Outcome of Non-Myeloablative Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis: A Single Center Summary of 511 Patients

Background: The MIST randomized trial of 100 patients (55 in each arm) of nonmyeloablative hematopoietic stem cell transplantation (HSCT) versus continued disease modifying therapy (DMT) for relapsing remitting multiple sclerosis (RRMS) demonstrated marked superiority for HSCT. However, no large trial of non‐myeloablative HSCT for RRMS has been published to date. Methods: Five hundred and eleven patients at Northwestern University between 7‐2003 and 10‐2019 underwent non‐myeloablative HSCT using a non‐selected graft and cyclophosphamide (Cy)/rabbit anti‐thymocyte globulin (ATG) (n = 376), Cy/ATG/rituximab (n = 63), Cy/ATG/intravenous immunoglobulin (IVIG) (n = 46), or Cy/alemtuzumab (n = 26). Either an intravenous cephalosporin cefepime (maxipimeâ) or piperacillin/tozobactam (zosyn®) was started on day 0 and continued until engraftment that usually occurred on day 9 or 10. Results: There was one treatment related death (0.19%, 1/511) due to legionella pneumonia acquired from the hospital room shower head. Only one of 511 patients developed bacteremia (Klebsiella pneumonia). Overall survival was 98.6%. Six patients had late non‐treatment related deaths, a cerebrovascular accident related to medication non‐compliance, a myocardial infarction, and during an elective cholecystectomy (unknown cause); colon cancer; and one died of respiratory failure from relapsed NMO (misdiagnosed as MS). The secondary autoimmune diseases (2ndADs) that occurred post HSCT were idiopathic thrombocytopenia (ITP) and hypo or hyperthyroidism. The incidence of ITP was highest with alemtuzumab (14%) and 0 to 2.8% for the non‐alemtuzumab regimens. Before HSCT, hypothyroidism was present in 10.4% (n = 53) and hyperthyroidism in 1.5% (n = 8) of patients. After HSCT, 16 patients developed hypothyroidism (3.5% 16/450 at risk) and 15 developed hyperthyroidism/Grave's disease (3.3%). Probability of relapse free survival at 6 months, and 1, 2, 3,4, and 5 years after HSCT was 99%, 96%, 94%, 92%, and 89.5%, respectively (figure 1A). Disability measured by the Expanded Disability Status Scale (EDSS) improved for the entire group (figure 1B) from a mean before HSCT of 4.0, to 3.04, 2.95, 2.96, 2.86, 2.78, and 2.54 at 6 months and 1, 2, 3, 4, and 5 years, respectively (all p < 0.00001). Patients treated with different non‐myeloablative conditioning regimens had similar post improvements in baseline EDSS (figure 1 B). Conclusions: Autologous non‐myeloablative HSCT provides drug free reversal of neurologic disability of greater than 1.0 EDSS points for greater than 5 years in 89% of patients with RRMS. The low incidence of bacteremia may be related to the use of non‐myeloablative regimens that do not cause mucositis, i.e. gut endothelium bacterial barrier remains closed, placement and removal of the large bore apheresis catheter on the same day and subsequent insertion of a PICC line in the upper inner arm on day of admission resulting in less risk of cutaneous barrier breaches, a HEPAfiltered floor, and to the use of pre‐emptive antibiotics when neutropenic. On the other hand, one patient developed legionella pneumonia that was subsequently cultured from the showerhead. Control over the hospital water supply is therefore of major importance. Care of these patients requires thoughtful monitoring, documentation, and prophylaxis of infections and 2ndADs.