Intermediate-Intensity Autologous Hematopoietic Stem Cell Transplantation Reduces Serum Neurofilament Light Chains and Brain Atrophy in Aggressive Multiple Sclerosis

Abstract

Background: Autologous haematopoietic stem cell transplantation (AHSCT) is highly effective in reducing new inflammatory activity in aggressive multiple sclerosis (MS). A remarkable decrease of serum neurofilament light chains (sNfL) concentration, a marker of axonal damage, was reported in MS following high-intensity regimen AHSCT, but hints for potential neurotoxicity had emerged. sNfL and brain atrophy were therefore analysed in a cohort of patients with aggressive MS treated with intermediate-intensity AHSCT, exploring whether sNfL might be a reliable marker of disability progression independent from new inflammation (i.e. relapses and/or new/gadolinium-enhancing MRI focal lesions).

Methods: sNfL concentrations were measured using SIMOA methodology in peripheral blood from relapsing-remitting (RR-) or secondary-progressive (SP-) MS patients undergoing AHSCT (MS AHSCT), collected before transplant and at months 6 and 24 following the procedure. sNfL measured at a single timepoint in SP-MS patients not treated with AHSCT without recent inflammatory activity (SP-MS CTRL) and healthy subjects (HD) were used as controls. The rate of brain volume loss (AR-BVL) was also evaluated by MRI in MS AHSCT cases.

Results: Thirty-eight MS AHSCT (28 RR-MS; 10 SP-MS), 22 SP-MS CTRL and 19 HD were included. Baseline median sNfL concentrations were remarkably higher in the MS AHSCT than in the SP-MS CTRL and HD groups (p = 0.005 and <0.0001, respectively), and levels correlated with recent inflammatory activity. After a marginal (not significant) median increase observed at month 6, at month 24 following AHSCT sNfL concentrations decreased compared to baseline by median 42.8 pg/mL (range 2.4-217.3; p = 0.039), reducing by at least 50% in 13 cases, and did not differ from SP-MS CTRL (p = 0.110) but were still higher than in HD (p < 0.0001). Post-AHSCT AR-BVL normalised in 55% of RR-MS and in 30% of SP-MS. The effectiveness and safety of AHSCT were aligned with the literature.

Conclusion: sNfL concentrations correlated with recent inflammatory activity and were massively and persistently reduced by intermediate-intensity AHSCT. Association with response to treatment assessed by clinical or MRI outcomes was not observed, suggesting a good sensitivity of sNfL for recent inflammatory activity but low sensitivity in detecting ongoing axonal damage independent from new focal inflammation.

Keywords: PIRA; biomarker; brain atrophy; hematopoietic (stem) cell transplantation (HSCT); multiple sclerosis; neurofilament light (NfL); progression independent of relapse activity.

Figure 1

Intermediate-intensity autologous haematopoietic stem cell transplantation reduces serum neurofilament light chain concentrations in treated MS patients. Serum neurofilament light chain (sNfL) concentrations in patients affected by aggressive relapsing-remitting (RR-) or secondary-progressive (SP-) multiple sclerosis (MS) before (T 0) and at months 6 (T 6) and 24 (T 24) following autologous haematopoietic stem cell transplantation (AHSCT, n = 38), compared with inactive SP-MS patients (i.e. without signs of recent clinical or radiological disease activity, SP-MS CTRL, n = 22) and with healthy individuals (HD, n = 19). (A) Overall MS AHSCT cohort. In AHSCT patients, baseline values of sNfL (median 13.4 pg/mL, range 4.4–229) were higher than in both SP-MS CTRL and HD groups (median 10.25 pg/mL, range 5.2–22.6, and median 6.4 pg/mL, range 4.0–18.4, p = 0.005 and <0.0001, respectively). SNfL at month 6 after transplant did not change compared to baseline (p = 0.427), but at T24 a reduction compared to baseline was observed (p=0.039), reaching levels similar to SP-MS CTRL (p = 0.110) but being still higher than in HD (p < 0.0001). (B) RR-MS and SP-MS AHSCT subgroups. At baseline, sNfL concentration in RR-MS cases was higher than in SP-MS CTRL (p = 0.001) and HD groups (p < 0.0001), whereas SP-MS AHSCT cases showed sNfL levels different from HD only (p = 0.040). SNfL concentrations at month 24 were reduced compared to baseline in the RR-MS AHSCT group (n = 28; 11.7 pg/mL, range 4.6–51.9, and 15 pg/mL, range 4.9–229, respectively; p = 0.042), whereas they did not differ from baseline in the SP-MS AHSCT group (n = 10; 10 pg/mL, range 2.0–17.3, and 10.8 pg/mL, range 4.4–42.8, respectively; p = 0.721). sNfL at month 24 were higher in RR-MS AHSCT cases compared both to SP-MS CTRL (p = 0.049) and HD (p < 0.0001); in SP-MS AHSCT group, values were higher than HD (p = 0.024).

Figure 2

Variation in serum NfL following AHSCT. Individual values of pre- and post-AHSCT sNfL for RR-MS (left) and SP-MS AHSCT patients (right) are connected with solid colour lines. Mean values of each group are connected with a dotted line, showing high sensitivity of the mean to the outliers with a significant reduction in the RR-MS group at months 6 (20.23 pg/mL) and 24 of follow-up (14.33 pg/mL) compared to baseline (45.06 pg/mL), p values 0.012 and 0.010 for month 6 and 24, respectively.

Figure 3

EDSS change following AHSCT. In the RR-MS AHSCT subgroup, EDSS decreased compared to baseline at each timepoint (p <0.005), whereas in the SP-MS AHSCT subgroup, median EDSS increased compared to baseline at month 24 after AHSCT (p = 0.047).

Figure 4

Brain atrophy following AHSCT. (A) Mean (95% CI) percentage of brain volume change (PBVC) in the first two years following AHSCT in the RR-MS and SP-MS AHSCT cases, compared to the baseline scan. The greatest reduction in PBVC was observed during the first year following AHSCT, followed by a reduction in AR-BVL. (B) Annualised rate of brain volume loss (AR-BVL) in RR- and SP-MS AHSCT cases at year 1, 2 and up to last follow-up available beyond year 2. The proportion of patients with normalisation of AR-BVL tended to be higher in RR vs. SP-MS cases and increased over follow-up.