Factors associated with outcomes following autologous haematopoietic stem cell transplantation for multiple sclerosis

Abstract

Background: Autologous haematopoietic stem cell transplantation (AHSCT) has emerged as a highly effective treatment for relapsing-remitting multiple sclerosis (RRMS), though patient selection remains challenging. The degree to which disease-modifying therapies (DMTs) and procedure-related complications affect treatment outcomes is unclear. The objective of this study was to investigate the factors that might influence outcomes following AHSCT.

Methods: Data from the multicentre, retrospective cohort study Haematopoietic Stem Cell Transplantation for Treatment of Multiple Sclerosis in Sweden (AutoMS-Swe) were analysed, comprising 174 patients with RRMS who received AHSCT before 1 January 2020. Primary outcomes included inflammatory disease activity, confirmed disability worsening (CDW) and overall evidence of disease activity. Confirmed disability improvement was investigated as a secondary outcome. Associations between variables of interest and outcomes were assessed using univariable Cox proportional hazards models.

Results: Patients who received rituximab as the last DMT before AHSCT had a reduced hazard of inflammatory disease activity (HR 0.18, 95% CI 0.04 to 0.78). Epstein-Barr virus detection was associated with a higher hazard of inflammatory disease activity (HR 2.3, 95% CI 1.05 to 5.07). CDW was associated with longer disease durations (HR 1.09, 95% CI 1.00 to 1.19) and was negatively associated with gadolinium-enhancing lesions (HR 0.08, 95% CI 0.01 to 0.64). No CDW events occurred in treatment-naive patients.

Conclusions: Prior rituximab treatment appears to be protective against inflammatory activity after AHSCT. Disease duration and gadolinium-enhancing lesions are major determinants of disability following AHSCT.

Keywords: MULTIPLE SCLEROSIS; NEUROIMMUNOLOGY.

Figure 1. Evidence of inflammatory disease activity (EIDA). Single variable Cox proportional hazards models for the outcome of inflammatory disease activity. HRs for each variable and their 95% CIs are presented as a forest plot. For each variable, the total number of patients in the model and the total number of events observed, including those in any comparison groups, are shown under ‘N’ and ‘events’, respectively. P values for the likelihood ratio tests are also presented. The reference groups for categorical variables are denoted by ‘(ref.)’. ^aStatistically significant covariate (also indicated by bold typeface). CMV, cytomegalovirus; Cy-ATG, cyclophosphamide with antithymocyte globulin; DMT, disease-modifying therapy; EBV, Epstein-Barr virus; EDSS, Expanded Disability Status Scale; GCSF, granulocyte colony-stimulating factor.

Figure 2. Confirmed disability worsening (CDW). Single variable Cox proportional hazards models for the outcome of CDW. HRs for each variable and their 95% CIs are presented as a forest plot. For each variable, the total number of patients in the model and the total number of events observed, including those in any comparison groups, are shown under ‘N’ and ‘events’, respectively. P values for the likelihood ratio tests are also presented. The reference groups for categorical variables are denoted by ‘(ref.)’. ^aStatistically significant covariate (also indicated by bold typeface). ^bHR unable to be calculated as no observed events in the treatment-naive group. CMV, cytomegalovirus; Cy-ATG, cyclophosphamide with antithymocyte globulin; DMT, disease-modifying therapy; EBV, Epstein-Barr virus; EDSS, Expanded Disability Status Scale; GCSF, granulocyte colony-stimulating factor.

Figure 3. Evidence of disease activity (EDA). Single variable Cox proportional hazards models for the outcome of EDA. HRs for each variable and their 95% CIs are presented as a forest plot. For each variable, the total number of patients in the model and the total number of events observed, including those in any comparison groups, are shown under ‘N’ and ‘events’, respectively. P values for the likelihood ratio tests are also presented. The reference groups for categorical variables are denoted by ‘(ref.)’. CMV, cytomegalovirus; Cy-ATG, cyclophosphamide with antithymocyte globulin; DMT, disease-modifying therapy; EBV, Epstein-Barr virus; EDSS, Expanded Disability Status Scale; GCSF, granulocyte colony-stimulating factor.

Figure 4. Kaplan-Meier estimates of freedom from inflammatory disease, CDW and confirmed disability improvement, stratified by last disease-modifying therapy, detection of EBV and presence of gadolinium-enhancing lesions before AHSCT. (A) Kaplan-Meier survival estimate of percentage of patients with freedom from inflammatory disease following AHSCT stratified by the last DMT prior to AHSCT; rituximab compared with all other DMTs. (B) Kaplan-Meier survival estimate of percentage of patients with freedom from inflammatory disease following AHSCT stratified by the detection of EBV following AHSCT. (C) Kaplan-Meier survival estimate of percentage of patients with freedom from CDW following AHSCT stratified by the presence of gadolinium-enhancing lesions on T1-weighted MRI before AHSCT. (D) Kaplan-Meier survival estimate of percentage of patients with confirmed disability improvement following AHSCT stratified by the last DMT prior to AHSCT; treatment-naïve patients against non-rituximab DMTs. AHSCT, autologous haematopoietic stem cell transplantation; CDW, confirmed disability worsening; DMT, disease-modifying therapy; EBV, Epstein-Barr virus; Gd +ve, gadolinium-enhancing.

Figure 5. Confirmed disability improvement (CDI). Single variable Cox proportional hazards models for the outcome of CDI. Disability improvement was only assessed in patients with a baseline EDSS score ≥2.0. HRs for each variable and their 95% CIs are presented as a forest plot. The total number of included patients and events for each model, including those in the reference group, are shown in ‘N’ and ‘events’ respectively. P values for the likelihood ratio tests are also presented. The reference groups for categorical variables are denoted by ‘(ref.)’. ^aStatistically significant covariate (also indicated by bold typeface). CMV, cytomegalovirus; Cy-ATG, cyclophosphamide with antithymocyte globulin; DMT, disease-modifying therapy; EBV, Epstein-Barr virus; EDSS, Expanded Disability Status Scale; GCSF, granulocyte colony-stimulating factor.