Autologous haematopoietic stem cell transplantation affects long-term progression independent of relapse activity in aggressive multiple sclerosis: a comparative matched study

Abstract

Background: Treatment of progression independent of relapse activity (PIRA) is a relevant unmet need in multiple sclerosis (MS), being only modestly affected by disease-modifying treatments (DMTs) which target predominantly adaptive immunity in the periphery. As chemotherapy administered during autologous haematopoietic stem cell transplantation (AHSCT) is bioavailable within the central nervous system (CNS), the hypothesis that AHSCT could affect long-term PIRA was explored in aggressive relapsing-remitting (RR)-MS.

Methods: Retrospective propensity-score matched study including RR-MS patients who received BEAM/ATG AHSCT or started natalizumab (NTZ, ie, controls) at our centre in Florence in the period 2007-2018.

Main outcome: cumulative proportion of patients with PIRA during NTZ treatment epoch (ie, censoring controls at NTZ discontinuation) and whole follow-up (NTZ-other[o]DMTs, that is, including switch from NTZ to alternative DMTs).

Results: Thirty RR-MS were included in each group; median follow-up duration was 106 (6-209) months. NTZ was discontinued by 29/30 patients, who subsequently started alternative DMTs. Cumulative proportion of patients with PIRA did not differ between the two groups during the NTZ treatment epoch (p=0.990), but it was lower in AHSCT-treated compared with NTZ-oDMTs treated patients over the whole follow-up, being 10% vs 21% at year 5, and 10% versus 49% at year 10, respectively (p=0.020). AHSCT was superior to NTZ on relapses and NEDA-3, and to NTZ-oDMTs on all the secondary outcomes analysed. Baseline age and Expanded Disability Status Scale independently predicted PIRA in the whole cohort.

Conclusion: Timely treatment with AHSCT or DMTs targeting inflammation in both the peripheral and CNS compartments might prevent long-term PIRA in aggressive RR-MS.

Keywords: IMMUNOTHERAPY; MULTIPLE SCLEROSIS.

Figure 1

Study design. Thirty patients who received autologous haematopoietic stem cell transplantation (AHSCT) and 30 control (CTRL) patients were selected adopting a 1:1 propensity score (PS) matching from two cohorts of 33 and 76 RR-MS patients including all the patients who had received AHSCT or started treatment with natalizumab (NTZ) at our centre in the index period, respectively. Study baseline was defined as mobilisation of haematopoietic stem cells and first NTZ administration for patients in the AHSCT and CTRL group, respectively. As AHSCT is a one-off treatment, no disease-modifying therapy (DMT) was routinely administered after transplant to patients in the AHSCT group, who therefore entered a period of clinical and MRI follow-up. Patients in the CTRL group received NTZ 300 mg intravenously every 4 to 6 weeks and discontinued NTZ treatment according to clinical practice, followed by treatment with other (o)DMTs up to last follow-up. Outcomes were analysed both during the NTZ treatment epoch (ie, censoring CTRLs at NTZ discontinuation and adopting pairwise censoring for disproportionate follow-up between groups) and the whole follow-up (ie, from baseline to the latest clinical assessment), including switch from NTZ to oDMTs.

Figure 2

Cumulative exposure (in months) to disease-modifying treatments (DMTs) before the study baseline in individual RR-MS patients from the AHSCT (n=30; A) and CTRL (n=30; B) groups. A higher number of DMTs was received by patients in the AHSCT group compared with those in the CTRL group (median 3 vs 2, respectively; p=0.001); one and two patients from the AHSCT and CTRL group, respectively, were treatment-naïve. Notably, 13/30 (43%) patients from the AHSCT group had previously received NTZ (red bars). AHSCT, autologous haematopoietic stem cell transplantation; CTRL, controls.

Figure 3

Disability outcomes in the AHSCT and CTRL groups over the NTZ treatment epoch (NTZ, ie, censoring CTRLs at NTZ discontinuation; A, C, E) and the whole follow-up including treatment with other (o)DMTs following NTZ withdrawal (NTZ-oDMTs; B, D, F). The cumulative proportion of cases with progression independent of relapse activity (PIRA; A, B), relapse-associated worsening (RAW; C, D) and EDSS worsening (E, F) did not differ between AHSCT and CTRL patients during the NTZ treatment epoch, but AHSCT was superior to NTZ-oDMTs in all the disability outcomes over the whole follow-up. The number of patients in observation at each timepoint is reported below each chart. AHSCT, autologous haematopoietic stem cell transplantation; CTRL, controls; DMTs, disease-modifying therapies; EDSS, Expanded Disability Status Scale; NTZ, natalizumab.

Figure 4

Cumulative proportion of cases with relapses (A, B) and no evidence of clinical and radiological disease activity (NEDA-3; C, D) in the AHSCT and CTRL groups during the treatment epoch (NTZ, ie, censoring CTRLs at NTZ discontinuation; A, C) and the whole follow-up including treatment with other (o)DMTs following NTZ withdrawal (NTZ-oDMTs; B, D). AHSCT was superior to both NTZ and NTZ-oDMTs in suppressing relapses and disease activity. The number of patients in observation at each timepoint is reported below each chart. AHSCT, autologous haematopoietic stem cell transplantation; CTRL, controls; DMTs, disease-modifying therapies; NTZ, natalizumab.