3.3 Personal Experience with Alemtuzumab in Routine Clinical Practice
In the absence of specific patient profiles and validated biomarkers, personal clinical experience will inevitably influence alemtuzumab-related treatment decisions. Collectively, we have treated 181 patients with alemtuzumab, either as a first-line or as an escalation therapy in patients with breakthrough disease activity on a previous DMT (Table
4).
Table 4
Summary of author experiences with alemtuzumab
National approval/reimbursement period | September 2013–May 2015 |
Patients treated, N
| 181 |
Female, n (%) | 129 (71) |
Age, mean (range), years | 35 (17–66) |
Alemtuzumab as: | |
First-line therapy, n (%) | 27 (15) |
Escalation therapy, n (%) | 154 (85) |
Most of our patients initiated treatment with alemtuzumab owing to breakthrough disease (i.e., having only a partial response to, or not responding to, other therapies). In general, these patients had experienced one or more relapses within the previous 12 months and demonstrated recent inflammatory disease activity (as evidenced either by gadolinium enhancement (Gd+) or by an obvious increase in T2 lesion load) on a brain MRI. Thus, alemtuzumab use in this group of patients was consistent with a treatment escalation paradigm. There was a consensus that more favorable treatment outcomes are typically observed in these patients if alemtuzumab treatment can be initiated early on in the disease course, particularly in patients who are younger, have highly active disease, and have low levels of disability at the start of treatment. Nevertheless, in clinical practice, we have also found alemtuzumab is efficacious in patients with already accumulating disability, particularly when used as a rescue therapy to stabilize disease and prevent further disability worsening if inflammatory disease activity (either clinically or on MRI) is still overt. We, therefore, recommend the use of alemtuzumab in patients with active RRMS, regardless of their level of disability.
However, 15% of our patients represented a very important treatment group, namely those who were treatment naïve but who presented with early, highly active disease. Compared with patients receiving alemtuzumab as an escalation therapy, these patients were generally younger and had a shorter, but more active disease course, usually with two or more relapses in the preceding 3–6 months (cluster of relapses). We feel that alemtuzumab may represent an effective treatment option in treatment-naïve patients with rapidly evolving MS (or a clinical relapse accompanied by an increase in the number of T
2 lesions and/or ongoing evidence of Gd
+ T
1 lesions), and, as experience grows and the favorable outcomes associated with early intervention with alemtuzumab become evident, alemtuzumab use in this patient population will increase. In CARE-MS I, alemtuzumab significantly reduced the rate of brain volume loss in treatment-naïve patients with MS by 42% compared with SC IFNβ-1a [
34], and, given the correlation between brain volume loss and disability and cognitive worsening [
47,
48], early treatment with alemtuzumab may be more favorable than delaying treatment (discussed in Sect.
3.4). Indeed, we feel that initiating alemtuzumab in treatment-naïve patients may be advantageous, as lymphocyte levels have not been affected by use of prior DMTs.
In our experience, alemtuzumab has a place in routine clinical practice for the treatment of patients relapsing on prior treatments, as well as those who are treatment naïve. Postponing treatment in favor of escalating patients through alternative DMTs, in effect retaining alemtuzumab as a last resort, is not advised, and we feel that initiating alemtuzumab as soon as possible, particularly in patients with low levels of disability, will be associated with the most favorable outcomes.
3.4 Alemtuzumab Early in Multiple Sclerosis
The importance of treating MS early in the disease course to prevent inflammatory processes that lead to irreversible brain loss is well established [
49‐
52]. Traditionally, the treatment paradigm is one of escalation therapy, during which drugs with greater efficacy (often with distinct mechanisms of action) but with increasing risk are used as disease progresses, with the most efficacious drugs (e.g., natalizumab, often considered following failure of one or more DMTs [
53,
54]) used as the last line of therapy. However, data from alemtuzumab clinical studies [
9,
11‐
13], coupled with its indication in the EU [
2], afford physicians the opportunity to start alemtuzumab treatment in patients with active MS early in the disease course to prevent potentially avoidable CNS damage and provide the patient with the best opportunity for favorable treatment outcomes. This may be particularly important for patients with active MS with poor prognostic signs, for example, patients presenting with motor, cerebellar, or sphincter involvement at onset or those experiencing frequent relapses with poor recovery during the early years of their disease [
55,
56]. The benefits of early intervention with other DMTs have been widely reported; for example, in the pivotal 2-year SC IFNβ-1a study (PRISMS) and its 2-year extension (PRISMS-4), patients who started treatment early had improved clinical outcomes compared with patients whose treatment was delayed [
57,
58]. These observations have been confirmed in long-term follow-up studies [
59‐
61]. Early intervention is thought to address the inflammatory component of the disease, thereby reducing development of further CNS pathology [
53,
62]. Aggressive therapy early on in the disease course may provoke an immunological reset and may, therefore, favorably affect long-term disease progression [
53].
However, the concept of early treatment of active disease with an immunomodulatory drug such as alemtuzumab, believed to rebalance the immune system, is not yet fully established and would represent a significant change in mindset for some physicians. In some European specialist MS centers, patients with highly active or rapidly evolving severe RRMS are already considered for first-line treatment with fingolimod or natalizumab (both considered typically second-line therapies in the EU), and, as noted above, alemtuzumab was used as a first-line therapy in 15% of all alemtuzumab-treated patients in our experience (Table
4). These observations perhaps indicate that MS treatment may be moving into a new era, away from the escalation paradigm and toward more robust early treatment of active disease.
3.5 Switching to Alemtuzumab from Prior Disease-Modifying Therapies
The efficacy of alemtuzumab in patients with active disease who had relapsed on prior DMTs is of particular clinical relevance; in such cases, switching therapies should be considered urgently to bring MS activity under control. As discussed briefly above (Sect.
2.1, Table
2), the CARE-MS II study demonstrated superior efficacy with alemtuzumab vs. SC IFNβ-1a in patients with active disease who had relapsed on prior DMTs [
12]. The opportunity to switch therapies may be particularly important for certain patient subgroups. For example, patients receiving natalizumab therapy for over 2 years and/or who are positive for anti-John Cunningham virus (anti-JCV) antibodies, as well as those having previously received other immunosuppressive medications, are at increased risk of developing PML and may require an alternative DMT [
63]. Here, too, alemtuzumab may provide a treatment alternative option.
However, transitioning from one particular DMT to another can be complex, and a washout period may be required in certain circumstances. Treatment cessation guidelines and recommended washout periods are sometimes provided within the respective label of each DMT (Table
5), although there are currently no recommendations for transitioning to alemtuzumab from these individual DMTs. However, in the CARE-MS II extension, patients who switched from SC IFNβ-1a to alemtuzumab were not required to undergo a washout period. Therefore, it is often unclear for which treatment transitions a washout period is required, how long it should be, or what long-term safety surveillance procedures should be implemented [
53]. Nevertheless, as with other immunomodulatory therapies, concomitant treatment, including initiation of alemtuzumab within the washout period of the previous DMT, is not advisable, owing to the potential risk of carry-over PML from previous treatment and additive effects on the immune system [
2]. Consequently, it is important to consider the half-life as well as the mechanism of action (MoA) of the previous DMT when transitioning to alemtuzumab [
53].
Table 5
General guidance for therapy cessation for common DMTs
Interferons, glatiramer acetate | No specific guidance for cessation of therapya
No washout period recommended based upon the mechanism of action [ 64] |
Teriflunomide | An AEP is available if rapid removal of teriflunomide from the circulation is desired [ 65] AEP will reduce plasma concentrations to 0.02 mg/L in 11 days. Complete elimination requires 8 months to 2 years in the absence of AEP [ 65, 66] |
Dimethyl fumarate | No specific guidance for cessation of therapy or requirement for washout [ 67] |
Fingolimod | A 6-week treatment-free period is required to clear fingolimod from circulation [ 39] |
Natalizumab | A washout period might be appropriate as the pharmacodynamic effects of natalizumab last for approximately 12 weeks following the last dose [ 40] |
Daclizumab | Washout period of 4 weeks is recommended b [ 68] |
Rituximab/ocrelizumabc
| Washout period of 6 months is recommended b [ 68] |
Despite the absence of specific guidance for switching to alemtuzumab from the DMTs listed in Table
5, there are some considerations that may help guide switching in clinical practice. The proposed MoA of fingolimod (preventing lymphocyte egress from peripheral lymphoid organs) results in low levels of circulating lymphocytes [
69]. Therefore, it may be advisable to wait until lymphocyte counts begin to recover before initiating treatment with a DMT, such as alemtuzumab, particularly given that the proposed MoA of alemtuzumab in MS requires effective targeting of circulating T and B cells, leading to their depletion and subsequent repopulation [
4,
5,
64]. Indeed, a recent report demonstrated clinical and MRI disease activity in alemtuzumab-treated patients who had switched from fingolimod but for whom a potentially insufficient washout period following fingolimod cessation had been used, resulting in lymphocyte counts below normal levels at the time of alemtuzumab treatment. The authors hypothesized that the sequestration of lymphocytes in lymph nodes, owing to the mechanism of action of fingolimod, coupled with an inadequate washout period (median 6 weeks, range 4–10 weeks) may have reduced the effectiveness of alemtuzumab [
70].
By contrast, the proposed MoA of dimethyl fumarate (DMF) (activation of the nuclear factor erythroid 2-related factor 2) would generally not predict any issues with rapid transition to another therapy, although DMF has also been shown to have a lymphopenic effect in certain patient populations. Thus, as for fingolimod, a washout period might be advisable when transitioning to alemtuzumab [
64,
71]. Unfortunately, for both fingolimod and DMF, the time period over which lymphocytes return to normal is variable and can take many weeks, during which time the patient is at risk of relapse [
64].
Teriflunomide is also associated with a reduction (~15%, mean within normal limits) in lymphocytes and neutrophil counts within the first 3 months following treatment; mean lymphocyte and neutrophil counts then remain within the normal range for white blood cell counts (3.8–10.7 × 10
9/L) during treatment [
72]. Patients receiving teriflunomide have the opportunity to undergo an accelerated elimination procedure, which can reduce plasma levels by >96% in 11 days [
66,
73], potentially allowing the initiation of alemtuzumab relatively quickly after stopping teriflunomide.
By contrast, natalizumab does not reduce circulating lymphocyte counts, rather it blocks their entry to the CNS resulting in only mild lymphocytosis [
64,
74], and there may be limited benefit in delaying initiating treatment with another DMT following natalizumab discontinuation [
64]. In fact, it has been suggested that starting a new treatment immediately after stopping natalizumab (i.e., no a washout period) may be preferable because the risk of developing PML, even in anti-JCV antibody-positive patients, is lower than the risk of a severe relapse [
75,
76]. In CARE-MS II, patients previously treated with natalizumab (3%) underwent a 6-month washout period before starting alemtuzumab [
12]. In real-world clinical settings, and, in contrast with clinical studies, it is likely that a washout period of no more than 2 months following natalizumab discontinuation would be desirable owing to the risk of rebound disease [
64,
76,
77]. Indeed, there are suggestions that use of a washout period when switching from natalizumab may do more harm than good [
78].
In this regard, long-term real-world data would be of immense value in providing additional information on switching strategies between different DMTs. A recent real-world switching study demonstrated that in the 6 months post-natalizumab treatment, none of the 200 patients who switched to alemtuzumab experienced a relapse. In addition, 43% (69/162) of patients with EDSS measurements showed improvements in their EDSS scores and only 1% (2/162) had EDSS worsening. Of patients with MRI data, 2% (3/160) demonstrated new lesions on MRI. Generally, AEs were mild and easily managed with few serious AEs (one death occurred because of urinary tract infection and unrecognized non-convulsive status epilepticus) and no cases of PML were detected. The average washout period during this study was ~9 weeks [
79]. Similar results were also observed in a second study from the same center, which evaluated outcomes in 250 patients who switched to alemtuzumab from prior DMTs, the majority (66%) having previously received natalizumab [
80].
Despite beneficial outcomes in the absence of a prolonged washout period, it is important when switching from natalizumab to alemtuzumab (or indeed to any other DMT) to confirm JCV status and exclude any PML carry-over in JCV-positive patients by MRI and, in some cases, by cerebrospinal fluid examination for JCV DNA, before treatment commences. Although JCV status was established in the natalizumab switching studies discussed previously, it was not reported that PML was excluded prior to initiation of alemtuzumab [
79,
80]. This is important, as the effects of alemtuzumab cannot be reversed in the short term, and, should carry-over PML develop following alemtuzumab treatment, it is unlikely that full immune cell repopulation will have occurred and patients will be unable to clear the virus. A bridging strategy may be useful in this case, where an alternative DMT or intravenous corticosteroids (methylprednisolone 1000 mg) can be used to prevent rebound disease, affording the opportunity to fully exclude PML [
78,
81].
3.7 Levels of Disease Activity Required for Initiating Alemtuzumab
Despite arguments against providing guidance on specific patient profiles, some clarification regarding the degree of disease activity required before considering alemtuzumab would be helpful. In general, clinical activity, or a combination of both clinical and MRI activity, should be present before treatment initiation (Table
6). However, it is important to consider each patient on a case-by-case basis and correlate any MRI findings with clinical activity. Relying solely on MRI findings alone could prove misleading, for example, in patients with pseudotumoral forms of MS, where single large lesions (>2 cm) mimic other tumor-like lesions such as neoplasms, infections, or infarctions [
84,
85]. Guidance on how to effectively use MRI findings to assist treatment decisions should also be provided to physicians.
Table 6
Author recommendations for level of disease activity required for use of alemtuzumab
Clinical activity |
≥2 relapses in previous year |
Clinical and MRI activity |
1 relapse within the previous year with new MRI activity attributable to MS |
1 relapse within the previous year with incomplete recovery associated with an increase of ≥2 new T2 or Gd+ lesions |
Cognitive decline with MRI activity attributable to MS |
Patients with breakthrough diseasea (activity on clinical or MRI assessments) |
The alemtuzumab EU label defines active disease as the presence of clinical or imaging features but gives no guidance as to the level of disease activity required before considering initiating therapy or retreatment [
2]. In the three clinical studies [
9,
11,
12], slightly differing criteria were used to define active disease, and MRI activity was only used to define active disease in CAMMS223 (Table
1) [
9,
13]. Nevertheless, MRI activity was part of the retreatment criteria (see footnote to Table
1) applied in the CAMMS223 clinical trial (Sanofi Genzyme, data on file) and the CARE-MS extension studies [
15].
3.8 Patients Unsuitable for Alemtuzumab
Currently, patients with inactive disease or those stable on current therapy (as per the approved label) would not be considered for treatment, and, as alemtuzumab has not been thoroughly evaluated in progressive MS, it is also not indicated for use in these patients [
2]. Of course, there are always exceptions, and, while some patients may meet eligibility criteria as per the EU indication, certain safety considerations and challenges with frequent post-treatment monitoring may preclude them from being considered suitable for treatment. In such instances, a physician’s experience and knowledge of their patient will prove invaluable in deciding upon the best approach. Compliance with the monitoring requirements associated with alemtuzumab treatment is vital to ensure identification of AEs promptly; therefore, a physician’s previous experience will enable them to make an educated assessment with regard to their patients’ suitability and likelihood of their adherence to the strict monitoring requirements. As alemtuzumab treatment is associated with a potential increased risk of developing serious infections, patients with signs of infectious disease may be precluded from initiating treatment until the infection is fully under control or has resolved [
65]. Likewise, given that alemtuzumab may increase the chance of developing certain cancers (thyroid cancer, skin cancer [melanoma], lymphoproliferative disorders, and lymphoma) caution should be exercised before initiating treatment with alemtuzumab in patients with a pre-existing and/or an ongoing malignancy [
2,
86].