Medical Policy

Subject: Alemtuzumab (Lemtrada®)
Document #: DRUG.00074 Current Effective Date:    03/29/2017
Status: Reviewed Last Review Date:    02/02/2017


This document addresses the use of alemtuzumab (Lemtrada® , Genzyme Corporation, Cambridge, MA). Lemtrada is a humanized monoclonal antibody directed at CD52 (a protein on the surface of immune cells) and is used for the treatment of multiple sclerosis (MS). This document does not address indications for the use of alemtuzumab (Campath® , Genzyme Corporation, Cambridge, MA)*.

Note: Please see the following related documents for additional information:

*Note: Effective September 04, 2012 alemtuzumab (Campath) was no longer commercially available; it is now accessible only through the Campath Distribution Program, free of charge, to clinically appropriate individuals.

Position Statement

Medically Necessary:

Alemtuzumab (Lemtrada) is considered medically necessary for the treatment of relapsing-remitting multiple sclerosis (RRMS) when the individual has met all the following criteria:

  1. Received prior treatment with at least two alternative drug therapies indicated for the treatment of MS (for example, interferons, glatiramer) and failed to achieve an adequate response or experienced intolerance of these drug therapies; and
  2. Human immunodeficiency virus (HIV) negative.

Investigational and Not Medically Necessary:

Alemtuzumab (Lemtrada) is considered investigational and not medically necessary when the medically necessary criteria are not met and including, but not limited to, the following diagnoses:

  1. Primary progressive MS (PPMS);
  2. Secondary progressive MS (SPMS).

Lemtrada has been studied for the treatment of adults with RRMS with active disease, defined by clinical or imaging features. In November 2014, Lemtrada received United States (U.S.) Food and Drug Administration (FDA) approval as a therapy for individuals who have failed at least two alternative therapies for the treatment of MS. Lemtrada's approval was limited to third-line therapy or later due to the unfavorable safety profile demonstrated in clinical trials relative to alternative therapies.

The efficacy and safety of Lemtrada in RRMS has been evaluated in several clinical trials as 1) first-line treatment for adults with treatment-naïve RRMS, Expanded Disability Status Scale (EDSS) scores less than or equal to 3.0 and disease duration of less than or equal to 3 years (CAMMS223; Coles, 2008; Cuker, 2011; Daniels, 2014), 2) as first-line treatment compared to interferon β-1a (IFNβ-1a) for active RRMS (CARE-MS I; Cohen, 2012), 3) as treatment for active RMMS compared with IFNβ-1a in adults on IFNβ-1a or glatiramer (CARE-MS II; Coles, 2012a), and, 4) in reducing the relapse rate and accumulation of disability compared with an IFNβ-1a through extended follow-up (CAMMS223; up to 60 months from baseline; Coles, 2012b).

In the CAMMS223 trial (Coles, 2008), Lemtrada reduced the rate of sustained accumulation of disability, as compared with IFNβ-1a (9.0% vs. 26.2%; hazard ratio [HR], 0.29; 95% confidence interval [CI], 0.16 to 0.54; p<0.001) and the annualized rate of relapse (0.10 vs. 0.36; HR, 0.26; 95% CI, 0.16 to 0.41; p<0.001). The mean disability score on a 10-point scale improved by 0.39 point in the alemtuzumab group and worsened by 0.38 point in the IFNβ-1a group (p<0.001). In the Lemtrada group, the lesion burden (as seen on T(2)-weighted magnetic resonance imaging [MRI]) was reduced, as compared with that in the IFNβ-1a group (p=0.005). From month 12 to month 36, brain volume (as seen on T(1)-weighted MRI) increased in the Lemtrada group but decreased in the IFNβ-1a group (p=0.02). Adverse events in the Lemtrada group, as compared with the IFNβ-1a group, included autoimmunity (thyroid disorders, 23% vs. 3%; immune thrombocytopenic purpura (ITP), 2.8% vs. 0.9%) and infections (66% vs. 47%). One participant died as a result of ITP and the data and safety monitoring board suspended the administration of Lemtrada between September 2005 and May 2007 after the report of 2 further cases. The suspension was lifted in April 2008 with implementation of a program to ensure prompt identification and management of ITP (Coles, 2011).

The two pivotal randomized, phase III studies compared treatment with Lemtrada to high-dose subcutaneous IFNβ-1a (Rebif® , EMD Serono, Inc., Rockland, MA) in adults with RRMS who have active disease and were either new to treatment (CARE-MS I) or who had relapsed while on prior therapy (CARE-MS II).

In the CARE-MS I trial, Cohen and colleagues (2012) conducted a rater-masked, randomized phase III controlled trial. Adults aged 18-50 years, who met the following eligibility criteria, were enrolled: previously untreated RRMS, EDSS score of 3 or less, disease duration of at least 5 years, at least 2 relapses in the previous 2 years, and cranial abnormalities on MRI attributable to MS. Individuals were ineligible who had a progressive disease course, previous MS therapy (other than corticosteroids), prior immunosuppressive, investigational, or monoclonal antibody therapy, or clinically significant autoimmune dysfunction, other than MS. Eligible participants were randomly allocated in a 2:1 ratio to receive intravenous alemtuzumab 12 mg per day (n=376) or subcutaneous IFNβ-1a 44 mg (n=187). IFNβ-1a was given 3 times a week and alemtuzumab was given once a day for 5 days at baseline and once a day for 3 additional days at 12 months. Primary outcomes were (1) relapse rate (defined as, "new or worsening neurological symptoms attributable to multiple sclerosis, lasting at least 48 hours, without pyrexia, after at least 30 days of clinical stability, with an objective change on neurological examination assessed by a masked rater") and (2) time to 6-month sustained accumulation of disability (defined as, "an increase from baseline of at least one EDSS point [or ≥ 1.5 points if baseline EDSS score was 0] confirmed over 6 months"). The relapse rate in the IFNβ-1a group was 122 events (40%, n=75) compared with 119 events (22%, n=82) in the alemtuzumab group (rate ratio [RR]=0.45 [95% CI, 0.32-0.63]; p<0.0001). Based on Kaplan-Meier estimates, 59% of the IFNβ-1a group was relapse-free at 2 years compared with 78% of the alemtuzumab group (p<0.0001). A total of 11% (n=20) of the IFNβ-1a group had sustained accumulation of disability compared with 8% (n=30) in the alemtuzumab group (HR=0.70 [95% CI, 0.40-1.23]; p=0.22). Overall, 14% of the alemtuzumab group had adverse reactions compared to only 8% of the IFNβ-1a. Adverse events in the alemtuzumab arm included infusion-associated reactions (90%; 3% of which were severe) and infections (67% vs 45% in IFNβ-1a group). At 2 years, 18% of the alemtuzumab group had thyroid-associated adverse events compared with only 6% in the IFNβ-1a group, and 1% (n=3) had immune thrombocytopenia compared with none in the interferon IFNβ-1a group. A total of 2 participants in the alemtuzumab group developed thyroid papillary carcinoma related to alemtuzumab and 1 died following study completion as a result of sepsis. Study limitations include the unblinded fashion of medication administration to either participants or medication administrators. The raters, however, were blinded to the treatment arm. Lemtrada was significantly more effective than IFNβ-1a at reducing annualized relapse rates; however, the difference observed in slowing disability progression did not reach statistical significance. The high rate of moderate to severe side effects compared to IFNβ-1a is also noteworthy.

The CARE-MS II trial, conducted by Coles and colleagues (2012a) was a 2-year, rater-masked, randomized controlled phase III trial. Adults aged 18-55 years with RRMS were enrolled if they had at least 1 relapse on IFNβ-1a or glatiramer, disease duration of 10 years or more, EDSS scores of 5 or less, 2 or more relapses in the previous 2 years, and cranial and spinal lesions on MRI attributable to MS. Individuals were ineligible who had a progressive disease course, previous MS therapy (other than corticosteroids), prior immunosuppressive, investigational, or monoclonal antibody therapy, or clinically significant autoimmune dysfunction, other than MS. Eligible participants were randomly allocated in a 1:2:2 ratio to receive: (1) subcutaneous IFNβ-1a 44 mg (n=202), (2) intravenous alemtuzumab 12 mg per day (n=426), or (3) intravenous alemtuzumab 24 mg per day (the 24 mg per day group was discontinued 1 year after study start to bolster recruitment). IFNβ-1a was given 3 times a week and alemtuzumab once a day for 5 days at baseline and for 3 additional days at 12 months. In accordance with the CARE-MS I trial, primary endpoints of this trial were (1) relapse rate and (2) time to 6-month sustained accumulation of disability. The relapsed rate in the IFNβ-1a group included 201 events (51%, n=104) compared with 236 events (35%, n=147) in the alemtuzumab group (RR=0.51 [95% CI 0.39-0.65]; p<0.0001). At 2 years, 47% of participants in the IFNβ-1a group were relapse-free compared with 65% in the alemtuzumab group (p<0.0001). In the IFNβ-1a group, 20% (n=40) had sustained accumulation of disability compared with only 13% (n=54) in the alemtuzumab group (HR 0.58 [95% CI 0.38-0.87]; p=0.008). Approximately 90% of the alemtuzumab group had infusion-associated reactions, 77% had infections (versus 66% of the in the IFNβ-1a group) that were mostly mild to moderate with 0 deaths, 16% had thyroid disorders, and 1% developed immune thrombocytopenia. Lemtrada was significantly more effective than IFNβ-1a at reducing annualized relapse rates, and accumulation of disability was significantly slowed in individuals treated with Lemtrada versus IFNβ-1a. Furthermore, radiologic findings from MRI confirmed that disease activity and progression favored the efficacy of treatment with alemtuzumab. The limitations of the CARE MS-I trial, lack of double-blinding and moderate to potentially severe side effects, were also limitations of the CARE MS-II trial. Investigators concluded, "For patients with first-line treatment-refractory relapsing-remitting multiple sclerosis, alemtuzumab could be used to reduce relapse rates and sustained accumulation of disability. Suitable risk management strategies allow for early identification of alemtuzumab's main adverse effect of secondary autoimmunity."

Tuohy and colleagues (2015) published long-term safety and efficacy data from an observational cohort study of 87 individuals diagnosed with RRMS, treated with alemtuzumab and followed for a median of 7 years (range, 33-144 months). The majority of individuals enrolled (52%) required only two cycles of alemtuzumab and the remaining were given additional cycles upon relapse in the following proportions; 36% received three cycles, 8% received four cycles, and 1% received five cycles. Based on a 6-month sustained accumulation of disability definition, 67.8% (n=59) of individuals had improved or unchanged disability from baseline measurements. Poorer long-term disability outcomes were associated with a higher baseline relapse rate and older age at onset of treatment. The most frequent adverse outcome was secondary autoimmunity which occurred in 48% of individuals, most often affecting the thyroid. The authors concluded that treatment with alemtuzumab provided disease stabilization in the majority of individuals in this study with highly active RRMS; no new safety concerns were reported over the long-term follow-up.

Early clinical trials of alemtuzumab in the treatment of MS established that although the drug reduced the relapse rate of individuals diagnosed with progressive forms of MS, overall sustained accumulation of disability remained unchanged. Authors theorized that the extent of axonal destruction in progressive disease may be beyond repair. As a result of these early studies, investigators concluded that the course of MS is ultimately unchanged by treatment with alemtuzumab once it is characterized by progression. Subsequent trials focused on the earliest stage of the disease, RRMS, which was found to have a modifiable disease course with alemtuzumab drug therapy (Coles, 2006).

In 2015, a Cochrane Review was conducted which included a meta-analysis of immunomodulators and immunosuppressant therapies for RRMS (Tramacere, 2015). A total of 39 studies were chosen for inclusion with 25,113 randomized participants. Of the 39 studies, 24 (60%) were placebo-controlled and 15 (40%) were head-to-head trials; 24 months was the median study duration across all trials. Using recurrence of relapse in RRMS as an outcome during the first 24 months of treatment, alemtuzumab, along with three other drugs, outperformed other treatments; alemtuzumab was labeled the most effective with a RR of 0.46 versus placebo (95% CI, 0.38-0.55), although the difference between it and two out of three of the other top performers was not statistically significant. Disability worsening was another outcome examined and alemtuzumab again performed favorably, in the top three drugs, relative to other treatments (RR=0.35, 95% CI, 0.26-0.48). The authors concluded:

Our review shows that alemtuzumab, natalizumab, and fingolimod are the best choices for preventing clinical relapses in people with RRMS, but this evidence is limited to the first 24 months of follow-up. For the prevention of disability worsening in the short term (24 months), only natalizumab shows a beneficial effect on the basis of moderate quality evidence (all of the other estimates were based on low to very low quality evidence) (Tramacere, 2015).

The authors caution that over 70% of the studies included in the review were sponsored by pharmaceutical companies which could introduce bias in the study results. They conclude by highlighting the need for more randomized trials of direct comparisons between active agents as well as follow-up from pivotal trials.

A more recent Cochrane review by Porfírio and colleagues (2016) evaluated alemtuzumab's efficacy and safety as a treatment for MS. Only three trials met criteria and were included in the study, they are described in detail above, CARE-MS, CAMMS223 and CARE-MS II, representing a total of 1713 study participants. The review concluded that alemtuzumab appears to be a better treatment than IFNβ-1a but the studies included were rated as 'low' to 'moderate' evidence and authors comment that further study is needed regarding other forms of MS and other doses of alemtuzumab.

A systematic review and meta-analysis was conducted by Fogarty and colleagues (2016) to compare disease-modifying therapies for the treatment of RRMS. A total of 28 randomized, placebo-controlled and direct comparative trials were included for analysis. Although alemtuzumab demonstrated consistently high rankings, the variation across studies in the definition of disability progression lead to difficulty in comparison between trials. The authors concluded that "Rigorously conducted comparative studies are required to fully evaluate the comparative treatment effects of disease modifying therapies for RRMS." Another systematic review and meta-analysis of 15 clinical trials, conducted by Mendes (2016), included alemtuzumab in its analysis but determined that IFNβ-1a and natalizumab appear to have the most favorable risk-benefit ratios among first and second-line disease-modifying therapies for RRMS, respectively. Post-hoc analysis of the pivotal clinical trial data continue to affirm alemtuzumab's efficacy and safety in the treatment of RRMS including a favorable impact on quality of life (Arroyo , 2016; Giovannoni, 2016).

The most common side effects of Lemtrada are infusion-associated reactions, infections (upper respiratory tract and urinary tract), lymphopenia and leukopenia. Serious autoimmune conditions can occur in individuals receiving alemtuzumab. Currently, a Risk Evaluation and Mitigation Strategy (REMS) program is in place to mitigate the risks of autoimmune conditions, infusion reactions, and malignancies associated with the administration of Lemtrada (FDA REMS_Lemtrada, 2014).


Multiple Sclerosis

According to the National Institute of Neurological Disorders and Stroke (NINDS, 2014), there are currently 250,000 to 350,000 people in the United States (US) diagnosed with MS. This estimate includes approximately 200 new cases diagnosed every week. Studies of the prevalence of individuals with MS indicate that the rate of the disease has increased steadily during the twentieth century.

The treatment of multiple sclerosis varies depending upon individual disease characteristics. RRMS is characterized by clearly defined relapses with full recovery or with sequelae and residual deficit upon recovery. There is no disease progression during the periods between disease relapses. RRMS is generally associated with a better prognosis than progressive disease. Certain immunomodulatory agents, including interferon beta preparations, glatiramer acetate, natalizumab, fingolimod, and teriflunomide, have shown beneficial effects for individuals with RRMS, including a decreased relapse rate and a slower accumulation of brain lesions on MRI.

Interferon beta agents and glatiramer acetate are administered in an effort to decrease the relapse rate and delay the progression of the disease. Multiple studies have demonstrated the efficacy of the beta interferon products or glatiramer acetate in the treatment of certain types of MS.

Adverse Events and Warnings

Black box warnings from the FDA Product Information Label (2014) include the following:

Additional warnings and recommendations from the FDA Product Information Label (2014) include:


Clinical lesion: An area of inflamed or demyelinated central nervous system tissue; synonymous with plaque.

Immune thrombocytopenic purpura (ITP): An immune mediated hematologic disorder characterized by impaired production of platelets in the bone marrow, and destruction of the peripherally circulating platelets.

Primary progressive MS (PPMS): A clinical course of MS characterized by progression of disability from onset without superimposed relapses. The term progressive-relapsing multiple sclerosis or PRMS, previously used to characterize individuals who had progressive disease from onset and clear acute relapses, is no longer preferred. An acute relapse in an individuals with progressive disease from onset is now considered to be PPMS with active disease, whereas those with progressive disease from onset without acute relapses are considered to have PPMS, not active but with progression.

Relapse: The appearance of new symptoms or the aggravation of old ones, lasting at least 24 hours (synonymous with exacerbation, attack, flare-up, or worsening); usually associated with inflammation and demyelination in the brain or spinal cord.

Relapsing-remitting MS (RRMS): A clinical course of MS characterized by clearly defined, acute relapses with full or partial recovery; no disease progression or worsening of disability develops between relapses.

Secondary progressive MS (SPMS): A clinical course of MS demonstrating sustained progression of physical disability occurring separately from relapses in individuals who previously had RRMS.


The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

J0202 Injection, alemtuzumab, 1 mg [Lemtrada]
ICD-10 Diagnosis  
G35 Multiple sclerosis

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.


Peer Reviewed Publications:

  1. Arroyo González R, Kita M, Crayton H, et al. Alemtuzumab improves quality-of-life outcomes compared with subcutaneous interferon beta-1a in patients with active relapsing-remitting multiple sclerosis. Mult Scler. 2016 Nov 24. [Epub ahead of print].
  2. 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 randomised controlled phase 3 trial. Lancet. 2012; 380 (9856):1819-1828.
  3. Coles AJ, Compston DA, Selmaj KW, et al. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med. 2008; 359:1786-1801.
  4. Coles AJ, Cox A, Le Page E, et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol. 2006; 253(1):98-108.
  5. Coles AJ, Fox E, Vladic A, et al. Alemtuzumab more effective than interferon β-1a at 5-year follow-up of CAMMS223 clinical trial. Neurology. 2012b; 78(14):1069-1078.
  6. Coles AJ, Fox E, Vladic A, et al. Alemtuzumab versus interferon β-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes. Lancet Neurol. 2011; 10(4):338-348.
  7. Coles AJ, Twyman CL, Arnold DL, et al.; CARE-MS II Investigators. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet. 2012a; 380(9856):1829-1839.
  8. Cuker A, Coles AJ, Sullivan H, et al. A distinctive form of immune thrombocytopenia in a phase 2 study of alemtuzumab for the treatment of relapsing-remitting multiple sclerosis. Blood. 2011; 118(24):6299-6305.
  9. Daniels GH, Vladic A, Brinar V, et al. Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis. J Clin Endocrinol Metab. 2014; 99(1):80-89.
  10. Fogarty E, Schmitz S, Tubridy N, et al. Comparative efficacy of disease-modifying therapies for patients with relapsing remitting multiple sclerosis: systematic review and network meta-analysis. Mult Scler Relat Disord. 2016; 9:23-30.
  11. Fox EJ, Wynn D, Coles AJ, et. al. Alemtuzumab improves neurological functional systems in treatment-naïve relapsing-remitting multiple sclerosis patients. J Neurol Sci.2016; 363:188-194.
  12. Giovannoni G, Cohen JA, Coles AJ, et al. Alemtuzumab improves preexisting disability in active relapsing-remitting MS patients. Neurology. 2016; 87(19):1985-1992.
  13. Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014; 83(3):278-286.
  14. Mendes D, Alves C, Batel-Marques F. Benefit-risk of therapies for relapsing-remitting multiple sclerosis: testing the Number Needed to Treat to Benefit (NNTB), Number Needed to Treat to Harm (NNTH) and the Likelihood to be Helped or Harmed (LHH): A systematic review and meta-analysis. CNS Drugs. 2016; 30(10):909-929.
  15. Tuohy O, Costelloe L, Hill-Cawthorne G, et al. Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy. J Neurol Neurosurg Psychiatry. 2015; 86(2):208-215.

Government Agency, Medical Society, and Other Authoritative Publications: 

  1. Alemtuzumab. In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated December 02, 2015. Available at: Accessed on January 5, 2017.
  2. Alemtuzumab Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS® ) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised December 01, 2010. Accessed on January 5, 2017.
  3. Lemtrada® . [Product Information] Cambridge, MA. Updated November, 2014. Available at: Accessed on January 5, 2017.
  4. Porfírio GJ, Torloni MR. Alemtuzumab for multiple sclerosis. Cochrane Database Syst Rev. 2016 Apr 15; 4: CD011203.
  5. Tramacere I, Giovane C, Salanti G, et al. Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis. Cochrane Database Syst Rev. 2015; (2):CD011381.
  6. U.S. Food and Drug Administration (FDA) Risk Evaluation and Mitigation Strategy (REMS). BLA 103948 LEMTRADA® (alemtuzumab) CD52-directed cytolytic antibody. Available at: Accessed on January 5, 2017.
Websites for Additional Information
  1. American Academy of Neurology. Multiple Sclerosis: Practice Guidelines. Available at: . Accessed on January 5, 2017.
  2. National Institute of Neurological Disorders and Stroke (NINDS). Multiple Sclerosis: Hope Through Research. Last Updated November 19, 2015. Available at: . . Accessed on January 06, 2016.
  3. National Institute of Neurological Disorders and Stroke (NINDS). Multiple Sclerosis Information Page. Last Updated on November 19, 2015. Available at: . Accessed on January 5, 2017.
  4. National Multiple Sclerosis Society. What is MS? Available at: Accessed January 5, 2017.
  5. Tarver, M. Kurtzke Expanded Disability Status Scale (EDSS). Department of Veterans Affairs: Multiple Sclerosis Centers for Excellence. Last Updated on July 2015. Available at: Accessed on January 5, 2017.


The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History
Status Date Action
Reviewed 02/02/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Updated Rationale and References sections.
Reviewed 02/04/2016 MPTAC review. Updated registered trademark in title. Updated Rationale and References sections.
  01/01/2016 Updated Coding section with 01/01/2016 HCPCS changes, removed Q9979 deleted 12/31/2015; also removed ICD-9 codes.
Reviewed 08/06/2015 MPTAC review. Updated Rationale and References. Updated Coding section with 10/01/2015 HCPCS changes.
New 02/05/2015 MPTAC review. Initial document development.