RRMS: Disease PROgression and Myeloid Profiling After Bone Marrow TRANSPLANTation and Second Line Therapies

Due to the limited availability of treatment in progressive multiple sclerosis (PMS), an in-depth analysis to better understand (1) the effect of disease-modifying therapies (DMTs) in preventing transition to secondary PMS (SPMS) and (2) the progression-related pathogenetic mechanisms, is essential. This could contribute to change the MS therapeutic perspective halting the progression independent of relapse activity putative processes, beside the prevention of relapse-associated worsening. Myeloablative autologous haematopoietic stem cell transplantation (aHSCT) in relapsing remitting multiple sclerosis (RRMS), differently from other widely used highly effective DMTs such as ocrelizumab and alemtuzumab, could modulate the myeloid activity inducing - after the depletion induced by conditioning regimen - a homeostatic expansion and enhanced immune regulation of monocytes/macrophages and dendritic cells. Currently used DMTs do not primarily target microglia/macrophage-mediated inflammation, and the effect on the abovementioned immune population could account for the advantage of aHSCT, compared to ocrelizumab and alemtuzumab, on progression free survival (PFS). Indeed, alemtuzumab and ocrelizumab achieve a long-term PFS lower than aHSCT. The results of such analyses could guide clinical decisions that will have a long-term impact, given the chronicity of the diseases, the duration of therapies, and the long-lasting effects of some treatments. Given this premise, by evaluating n.10 consecutively recruited patients with RRMS treated with myeloablative aHSCT in comparison with patients (n.10 per group) treated with anti-cluster of differentiation (CD) 52 monoclonal antibody (alemtuzumab) and anti-CD20 monoclonal antibody (ocrelizumab or ofatumumab), the aims of this longitudinal study are the following: Aim 1: To evaluate the impact of the studied treatments (myeloablative aHSCT, alemtuzumab and ocrelizumab/ofatumumab) on biomarkers of disease progression in MS. Since to clinically evaluate conversion to SPMS a long follow-up is required, the evaluation of progression's surrogate biomarkers (clinical, neuroradiological and biological) will allow a better and faster identification of the disease course. Aim 2: To characterize the myeloid compartments' longitudinal changes induced by each treatment (aHSCT, alemtuzumab and ocrelizumab/ofatumumab) in the enrolled patients. Aim 3: To explore a correlation between characteristics of the myeloid profile and surrogate endpoints of disease progression, assessing whether the treatment-induced homeostatic expansion and enhanced immune regulation of the myeloid compartment are related to surrogate endpoints of progression.