Multiple Sclerosis and Related Disorders (2013) 2, 92–95
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
COMMENTARY
Lessons from clinical trials of alemtuzumab in multiple sclerosis Abhijit Chaudhuria,n, Peter O. Behanb a
Essex Centre for Neurological Sciences, Consultant Neurologist, Queen’s Hospital, Rom Valley Way, Romford, Essex, RM7 0AG, United Kingdom b Division of Clinical Neurosciences, University of Glasgow, United Kingdom Received in revised form 21 August 2012
Alemtuzumab is a humanised monoclonal antibody that selectively targets CD52 leucocytes. Originally developed in the Cambridge Pathology laboratory (hence its earlier name Campath 1-H), subcutaneous injection of alemtuzumab is currently licensed as a second or third line therapy of chronic lymphocytic leukaemia, and has also been used as an induction agent in renal transplantation costing an average of US $2000 per treatment course. Alemtuzumab causes profound and long term depletion of lymphocytes and after a single subcutaneous dose, CD4+and CD8+T-cells, CD3-/ CD56+NK cells, CD3+/CD56+T-cells and CD19+/CD5- B-cells were all decreased to o25% of baseline at 9 months (Lundin et al., 2004). B-cell suppression generally recovers earlier than T-cells, usually within 3–4 months; and patients with rheumatoid arthritis remained lymphopenic 12 years after a single dose of alemtuzumab, indicating that its lymphocytotoxic effect results in permanent alteration in T-and B-lymphocyte subsets (Anderson et al., 2012). Alemtuzumab was first introduced to the therapeutics of multiple sclerosis (MS) by the Cambridge neurologists in the 1990s. After intravenous alemtuzumab, the disease activity was found to persist for several weeks before stabilisation of clinical symptoms in a small group of 27 MS patients (Coles et al., 1999). Infusion-associated reactions after alemtuzuab were caused by cytokine release syndrome, and necessitated use of high dose corticosteroids, antin
Corresponding author. E-mail address: [email protected] (A. Chaudhuri).
2211-0348/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2012.08.005
histamine and analgesics as pre-medications. Patients experienced transient exacerbation of disease symptoms after alemtuzumab and in about half all cases, disability and brain atrophy continued to progress regardless of treatment, that was presumptively attributed to pre-existing disease burden. This initial unblinded study was followed by a phase II single (rater)- blinded randomised clinical trial of treatment-naı¨ve relapsing remitting MS patients with low disability (EDSS score r3.0) and early symptomatic disease (duration r3 years). In this trial (CAMMS 223), frequent administration of alemtuzumab (up to 3 annual intravenous pulses of 3–5 day cycles) was more effective than thrice weekly subcutaneous injection of high dose (44 mg) interferon b-1a in reducing annualised relapse rates (CAMMS223, 2008). There was no difference in clinical outcome between the two dosages of alemtuzumab (12 mg and 24 mg/day) in this clinical trial to confirm the hypothesis that dose-dependent suppression of inflammatory activity early in the course of relapsing-remitting MS is alters the natural history of the disease. There is no published dose-response study of alemtuzumab in relapsing-remitting MS to suggest that doses lower than 12 mg/day would not be effective or safer. The phase II clinical trial (CAMS 223) however exposed some unusual side effects of alemtuzumab. Its use in the clinical trial was briefly suspended after immune thrombocytopenic purpura (ITP) developed in three study patients resulting in one fatality. In the same year when the Phase II study was published, the first report of two patients (one of them had MS) developing anti-glomerular basement
Lessons from clinical trials of alemtuzumab in multiple sclerosis membrane (GBM)-antibody mediated renal disease (Goodpasture’s syndrome) after alemtuzumab therapy was presented from Cambridge (Clatworthy et al., 2008). From a safety point of view, there was also a concern about the cumulative risk of autoimmune disease on alemtuzumab, and the obvious paradox that a treatment targeting presumed autoimmune disease mechanisms in MS increased the risk of other organ-specific and systemic autoimmune diseases. The investigators of the CAMMS 223 trial have recently published their 5-year follow up results (Coles et al., 2012). Of the 334 patients recruited in the original study, data were available in about 60% (183) patients at the end of 5 years (month 60) and 12% (40 patients) at 6 years (month 72); nearly half of interferon b-1a (20 out of 42) arm and three quarters (107 out of 141) of patients assigned to two treatment doses of alemtuzumab were not on any disease-specific treatment by the end of fifth year. The authors observed a statistically significant difference in the 5-year change of disability, measured as changes in EDSS scores, between treatment groups (0.30 point improvement with alemtuzumab,0.46 point worsening with interferon) and annualised relapse rates (0.11 with alemtuzumab, 0.35 with interferon). There were three deaths in alemtuzumab arm (ITP, non-EBV associated Burkitt’s lymphoma and cardiovascular disease); there were six malignancies (lymphoma, breast, cervical cancer, papillary carcinoma of thyroid and basal cell carcinoma). The only death in the interferon arm was because of an accident. There was 30% incidence of thyroid-associated autoimmunity in alemtuzumab arm with a progressive increase in incidence in later years; one patient developed anti-GBM antibody disease. Serious infections were seen in over twice as many patients on alemtuzumab (7% vs. 3% in interferon b-1a arm). In an open label study of 39 patients selected across three centres with aggressive relapsing MS and a mean follow up period just short of 2 years, alemtuzumab was considered to be effective, although transient worsening neurological symptoms was observed in three patients and nearly a third developed autoimmune thyroid or skin disease (Hirst et al., 2008). The mean improvement in EDSS score was less than the average change at or after the first year of treatment. There is no information from clinical trials yet that the potential benefits of alemtuzumab outweigh the safety risks in highly aggressive or actively relapsing remitting MS, and hence the possible use of alemtuzumab as a second or third line rescue treatment option remains unsubstantiated at present. The superiority of alemtuzumab over high dose high frequency interferon b-1a in reducing disability progression in relapsing-remitting MS was not entirely reproduced in one of the phase III trials (CARE-MS 1) the interim results of which were presented at the ECTRIMS congress in October 2011. Like CAMMS 223, CARE-MS 1 was similar in design to CAMMS 223 trial, a rater-blinded active comparator study against thrice weekly high dose interferon b-1a, but this phase III study only evaluated a single 12 mg/day dose of alemtuzumab (given in 2 short annual cycles of 5 day and 3 day); however the recruitment phase was extended to first 5 years of disease onset. There was no statistically significant difference in disability progression between the two treatment arms, but the relative reduction of annualised relapse rate on alemtuzumab (55%) was broadly similar to the rate observed in the extended follow up period of the
93
phase-II study (69%). There were three cases of ITP, two cases of thyroid cancer and twice as many cases of serious infection in patients receiving alemtuzumab. Patients with onset of disease symptoms within 10 years and on an existing first-line treatment (beta-interferon or glatiramer for six months or longer) were enroled in a second Phase III trial (CARE MS 2); results presented at the American Academy of Neurology meeting in April 2012 showed that 47% patients on high dose, thrice weekly interferon b-1a and 65% of patients on the annual cycle of 12 mg/day alemtuzumab were relapse-free after 2 years; the EDSS score change at the end of two years was 0.41 in favour of alemtuzumab (mean change of -0.17 on alemtuzumab and 0.24 on interferon b-1a from baseline scores). There was a higher incidence of infections in the alemtuzumab group; the most common infections included upper respiratory and urinary tract infections, cutaneous fungal infections and oral herpes. Serious infections occurred in 3.7 percent of the alemtuzumab group as compared to 1.5 percent of the interferon b-1a group. Within the two year period, one of every six alemtuzumab-treated patients developed autoimmune thyroid disorder compared to one of twenty patients on interferon b-1a; 0.9% of alemtuzumab-treated patients developed ITP. Based on these results, Genzyme (manufacturer of alemtuzumab) submitted licensing applications to FDA and EMA in June 2012. If approved as a treatment for relapsing-remitting MS, the cost of intravenous alemtuzumab is anticipated to be around US$60,000 per patient per year. How persuasive are the efficacy and safety data to justify alemtuzumab as a treatment in relapsing-remitting MS? Available evidence from the published phase II trial suggests a benefit of alemtuzumab in reducing relapse frequency, but only in early disease (o3 years) and in treatment-naı¨ve patients with low baseline levels of disability (EDSSr3.0). From the presented but unpublished phase III trials, alemtuzumab is seen as superior to interferon b-1a as a treatment option for relapsing-remitting MS, but given the projected cost of therapy (US $60,000 per annum), whether this fact alone can meet the QALY target of health economics in MS patients with relatively early disease and mild to moderate disability is difficult to predict. In our opinion, the projected benefit of alemtuzumab in prevention of disability progression is rather modest in terms of clinical outcome. Assuming that a patient started a first line treatment on an EDSS score of 3.0, based on the long term data of CAMMS 223 trial, an average alemtuzumab-treated patient would be better off to a score of 2.7 (clinical EDSS 3.0) compared to a patient on interferon b-1a who would be worse off to a score of 3.4 (clinical EDSS 3.5) after 5 years of treatment. The clinical benefit after 2 years based on mean EDSS score change in phase III trial also seems to be marginal (2.8 and 3.2 for alemtuzumab and interferon b-1a respectively, both approximate to a clinical score of 3.0). The key issue, clearly, is the long term safety of alemtuzumab and associated risks of local and systemic infections, organ-specific autoimmune disease and malignancy (thyroid papillary carcinoma and lymphoma), in a target population of predominantly young and women patients. Depletion of CD4+ -T cells after alemtuzumab may last for many years (Anderson et al., 2012) creating a state of chronic immune deficiency in patients on regular
94 treatment. This is evident from longer experience of alemtuzumab use in haematological disorders that suggests that the risks of serious viral, bacterial and fungal infections are real, may be life threatening and long-term antiviral and antibiotic prophylaxis are necessary (Thursky et al., 2005) similar to the current practice in immunosuppressed HIV patients. In organ transplant recipients, alemtuzumab use for the treatment of allograft rejection was associated with higher risk of opportunistic infections leading to recommendation for routine antimicrobial prophylaxis (Peleg et al., 2007). However, despite the use of herpesvirus and Pneumocystis prophylaxis, patients receiving alemtuzumab for lymphoproliferative disorders experienced a varied and diverse range of infections secondary to immunosuppression (Martin et al., 2006). A related concern is that opportunistic infections in alemtuzumab-treated patients could be unusual and difficult to diagnose (Desoubeaux et al., 2012). While it could possibly be argued that immune constitution of MS patients is sufficiently different from patients with lymphoproliferative disorders and organtransplant recipients so that serious infectious complications would not be a logical risk and antimicrobial prophylaxis would not be required for patients receiving long-term alemtuzumab therapy, systemic infections, however, are of common occurrence in MS patients even without immunotherapy and a cohort of patients eligible for alemtuzumab are likely to have been exposed to previous immunomodulatory treatment. Leaving aside the risks of rare and opportunistic infections, it is important to remember that bacterial as well as viral infections are known to induce relapses and contribute to disease progression in MS (Loebermann et al., 2012). The lessons from clinical trials of natalizumab, the first humanised monoclonal antibody therapy approved in MS, should not be forgotten (Chaudhuri, 2006): the first case of progressive multifocal leukoencephalopathy due to opportunistic John Cunningham virus infection developing as a fatal complication of natalizumab therapy occurred (and was initially overlooked) in a Crohn’s disease patient. Alemtuzumab is also associated with a significant and cumulative risk of systemic autoimmune disease due to immunosuppression. B-cell recovery after alemtuzumab therapy tends to precede T-cell recovery, and antibody-mediated autoimmune diseases in alemtuzumab-treated patients respond to therapies achieving B-cell depletion (Clatworthy et al., 2008). There is a high incidence of autoimmune thyroid disease in MS patients receiving alemtuzumab and thyroid autoimmunity is regarded as a non-specific marker of systemic autoimmune diseases. The cumulative risk for autoimmune disease on alemtuzumab was recently estimated to be 22.2% over a median follow up period of 34.3 months (range 6.7– 107.3 months), with the highest incidence occurring between 12 and 18 months after treatment initiation (Cossburn et al., 2011). The time course of developing organ specific autoimmune disease on alemtuzumab is however unpredictable and can occur even after treatment withdrawal. One patient developed Goodpasture’s syndrome 39 months after the second dose of alemtuzumab in the extension study (Coles et al., 2012). There is a close relationship between papillary thyroid cancer and thyroid inflammation due to autoimmune lymphocytic thyroiditis (Muzza et al., 2010) and the high risk of thyroid autoimmunity on alemtuzumab therapy is likely to
A. Chaudhuri, P.O. Behan increase the incidence of papillary thyroid carcinoma over a period of time as already observed in clinical trials. Cases of lymphoma were also reported among alemtuzumab-treated patients in the extension phase of CAMMS 223 trial, and as with any long-term immunosuppressive therapy, the risk of cancer will gradually rise over the life time of a patient with longer exposure to alemtuzumab. There has been a recent surge of interest in B-cell mediated disease mechanisms and immunotherapy in MS, and intuitively it begs the question if an overactive B-cell mediated immune response developing in later years after alemtuzumab treatment could undermine its early benefit in MS and increase the cumulative risks of infection and malignancy in patients from additional B-cell based therapies for secondary autoimmune diseases. Statutory requirement of long term patient monitoring will also substantially increase the indirect cost of alemtuzumab use in clinical practice. Phase II and III clinical trials of alemtuzumab were single(rater) blind and patient-reported outcome measures (e.g. relapse symptoms) and perceived efficacy (high expectations of clinical benefit from alemtuzumab) could introduce a potential source of bias in trial outcome data. The clinical impact of efficacy data in terms of disability limitation in unpublished phase III clinical trials are timed to 6–12 months, too short a period in our opinion to judge the benefit of a potentially lifelong therapy with profound effect on immunity. From the analysis presented here, we feel alemtuzumab will increase the life-time risk of infection, autoimmune diseases and possibly thyroid cancer substantially and would not be safe as an unrestricted first-line long term therapy in relapsing-remitting MS patients. A possible alternative would be to limit its use to a shorter period of time, probably 12–18 months, but whether treatment of relapsing-remitting MS divided between a shorter induction phase of 12–24 months with a monoclonal antibody and a long term maintenance period with an oral agent is practical, sufficiently costeffective and of measurable clinical benefit needs testing in a large controlled clinical trial carried over for a period of 4–5 years. It is unlikely that the pharmaceutical industry will have the appetite to resource such a study in the current economic environment. We however do have a fundamental concern about the leap of faith that is driving the development of alemtuzumab and similar biological therapies in MS. The presumption of autoimmunity in MS is still an unproven hypothesis (Behan et al., 2002). Autoimmune diseases are broadly defined as conditions where antibodies or sensitised lymphocytes react with specific targets in host tissue but this has never been shown to be true in MS. We consider MS to be primarily a neurodegenerative disorder and not an autoimmune disease (Chaudhuri et al., 2004) where inflammatory changes are essentially reactive or secondary and occur in response to tissue destruction; in this model primary progressive MS is the ‘‘prototype’’ neurodegenerative disease and the relapsing-remitting MS represent the female predominant younger phenotype determined by the combined metabolic influence of solar exposure in early life, age and gender effects. Conventional disease modifying therapies in MS target a secondary process, an epiphenomenon in MS pathology, without substantially influencing the natural history of the primary neurodegenerative disease. Indeed, long term data from beta interferon therapy over past two decades in multiple sclerosis (Shirani et al., 2012) attest
Lessons from clinical trials of alemtuzumab in multiple sclerosis to our view that reduction of relapse rates in MS does not translate into long term limitation of disability progression (Behan et al., 2002; Chaudhuri et al., 2004). Experience has shown that aggressive immunosuppression with cytotoxic drugs, total body irradiation or anti-lymphocytic globulin was never effective in MS (Chaudhuri et al., 2004). Historically, autoimmune diseases have been regarded as the product of a selective imbalance between immune response pathways; a view that is supported by the high prevalence of autoimmune diseases among patients with immune deficiencies (Fundenberg, 1971). Therapeutic use of alemtuzumab in MS is likely to induce this imbalance of immunity in a group of patients who may not, after all, have an antibody or cell mediated primary autoimmune disease of their central nervous system.
Conflict of interest statement We affirm that the work in original and that all authors meet the criteria for authorship, including acceptance of responsibility for the scientific content of the manuscript. We declare no potential conflicts of interest.
References Anderson AE, Lorenzi AR, Pratt A, et al. Immunity 12 years after alemtuzumab in RA: CD5+ B-cell depletion, thymus-dependent T-cell reconstitution and normal vaccine responses. Rheumatology 2012;51:1397–406. Behan PO, Chaudhuri A, Roep BO. Pathogenesis of multiple sclerosis revisited. Journal of the Royal College of Physicians of Edinburgh 2002;32:244–65. Coles A, Wing M, Molyneux P, et al. Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Annals of Neurology 1999;46:296–304. CAMMS223. Trial investigators. Alemtuzumab vs. interferon ß-1a in early multiple sclerosis. New England Journal of Medicine 2008; 359:1786–801. Clatworthy MR, Wallin EF, Jane DR. Anti-glomerular basement membrane disease after alemtuzumab. New England Journal of Medicine 2008;359:768–9. Coles AJ, Fox E, Vladic A, et al. Alemtuzumab more effective than interferon ß-1a at 5 year follow-up of CAMMS223 clinical trial. Neurology 2012;78:1069–78.
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Chaudhuri A. Lessons for clinical trials from natalizumab in multiple sclerosis. British Medical Journal 2006;332:416–9. Cossburn M, Pace AA, Jones J, et al. Autoimmune disease after alemtuzumab treatment for multiple sclerosis in a multicenter cohort. Neurology 2011;77:573–9. Chaudhuri A, Behan PO. Multiple sclerosis is not an autoimmune disease. Archives of Neurology 2004;61:1610–2. Desoubeaux G, Caumont C, Passot C, et al. Two cases of opportunistic parasite infections in patients receiving alemtuzumab. Journal of Clinical Pathology 2012;65:92–5. Fundenberg HH. Are autoimmune diseases immunologic deficiency states? In: Good RA, Fisher DW, editors. Immunobiology: Current Knowledge of Basic Concepts in Immunology and Their Clinical Applications. Stanford, Connecticut: Sinauer Association Inc; 1971. p. 175–83. [Chapter 18]. Hirst CL, Pace A, Pickersgill TP, et al. Campath 1-H treatment with aggressive relapsing remitting multiple sclerosis. Journal of Neurology 2008;255:231–8. Lundin J, Porwitt-MacDonald A, Rossman ED, et al. Cellular immune reconstitution after subcutaneous alemtuzumab (anti-CD52 monoclonal antibody, CAMPATH 1-H) treatment as first line therapy for patients with chronic B-cell lymphocytic leukaemia. Leukemia 2004;18:484–90. Loebermann A, Winkelmann A, Hartung HP, et al. Vaccination against infection in patients with multiple sclerosis. Nature Reviews Neurology 2012;8:143–51. Martin SI, Marty FM, Fiumara K, et al. Infectious complications associated with alemtuzumab use in lymphoproliferative disorders. Clinical Infectious Diseases 2006;43:16–24. Muzza M, Degl’Innocenti D, Colombo C, et al. The tight relationship between autoimmune thyroid cancer, autoimmunity and inflammation: clinical and molecular studies. Clinical Endocrinology 2010;72:702–8. Peleg AY, Husain S, Kwak EJ, et al. Opportunistic infections in 547 organ transplant receipients receiving alemtuzumab, a humanised monoclonal CD52 antibody. Clinical Infectious Diseases 2007;44:204–12. Shirani A, Zhao Y, Karim ME, et al. Association between use of interferon beta and progression of disability in patients with relapsing-remitting multiple sclerosis. Journal of the American Medical Association 2012;308:247–56. Thursky KA, Worth LJ, Seymour JF, Prince HM, Slavin MA. Spectrum of infection, risk and recommendations for prophylaxis and screening among patients with lymphoproliferative disorders treated with alemtuzumab. British Journal of Haematology 2005;132:3–12.
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
COMMENTARY
Lessons from clinical trials of alemtuzumab in multiple sclerosis Abhijit Chaudhuria,n, Peter O. Behanb a
Essex Centre for Neurological Sciences, Consultant Neurologist, Queen’s Hospital, Rom Valley Way, Romford, Essex, RM7 0AG, United Kingdom b Division of Clinical Neurosciences, University of Glasgow, United Kingdom Received in revised form 21 August 2012
Alemtuzumab is a humanised monoclonal antibody that selectively targets CD52 leucocytes. Originally developed in the Cambridge Pathology laboratory (hence its earlier name Campath 1-H), subcutaneous injection of alemtuzumab is currently licensed as a second or third line therapy of chronic lymphocytic leukaemia, and has also been used as an induction agent in renal transplantation costing an average of US $2000 per treatment course. Alemtuzumab causes profound and long term depletion of lymphocytes and after a single subcutaneous dose, CD4+and CD8+T-cells, CD3-/ CD56+NK cells, CD3+/CD56+T-cells and CD19+/CD5- B-cells were all decreased to o25% of baseline at 9 months (Lundin et al., 2004). B-cell suppression generally recovers earlier than T-cells, usually within 3–4 months; and patients with rheumatoid arthritis remained lymphopenic 12 years after a single dose of alemtuzumab, indicating that its lymphocytotoxic effect results in permanent alteration in T-and B-lymphocyte subsets (Anderson et al., 2012). Alemtuzumab was first introduced to the therapeutics of multiple sclerosis (MS) by the Cambridge neurologists in the 1990s. After intravenous alemtuzumab, the disease activity was found to persist for several weeks before stabilisation of clinical symptoms in a small group of 27 MS patients (Coles et al., 1999). Infusion-associated reactions after alemtuzuab were caused by cytokine release syndrome, and necessitated use of high dose corticosteroids, antin
Corresponding author. E-mail address: [email protected] (A. Chaudhuri).
2211-0348/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2012.08.005
histamine and analgesics as pre-medications. Patients experienced transient exacerbation of disease symptoms after alemtuzumab and in about half all cases, disability and brain atrophy continued to progress regardless of treatment, that was presumptively attributed to pre-existing disease burden. This initial unblinded study was followed by a phase II single (rater)- blinded randomised clinical trial of treatment-naı¨ve relapsing remitting MS patients with low disability (EDSS score r3.0) and early symptomatic disease (duration r3 years). In this trial (CAMMS 223), frequent administration of alemtuzumab (up to 3 annual intravenous pulses of 3–5 day cycles) was more effective than thrice weekly subcutaneous injection of high dose (44 mg) interferon b-1a in reducing annualised relapse rates (CAMMS223, 2008). There was no difference in clinical outcome between the two dosages of alemtuzumab (12 mg and 24 mg/day) in this clinical trial to confirm the hypothesis that dose-dependent suppression of inflammatory activity early in the course of relapsing-remitting MS is alters the natural history of the disease. There is no published dose-response study of alemtuzumab in relapsing-remitting MS to suggest that doses lower than 12 mg/day would not be effective or safer. The phase II clinical trial (CAMS 223) however exposed some unusual side effects of alemtuzumab. Its use in the clinical trial was briefly suspended after immune thrombocytopenic purpura (ITP) developed in three study patients resulting in one fatality. In the same year when the Phase II study was published, the first report of two patients (one of them had MS) developing anti-glomerular basement
Lessons from clinical trials of alemtuzumab in multiple sclerosis membrane (GBM)-antibody mediated renal disease (Goodpasture’s syndrome) after alemtuzumab therapy was presented from Cambridge (Clatworthy et al., 2008). From a safety point of view, there was also a concern about the cumulative risk of autoimmune disease on alemtuzumab, and the obvious paradox that a treatment targeting presumed autoimmune disease mechanisms in MS increased the risk of other organ-specific and systemic autoimmune diseases. The investigators of the CAMMS 223 trial have recently published their 5-year follow up results (Coles et al., 2012). Of the 334 patients recruited in the original study, data were available in about 60% (183) patients at the end of 5 years (month 60) and 12% (40 patients) at 6 years (month 72); nearly half of interferon b-1a (20 out of 42) arm and three quarters (107 out of 141) of patients assigned to two treatment doses of alemtuzumab were not on any disease-specific treatment by the end of fifth year. The authors observed a statistically significant difference in the 5-year change of disability, measured as changes in EDSS scores, between treatment groups (0.30 point improvement with alemtuzumab,0.46 point worsening with interferon) and annualised relapse rates (0.11 with alemtuzumab, 0.35 with interferon). There were three deaths in alemtuzumab arm (ITP, non-EBV associated Burkitt’s lymphoma and cardiovascular disease); there were six malignancies (lymphoma, breast, cervical cancer, papillary carcinoma of thyroid and basal cell carcinoma). The only death in the interferon arm was because of an accident. There was 30% incidence of thyroid-associated autoimmunity in alemtuzumab arm with a progressive increase in incidence in later years; one patient developed anti-GBM antibody disease. Serious infections were seen in over twice as many patients on alemtuzumab (7% vs. 3% in interferon b-1a arm). In an open label study of 39 patients selected across three centres with aggressive relapsing MS and a mean follow up period just short of 2 years, alemtuzumab was considered to be effective, although transient worsening neurological symptoms was observed in three patients and nearly a third developed autoimmune thyroid or skin disease (Hirst et al., 2008). The mean improvement in EDSS score was less than the average change at or after the first year of treatment. There is no information from clinical trials yet that the potential benefits of alemtuzumab outweigh the safety risks in highly aggressive or actively relapsing remitting MS, and hence the possible use of alemtuzumab as a second or third line rescue treatment option remains unsubstantiated at present. The superiority of alemtuzumab over high dose high frequency interferon b-1a in reducing disability progression in relapsing-remitting MS was not entirely reproduced in one of the phase III trials (CARE-MS 1) the interim results of which were presented at the ECTRIMS congress in October 2011. Like CAMMS 223, CARE-MS 1 was similar in design to CAMMS 223 trial, a rater-blinded active comparator study against thrice weekly high dose interferon b-1a, but this phase III study only evaluated a single 12 mg/day dose of alemtuzumab (given in 2 short annual cycles of 5 day and 3 day); however the recruitment phase was extended to first 5 years of disease onset. There was no statistically significant difference in disability progression between the two treatment arms, but the relative reduction of annualised relapse rate on alemtuzumab (55%) was broadly similar to the rate observed in the extended follow up period of the
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phase-II study (69%). There were three cases of ITP, two cases of thyroid cancer and twice as many cases of serious infection in patients receiving alemtuzumab. Patients with onset of disease symptoms within 10 years and on an existing first-line treatment (beta-interferon or glatiramer for six months or longer) were enroled in a second Phase III trial (CARE MS 2); results presented at the American Academy of Neurology meeting in April 2012 showed that 47% patients on high dose, thrice weekly interferon b-1a and 65% of patients on the annual cycle of 12 mg/day alemtuzumab were relapse-free after 2 years; the EDSS score change at the end of two years was 0.41 in favour of alemtuzumab (mean change of -0.17 on alemtuzumab and 0.24 on interferon b-1a from baseline scores). There was a higher incidence of infections in the alemtuzumab group; the most common infections included upper respiratory and urinary tract infections, cutaneous fungal infections and oral herpes. Serious infections occurred in 3.7 percent of the alemtuzumab group as compared to 1.5 percent of the interferon b-1a group. Within the two year period, one of every six alemtuzumab-treated patients developed autoimmune thyroid disorder compared to one of twenty patients on interferon b-1a; 0.9% of alemtuzumab-treated patients developed ITP. Based on these results, Genzyme (manufacturer of alemtuzumab) submitted licensing applications to FDA and EMA in June 2012. If approved as a treatment for relapsing-remitting MS, the cost of intravenous alemtuzumab is anticipated to be around US$60,000 per patient per year. How persuasive are the efficacy and safety data to justify alemtuzumab as a treatment in relapsing-remitting MS? Available evidence from the published phase II trial suggests a benefit of alemtuzumab in reducing relapse frequency, but only in early disease (o3 years) and in treatment-naı¨ve patients with low baseline levels of disability (EDSSr3.0). From the presented but unpublished phase III trials, alemtuzumab is seen as superior to interferon b-1a as a treatment option for relapsing-remitting MS, but given the projected cost of therapy (US $60,000 per annum), whether this fact alone can meet the QALY target of health economics in MS patients with relatively early disease and mild to moderate disability is difficult to predict. In our opinion, the projected benefit of alemtuzumab in prevention of disability progression is rather modest in terms of clinical outcome. Assuming that a patient started a first line treatment on an EDSS score of 3.0, based on the long term data of CAMMS 223 trial, an average alemtuzumab-treated patient would be better off to a score of 2.7 (clinical EDSS 3.0) compared to a patient on interferon b-1a who would be worse off to a score of 3.4 (clinical EDSS 3.5) after 5 years of treatment. The clinical benefit after 2 years based on mean EDSS score change in phase III trial also seems to be marginal (2.8 and 3.2 for alemtuzumab and interferon b-1a respectively, both approximate to a clinical score of 3.0). The key issue, clearly, is the long term safety of alemtuzumab and associated risks of local and systemic infections, organ-specific autoimmune disease and malignancy (thyroid papillary carcinoma and lymphoma), in a target population of predominantly young and women patients. Depletion of CD4+ -T cells after alemtuzumab may last for many years (Anderson et al., 2012) creating a state of chronic immune deficiency in patients on regular
94 treatment. This is evident from longer experience of alemtuzumab use in haematological disorders that suggests that the risks of serious viral, bacterial and fungal infections are real, may be life threatening and long-term antiviral and antibiotic prophylaxis are necessary (Thursky et al., 2005) similar to the current practice in immunosuppressed HIV patients. In organ transplant recipients, alemtuzumab use for the treatment of allograft rejection was associated with higher risk of opportunistic infections leading to recommendation for routine antimicrobial prophylaxis (Peleg et al., 2007). However, despite the use of herpesvirus and Pneumocystis prophylaxis, patients receiving alemtuzumab for lymphoproliferative disorders experienced a varied and diverse range of infections secondary to immunosuppression (Martin et al., 2006). A related concern is that opportunistic infections in alemtuzumab-treated patients could be unusual and difficult to diagnose (Desoubeaux et al., 2012). While it could possibly be argued that immune constitution of MS patients is sufficiently different from patients with lymphoproliferative disorders and organtransplant recipients so that serious infectious complications would not be a logical risk and antimicrobial prophylaxis would not be required for patients receiving long-term alemtuzumab therapy, systemic infections, however, are of common occurrence in MS patients even without immunotherapy and a cohort of patients eligible for alemtuzumab are likely to have been exposed to previous immunomodulatory treatment. Leaving aside the risks of rare and opportunistic infections, it is important to remember that bacterial as well as viral infections are known to induce relapses and contribute to disease progression in MS (Loebermann et al., 2012). The lessons from clinical trials of natalizumab, the first humanised monoclonal antibody therapy approved in MS, should not be forgotten (Chaudhuri, 2006): the first case of progressive multifocal leukoencephalopathy due to opportunistic John Cunningham virus infection developing as a fatal complication of natalizumab therapy occurred (and was initially overlooked) in a Crohn’s disease patient. Alemtuzumab is also associated with a significant and cumulative risk of systemic autoimmune disease due to immunosuppression. B-cell recovery after alemtuzumab therapy tends to precede T-cell recovery, and antibody-mediated autoimmune diseases in alemtuzumab-treated patients respond to therapies achieving B-cell depletion (Clatworthy et al., 2008). There is a high incidence of autoimmune thyroid disease in MS patients receiving alemtuzumab and thyroid autoimmunity is regarded as a non-specific marker of systemic autoimmune diseases. The cumulative risk for autoimmune disease on alemtuzumab was recently estimated to be 22.2% over a median follow up period of 34.3 months (range 6.7– 107.3 months), with the highest incidence occurring between 12 and 18 months after treatment initiation (Cossburn et al., 2011). The time course of developing organ specific autoimmune disease on alemtuzumab is however unpredictable and can occur even after treatment withdrawal. One patient developed Goodpasture’s syndrome 39 months after the second dose of alemtuzumab in the extension study (Coles et al., 2012). There is a close relationship between papillary thyroid cancer and thyroid inflammation due to autoimmune lymphocytic thyroiditis (Muzza et al., 2010) and the high risk of thyroid autoimmunity on alemtuzumab therapy is likely to
A. Chaudhuri, P.O. Behan increase the incidence of papillary thyroid carcinoma over a period of time as already observed in clinical trials. Cases of lymphoma were also reported among alemtuzumab-treated patients in the extension phase of CAMMS 223 trial, and as with any long-term immunosuppressive therapy, the risk of cancer will gradually rise over the life time of a patient with longer exposure to alemtuzumab. There has been a recent surge of interest in B-cell mediated disease mechanisms and immunotherapy in MS, and intuitively it begs the question if an overactive B-cell mediated immune response developing in later years after alemtuzumab treatment could undermine its early benefit in MS and increase the cumulative risks of infection and malignancy in patients from additional B-cell based therapies for secondary autoimmune diseases. Statutory requirement of long term patient monitoring will also substantially increase the indirect cost of alemtuzumab use in clinical practice. Phase II and III clinical trials of alemtuzumab were single(rater) blind and patient-reported outcome measures (e.g. relapse symptoms) and perceived efficacy (high expectations of clinical benefit from alemtuzumab) could introduce a potential source of bias in trial outcome data. The clinical impact of efficacy data in terms of disability limitation in unpublished phase III clinical trials are timed to 6–12 months, too short a period in our opinion to judge the benefit of a potentially lifelong therapy with profound effect on immunity. From the analysis presented here, we feel alemtuzumab will increase the life-time risk of infection, autoimmune diseases and possibly thyroid cancer substantially and would not be safe as an unrestricted first-line long term therapy in relapsing-remitting MS patients. A possible alternative would be to limit its use to a shorter period of time, probably 12–18 months, but whether treatment of relapsing-remitting MS divided between a shorter induction phase of 12–24 months with a monoclonal antibody and a long term maintenance period with an oral agent is practical, sufficiently costeffective and of measurable clinical benefit needs testing in a large controlled clinical trial carried over for a period of 4–5 years. It is unlikely that the pharmaceutical industry will have the appetite to resource such a study in the current economic environment. We however do have a fundamental concern about the leap of faith that is driving the development of alemtuzumab and similar biological therapies in MS. The presumption of autoimmunity in MS is still an unproven hypothesis (Behan et al., 2002). Autoimmune diseases are broadly defined as conditions where antibodies or sensitised lymphocytes react with specific targets in host tissue but this has never been shown to be true in MS. We consider MS to be primarily a neurodegenerative disorder and not an autoimmune disease (Chaudhuri et al., 2004) where inflammatory changes are essentially reactive or secondary and occur in response to tissue destruction; in this model primary progressive MS is the ‘‘prototype’’ neurodegenerative disease and the relapsing-remitting MS represent the female predominant younger phenotype determined by the combined metabolic influence of solar exposure in early life, age and gender effects. Conventional disease modifying therapies in MS target a secondary process, an epiphenomenon in MS pathology, without substantially influencing the natural history of the primary neurodegenerative disease. Indeed, long term data from beta interferon therapy over past two decades in multiple sclerosis (Shirani et al., 2012) attest
Lessons from clinical trials of alemtuzumab in multiple sclerosis to our view that reduction of relapse rates in MS does not translate into long term limitation of disability progression (Behan et al., 2002; Chaudhuri et al., 2004). Experience has shown that aggressive immunosuppression with cytotoxic drugs, total body irradiation or anti-lymphocytic globulin was never effective in MS (Chaudhuri et al., 2004). Historically, autoimmune diseases have been regarded as the product of a selective imbalance between immune response pathways; a view that is supported by the high prevalence of autoimmune diseases among patients with immune deficiencies (Fundenberg, 1971). Therapeutic use of alemtuzumab in MS is likely to induce this imbalance of immunity in a group of patients who may not, after all, have an antibody or cell mediated primary autoimmune disease of their central nervous system.
Conflict of interest statement We affirm that the work in original and that all authors meet the criteria for authorship, including acceptance of responsibility for the scientific content of the manuscript. We declare no potential conflicts of interest.
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