Lemtrada is indicated to be administered as an intravenous (IV) infusion for two treatment courses separated by 12 months from initial infusion. In January 2019, the FDA labeled package insert was updated to expand for subsequent treatment courses after two courses of treatment. As per the FDA labeled package insert, following the second treatment course, subsequent treatment courses of 12 mg per day on 3 consecutive days (36 mg total dose) may be administered, as needed, at least 12 months after the last dose of any prior treatment course. Data beyond 3 treatment courses is limited as per clinical trial section in the FDA approved package insert.

Lemtrada contains a boxed warning concerning its potential for causing serious autoimmune conditions, malignancies and life-threatening infusion reactions. It must be administered in a setting with appropriate equipment and personnel to manage anaphylaxis or serious infusion reactions, and patients must be monitored for two hours after each infusion. Due to Lemtrada’s safety concerns, it was approved with a Risk Evaluation and Mitigation Strategy (REMS) that includes a restricted distribution program. Under the LEMTRADA REMS program, only prescribers, healthcare facilities and pharmacies registered with this program will be able to prescribe, distribute or infuse the drug. Lemtrada is to be administered to patients who are enrolled in and meet all of the conditions of the REMS program as per the FDA-approved product labeling.

The active ingredient of Lemtrada, alemtuzumab, was previously marketed under the brand name Campath. Campath was FDA approved for the treatment of B-cell chronic lymphocytic leukemia (B-CLL) in patients who have failed treatment with certain other cancer medicines. Campath was withdrawn from the market in September 2012 and is only available currently through the Campath Distribution Program to eligible patients free of charge. Campath was available in 30 mg/1 mL single use vial, and dosed at 30mg/day three times per week for 12 weeks. Lemtrada is available at 12mg/1.2mL single use vial, dosed as 12mg/day for 5 consecutive days followed by 3 consecutive days per year. Off label indications for Campath were based on small studies with low levels of evidence.

[INFORMATIONAL NOTE: Lemtrada packaging includes the following BLACK BOX WARNINGS:

• Lemtrada causes serious, sometimes fatal, autoimmune conditions such as immune thrombocytopenia and anti-glomerular basement membrane disease. Monitor complete blood counts with differential, serum creatinine levels and urinalysis with urine counts at periodic intervals for 48 months after the last dose.
• Lemtrada causes serious and life-threatening infusion reactions. Lemtrada must be administered in a setting with appropriate equipment and personnel to manage anaphylaxis or serious infusion reactions. Monitor patients for two hours after each infusion. Make patients aware that serious infusion reactions can also occur after the 2 hour monitoring period
• Lemtrada may cause an increased risk of malignancies, including thyroid cancer, melanoma, and lymphoproliferative disorders. Perform baseline and yearly skin exams
• Serious and life-threatening stroke ( including ischemic and hemorrhagic) has been reported within 3 days of Lemtrada administration. Instruct patients to seek immediate medical attention if symptoms of stroke occur.
  • In the postmarketing setting, most cases occurred within 1 day of Lemtrada administration. In the postmarketing setting, cases of cervicocephalic (e.g., vertebral, carotid) arterial dissection involving multiple arteries have been reported within 3 days of Lemtrada administration. Ischemic stroke was reported in one of these cases.
• Lemtrada is available only through a restricted distribution program.]

a) Member has a confirmed diagnosis (i.e. MRI report) of relapsing forms of MS (please refer to table 1 under Informational Note for complete diagnosis criteria for relapsing-remitting form of MS) AND
b) Member is 18 years or older AND
c) Member has failed at least two or more MS therapies (ie. interferon beta 1a, interferon beta 1b, glatiramer, natalizumab, ocrelizumab, daclizumab, dimethyl fumarate, fingolimod, and teriflunomide); AND
d) Member will not be receiving Lemtrada in combination with other medications indicated for MS; AND
e) Enrolled in Lemtrada REMS (Risk Evaluation and Mitigation Strategy) AND
f) Member has tested negative for Human Immunodeficiency Virus (HIV) AND
g) Member is not receiving concomitant antineoplastic or immunosuppressive therapies; AND
h) Member will not receive live vaccines during therapy; AND
i) Member has received a baseline skin exam to rule out melanoma; AND
j) Member has received baseline complete blood count with differential, serum creatinine levels, urinalysis with urine cell counts, and thyroid function; AND
k) Member has had a tuberculosis screening prior to treatment; AND
l) Member has been evaluated and screened for the presence of varicella zoster virus (VZV) and vaccinated, if required, prior to initiating treatment

[INFORMATION NOTES:
The safety and efficacy of Lemtrada was demonstrated in two studies (Study 1 and 2) that evaluated Lemtrada 12 mg in patients with relapsing-remitting multiple sclerosis (RRMS). Both studies included patients who had experienced at least 2 relapses during the 2 years prior to trial entry and at least 1 relapse during the year prior to trial entry. Both studies were 2 year randomized, open-label, rater-blinded, active comparator (interferon beta-1a 44 micrograms administered subcutaneously three times a week) controlled study in patients with RRMS. Study 1 enrolled patients who had an adequate trial of disease modifying therapies but continued to relapse while Study 2 enrolled untreated patients.

In both studies the annualized relapse rate was significantly lower in patients treated with Lemtrada than in patients who received interferon beta-1a. Study 1 showed a relative reduction of 49% (p <0.00001) while Study 2 showed a relative reduction of 55% (p <0.0001). There were no significant difference between the treatment groups for the change in T2 lesion volume in both studies (Study 1: p=0.14; Study 2: p=0.31). Study 1 showed a relative risk reduction of 42% for proportion of patients with disability progression at Year 2 (p = 0.0084), while Study 2 showed a relative risk reduction of 30% (p=0.22).

Study 1 and 2 enrolled only members who were 18 years or older.

The Lemtrada REMS program requires enrollment by the prescriber and the pharmacy or healthcare facility (enrollment in the pharmacy and healthcare facility must be renewed every 2 years). The program includes a REMS Letter for Healthcare Providers, a REMS website (www.LemtradaREMS.com), and Elements to Assure Safe Use to ensure prescribers are specially certified, Lemtrada is only dispensed in certain, specially certified healthcare settings, patients are monitored to evaluate and assure safe use, and a timetable for submission of REMS assessments to the FDA.

U.S. Food and Drug Administration: Drug Safety. BLA 103948 Lemtrada® (alemtuzumab) CD52-directed cytolytic antibody REMS. Sep 2015. [Available at: http://www.accessdata.fda.gov/drugsatfda_docs/rems/Lemtrada_2015-09-18_REMS_document.pdf

Adopted from Lancet Neurology – Diagnosis of multiple sclerosis: 2017 revisions of the McDonald Criteria

*Definitive diagnosis of MS with a relapsing-remitting course is based upon BOTH dissemination in time and space. Unless contraindicated, MRI should be obtained (even if criteria are met).
Dissemination in time (Development/appearance of new CNS lesions over time)	Dissemination in space (Development of lesions in distinct anatomical locations within the CNS; multifocal)
· ≥ 2 clinical attacks; OR · 1 clinical attack AND one of the following: o MRI indicating simultaneous presence of gadolinium-enhancing and non-enhancing lesions at any time or by a new T2-hyperintense or gadolinium-enhancing lesion on follow-up MRI compared to baseline scan o CSF-specific oligoclonal bands	· ≥ 2 lesions; OR · 1 lesion AND one of the following: o Clear-cut historical evidence of a previous attack involving a lesion in a distinct anatomical location o MRI indicating ≥ 1 T2-hyperintense lesions characteristic of MS in ≥ 2 of 4 areas of the CNS (periventricular, cortical or juxtacortical, infratentorial, or spinal cord)



The 2017 McDonald criteria for diagnosis of multiple sclerosis I patients with a disease course characterized by progression from onset (primary progressive multiple sclerosis) include
- 1 year of disability progression (retrospectively or prospectively determined) independent of clinical relapse
- PLUS two of the following
o one or more T2-hyperintense lesions characteristic of multiple sclerosis in one or more of the following brain regions: periventricular, cortical or juxtacortical, or infratentorial
o two or more T2-hyperintense lesions in the spinal cord presence of CSF-specific olioclonal bands]

[INFORMATIONAL NOTE: As per the FDA approved package insert dosing and administration section (2.2): Premedicate patients with high dose corticosteroids (1,000 mg methylprednisolone or equivalent) immediately prior to Lemtrada infusion and for the first 3 days of each treatment course. Administer anti-viral prophylaxis for herpetic viral infections starting on the first day of each treatment course and continue for a minimum of two months following treatment with Lemtrada or until the CD4+ lymphocyte count is at least 200 cells per microliter, whichever occurs later.]

a) Clinical documentation that the member has received the first course of treatment at least 12 months ago
b) Member has been monitoring CBC, SCr and urinalysis with urine cell counts on a monthly basis
c) Member has been monitoring thyroid stimulating hormone level once every 3 months

[INFORMATIONAL NOTE: Lemtrada 12 mg has a dosing and administration schedule of two annual treatment courses. The first treatment course of Lemtrada is administered via intravenous infusion on five consecutive days, and the second course is administered on three consecutive days, 12 months later. There is no Lemtrada treatment between the two courses. Subsequent treatment courses of 12 mg per day on 3 consecutive days (36 mg total dose) may be administered, as needed, at least 12 months after the last dose of any prior treatment course. The FDA approved package insert notes to monitor complete blood counts with differential, serum creatinine levels,and urinalysis with urine cell counts at periodic intervals for 48 months after the last dose of Lemtrada]

a) Clinical documentation that the member has received the last dose of prior treatment at least 12 months ago
b) The requested dose is within a total of 3 treatment courses; member should not receive more than a total of 3 treatment courses
b) Member has been monitoring CBC, SCr and urinalysis with urine cell counts on a monthly basis
c) Member has been monitoring thyroid stimulating hormone level once every 3 months

Medicare Coverage
There is no National Coverage Determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of Local Medicare Carriers. Novitas Solutions, Inc, the Local Medicare Carrier for jurisdiction JL, has not issued a determination for this service. Therefore, Medicare Advantage Products will follow the Horizon Policy.

Medicaid Coverage

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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Lemtrada
Alemtuzumab
Multiple sclerosis

References:

1. Lemtrada [package insert]. Cambridge, MA; Genzyme Corporation; July 2019. Accessed September 2019.

2. Gold Standard, Inc. Alemtuzumab. Clinical Pharmacology [database online]. Available at: http://www.clinicalpharmacology.com. Accessed May 21, 2015.

3. Alemtuzumab. In: DrugDex® system [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically. Accessed May 21, 2015.

4. Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomized controlled phase 3 trial. The Lancet. 2012 Nov; 380(9856):1819-1828.

5. Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. The Lancet. 2012 Nov; 380(9856): 1829-1839.

6. Campath (alemtuzumab) package insert. Cambridge, MA: Genzyme Corporation; 2014 Sep.

7. Hillmen P, Skotnicki AB, Robak T, et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007;25:5616-23

8. Lundin J, Kimby E, Bjorkholm M, et al. Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL). Blood 2002;100:768-773.

9. Karlsson C, Norin S, Kimby E, et al. Alemtuzumab as first-line therapy for B-cell chronic lymphocytic leukemia: long-term follow-up of clinical effects, infectious complications and risk of Richter transformation. Leukemia 2006;20:2204-2207.

10. Stilgenbauer S, Zenz T, Winkler D, et al. Subcutaneous alemtuzumab in fludarabine-refractory chronic lymphocytic leukemia: clinical results and prognostic marker analyses from the CLL2H study of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 2009;27:3994-4001.

11. Cortelezzi A, Pasquini MC, Sarina B, et al. A pilot study of low-dose subcutaneous alemtuzumab therapy for patients with hemotherapy-refractory chronic lymphocytic leukemia. Haematologica 2005;90:410-412.

12. Cortelezzi A, Pasquini MC, Gardellini A, et al. Low-dose subcutaneous alemtuzumab in refractory chronic lymphocytic leukaemia (CLL): results of a prospective, single-arm multicentre study. Leukemia 2009;23:2027-2033.

13. Faderl S, Thomas DA, O'Brien S, et al. Experience with alemtuzumab plus rituximab in patients with relapsed and refractory lymphoid malignancies. Blood 2003;101:3413-3415.

14. Faderl S, Ferrajoli A, Wierda W, et al. Alemtuzumab by continuous intravenous infusion followed by subcutaneous injection plus rituximab in the treatment of patients with chronic lymphocytic leukemia recurrence. Cancer 2010;116:2360-2265.

15. Elter T, Gercheva-Kyuchukova L, Pylylpenko H, et al. Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial. Lancet Oncol 2011;12(13):1204-1213.

16. Ferrajoli A, O'Brien SM, Cortes JE, et al. Phase II study of alemtuzumab in chronic lymphoproliferative disorders. Cancer 2003;98:773-8.

17. Keating MJ, Cazin B, Coutre S, et al. Campath-1H treatment of T-cell prolymphocytic leukemia in patients for whom at least one prior chemotherapy regimen has failed. J Clin Oncol 2002;20:205-213.

18. Lundin J, Osterborg A, Brittinger G, et al. CAMPATH-1H monoclonal antibody in therapy for previously treated low-grade non-Hodgkin's lymphomas: a phase II multicenter study. J Clin Oncol 1998;16:3257-63.

19. Lundin J, Hagberg H, Repp R, et al. Phase 2 study of alemtuzumab (anti-CD52 monoclonal antibody) in patients with advanced mycosis fungoides/Sezary syndrome. Blood 2003;101:4267-72.

20. Querfeld C, Mehta N, Rosen ST, et al. Alemtuzumab for relapsed and refractory erythrodermic cutaneous T-cell lymphoma: a single institution experience from the Robert H Lurie Comprehensive Cancer Center. Leuk Lymphoma 2009;50:1969-1976.

21. Peggs KS, Sureda A, Qian W, et al. Reduced-intensity conditioning for allogeneic haematopoietic stem cell transplantation in relapsed and refractory Hodgkin lymphoma: impact of alemtuzumab and donor lymphocyte infusions on long-term outcomes. Br J Haematol 2007;139:70-80.

22. Kottaridis PD, Milligan DW, Chopra R, et al. In vivo CAMPATH-1H prevents graft-versus-host disease following nonmyeloablative stem cell transplantation. Blood 2000;96:2419-2425.

23. Chakraverty R, Orti G, Roughton M, et al. Impact of in vivo alemtuzumab dose before reduced intensity conditioning and HLA-identical sibling stem cell transplantation: pharmacokinetics, GVHD, and immune reconstitution. Blood 2010;116:3080-3088.

24. Perez-Simon JA, Kottaridis PD, Martino R, et al. Nonmyeloablative transplantation with or without alemtuzumab: comparison between 2 prospective studies in patients with lymphoproliferative disorders. Blood 2002;100:3121-3127.

25. Goodin DS, Frohman EM, Garmany GP Jr, et al. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology. 2002 Jan 22;58(2):169-78.

26. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018 Feb;17(2):162-173. doi: 10.1016/S1474-4422(17)30470-2.

27. Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis, Study One (CARE-MS I). ClinicalTrials.gov Identifier: NCT00530348. Available at: https://clinicaltrials.gov/ct2/show/NCT00530348

28. An Extension Protocol for Multiple Sclerosis Patients Who Participated in Genzyme-Sponsored Studies of Alemtuzumab. ClinicalTrials.gov Identifier: NCT00930553. Available at: https://clinicaltrials.gov/ct2/show/NCT00930553

29. Clinicaltrials.gov Lemtrada. Available at: https://clinicaltrials.gov/ct2/results?cond=&term=lemtrada&cntry=&state=&city=&dist=

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

HCPCS
J0202

* CPT only copyright 2019 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.

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Medical policies can be highly technical and are designed for use by the Horizon BCBSNJ professional staff in making coverage determinations. Members referring to this policy should discuss it with their treating physician, and should refer to their specific benefit plan for the terms, conditions, limitations and exclusions of their coverage.

The Horizon BCBSNJ Medical Policy Manual is proprietary. It is to be used only as authorized by Horizon BCBSNJ and its affiliates. The contents of this Medical Policy are not to be copied, reproduced or circulated to other parties without the express written consent of Horizon BCBSNJ. The contents of this Medical Policy may be updated or changed without notice, unless otherwise required by law and/or regulation. However, benefit determinations are made in the context of medical policies existing at the time of the decision and are not subject to later revision as the result of a change in medical policy
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