Allogeneic Hematopoietic Stem Cell Transplantation For Severe Neuromyelitis Optica

Background Neuromyelitis Optica (NMO), also known as Devic’s disease, is a rare inflammatory and demyelinating disorder of the central nervous system characterized by recurrent attacks of optic neuritis (ON) and longitudinally extensive trasverse myelitis (LETM). Previously considered as a severe variant of multiple sclerosis, NMO has been recently recognized as a distinct disorder associated with peculiar pathogenic auto-antibodies to aquaporin-4 (AQP4). Despite transient control of disease activity, standard treatments are often followed by relapses with accumulating disability and ultimately a poor prognosis. Thus, new therapeutic strategies for NMO are warranted. Hematopoietic Stem Cell Transplantation (HSCT) can induce stable remissions in patients with severe treatment-refractory Autoimmune Diseases. Here we report our investigational experience on allogeneic HSCT in two patients with severe and refractory forms of the disease. Methods Both treated patients had aggressive forms of NMO and serum positivity for AQP4 antibodies. Upn#1 is a 30 yrs old male affected by severe relapsing LETM, with paraparesis and thoracic spinal cord lesion on magnetic resonance imaging (MRI). Upn#2 is a 28 yrs female with recurrent attacks of ON and LETM. Both had received several lines of treatment without benefit, including high-dose corticosteroids, cyclophosphamide, rituximab, natalizumab, alemtuzumab, plasma exchange, high-dose thiotepa/cyclophosphamide and/or BEAM with Anti-Thymocyte Globulin (ATG) and cyclosporine followed by autologous HSCT rescue. Before HSCT the two patients showed an Kurtzke Expanded Disability Status Score (EDSS) of 6 (assistance required to walk) and 8.5 (restricted to bed, paraplegia) respectively, while both of them presented active contrast enhancing lesions on MRI and positivity for the pathogenic AQP4 auto-antibodies. Upn#1 underwent allogeneic HSCT from his HLA-identical sibling, while Upn#2 from a matched unrelated donor. Conditioning regimen consisted of full-dose treosulfan and fludarabine. Graft versus host disease (GvHD) prophylaxis combined ATG-Fresenius with cyclosporine and a short course of methotrexate (Upn#1) or mycophenolate and rapamycin (Upn#2); B cell depletion of both patients and graft was obtained by rituximab. Results Hematopoietic recovery occurred in both patients within day 30, and was accompanied by rapid achievement of full donor chimerism. Each patient experienced an episode of febrile neutropenia and one of them a CMV reactivation, both responsive to medical therapy; no serious adverse events were reported. None of the patients experienced neither acute nor chronic GvHD. MRI demonstrated the disappearance of the inflammatory lesions, without evidence of new ones. The immunological data obtained from the follow-up of these two patients suggest that allogeneic HSCT can alter the course of NMO through several concurring mechanisms: the eradication of autoreactive cell clones by high-dose chemotherapy and by the in vivo T and B cell depletion used for conditioning, the disappearance of the pathogenetic anti-AQP4 antibodies and achievement of a stable full-donor hematopoietic chimerism by donor T cell-mediated alloreactivity; the re-establishment of thymic central tolerance and renewal of the immune repertoire. Strikingly, these results correlated with a marked improvement of neurological functions in both treated patients. In UPN#1 EDSS dropped from 6 to 3.5 (fully ambulatory but with moderate disability in one functional neurological system), while in UPN#2 EDSS decreased from 8.5 to 7.5 (unable to take more than a few steps, restricted to wheelchair). At last follow-up (48 and 36 months after HSCT, respectively), both patients are alive, well and relapse-free. Conclusions These findings suggest that allogeneic HSCT may be beneficial in patients who have aggressive forms of NMO, by renewing the immune repertoire of T- and B-cells, thus reducing disease activity and arresting disability progression. The preliminary evidence of long-term disease control in these two refractory patients paves the way for further prospective phase I-II clinical trials to validate allogeneic HSCT as promising novel option for aggressive forms of NMO. Disclosures: Bonini: MolMed S.p.A: Consultancy.