SPECIAL REPORT

It is now generally accepted that patients with relapsing-remitting multiple sclerosis will require more than one disease-modifying therapy (DMT) during their clinical course. Although a proportion of patients appear to be clinically stable on a platform therapy (beta-interferons and glatiramer acetate), it has been difficult to demonstrate the long-term benefits of this approach. A recent analysis of patients who initiated a DMT in the period 1995-2002 and received treatment for 13 years found no difference in time to onset of secondary-progressive MS (SPMS) between treated patients and untreated natural history cohorts (Coret et al. Mult Scler J Exp Transl Clin 2018;4:2055217318783347).

Escalation to a higher-efficacy therapy has been shown to further reduce inflammatory disease activity and appears to be a better strategy than a lateral switch to another first-line agent. For example, a Canadian study reported that patients were 46% less likely to relapse in the year after switching to fingolimod from an injectable DMT compared to switching to another injectable (Freedman et al. Curr Med Res Opin 2019;35:767-776). The Danish MS Group found that switching to a higher-efficacy DMT rather than a medium-efficacy drug resulted in a 30% reduced risk of relapse over a three-year follow-up period (Chalmer et al. J Neurol 2019;266:306-315). The MSBase group has reported similar findings (He et al. JAMA Neurol 2015;72:405-413).

One retrospective study suggested that the proportion of patients who achieve no evidence of disease activity (NEDA) is similar with a lateral switch or escalation (D’Amico et al. J Neurol 2016;263:1802-1809). However, it should be noted that patients in the escalation cohort had more severe MS and a significantly higher burden of disease, so the comparison groups were not well-matched. More useful is a recent MSBase analysis, which found a 24% reduction in the risk of conversion to SPMS when patients on an injectable DMT were escalated to fingolimod, natalizumab or alemtuzumab; the five-year absolute risk of SPMS was 14% with an injectable versus 8% with a higher-efficacy therapy (Brown et al. JAMA 2019;321:175-187).

A number of analyses have looked at the relative benefits of switching to different higher-efficacy therapies. MSBase found that the annualized relapse rate was similar after switching either to fingolimod or natalizumab (0.4 vs. 0.2), although natalizumab-treated patients were more likely to experience disability improvement (Kalincik et al. Ann Neurol 2015;77:425-435). A more recent analysis found that all higher-efficacy therapies were superior to beta-interferon with respect to relapse risk; fingolimod and oral cladribine were similarly effective, but somewhat inferior to natalizumab (Kalincik et al. Mult Scler 2018;24:1617-1626). The risk of disability accumulation was lowest with natalizumab; the probability of disability improvement was highest with oral cladribine.

Second-line sequencing
There are few data to guide decision-making for patients with a suboptimal response to a second-line agent. The most commonly-studied scenario is switching from natalizumab to another agent, often due to concerns about the cumulative risk of progressive multifocal leukoencephalopathy (PML). The University of Colorado MS group found that the risk of increased disease activity in the year following a switch from natalizumab to fingolimod depended on the duration of the washout period (Vollmer et al. J Neurol Sci 2018;390:89-93). The proportion of patients with relapses, new T2 lesions or Gd+ lesions was 0%, 11.1% and 3.3%, respectively, when the washout period was < 1 month. Ongoing disease activity was substantially higher if the washout period was 1-2 months (relapses 12.5%, T2 16.3%, Gd+13.0%) or 3-6 months (relapses 37.5%, T2 33.3%, Gd+21.40%). A shorter washout period was considered safe, although it would be important to rule out subclinical PML before making the switch.

A switch from natalizumab to off-label rituximab was more effective than switching to fingolimod in a Swedish multicentre analysis (Alping et al. Ann Neurol 2016;79:950-958). In the 1.5 years after the switch, 1.8% of rituximab-treated patients relapsed compared to 17.6% of those on fingolimod. The OCTAVE study is currently investigating the switch from natalizumab to ocrelizumab. According to the interim analysis presented at the AAN annual meeting, ocrelizumab appeared to be an effective option, however, concerns were raised about severe adverse events, including one case of breast cancer (Smoot et al. AAN 2019; abstract P3.2.056).

A retrospective German study examined patients with ongoing disease activity while on natalizumab who were switched to fingolimod or alemtuzumab (Pfeuffer et al. J Neurol 2019;266:165-173). Alemtuzumab was the more effective drug in reducing relapses, although some clinicians might be hesitant to induce prolonged immunosuppression in JC virus-antibody-positive patients. That said, a separate European study has suggested an even more aggressive switch: from natalizumab to autologous hematopoietic stem-cell transplantation (aHSCT) (Mariottini et al. Eur J Neurol 2019;26:624-630). The study compared 11 patients who underwent aHSCT and 41 who received another DMT following natalizumab. Patients scheduled for aHSCT were bridged with cyclophosphamide or corticosteroids during the 6-month washout prior to surgery. At three years after natalizumab discontinuation, the proportion of patients with NEDA was 54.5% with aHSCT versus 11.5% on another DMT; all cases of disease reactivation with aHSCT occurred during the washout/bridging period. No PML cases were reported.

Few studies have looked at other second-line switches. There are two recent case reports of severe rebound after switching from fingolimod to ocrelizumab (Schmidt & Schulten. Ther Adv Neurol Disord 2019;12:1756286419846818). Disease activity increased after fingolimod withdrawal then further worsened after ocrelizumab was initiated. The authors speculated that ocrelizumab may have complicated recovery from rebound but this issue requires further study. A more effective option may be switching from fingolimod to alemtuzumab, which has been reported to significantly lower ARR and reduce the proportion of patients with Gd+ lesions (Gonzalez et al. AAN 2019; abstract P3.2.050). A recent comparison of fingolimod-treated patients switched either to rituximab or alemtuzumab found that outcomes (ARR, EDSS change, NEDA) were numerically superior with alemtuzumab, although differences were not statistically significant (Alcala et al. J Neurol 2019;266:726-734). However, some caution is required. A German study of alemtuzumab rescue therapy in 50 patients who failed prior fingolimod reported one death due to necrotizing leukoencephalopathy and hemolytic anemia (Huhn et al. J Neurol 2018;265:1521-1527).

An issue of potential concern with sequential DMT use is the cumulative effect on lymphocytes. Lymphocyte kinetics were recently examined following a switch from either fingolimod or natalizumab to oral cladribine, which depletes T and B lymphocytes as its mechanism of action (Hodgkinson et al. AAN 2019; abstract P4.2.034). Following fingolimod discontinuation, cladribine was initiated when the lymphocyte count was at or around the lower limit of normal. Over the six-month follow-up, the magnitude of reduction in lymphocyte counts was somewhat less, which was attributed to late lymphocyte egress from lymphoid organs; this phenomenon of late egress mitigating the effects of subsequent therapy has also been attributed to alemtuzumab (Willis et al. Neurol Neuroimmunol Neuroinflamm 2017;4:e320). In contrast, patients switching off natalizumab typically have elevated peripheral lymphocyte counts; in this scenario, the magnitude of reduction in lymphocyte counts was somewhat higher after cladribine was introduced. Despite these differing effects on lymphocyte counts, the authors noted that lymphocyte kinetics with cladribine were predictable and a similar nadir was seen following the transition to cladribine from a prior DMT. It should be noted that with cladribine use, the lymphocyte count must be within normal range at treatment initiation, and no more than Grade 0 lymphopenia at the start of the second-year course of therapy.