Early Morbidity of Autologous Haematopoietic Stem Cell Transplantation in Multiple Sclerosis- A Real World Experience

Background: Autologous Haematopoietic Stem Cell Transplantation (aHSCT) is increasingly being used in treatment of patients with active inflammatory form of Multiple sclerosis (MS). The efficacy from this therapy is superior to some highly active disease modifying therapies (MIST study) and although transplant related mortality risk is low, potential toxicity from such treatments remain a significant barrier. We present data of a single centre experience focussing on early morbidity and complications. Methods: We retrospectively analysed MS patients who underwent HSCT (n-84) in our centre at Kings College Hospital NHS Foundation Trust, London between 2012- 2019 for relapsing remitting, RRMS(n-38); primary progressive, PPMS(n-22) and secondary progressive SPMS(n- 24) disease. Patients had Cyclophosphamide (4gm/m2 or 2gm/m2 post 2018)-GCSF primed stem cell harvest followed by Cyclophosphamide (200 mg/Kg)-rabbit ATG (7.5mg/kg) conditioning and stem cell return. We collected detailed data on complications experienced by patients during mobilisation and after aHSCT analysed in pseudo-anonymous format using standard descriptive statistics. Results: Baseline patient characteristics were compared between RRMS, SPMS and PPMS, with some differences noted in median age, previous treatments, median EDSS (Expanded disability symptom scale), median time from diagnosis to aHSCT between the groups. Median time to neutrophil engraftment was similar across all groups. Median length of hospitalisation was 26 days (range 6- 103), with 5 patients staying longer than 28 days and one death pre-HSCT infusion from suspected ATG related cardiac event. One patient died due to conditioning related acute respiratory distress. Overall transplant related mortality was 2.4%. A large proportion of patients (95%) developed febrile episodes following conditioning, 45% had ATG related fevers & rashes. A significant number of patients developed Gram negative sepsis (35%) post aHSCT, although a similar proportion had no source identified despite extensive investigations. More concerningly, 80% of patients experienced significant fluid overload during aHSCT (defined by >5% weight gain or pulmonary oedema/hypoxia requiring diuretics), with 41% of them developing symptomatic mild-severe pulmonary oedema and 9% patients required intensive care unit admission. Interestingly, 31% patients also suffered from transient worsening of neurology symptoms (pseudo-MS), mostly related to infection episodes and EBV viraemia. 13% patients developed hematuria, almost all happened related to 4gm/m2 cyclophosphamide dose as priming and none after dose reduction to 2gm/m2. Patients were subsequently analysed for morbidity events based on the EDSS group (≤5.0 vs >5.0) (Fig. 1b). Patients with higher EDSS (>5.0) had significantly prolonged hospitalization post cell return (median 21d vs 15d, p-0.03). Although there was no significant difference in morbidity events, but all cardiac events and deaths were unfortunately noted in higher EDSS group. Overall efficacy of treatment was 80% in terms of relapse free survival at 3 years. Conclusions: Our experience describes in detail some of the key early morbidity issues faced by MS patients undergoing aHSCT, namely cardio-pulmonary events, gram negative septicaemia, fluid overload with a potential impact on underlying MS symptoms, which highlights the challenges in appropriate patient selection, close monitoring and specialist input required to safely manage these transplants.