+Model ARTICLE IN PRESS Neurología. 2020;xxx:xxx—xxx NEUROLOGÍA www.elsevier.es/neurologia ORIGINAL ARTICLE Consensus statement on the use of alemtuzumab in daily clinical practice in Spain夽 J.E. Meca-Lallana a,∗ , M. Fernández-Prada b , E. García Vázquez c , S. Moreno Guillén d , S. Otero Romero e , M. Rus Hidalgo f , L.M. Villar Guimerans d , S. Eichau Madueño f , Ó. Fernández Fernández g , G. Izquierdo Ayuso h , J.C. Álvarez Cermeño d , C. Arnal García i , R. Arroyo González j , L. Brieva Ruiz k , C. Calles Hernández l , A. García Merino m , M. González Plata n , M.Á. Hernández Pérez o , E. Moral Torres p , J. Olascoaga Urtaza q , P. Oliva-Nacarino r , C. Oreja-Guevara s , R. Ortiz Castillo t , A. Oterino u , J.M. Prieto González v , L. Ramió-Torrentá w , A. Rodríguez-Antigüedad x , A. Saiz y , M. Tintoré e , X. Montalbán Gairin e a CSUR Esclerosis Múltiple, Servicio de Neurología, Hospital Clínico Universitario Virgen de la Arrixaca (IMIB-ARRIXACA), Cátedra de Neuroinmunología Clínica y Esclerosis Múltiple, UCAM, Universidad Católica San Antonio, Murcia, Spain b Servicio de Medicina Preventiva y Salud Pública, Hospital Vital Álvarez-Buylla, Mieres (Asturias), Spain c Servicio de MI-Infecciosas. Hospital Clínico Universitario Virgen de la Arrixaca, Departamento de Medicina, Facultad de Medicina, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain d Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Hospital Universitario Ramón y Cajal, Madrid, Spain e Centro de Esclerosis Múltiple de Cataluña (Cemcat), Servicio de Neurología/Neuroinmunología, Hospital Universitario Vall de Hebrón, Barcelona, Spain f Servicio de Neurología, Hospital Virgen Macarena, Sevilla, Spain g Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Málaga, Spain h Unidad de Investigación y Tratamiento de Esclerosis Múltiple, Hospital Vithas Nisa, Castilleja de la Cuesta (Sevilla), Spain i Servicio de Neurología, Hospital Universitario Virgen de las Nieves, Hospital General, Granada, Spain j Hospital Universitario Quirónsalud Madrid, Pozuelo de Alarcón (Madrid), Spain k Servicio de Neurología, Hospital Arnau de Vilanova, IRBLLEIDA, Lérida, Spain l Hospital Universitario Son Espases, Palma de Mallorca, Spain m Servicio de Neurología, Unidad de Neuroinmunología, Hospital Universitario Puerta de Hierro, Majadahonda (Madrid), Spain n Hospital Universitario de Canarias, La Cuesta (Santa Cruz de Tenerife), Spain o Servicio de Neurología, Hospital Universitario Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, Spain p Servicio de Neurología, Hospital Moisés Broggi y Hospital General de l’Hospitaletí, Sant Joan Despí (Barcelona), Spain q Unidad de EM Hospital Universitario Donostia-Instituto de Investigación BIODONOSTIA, San Sebastián (Guipúzcoa), Spain r Servicio de Neurología, Hospital Universitario Central de Asturias, Oviedo, Spain s Neurología, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, Spain t Unidad de Esclerosis Múltiple, Sanofi-Genzyme, Madrid, Spain u Servicio de Neurología, Hospital Universitario Marqués de Valdecilla, Santander, Spain 夽 Please cite this article as: Meca-Lallana JE, Fernández-Prada M, García Vázquez E, Moreno Guillén S, Otero Romero S, Rus Hidalgo R, et al. Consenso de expertos sobre el uso de alemtuzumab en la práctica clínica diaria en España. Neurología. 2020. https://doi.org/10.1016/j.nrl.2019.11.003 ∗ Corresponding author. E-mail address: pmecal@gmail.com (J.E. Meca-Lallana). 2173-5808/© 2019 Sociedad Española de Neurologı́a. Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). NRLENG-1374; No. of Pages 16 +Model ARTICLE IN PRESS 2 J.E. Meca-Lallana et al. v Servicio de Neurología, Hospital Clínico Universitario de Santiago, Santiago de Compostela (La Coruña), Spain w Unidad de Neuroinmunología y Esclerosis Múltiple Territorial de Gerona, Servicio de Neurología, Hospital Universitario Doctor Josep Trueta, Grupo Neurodegeneración y Neuroinflamación, IDIBGI, Facultad de Medicina, Universidad de Gerona, Gerona, Spain x Servicio de Neurología, Hospital Cruces, Baracaldo, Spain y Servicio de Neurología, Hospital Clínico, Universidad de Barcelona, Barcelona, Spain Received 27 September 2019; accepted 4 November 2019 KEYWORDS Alemtuzumab; Abstract Effectiveness; Introduction: Alemtuzumab is a highly effective drug approved by the European Medicines Multiple sclerosis; Agency as a disease-modifying drug for the treatment of relapsing-remitting multiple sclerosis. Daily clinical Objective: A consensus document was drafted on the management of alemtuzumab in routine practice; clinical practice in Spain. Safety; Development: A group of multiple sclerosis specialists reviewed articles addressing treatment Spain with alemtuzumab in patients with multiple sclerosis and published before December 2017. The included studies assessed the drug’s efficacy, effectiveness, and safety; screening for infections and vaccination; and administration and monitoring aspects. The initial proposed recommen- dations were developed by a coordinating group and based on the available evidence and their clinical experience. The consensus process was carried out in 2 stages, with the initial threshold percentage for group agreement established at 80%. The final document with all the recom- mendations agreed by the working group was submitted for external review and the comments received were considered by the coordinating group. Conclusion: The present document is intended to be used as a tool for optimising the mana- gement of alemtuzumab in routine clinical practice. © 2019 Sociedad Española de Neurologı́a. Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/). PALABRAS CLAVE Consenso de expertos sobre el uso de alemtuzumab en la práctica clínica diaria en Alemtuzumab; España Eficacia; Esclerosis múltiple; Resumen España; Introducción: Alemtuzumab es un fármaco de alta eficacia aprobado por la Agencia Europea Práctica clínica de Medicamentos como tratamiento modificador de la enfermedad en pacientes con esclerosis habitual; múltiple remitente recurrente. Seguridad Objetivo: Elaborar un documento de consenso sobre el manejo de alemtuzumab en la práctica clínica habitual, que sea de aplicación en el ámbito español. Desarrollo: Un grupo de expertos en esclerosis múltiple revisó las publicaciones disponibles hasta diciembre de 2017, de tratamiento con alemtuzumab y esclerosis múltiple. Se incluyeron trabajos sobre eficacia, efectividad y seguridad, despistaje de infecciones y vacunación, admin- istración y monitorización. La propuesta inicial de recomendaciones fue desarrollada por un grupo coordinador con base en la evidencia disponible y en su experiencia clínica. El proceso de consenso se llevó a cabo en 2 etapas; se estableció como porcentaje inicial de acuerdo grupal el 80%. El documento final con todas las recomendaciones acordadas por el grupo de trabajo se sometió a revisión externa y los comentarios recibidos fueron considerados por el grupo coordinador. Conclusiones: El documento aportado pretende ser una herramienta útil para facilitar el manejo del fármaco en condiciones de práctica clínica habitual. © 2019 Sociedad Española de Neurologı́a. Publicado por Elsevier España, S.L.U. Este es un artı́culo Open Access bajo la licencia CC BY-NC-ND (http://creativecommons.org/licenses/by- nc-nd/4.0/). +Model ARTICLE IN PRESS Consensus statement on the use of alemtuzumab in daily clinical practice in Spain 3 Introduction a change in the pathological inflammatory response towards a more tolerogenic phenotype. As a result, a high percentage The growing number of therapeutic options for multiple scle- of patients present prolonged disease remission. rosis (MS) and their increasing efficacy have led to a rise in the complexity of treatment management. Consequently, there is a need for consensus documents that standardise Clinical development of alemtuzumab the use of these treatments and enable adequate interpre- tation of their effectiveness, monitoring, and benefit/risk The efficacy and safety of alemtuzumab 12 mg have pre- balance. viously been evaluated in 3 clinical trials in which it was Alemtuzumab is a recombinant humanised monoclonal compared against subcutaneous interferon beta-1a (44 mg) antibody which was approved by the European Medicines in patients with active RRMS. The first 2 trials included treat- Agency (EMA) in September 2013 as a disease-modifying ment naïve patients (CAMMS223, phase II,12 3-year duration, treatment for relapsing-remitting multiple sclerosis (RRMS); and CARE-MS I, phase III,13 2-year duration), while the it was first marketed in March 2015.1 third was based on patients showing inadequate response The high efficacy of alemtuzumab in treating MS, its to previous treatment (CARE-MS II, phase III,14 2-year dura- innovative action mechanism, and the increasing level of tion). management required in its administration have given rise to the need for an in-depth analysis regarding its use. To date, several authors have published recommendations Effectiveness of alemtuzumab and guidelines on specific aspects of the management of alemtuzumab.2—5 Effectiveness in randomised trials The main aim of this consensus statement is to con- According to data from these studies, patients treated tribute to the knowledge of the practical management of with alemtuzumab 12 mg showed a significant reduction in alemtuzumab, addressing questions related to effective- relapses (69%,12 55%,13 and 49% of patients,14 respectively; ness, tolerability, and the management of possible adverse P < .001), as well as a significant reduction in confirmed dis- effects, as well as the selection of candidate patients. This ability progression (hazard ratios 0.25 [P < .001]12 and 0.58 consensus document includes recommendations based on [P = .008]),12,14 compared to patients receiving interferon evidence from observational studies, case series, and expert beta-1a (the CARE-MS I study showed a hazard ratio of 0.70 recommendations. [P = .22]).13 Table A.1 (Appendix A) shows the main clinical and magnetic resonance imaging (MRI) results of the two CARE-MS pivotal studies.13,14 Action mechanism Long-term effectiveness in extension studies Alemtuzumab is a humanised monoclonal antibody that In the CARE-MS extension studies (5 years of follow-up), the recognises CD52, a molecule that is abundantly expressed patient retention rates were 96%15 and 91%16 from the begin- in mature T and B lymphocytes but not in their precursors, ning of the extension phase, and 89%15 and 82%16 from the and that is expressed in very low amounts in innate response beginning of the pivotal studies.17 Given these high retention cells such as granulocytes.6,7 rates, data on the efficacy of alemtuzumab are very robust Alemtuzumab binds to CD52 molecules present in the when compared to long-term studies into other disease- membrane of circulating lymphocytes in the peripheral modifying treatments.18—20 blood and induces their lysis via complement action or The reduction observed in the annual relapse rate per- via antibody-mediated cytotoxicity. This induces marked sisted over time, shifting from 0.18 and 0.28 at the end of lymphocytopaenia; the drug’s effect is less pronounced in the pivotal studies (year 2, cumulative annual rate for years secondary lymphoid organs such as the lymph nodes and 0-2)13,14 to 0.16 and 0.21 in the extension studies (year 5, the spleen, and nearly absent in bone marrow.8 The preser- cumulative annual rate for years 3-5)15,16 (Fig. 1). vation of lymphoid progenitors in bone marrow enables At 5 years, 94%-95% of patients remained free of con- the reconstitution of blood lymphocyte populations. During firmed disability progression and 33%-43% showed confirmed this reconstitution, the new immune response is repro- disability improvement (CDI), over a period of 6 months.15,16 grammed, with an increase in the ratio of regulatory to The data demonstrate an increase in the proportion of effector cells, a marked increase in the production of patients with CDI from year 2 to year 5 (CDI in years 2, 3, 4 anti-inflammatory cytokines, and a decrease in proinflam- and 5: 24%, 28%, 30%, and 33% in CARE-MS I and 29%, 35%, matory cytokines.9,10 This induces prolonged stabilisation 41%, and 43% in CARE-MS II).15,16 or improvement of the disease in a high percentage of Data on MRI lesions (in gadolinium-enhanced T1-weighted patients, despite occasionally provoking new autoimmune and T2-weighted sequences) from the extension studies pathology. The preservation of the innate immune response, showed an absence of new lesions or worsening of existing and the fact that lymphocytes not eliminated by the ones in >75% of patients in all studies (Fig. 1).15,16 treatment remain fully functional,11 may account for the The annualised percentage of patients displaying ‘‘no low rate of severe infections after treatment with alem- evidence of disease activity’’ (NEDA) status (composed vari- tuzumab. able of: absence of clinical [relapses or disease progression] In summary, alemtuzumab causes depletion of circulating or radiological progression [absence of lesions with con- lymphocytes, with a subsequent repopulation that instigates trast uptake, new lesions, or lesions increasing in size on T2 +Model ARTICLE IN PRESS 4 J.E. Meca-Lallana et al. CARE MS I Treatment-naïve patients Key efficacy outcomes 100 90 80 94 94 93 89 88 85 87 70 85 Patients (%) 78 77 60 70 66 68 50 62 Year 2 40 Year 5 30 20 10 0 Free from No evidence of Free from clinical Free from new Free from new Free from Free from relapse confirmed disease activity activity gadolinium- T2 lesions radiological activity disability worsening (annual NEDA) enhancing lesions CARE MS II Patient with failed previous treatment Key efficacy outcomes 100 90 80 92 95 91 90 70 85 79 81 Patients (%) 73 76 76 60 68 69 50 Year 2 58 58 40 Year 5 30 20 10 0 Free from No evidence of Free from clinical Free from new Free from new Free from disease activity Free from relapse confirmed activity gadolinium- T2 lesions radiological activity (annual NEDA) disability worsening enhancing lesions Figure 1 Main efficacy results for alemtuzumab: pivotal and extension studies. sequences]) remained stable at approximately 60% through- Safety data for alemtuzumab out the extension studies.15,16 The results of the TOPAZ study (joint extension of Safety in randomised trials CARE-MS I and II after 7 years of follow-up), presented Alemtuzumab has a good safety profile, with an effective at the 7th Joint ECTRIMS-ACTRIMS Meeting, consolidates protocol for detecting and treating adverse events. the previous findings on efficacy in the absence of The CAMMS223, CARE-MS I and CARE-MS II studies mainly continued treatment, both in treatment naïve patients report reactions associated with perfusion (> 90%), infec- and non-responders to previous disease-modifying treat- tions (66%, 67%, and 77%, respectively), and secondary ments, showing a sustained reduction in MRI activity and autoimmune diseases, with thyroid disorders in 26%, 16%, loss of brain volume21,22 and an improvement in clinical and 18% of patients, immune thrombocytopaenia in 1.9%, variables.23,24 1%, and 1%, and nephropathies in 0.3% of patients (all 3 The majority of patients did not receive additional groups).12,14 courses of alemtuzumab after the second course (Fig. 2). In those who did require additional courses, the rea- sons, over a 7-year period, were (for CARE-MS I and II, Long-term safety in extension studies respectively) relapse in 50% and 57% of patients, radi- Alemtuzumab presents good long-term safety, with the ological activity in 28% and 19%, and both in 20% and annual incidence of adverse events decreasing after the first 21%.23,24 year of treatment. Clear long-term benefits are reported for treat- The exposure-adjusted incidence rate for all adverse ment with 2 courses of alemtuzumab in patients events was lower in the extension studies than in the pivotal presenting relapses between the first and second studies.15,16 courses.25,26 Most adverse events were of mild or moderate sever- New data suggest that a third course of alemtuzumab also ity; no study participant dropped out due to adverse has clear benefits for patients presenting disease activity events.15,16 Adverse events related to perfusion were minor after the first 2 courses.25,27 and none were serious. The main reactions associated +Model ARTICLE IN PRESS Consensus statement on the use of alemtuzumab in daily clinical practice in Spain 5 100 90 80 70 Patients (%) 60 50 61% CARE MS I 40 52% CARE MS II 30 20 15% 28% 10 24% 9% 6% 2% 0.6% 1.5% 0% 0.5% 0 0 1 2 3 4 5 Number of patients receiving additional courses of alemtuzumab in long-term studies (7 years) Figure 2 Percentage of patients receiving successive courses of alemtuzumab over 7 years of follow-up. with perfusion were headache, pyrexia, and rash.15,16 Subsequently, the working group received an email The incidence of infections also did not increase, and including a summary of the available evidence about the pro- most were mild or moderate (99.2% and 97.7%).15,16 The posed recommendations and the percentage of agreement most frequent reactions were nasopharyngitis, urinary tract during the first round (Appendix B). infection, upper respiratory tract infection, and herpes During the second stage, the members of the coordi- infections.15,16 nating group and the working group met at a face-to-face The most common autoimmune adverse events were thy- consensus meeting led by 2 moderators belonging to the roid disorders, with peak incidence occurring in the third coordinating group (XM and OF). At the meeting, the year (16.7% and 16.5%).15,16 results of the first round of voting were presented anony- The 7-year safety studies point to a reduction in adverse mously. Recommendations with less than 80% agreement events compared to pivotal studies. The incidence of thy- were redrafted, and a second round of voting was car- roid disorders and infections was 1.6% and 30.8% in year 7, ried out by show of hands. Those recommendations that vs. 6.4% and 56.1% in year 1.23 Similar results are reported could not be approved during the face-to-face meet- for patients not responding to previous disease-modifying ing due to time constraints were subsequently agreed treatments (CARE-MS II).24 upon via email. Finally, recommendations not approved Safety findings from the CAMMS223 extension study (10- during this stage were excluded from the consensus state- year follow-up) are consistent with those from the main ment. study.28 Recommendations Consensus process Selection of candidate patients for treatment with alemtuzumab A formal consensus methodology was followed in the prepa- ration of this consensus statement (modified nominal group According to the summary of product characteristics, alem- technique).29 The consensus process was performed in two tuzumab can be used in adult patients with RRMS presenting stages and a threshold of 80% agreement was established a clinical or radiological disease activity.30 In the CARE-MS II priori for accepting a recommendation. study, the most frequent disease-modifying treatments pre- During the first stage, participants were sent an email viously used were interferon beta and glatiramer acetate; containing a summary of the available evidence on the natalizumab only accounted for 3% of previous treatments different priorities for the statement (efficacy, safety and and fingolimod had not been approved at the time of the effectiveness, infection screening, vaccination, administra- trial.14 Therefore, the current evidence on the manage- tion, and monitoring) and a list of possible recommendations ment of patients receiving alemtuzumab after treatment proposed by the multidisciplinary panel, based on the evi- with fingolimod, natalizumab, and other immunosuppres- dence available and their clinical experience. Participants sants is mainly from published case series from clinical also received a general explanation of the methodology practice.31 and a form for classifying their level of agreement on a 9-point Likert-type scale: 1-3 (inappropriate strategy), 4- 6 (uncertain), and 7-9 (appropriate strategy) (Appendix B). Recommendation 1 During this phase, recommendations were submitted to a If we combine the recommendations of the summary of first round of individual voting in which all members of product characteristics and the baseline clinical profiles of the working group used this scale to rate their level of patients included in the CARE-MS I and II clinical trials, agreement. Participants were also able to add new recom- we may conclude that the characteristics of the candidate mendations or modify the proposed ones in the event of patient for alemtuzumab should be similar to the following: disagreement. clinical or radiological disease activity and/or suboptimal +Model ARTICLE IN PRESS 6 J.E. Meca-Lallana et al. response to a full course of disease-modifying treatment it is important to assess the drug’s mechanism of action to and/or rapid and aggressive disease progression. select the optimal moment for vaccination, with a view to ensuring the greatest protective effect. Recommendation 2 Although the use of alemtuzumab in patients with MS previ- Vaccination strategies with alemtuzumab ously receiving selective disease-modifying treatment with immunosuppressants has not been associated with safety Recommendation 4 problems in clinical case series published to date, additional It is advisable to evaluate the need for vaccination before safety measures should be adopted beyond those established starting treatment with alemtuzumab. To this end, it is in the summary of product characteristics in patients who essential that we (1) know the patient’s serological status have previously been treated with other immunosuppres- against measles, varicella, hepatitis A, and hepatitis B; and sants. (2) document the patient’s vaccination history, with special emphasis on seasonal influenza, pneumococcus, hepatitis A and B virus, tetanus/diphtheria, varicella, measles and Questions to be considered before treatment human papillomavirus. onset Recommendation 5 It is advisable to evaluate vaccination in patients starting Infections associated with the use of alemtuzumab alemtuzumab treatment, as specified in Table 1. The table describes the vaccines to be evaluated, their composition, There was no increase in the incidence of severe or oppor- and the pattern of both primary vaccination and booster tunistic infections in the patients included in the CARE-MS doses. I and II studies. However, cases were described of patients with active tuberculosis (0.3%), mainly from endemic areas. Clinical series report isolated cases of listeriosis,32,33 nocar- Recommendation 6 diosis of the central nervous system,34 pneumonitis,30 and pneumonitis associated with pericarditis.35 No cases of pro- Vaccination processes can extend from 2 months to a year; gressive multifocal leukoencephalopathy (PML) have been clinicians must therefore assess the risks/benefits of vac- reported. No data are available on the potential reactiva- cination. If onset of alemtuzumab treatment cannot be tion of chronic infections due to hepatitis B or C virus as delayed, safety intervals should be observed between vac- these patients were excluded from the clinical trials. cination and treatment onset, as established in Table 2. No specific risk factors for infection have been identified in patients with RRMS treated with alemtuzumab. Although Minimising the risk of infection: recommendations there is a somewhat higher incidence rate in the first month after administration of the drug, infections are distributed Before administrating alemtuzumab evenly over the follow-up period and tend to decrease over • Active infections should be excluded through clinical time.36 Lymphocyte count (total and CD4+ T lymphocytes) history taking, physical examination, and appropriate has not been correlated with the appearance of infections.37 complementary tests. The presence of an active infection requires proper treatment and postponement of alem- Infections preventable by vaccination tuzumab treatment until the infection resolves. Vaccination of patients with MS receiving treatment with Recommendation 7 immunosuppressants or immunomodulators is part of the • Screening for latent tuberculosis infection is recom- multidisciplinary management of the disease. The effect of mended, preferably by means of interferon-gamma these drugs on the immune system may increase the risk of release assays and/or tuberculin test, in accordance such infections as encephalitis and meningitis due to herpes with each hospital’s protocols. Patients positive for simplex virus or varicella zoster.38,39 tuberculous infection should be treated with isoniazid From a legal perspective, indicating vaccination in these (300 mg/day under fasting conditions, for 6 months) sup- patients in accordance with official vaccination recommen- plemented with vitamin B6 . Treatment of the tuberculous dations does not require written informed consent. infection should not delay the onset of treatment with alemtuzumab. Depending on the circumstances, a delay Recommendation 3 of 2-4 weeks is recommended to check the tolerability Vaccination early in the course of the disease is recom- and non-toxicity of isoniazid. mended to ensure greater vaccine response. For instance, it has been shown that in the case of vaccination against Recommendation 8 pneumococcus, immunogenicity is lower in patients receiv- ing immunosuppressants in monotherapy.40 As a rule, live • Screening for other infections is recommended to inform attenuated vaccines are contraindicated in pregnant women decisions about the most appropriate vaccine and the and in patients receiving immunosuppressants. On the con- possible risk of complications (hepatitis B and C, trary, there is no contraindication for inactivated vaccines in human immunodeficiency virus, cytomegalovirus, vari- patients receiving disease-modifying treatment,41 although cella zoster, human papillomavirus, and Strongyloides in +Model ARTICLE IN PRESS Consensus statement on the use of alemtuzumab in daily clinical practice in Spain 7 Table 1 Vaccinations to consider before alemtuzumab administration.47,48 Vaccine Type Indication Schedule Booster dose Seasonal influenza Inactivated Yes 1 annual dose during Not required Fractional or subunits influenza vaccination campaign (October-December) Pneumococcal Inactivated Yes 1 dose Not required 13-valent Protein-conjugate polysaccharide Pneumococcal Inactivated Yes 1 dose At 5 years 23-valent Polysaccharide At least 2 months after administration of the pneumococcal 13-valent conjugate vaccine Hepatitis Ba Inactivated Yes, provided 0-1-2-6 monthsd Not required Surface antigen anti-HBs < 10 IU/mL Hepatitis A Inactivated Yes, provided IgG HAV 0-6 months Not required Whole viruses (—) Tetanus/diphtheria Inactivated Yes. Primary Primary vaccination Two doses: the first Tetanus toxoid vaccination should be (3 doses): should be started if not 0-1-6 months or administered 10 years received in the past, 0-1-12 months after primary or complemented vaccination and the with booster dosing second 10 years after the first booster dose Human Inactivated Yesb 0-1-6 months or 0-2-6 Not required papillomavirus Subunits months Varicellac Live attenuated Yes, provided IgG 0-1 month Not required Whole virus varicella (—) Triple viral Live attenuated Yes, provided IgG 0-1 months Not required (Measles, mumps, Whole virus measles (—) and rubellac ) Anti-HBs: Hepatitis B surface antibody; HAV: Hepatitis A virus; Ig: immunoglobulin. a Clinicians may consider administering AS04C adjuvanted vaccine, high-load (40 ␮g) HBV vaccine, or double dose of the conventional vaccine, maintaining the same vaccination schedule. b Preferably in women under 26 years of age who have not received the vaccine according to the systematic calendar for children. Also in women scheduled to undergo cervical excision procedures due to high-grade lesions (HSIL/CIN 2-3). In this case, the vaccine should be administered early after diagnosis of the lesion, before the intervention if possible and up to 12 months thereafter. c If vaccination with more than one live attenuated vaccine is indicated, they should be administered at the same consultation in different anatomical regions. If they are not administered together, an interval of at least 4 weeks between vaccinations should be observed. d Post-vaccination serology tests should be performed one month after completion of the vaccination schedule to confirm correct response to the vaccine (anti-HBs titre >10 UI/mL). In patients not showing seroconversion, vaccination should be repeated with three additional doses at monthly intervals. Revaccination should use AS04 adjuvanted vaccine or a high-load vaccine (40 ␮g). Patients not showing seroconversion after revaccination will be considered non-responders, and post-exposure prophylaxis should be considered in situations of risk. immigrants from certain endemic areas, such as Latin (200 mg/12 hours for 4-8 weeks). Alternatively, valaci- America and North Africa). clovir (500 mg/day) may be administered for the same period. During administration of alemtuzumab Recommendation 10 Recommendation 9 • Listeria infection risk reduction: consumption of raw or • Prevention of herpes infection: during phase III clinical undercooked meat and unpasteurised dairy foods should trials, aciclovir showed a protective effect against these be avoided for two weeks before treatment onset and for infections.13,42 Oral prophylaxis with aciclovir should at least one month after administration or until systemic be administered from the first dose of alemtuzumab immune reconstitution, on an individual basis. +Model ARTICLE IN PRESS 8 J.E. Meca-Lallana et al. Table 2 Vaccination strategy when alemtuzumab treatment is indicated. Vaccination before Live attenuated vaccines Inactivated vaccines alemtuzumab No previous Vaccination protocol should be completed at least 6 No contraindication to vaccination and no disease-modifying weeks before starting alemtuzumab. minimum interval for the start of treatment, treatment although the response may be less than expected Recent corticosteroid Vaccination should be started at least one month No contraindication to vaccination, although therapy (treatment of a after the last dose in patients receiving prednisone the response may be less than expected when relapse) >20 mg/day (or equivalent) for more than 15 days. corticosteroids are used at immunosuppressive If the patient has received a corticosteroid bolus in doses the last three months, individual assessment of immune condition is advised. Vaccination protocol should be completed at least 6 weeks before starting alemtuzumab. Active treatment with No contraindication to vaccination during treatment interferon beta or with these drugs (except when combined with glatiramer acetate immunosuppressants), although the response may be less than expected Vaccination protocol should be completed at least 6 No contraindication to vaccination, although weeks before starting alemtuzumab. the response may be less than expected Active treatment with Vaccination should be started once the washout No contraindication to vaccination, although teriflunomide or period has been completed (Table 3).a the response may be less than expected dimethyl fumarate Vaccination protocol should be completed at least 6 weeks before starting alemtuzumab. Active treatment with Vaccination should be started at least three months No contraindication to vaccination, although specific after the last dose of any of these drugs.a the response may be less than expected immunosuppressors: natalizumab or fingolimod Vaccination protocol should be completed at least 6 weeks before starting alemtuzumab. Active treatment with Contraindicated during treatment. Vaccination No contraindication to vaccination, although alemtuzumab should be administered after alemtuzumab. the response may be less than expected Vaccination should be postponed (until after alemtuzumab) to ensure effective immunisation. Vaccination after Live attenuated vaccines Inactivated vaccines alemtuzumab Contraindicated for 6 months and until systemic No contraindication, although the response immune reconstitution is achievedb may be less than expected. Systemic immune reconstitution should be achievedb DMF: dimethyl fumarate. a As the window period can be prolonged, physicians should consider starting alemtuzumab and proceed to the post-alemtuzumab vaccination section. This should not be a limitation for starting alemtuzumab, since the appropriate vaccination/immunisation schedule should have been confirmed before starting treatment with interferon beta, glatiramer acetate, teriflunomide, DMF, natalizumab or fingolimod. Each case should be assessed individually. b Starting 6 months after completion and only if CD4+ T lymphocyte count is greater than 200 cells/␮L. After the administration of alemtuzumab to rule out severe infections, whether opportunistic or otherwise. Recommendation 11 Periods of treatment with alemtuzumab • After the administration of alemtuzumab, systematic use of specific preventive measures against bacterial, In this consensus document we differentiate three periods fungal or parasitic infections is not advised. However, of alemtuzumab treatment: pre-treatment, treatment and in patients with suggestive symptoms, it is necessary post-treatment. +Model ARTICLE IN PRESS Consensus statement on the use of alemtuzumab in daily clinical practice in Spain 9 Pretreatment • Vaccination protocol (see ‘‘Questions to be considered before treatment onset’’). • Patients should be informed about the balance of risks and benefits of the treatment and the importance of the Recommendation 15 follow-up plan (risk minimisation plan). • Dietary indications should be established for the preven- • Electrocardiogram and recent chest radiography are tion of listeria infection (see Recommendation 10). recommended. In asymptomatic patients, an X-ray per- formed in the 2 months prior to the day of perfusion may be valid. Recommendation 12 • Written informed consent must be obtained. Treatment Recommendation 13 The recommended dose of alemtuzumab is 12 mg/day, • Previous (washout) and concomitant treatments should be administered by intravenous infusion in 2 initial courses of evaluated (Table 3). treatment, with up to 2 additional courses of treatment if • Baseline blood and urine analysis should be conducted needed, in accordance with the summary of product char- before perfusion: renal and thyroid function, biochem- acteristics (first course: 5 days of treatment; second and istry, complete blood count, and proteinuria screening. posterior courses: 3 consecutive days).30 Recommendation 14 Recommendation 16 • Pregnancy test and contraception. Women of childbear- • The administration of alemtuzumab can be performed on ing age should use effective contraceptive methods while an inpatient or an outpatient basis. Both options are valid receiving treatment with alemtuzumab and for 4 months and the choice of which approach to follow will depend after the course of treatment.15,16 on the infrastructure available at the hospital, access to • Screening should be performed for active, preventable, hospital beds, hospital timetables, and other factors. and latent tuberculosis infections. See ‘‘Questions to be • In accordance with the recommendations included in considered before treatment onset.’’ the section on infection risk, aciclovir (200 mg/12 hours) Table 3 Evaluation of previous treatments (washout) and concomitant treatments. Other recommendations Waiting time Other recommendations Without previous treatment None — Interferon beta Glatiramer acetate Teriflunomide — Accelerated elimination procedure 11 days after end of treatment: 8 g of cholestyramine orally, 3 times a day, or 50 g activated charcoal orally, twice a day Blood levels should be below 0.02 mg/L.4 Dimethyl fumarate — Provided that lymphocyte count is above 800 cells/␮L49 Fingolimod 6 weeks Provided that lymphocyte count is above 800 cells/␮L50 Natalizumab 12 weeks JC (—), 12 weeks after the last infusion of natalizumab9 ; a gadolinium-enhanced brain MRI should be performed before perfusion of alemtuzumab to screen for PML. JC (+) the window period should allow for latent PML to be ruled out before the perfusion of alemtuzumab, although the excessive duration could favour additional relapses (also called ‘‘IRIS-like’’) due to natalizumab withdrawal. In these cases, a study of the number of JC copies in the CSF should be considered to rule out latent PML.39 A gadolinium-enhanced brain MRI should also be performed to screen for PML before perfusion of alemtuzumab, and 6 months and a year after the administration of alemtuzumab.51 Other immunosuppressants Between 3 and 6 Provided lymphocyte count is >800 cells/␮L and the CD4 count (azathioprine, months >200 cells/␮L cyclophosphamide, rituximab) CSF: cerebrospinal fluid; IRIS: immune reconstitution inflammatory syndrome; JC: John Cunningham virus; MRI: magnetic resonance imaging; PML: progressive multifocal leukoencephalopathy. +Model ARTICLE IN PRESS 10 J.E. Meca-Lallana et al. Management of infusion-related Pre-medication Preparation for infusion Infusion rate reactions 1. Oral or intravenous antipyretic Alemtuzumab is supplied in vials Time Grade 1 medication: 1 g paracetamol, Infusion rate (mild) • Symptomatic medication should be containing 1.2 ml of a clear liquid and Time range pre-infusion, on each infusion day administered. should be refrigerated (not frozen). (total duration) (approx. 120 minutes before Preparation requires aseptic technique (No need or minimal alemtuzumab is advised). (laminar flow cabinet not required). Minutes need for medical • Perfusion should be continued Paracetamol may be prescribed on 5 mL/h intervention/treatment) It must be mixed with 100 mL of 0.9% 0 to 30 (30 min) demand for the rest of the day saline solution or 5% glucose saline according to patient needs. solution. The mixture must not be Minutes 10 mL/h agitated and must be protected from 30 to 60 (30 min) Grades 2-3 • Infusion rate should be reduced by 2. Oral or intravenous antihistamine: the light in an opaque bag (the infusion (moderate) 50% or infusion stopped. 5 mg dexchlorpheniramine, pre-infusion, system does not need to be opaque). Minutes 15 mL/h • Line should be flushed with saline on each infusion day (approx. 120 60 to 90 (30 min) (Need for medical solution. minutes before alemtuzumab is intervention/ • Symptomatic medication should be advised). Dexchlorpheniramine may Minutes treatment, administered. be prescribed on demand for the rest 20 mL/h The solution should be administered 90 to 150 (60 min) possible • Clinicians must wait for symptoms to of the day according to patient needs. immediately after mixing. Alternatively, hospitalisation) subside. it may be stored in a refrigerator for a Minute • Infusion should be resumed at 50% of 25 mL/h maximum of 8 hours at 2-8°C, 150 to end (156 min) the rate at which it was stopped. protected from light.6 3. Intravenous methylprednisolone: Grade 4 • Infusion should be stopped/ 90 minutes before alemtuzumab. (severe) discontinued. First course. Days 1 and 2: 1000 mg; The dilution should be prepared by day 3: 500 mg; days 4 and 5: 250 mg. trained staff in order to establish the (Need for major • Line should be flushed with saline medical intervention solution. Second course. Day 1: 750 mg; day 2: optimum starting time and infusion /treatment, probable • Symptomatic medication should be 500 mg; day 3: 250 mg. rate. The infusion system (which does hospitalisation) administered. not need to be opaque) must be 4. Gastric protector: proton pump purged with the drug solution, not with inhibitor, such as oral pantoprazole physiological saline solution. 40 mg/24 h. After infusion, administration of the medication remaining in the infusion system must be ensured. Figure 3 Perfusion characteristics and proposed perfusion rate. should be started before administering alemtuzumab and of observation after perfusion. Dermatological inspec- maintained for a minimum of 4-8 weeks. tions may also be conducted to detect the presence of hives, rash, and other less frequent dermatological or Prevention of infusion-related reactions: vascular lesions. pre-medication b) Management of infusion-related reactions. Recommendation 17 • Pre-medication should be administered to reduce the inci- Recommendation 20 dence and intensity of infusion-related reactions (Fig. 3, • Infusion-related reactions should be treated according to pre-medication panel). their severity, according to the indications included in Fig. 3. Alemtuzumab administration Recommendations for the post-perfusion period Recommendation 18 and after the completion of each course Perfusion rate • Symptomatic treatment with oral antihistamines and • The drug should be administered in a period not shorter antipyretics may be used at home if symptoms such as than 4 hours or longer than 8 hours; perfusion rate may be rashes or headache present. Patient should be instructed reduced if the patient presents an infusion-related reac- to return to the hospital if symptoms persist or worsen tion. The perfusion rate shown in Fig. 3 was established after treatment. by consensus. • A patient’s card with the administered medication (risk minimisation plan) should be provided. After perfusion, patients should remain under obser- • General recommendations to reduce the risk of infection: vation for 2 hours, with the peripheral venous catheter maintaining proper bodily and hand hygiene and avoiding remaining in place. poorly ventilated environments and places where human overcrowding occur. Monitoring during perfusion and management of infusion-related reactions Post-treatment a) Monitoring and observation during and after perfusion. • Dietary indications should be maintained. • Blood and urine analysis should be performed monthly for Recommendation 19 48 months after the last course: complete blood count, • Heart rate, blood pressure, and temperature should be renal function, thyroid function (quarterly), biochemistry, taken every hour during infusion and during the two hours and proteinuria screening. +Model ARTICLE IN PRESS Consensus statement on the use of alemtuzumab in daily clinical practice in Spain 11 NEPHROPATHIES THYROID DISORDERS • Do you urinate less, or have blood in the urine or dark urine? • Have you noticed unexplained changes in weight? • Do you notice heat or cold more than normal? • Have you noticed swelling of the legs? • Do you have more diarrhoea or constipation than normal? HAEMATOLOGY INFECTIONS • Have you suffered nose bleed, bleeding of the mouth or • Have you had a fever? gums, or bleeding on coughing? • Have you suffered infections such as herpes, common cold, • Have you experienced heavier than normal menstrual fungal infections, etc? bleeding? • Have you noticed a tendency to suffer bruises? • Do you have new skin stains? Figure 4 Proposed checklist of symptoms indicating complications and adverse reactions. • Access to other specialists (e.g., endocrinology, haema- patients receiving alemtuzumab presented a significantly tology, nephrology) should be ensured to consult about reduced annual relapse rate (from 1.29 to 0.34 in the first any adverse events. year after the second course) and did not receive additional treatment for 6 years.25,26 Recommendation 21 • Patients should be informed of potential symptoms sug- Recommendation 24 gestive of immunological alterations that may present in • In the second and subsequent courses of alemtuzumab, the long term, following the checklist proposed in Fig. 4. the same procedures should be followed during the three established periods as in the first course. Recommendation 22 • Gynaecological cytology tests for human papillomavirus Evaluation of treatment response. Criteria for should be performed annually in women treated with further courses after the second course alemtuzumab. During the CARE-MS extension studies, the administration A summary of the 3 periods is included in Fig. 5. of additional courses of alemtuzumab was permitted 12 months or more after the last course, according to the fol- Administration of the second and subsequent lowing clinical criteria: ≥ 1 relapses as defined by protocol courses or ≥ 2 new hyperintense lesions/increases in size of pre- existing lesions on the T2-weighted sequence, or lesions showing gadolinium uptake on the T1-weighted sequence. Recommendation 23 Decisions around whether to administer additional courses • Twelve months must pass between the first and second in eligible patients were taken by physicians and patients, courses of alemtuzumab. This period should be extended as was the decision to start other disease-modifying for patients not displaying systemic immune reconstitu- therapies.15,16 tion (CD4+ T lymphocyte count >200 cells/␮L) or in the An analysis of patients receiving a third course of alem- event of some active complication due to the first course tuzumab showed that the annualised relapse rate in these (for example, a thyroid alteration). patients decreased from 0.74 in the year prior to this course to less than 0.1 in the following 3 years.27 Similar figures In clinical trials, administration of a second course has are observed in patients who did not receive an additional demonstrated efficacy in patients presenting relapses after course. The average score on the Expanded Disability Status the first course.25,26 Preliminary data show that 42% of Scale in the 12 months after the third course decreased by +Model ARTICLE IN PRESS 12 J.E. Meca-Lallana et al. PERIOD RECOMMENDATION Period 1. • Recommendations for the patient and consent Before administration • Non-pasteurised dairy products and raw fish/meat should be avoided in the 2 weeks before administration. • Blood and urine testing: kidney and thyroid function, blood count, biochemistry, and screening for proteinuria • Pregnancy test • Evaluation of previous (washout) and concomitant treatments • Screening for active infections and latent tuberculosis • Screening for infections preventable through vaccination (HBV, VZV, HPV) and for other latent infections that may give rise to complications (HBV, HCV, HIV, CMV, Strongyloides in immigrants from highly endemic regions) • Vaccination protocol. Completed 6 weeks before infusion. (See section on vaccination). • Baseline chest x-ray • Baseline ECG study Period 2. • Aciclovir (200 mg/12 h for at least 4 weeks) During administration • Pre-medication to prevent infusion-related reactions • Monitoring Period 3. • Non-pasteurised dairy products and raw or undercooked meat should be avoided for one month or until immune After administration reconstitution, according to the clinician’s judgement • Monthly blood and urine testing for 48 months after the last treatment course; bone marrow, kidney, and thyroid function (every 3 months), biochemistry, and screening for proteinuria • Monthly clinical screening for complications based on a checklist • Infections should be ruled out in the event of suggestive symptoms. • In women, annual HPV screening until 4 years after the last dose Figure 5 Summary of recommendations for the first 3 courses of alemtuzumab. CMV: cytomegalovirus; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; HPV: human papillomavirus; IRR: infusion-related reactions; VZV: varicella zoster virus. 0.12, with 71% of patients scoring the same or better after Pregnancy and breastfeeding this course of treatment. The safety profile in the patients receiving a third course did not change with respect to the Recommendation 26 first 2 courses. • Data on the use of alemtuzumab in pregnant women are At present, up to 2 additional courses of treatment limited. Alemtuzumab should only be administered during can be administered if needed: the third or fourth course pregnancy if the potential benefits justify the potential (12 mg/day for 3 consecutive days) must be adminis- risks to the foetus.30 tered at least 12 months after the previous course of treatment in patients presenting evidence of disease Recommendation 27 activity.30 • Women of childbearing age receiving alemtuzumab should use adequate contraception during the 4 months following the infusion.30 Special situations Recommendation 28 Vaccination of cohabitants • It is unclear whether alemtuzumab is excreted in human breast milk. Risks for nursing infants cannot be ruled Recommendation 25 out. Therefore, breastfeeding should be interrupted dur- ing each course of treatment with alemtuzumab and for • Cohabitants and people in the immediate environ- the 4 months after the last infusion of each course of ment of patients treated with such immunosuppres- treatment.30 sants as alemtuzumab can be a potential source of infection. In patients with negative serology find- Paediatric populations ings who have already begun treatment with alem- tuzumab, it is advisable to evaluate vaccination of susceptible cohabitants against varicella and/or The safety and efficacy of alemtuzumab in patients with MS measles. between 0 and 18 years of age are yet to be established. +Model ARTICLE IN PRESS Consensus statement on the use of alemtuzumab in daily clinical practice in Spain 13 There is no specific recommendation for alemtuzumab use activities supported by Pfizer, in expert meetings pro- in children aged between 0 and 10 years.30 moted by Sanofi-Genzyme and GlaxoSmithKline (GSK), and collaborated in the creation of educational material for Surgical interventions GSK; Elisa García Vázquez has received consulting fees from Sanofi-Genzyme; Santiago Moreno Guillén has received Recommendation 29 research funding and spoken at activities promoted by Abb- vie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, • Given the transient immunosuppression caused by alem- GSK, Janssen Cilag, Merck Sharp & Dohme, Pfizer, Roche, tuzumab, it seems reasonable to delay any type of surgical and Viiv Healthcare; Susana Otero Romero has received intervention until adequate systemic immune reconstitu- consulting fees from Sanofi-Genzyme and lecture hono- tion is achieved, if the clinical reason for surgery allows raria from Biogen-Idec and Merck Sharp & Dohme, as it. If the patient urgently requires surgical interven- well as research funding from Novartis; Macarena Rus tion during the period of severe lymphocytopaenia, the Hidalgo has received consulting fees from Novartis, Merck- usual protocol for immunosuppressed patients should be Serono, Sanofi-Genzyme, Biogen-Idec, Almirall, and Bayer; applied. Luisa M Villar Guimerans has received fees for speaking, research, and meeting and conference attendance from Merck, Biogen, Sanofi-Genzyme, Roche, and Novartis; Sara Conclusions Eichau Madueño has received consulting fees and lec- ture honoraria from Biogen-Idec, Novartis, Sanofi-Genzyme, • The high efficacy of alemtuzumab and its rapid imple- Merck-Serono, Roche, and Almirall; Óscar Fernández has mentation into MS management give rise to the need received fees for consulting, moderating, speaking, and clin- for consensus on the practical clinical management of ical trial and research project participation from Bayer, patients receiving this treatment. Biogen-Idec, Merck-Serono, Teva, Novartis, Allergan, Almi- • This consensus statement on the use of the drug in rall, Sanofi-Genzyme, and Roche; Guillermo Izquierdo patients with MS should not be used as guidelines for its Ayuso has received consulting fees and lecture honoraria management, but is intended to optimise and facilitate from Bayer, Biogen-Idec, Novartis, Sanofi-Genzyme, Merck- its use and follow-up in routine clinical practice. Serono, Almirall, Roche, Actelion, Celgene, and Teva. He • A total of 29 recommendations have been agreed upon by has also received fees for research projects promoted the panel of MS experts, and mainly cover the following by Bayer, Biogen-Idec, Novartis, Sanofi-Genzyme, Merck- aspects of treatment with alemtuzumab: characteristics Serono, Almirall, and Teva. José Carlos Álvarez Cermeño of candidate patients, safety measures, vaccination of has received consulting fees from Sanofi-Genzyme, Celgene, patients and cohabitants, risk of infections, previous and and Merk; Carmen Arnal García has received consulting concomitant treatments and washout periods, contra- fees from Sanofi-Genzyme; Rafael Arroyo González has ception, complementary tests (electrocardiography and spoken at meetings promoted by Sanofi-Genzyme, Novar- chest x-rays), cytology testing with human papillomavirus tis, Teva, Roche, Biogen-Idec, Merck-Serono, and Almirall; determination, infusion-related reactions, pregnancy and Luis Brieva Ruíz has received research funding and hono- lactation, surgical intervention, perfusion of the drug, and raria for meetings promoted by Bayer, Biogen-Idec, Roche, the administration of successive courses after the first Merck, Novartis, Allmirall, and Sanofi-Genzyme; Carmen course of treatment. Calles Hernández has received consulting fees from Sanofi- • This consensus document does not address the mana- Genzyme; Antonio García Merino has received consulting gement of possible adverse effects. This question is fees and travel and meeting expenses from Bayer, Merck- consulted in previous consensus documents on the Serono, Teva, Biogen-Idec, Novartis, Roche, Almirall, and management of adverse autoimmune effects with Sanofi-Genzyme, and research funding from Novartis and alemtuzumab.43—46 Biogen-Idec; Montserrat González Plata has received lec- ture honoraria and travel expenses from Sanofi-Genzyme, Novartis, Roche, and Merck; Miguel Ángel Hernández Pérez has received consulting fees from Almirall, Biogen, Merck, Funding Novartis, Roche, Teva, and Sanofi-Genzyme; Ester Moral Tor- res has received fees for consulting, speaking, and clinical Sanofi-Genzyme provided financial support to this project. trial participation from Bayer, Biogen-Idec, Merck-Serono, Teva, Novartis, Almirall, Sanofi-Genzyme, Actelion, and Roche; Javier Olascoaga Urtaza has received consulting fees Conflicts of interest from Biogen-Idec, Novartis, Roche, and Sanofi-Genzyme, and fees for moderating, speaking, and organising meet- José E Meca-Lallana has received consulting fees as a ings and for involvement in research and clinical trials consultant and lecture honoraria from Biogen-Idec, Cel- from Almirall, Bayer, Biogen-Idec, Merck-Serono, Novartis, gene, Sanofi-Genzyme, Merck-Serono, Novartis, Roche, and Roche, Sanofi-Genzyme, and Teva; Pedro Oliva Nacarino Teva; María Fernández-Prada has participated in teaching has received consulting fees from Biogen-Idec, Bayer, +Model ARTICLE IN PRESS 14 J.E. Meca-Lallana et al. and Sanofi-Genzyme, and lecture honoraria from Bio- recommendations for infusion in patients with multiple scle- gen, Novartis, Roche, Merck-Serono, Sanofi-Genzyme, Teva, rosis. J Infus Nurs Off Publ Infus Nurses Soc. 2016;39:93—104. and Almirall; Celia Oreja-Guevara has received consulting 4. Scolding N, Barnes D, Cader S, Chataway J, Chaudhuri A, Coles fees and lecture honoraria from Biogen-Idec, Merck- A, et al. Association of British Neurologists: revised (2015) Serono, Novartis, Roche, Sanofi-Genzyme, and Teva; Rafa guidelines for prescribing disease-modifying treatments in mul- tiple sclerosis. Pract Neurol. 2015;15:273—9. Ortiz Castillo is a medical consultant for Sanofi-Genzyme; 5. Berger T, Elovaara I, Fredrikson S, McGuigan C, Moiola L, Myhr Agustín Oterino has received lecture honoraria from Sanofi- K-M, et al. Alemtuzumab use in clinical practice: recommen- Genzyme, Merck-Serono, Biogen-Idec, Almirall, Allergan, dations from European multiple sclerosis experts. CNS Drugs. and Teva, and has received research funding through 2017;31:33—50. IDIVAL from Novartis and Sanofi-Genzyme; José María 6. Havrdova E, Horakova D, Kovarova I. Alemtuzumab in the Prieto González is a consultant for Bayer, Biogen-Idec, treatment of multiple sclerosis: key clinical trial results and Sanofi-Genzyme, Novartis, Sanofi-Aventis, Teva, Roche, considerations for use. Ther Adv Neurol Disord. 2015;8:31—45. Merck-Serono, and Almirall. He has spoken at meetings 7. Tintore M, Vidal-Jordana A, Sastre-Garriga J. Treatment of mul- promoted by Almirall, Bayer, Biogen-Idec, Sanofi-Genzyme, tiple sclerosis: success from bench to bedside. Nat Rev Neurol. Merck-Serono, Novartis, Sanofi-Aventis, and Teva. He has 2019;15:53—8. 8. Hu Y, Turner MJ, Shields J, Gale MS, Hutto E, Roberts BL, received research funding from Almirall, Biogen-Idec, et al. Investigation of the mechanism of action of alemtuzumab Novartis, and Sanofi-Genzyme. Lluís Ramió-Torrentá has in a human CD52 transgenic mouse model. Immunology. received consulting fees, lecture honoraria, and travel 2009;128:260—70. expenses from Biogen, Merck, Teva, Sanofi-Genzyme, Roche, 9. De Mercanti S, Rolla S, Cucci A, Bardina V, Cocco E, Vladic Bayer, Almirall, and Mylan; Alfredo Rodríguez-Antigüedad A, et al. Alemtuzumab long-term immunologic effect: treg has received lecture honoraria and fees for moderating and suppressor function increases up to 24 months. Neurol Neuroim- participating in clinical trials and other research projects munol Neuroinflammation. 2016;3:e194. from Bayer-Schering, Biogen-Idec, Sanofi-Genzyme, Merck, 10. Gross CC, Ahmetspahic D, Ruck T, Schulte-Mecklenbeck A, Novartis, Teva, and Roche; Albert Sáiz has received Schwarte K, Jörgens S, et al. Alemtuzumab treatment alters circulating innate immune cells in multiple sclerosis. Neurol consulting fees and lecture honoraria from Bayer-Schering, Neuroimmunol Neuroinflammation. 2016;3:e289. Merck-Serono, Novartis, Teva, Sanofi-Genzyme, Biogen- 11. Turner MJ, Lamorte MJ, Chretien N, Havari E, Roberts BL, Idec, and Roche; Mar Tintoré has received consulting Kaplan JM, et al. Immune status following alemtuzumab fees and lecture honoraria from Almirall, Bayer, Scher- treatment in human CD52 transgenic mice. J Neuroimmunol. ing, Biogen-Idec, Sanofi-Genzyme, Merck-Serono, Novartis, 2013;261:29—36. Roche, Sanofi-Aventis, and Teva; Xavier Montalbán Gairin has 12. CAMMS223 Trial InvestigatorsColes AJ, Compston DA, Selmaj received fees for consulting in clinical trials and organising KW, Lake SL, Moran S, MArgolin DH, et al. Alemtuzumab vs. meetings from Actelion, Bayer, Biogen-Idec, Celgene, Merck- interferon beta-1a in early multiple sclerosis. N Engl J Med. Serono, Novartis, Roche, Sanofi-Genzyme, Teva, Excemed, 2008;359:1786—801. MSIF, and NMSS. 13. Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung H-P, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple scle- rosis: a randomised controlled phase 3 trial. Lancet Lond Engl. Acknowledgements 2012;380:1819—28. 14. Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ, et al. Alemtuzumab for patients with relapsing The authors thank Mónica Giménez for her help in drafting, multiple sclerosis after disease-modifying therapy: a ran- reviewing, and submitting the manuscript domised controlled phase 3 trial. Lancet Lond Engl. 2012;380: 1829—39. 15. Havrdova E, Arnold DL, Cohen JA, Hartung H-P, Fox EJ, Giovan- noni G, et al. 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