Autologous haematopoietic stem cell transplantation versus low-dose immunosuppression in secondary-progressive multiple sclerosis

Abstract

Background and purpose: Effectiveness of autologous haematopoietic stem cell transplantation (AHSCT) in relapsing-remitting multiple sclerosis (MS) is well known, but in secondary-progressive (SP)-MS it is still controversial. Therefore, AHSCT activity was evaluated in SP-MS using low-dose immunosuppression with cyclophosphamide (Cy) as a comparative treatment.

Methods: In this retrospective monocentric 1:2 matched study, SP-MS patients were treated with intermediate-intensity AHSCT (cases) or intravenous pulses of Cy (controls) at a single academic centre in Florence. Controls were selected according to baseline characteristics adopting cardinality matching after trimming on the estimated propensity score. Kaplan-Meier and Cox analyses were used to estimate survival free from relapses (R-FS), survival free from disability progression (P-FS), and no evidence of disease activity 2 (NEDA-2).

Results: A total of 93 SP-MS patients were included: 31 AHSCT, 62 Cy. Mean follow-up was 99 months in the AHSCT group and 91 months in the Cy group. R-FS was higher in AHSCT compared to Cy patients: at Year 5, 100% versus 52%, respectively (p < 0.0001). P-FS did not differ between the groups (at Year 5: 70% in AHSCT and 81% in Cy, p = 0.572), nor did NEDA-2 (p = 0.379). A sensitivity analysis including only the 31 "best-matched" controls confirmed these results. Three neoplasms (2 Cy, 1 AHSCT) and two fatalities (2 Cy) occurred.

Conclusions: This study provides Class III evidence, in SP-MS, on the superior effectiveness of AHSCT compared to Cy on relapse activity, without differences on disability accrual. Although the suppression of relapses was observed in the AHSCT group only, AHSCT did not show advantages over Cy on disability, suggesting that in SP-MS disability progression becomes based more on noninflammatory neurodegeneration than on inflammation.

Keywords: autologous hematopoietic stem cell transplantation; case-control study; disability progression; multiple sclerosis; progressive multiple sclerosis.

FIGURE 1

Patient inclusion diagram. Secondary–progressive multiple sclerosis (SP‐MS) patients treated with autologous haematopoietic stem cell transplantation (AHSCT; n = 31) were matched with control patients selected from a cohort of 108 SP‐MS patients treated with cyclophosphamide (Cy) using six covariates as confounders. After estimating propensity score (PS) for all patients, the sample of Cy patients was trimmed by removing 43 patients with values of the estimated PS lower than the smallest estimated PS for the AHSCT cases. The remaining 65 control patients were used as a donor pool, from which a subsample of 31 matched controls was selected with cardinality matching (“best” matched controls). These controls were then removed from the donor pool, and cardinality matching was reapplied to the residual donor pool to select another subsample of 31 matched controls, by slightly relaxing the constraints on the standardized mean differences (“second best” matched controls). All the 62 matched controls were included in the primary analysis; a sensitivity analysis was then performed including the 31 “best” matched controls only

FIGURE 2

(a) Relapse‐free survival (R‐FS) following autologous haematopoietic stem cell transplantation (AHSCT; red) and treatment with cyclophosphamide (Cy; blue) during the treatment epoch was higher in AHSCT compared to Cy patients: 100% versus 55% at Year 3, respectively, p < 0.0001. (b) R‐FS over the whole follow‐up period following treatment start was higher in the AHSCT group compared to the Cy group: 100% and 52% at Year 5, respectively (p < 0.0001). The number of patients in observation at each timepoint is reported below the corresponding chart. (c) Annualized relapse rate (ARR) over 2 years prior to treatment start (blue) and during the first 2 years of treatment (red) in the AHSCT (right panel) and Cy (left panel) groups. ARR dropped in both groups (p < 0.0001) following treatment start. Pretreatment ARR did not differ between the two groups (p = 0.574), but ARR on treatment was lower in the AHSCT group compared to the Cy group (p < 0.001), suggesting that only AHSCT was able to induce the complete suppression of new inflammatory activity [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 3

(a) Expanded Disability Status Scale worsening‐free survival (W‐FS) following autologous haematopoietic stem cell transplantation (AHSCT; red) and start of treatment with cyclophosphamide (Cy; blue) up to the last follow‐up available. W‐FS at Year 3 was 45% in the AHSCT and 64% in the Cy group; at Year 5, it was 45% and 48%, respectively (p = 0.717). (b) Disability progression‐free survival (P‐FS) over follow‐up did not differ between the AHSCT group and the Cy group, being at Year 5 following treatment commencement 70% and 81%, respectively (p = 0.572). The number of patients in observation at each timepoint is reported below the corresponding chart. (c, d) Cox estimated distribution of W‐FS (c) and P‐FS (d) in the AHSCT and Cy groups, adjusted for age at treatment, progressive phase duration, and number of previous disease‐modifying treatments received. No differences were observed between the two groups in both the analyses (p = 0.924 and p = 0.320, respectively). These data indicate no differences of effectiveness on disability worsening and on disability progression between the treatments. However, after applying the Cox model, a hint of higher effectiveness of AHSCT can be observed, suggesting insufficient power of this study for this outcome measure [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 4

(a) Distribution of Expanded Disability Status Scale (EDSS) at baseline, at Month 36 following treatment start, and at last follow‐up available in the autologous haematopoietic stem cell transplantation (AHSCT; right panel) and cyclophosphamide (Cy; left panel) groups. EDSS deterioration was observed at Month 36 compared to baseline in the AHSCT group (p = 0.017) and at last follow‐up compared to baseline in both groups (p < 0.001 and <0.0001 for the AHSCT and Cy groups, respectively). (b) Proportion of patients with a definite EDSS at baseline and last follow‐up in the two groups. No differences in distribution were observed; at last follow‐up, the proportion of the patients with EDSS ≥ 8 was 6% in the AHSCT group and 18% in the Cy group, p = 0.127. (c) No evidence of disease activity 2 (NEDA‐2) survival (i.e., survival free from both relapses and EDSS worsening) did not differ between groups, being at Year 5 following treatment start 45% in the AHSCT and 36% in the Cy group (p = 0.379). (d) Cox estimated distribution of NEDA‐2 survival in the AHSCT and Cy groups, adjusted for age at treatment, progressive phase duration, and number of previous disease‐modifying treatments received. No differences were observed between the groups, p = 0.311 [Colour figure can be viewed at wileyonlinelibrary.com]