Immune Reconstitution Therapy or Continuous Immunosuppression for the Management of Active Relapsing–Remitting Multiple Sclerosis Patients? A Narrative Review

The key characteristic of an IRT is a long-lasting period of efficacy (however measured, see below) that follows an initial short course of treatment, without continued exposure to the drug. Autologous hematopoietic stem cell transplantation (aHSCT) provides a useful working definition of an IRT [16].

Briefly, in aHSCT HCSs are mobilized from the bone marrow and harvested, following which the patient’s pathological immune system is ablated entirely using strong immunosuppressive drugs; subsequent reinfusion of the HSCs allows the immune system to rebuild, without further autoimmunity if the treatment is successful [16, 17]. Clinical studies suggest that aHSCT is an effective treatment, with progression-free survival in 70–91% of patients, MRI event-free survival in 85–100% and “no evidence of disease activity” (NEDA) in 68–70%, at 4–5 years post-treatment [16]. The toxicity of aHSCT includes a low but measureable risk of treatment-related mortality, the possibility of prolonged hospitalization, viral reactivation and secondary autoimmunity and a probable impact on fertility [16]. Therefore, aHSCT is unsuitable for wide use.

The effects of aHSCT on immune cell populations appear to be more profound than those with any pharmacologic DMD [18]. However, DMDs with the characteristics of an IRT may present a more practicable alternative for most patients requiring high-efficacy therapy for MS [19‐21]. Key therapeutic properties of these DMDs are summarized below.

Alemtuzumab is administered over treatment periods consisting of five daily infusions followed by three daily infusions 1 year later [22]. One or two additional 3-day courses are supported if clinical MS events or MS events based on imaging criteria occur, with a minimum of 1 year between courses. Treatment with alemtuzumab rapidly and selectively removes about 95% of circulating lymphocytes [23]. The authors of a systematic review suggested that alemtuzumab reduces CD4+ and CD8+ T cells to a greater extent than does Cladribine Tablets, with a similar effect on B cells [18]. The molecular target of alemtuzumab, CD52 antigen, is also present on components of the innate immune system, including monocytes and dendritic cells, which are reduced in number following treatment with alemtuzumab [24‐26]. The levels of these cells may recover over a period of about 6 months. Severe neutropenia is rare during treatment with alemtuzumab, however, and the extent of depletion of neutrophils is mild in most patients [27]. The nadir of lymphocyte count occurs at 1 month post-treatment; B cells recover over a period of about 3 months (and markedly overshoot the pretreatment value), while repopulation of T cells takes at least 1 year [23, 24]. In one study, CD4 and CD8 counts were 30–40% of pretreatment values at 18 months after treatment [28].

The clinical benefits of alemtuzumab (reduced MS relapses and reduced disability) have been observed for up to a 5-year period of follow-up, without further DMD treatment [23, 28]. Accordingly, alemtuzumab acts like an IRT, with some effect on both the innate and adaptive immune systems (see Fig. 1). Indeed, an action on the innate immune system has been described as an important contributor to the efficacy of alemtuzumab [28]. Improved efficacy without additional safety concerns has been found with continuance of the second course of alemtuzumab when relapses occurred after the first course [29] and administration of additional courses of alemtuzumab when RMS disease activity continued after the second course [30].

Treatment with alemtuzumab is associated with an increased risk of bacterial infections (including listeriosis and tuberculosis [TB]), viral infections (herpes simplex and zoster and human papillomavirus) and fungal infections [31, 32]. The increased incidence of bacterial and fungal infections may be consistent with the drug’s suppression of innate and adaptive immunity [33]. A high incidence of secondary autoimmunity, especially in the thyroid (where Graves’ hyperthyroidism and Hashomoto thyroiditis account for about three-quarters of cases of thyroid dysfunction [34]) and platelets (which can cause immune thrombocytopenia), is believed to be associated with reconstitution of the lymphocytes [32, 35]. To date, there has been no clear signal for a general increase in the risk of malignancy with alemtuzumab, compared with other DMDs. The European labeling for the drug cites a risk of thyroid cancer associated with secondary autoimmunity [22], but it is unclear to what extent this was based on observation bias arising from increased monitoring of the thyroids of alemtuzumab-treated patients [36]. The US label for alemtuzumab identifies an elevated risk of lymphoproliferative disorders, lymphomas and malignant melanoma [37]. The long-term safety profile of alemtuzumab in a global safety database is consistent with the known tolerability and safety profiles of this agent [38]. At the time of writing, the use of alemtuzumab has been restricted due to safety concerns, including severe neutropaenia, immune-mediated reactions and adverse events in the cardiovascular system (such as pulmonary bleeding, stroke, myocardial infarction, cervicocephalic arterial dissection [39, 40]).

Cladribine Tablets 3.5 mg/kg is a relatively newly introduced management option for MS. Four sessions of treatment are required in total: two periods of 5 consecutive days of treatment are given 1 month apart at the initiation of treatment, which is repeated after 1 year [41]. The labeling also states that there is “no requirement” for further treatment for years 3 and 4.

A profound and almost complete reduction in B cells (CD19+) is observed within weeks of administration of Cladribine Tablets 3.5 mg/kg; recovery to the normal range is usually achieved at around 12 months post-treatment [42‐44]. A more gradual, but incomplete, reduction, in CD4+ and CD8+ T cells occurs; CD4+ cells recover to the normal range in about 18 months, while CD8+ cells do not fall below the normal range. Mild-to-moderate reductions in neutrophil counts have been observed in about 25% of patients according to the US Prescribing Information [45]. Importantly, other cell types, including monocytes, are little affected by Cladribine Tablets 3.5 mg/kg, indicating a relatively minor effect on the innate immune system.

Clinical trials have demonstrated the efficacy of Cladribine Tablets 3.5 mg/kg over 2 years of follow-up in patients with RMS, including reductions in relapse rates, magnetic resonance imaging (MRI)-based disease activity and progression of disability [46‐48]. Longer-term efficacy was observed in an extension to a clinical trial in RMS patients that involved a total of 4 years of follow-up [49, 50]. Importantly, in this extension study, relapse rates were similar for patients who continued to receive Cladribine Tablets 3.5 mg/kg and those who were re-randomized to placebo [49]. Overall, the short course of treatment and extended period of efficacy beyond the period of reduction in lymphocyte counts observed in many patients is consistent with an IRT-like mechanism (Fig. 1) [17]. Treatment with Cladribine Tablets 3.5 mg/kg also reduced the rate of conversion to clinically definite MS over 2 years in patients with a first demyelinating event [51].

Treatment with Cladribine Tablets 3.5 mg/kg may be associated with reactivation of herpes zoster or TB, in particular in patients with profound lymphopenia (grade 3 or 4), as described in its labeling [41]. There has also been a recent case report of lichenoid rash associated with Cladribine Tablets in a single patient, which resolved with appropriate management [52].

The prescribing information describes a numerical increase in the risk of malignancy. A meta-analysis of 11 clinical trials performed with various DMDs demonstrated an unexpected absence of malignancy in the placebo group of the principal Phase 3 study of Cladribine Tablets, and this was significantly lower than that in the placebo groups of the trials of other DMDs. Moreover, in this meta-analysis, the incidence of malignancy was not higher for Cladribine Tablets 3.5 mg/kg compared to the other DMDs [53]. Epidemiological analyses based on the GLOBOCAN reference database support those findings, since they showed that Cladribine Tablets-treated subjects did not show an excess of malignancies compared with the general population, with a standardized incidence ratio for any cancer of 0.97 (95% confidence interval [CI] 0.44–1.85) for Cladribine Tablets 3.5 mg/kg and 0.48 (95% CI 0.14–1.53) for placebo [54]. An integrated analysis of clinical evaluations of Cladribine Tablets 3.5 mg/kg that included all patients who received this treatment revealed an excess risk of 0.20 events/100 patient-years (95% CI − 0.0785 to 0.3947) versus placebo, which was not statistically significant [55].

The anti-CD20 mechanism of ocrelizumab has the potential to act like an immune reconstitution therapy, and ocrelizumab has been described in these terms [56]. However, this agent is given continuously, albeit with a long dosing interval of 6 months during maintenance treatment [57], consistent with the manner of its administration in its pivotal clinical trials in persons with MS [9]. Ocrelizumab is effective in RMS, achieving reductions of 46–47% in relapse rates and reduced rates of disability progression, compared with interferon-beta [9]. However, it is not known whether the efficacy of ocrelizumab outlasts the period of its administration in the manner of other treatments hypothesized to act like an IRT [19]. Reviews in this area have described ocrelizumab as an agent which “might be either called a chronic immunosuppressive or pulsed immune reconstitution therapy” [19] or have placed this agent in a class of its own between maintenance therapy and IRT [20].

With the increasing efficacy of treatments for RMS, attention is shifting from the use of relapse rates as a marker of efficacy towards the use of NEDA as a treatment outcome [59‐61]. NEDA is linked to both improved short-term patient outcomes and also to the prevention of long-term disability in MS. Ongoing research will define which of several versions of NEDA to use. NEDA-3 requires the observation of no new MRI-based events plus no disability progression, and NEDA-4 adds a measure of brain atrophy [60, 61]. “Minimal evidence of disease activity” (MEDA) has also been proposed as a treatment outcome in order to allow for a low level of MRI activity [61].

Substantial proportions of patients with RMS in analyses from recent trials have achieved NEDA for up to 2 years, including those in trials evaluating Cladribine Tablets 3.5 mg/kg (44 vs. 16% on placebo over 96 weeks in the CLARITY study [46, 62]), ocrelizumab (48 vs. 25–29% on interferon-beta-1a in the OPERA I and II trials [9, 63]) and alemtuzumab (39 vs. 27% and 32 vs. 14%, each compared with interferon-beta-a in the CARE MS I and CARE MS II trials, respectively [64, 65]). Other high-efficacy DMDs have also demonstrated high achievement of NEDA, such as natalizumab (37 vs. 7% on placebo in the AFFIRM study [66, 67]), fingolimod (33 vs. 13% on placebo in the FREEDOMS study [68, 69]), dimethyl fumarate (28 vs. 15% on placebo in the DEFINE study [70, 71]) and teriflunomide (23% in the TEMSO study [72, 73]). Accordingly, the use of NEDA as an outcome may influence the application of therapy in the IRT era. It has been suggested that while a relapse on maintenance/escalation therapy would lead to a switch to a higher-activity DMD, the re-emergence of disease activity in a patient receiving an IRT-like DMD may lead to further application of the same treatment before a switch [62].

The prospect of long-term remission of RMS with DMDs that resemble IRTs challenges the traditional escalation/maintenance treatment pathway of starting patients on a classical first-line agent and switching them to more active therapies only with relapse. A recent benefit:risk assessment of Cladribine tablets for patients with RMS, compared with other DMDs using a multi-criteria decision analysis model, confirmed the applicability of Cladribine Tablets for use in patients with RMS, especially for those with high disease activity [74]. The IRT approach provides an additional management option, especially for patients presenting with highly active disease: such patients now have the option of a trade-off between an increased risk of side-effects with a highly active therapy, such as an IRT, and the potential of greater long-term efficacy. The low treatment and monitoring burden of Cladribine Tablets 3.5 mg/kg may be an important factor in the choice of therapy for such patients.