive markers to identify patients who will develop aggressive MS early in the disease and that some patients may obtain long-lasting benefit from currently used drugs.
Against this scenario, immunoablative therapy followed by autologous hematopoietic stem cell transplantation (aHSCT) has been investigated for the past two decades to manage severe and treatment-refractory MS [1]. The target of this treatment is the eradication of self-reactive abnormal immune system by intense immunosuppression, followed by the infusion of autologous hematopoietic stem cells aimed at restoring the hemato-lymphopoietic system. The premise of aHSCT is that it produces an ‘immune reset’, whereby the aberrantly overactive immune system is eliminated by intense immunosuppression, and a more tolerant immunity arises, devoid of or with better control of any disease-inducing cells. Early clinical trials of high-dose immunosuppressive therapy were conducted in patients with advanced disabilities and progressive forms of MS. Many patients continued to lose neurologic function, consistent with the contribution of noninflammatory factors to progressive neurodegeneration. Almost all the studies evaluating aHSCT in MS were observational cohort studies; only one comparative phase II randomized clinical trial assessing the effect of aHSCT versus Mitoxantrone in aggressive RR or SPMS patients has been published (ASTIMS trial) [2]. Despite the lesser number of subjects enrolled (n = 21) and some methodological limitations [2], the results were positive for aHSCT, which reduced by 79% the number of new T2 lesions appearing over 4 years as compared to mitoxantrone (p = 0.00016). Patients enrolled in the ASTIMS trial were mostly progressive patients (67%).
The more recent experience with aHSCT indicates that the therapy may be more successful if instituted in the earlier inflammatory stages of MS [3–5]. Three recent studies of aHSCT in patients with RRMS have been published: the 3-year interim analysis of the high-dose immunosuppression and AutoLogous Transplantation for Multiple Sclerosis trial [3]; a single-center patient cohort enrolled and treated at Northwestern University [4] (Burt, JAMA 2015) and a 4-year follow up of the Swedish multicenter experience [5]. The HALT-MS study included 25 patients treated with aHSCT who all had RRMS and breakthrough disease activity. The Northwestern cohort included 145 patients (81% RRMS). The Swedish study included 41 patients (85% RRMS). The proportion of patients with a complete control of the diseases...
FULL ARTICLE: http://www.tandfonline.com/doi/full/...5.2016.1158648