Off-Label Use of Alemtuzumab Yields Benefits and Risks in MS

WASHINGTON, DC—A retrospective study of patients with multiple sclerosis (MS) treated off-label with the anti-CD52 monoclonal alemtuzumab found an improved short-term disability in most patients with treatment-refractory MS but also a notable risk of adverse effects, according to Heli M. Hunter, MSN, and Samuel F. Hunter, MD, PhD. The researchers, both affiliated with the Advanced Neurosciences Institute and the Novel Pharmaceutics Institute in Nashville, presented their findings at the 21st Annual Meeting of the Consortium of Multiple Sclerosis Centers.

“We present a retrospective review of 19 serial patients for whom 14 have short-term disability follow-up of treatment responses,” stated the researchers. “This treatment-refractory cohort with very active MS had improved short-term disability in a majority with excellent patient subjective responses. Early relapses were not uncommon, but [patients] responded to corticosteroids. Early data support [the theory] that the relapse rate is perhaps improved as compared to the pre-alemtuzumab treatment regimens.... Potential cost savings and simplicity are attractive, but careful education, monitoring, and preparation are required for possible severe infusion reactions or other toxicity.”

TREATMENT IN MS

Although preliminary data have shown favorable results regarding alemtuzumab, there was growing concern that the drug would not be approved for the treatment of MS for some time. “Given the current regulatory environment in North America, alemtuzumab appears to be years away from formal labeling for MS, but efficacy data warrant consideration for use in suboptimal treatment responders or those with risk factors for poor prognosis,” said the researchers.

The patients in this study had treatment-refractory MS with poor response to prior interferon beta or contraindications to its use, and most had tried glatiramer acetate and/or other alternatives. Patients were treated with a single 60-mg dose of alemtuzumab that was administered for three to five days with three days of high-dose IV methylprednisolone, oral diphenhydramine, acetaminophen, and meperidine to reduce adverse effects. The researchers plan a second-year treatment of 30 mg of alemtuzumab. Because so many patients had prior immunosuppressive therapy and were older (median age, 45), all were given acyclovir to protect against herpes infection, and trimethoprim-sulfamethoxazole or dapsone, to protect against Pneumocystis carinii pneumonia.

“We infused clients as outpatients with continuous observation by a skilled registered nurse experienced in management of infusion reactions, including anaphylactoid reactions,” reported the investigators. “IV and oral diphenhydramine, saline, epinephrine, dexamethasone, and acetaminophen were available if needed. It is strongly recommended that reclining infusion chairs and continuous physician supervision be employed. Reliable IV access is not optional.”

Infusion rates began at 10 to 20 cc/hour and were doubled every 20 to 30 minutes if well tolerated. The infusion rate was slowed, and the course expanded to four to five days for patients who had symptoms that were more severe than minimal.

“We quickly recognized that failure to halt or limit the infusion rate in patients with premonitory pruritus led to more widespread rashes and then urticaria,” noted the researchers, who are now routinely administering an additional 50 mg of oral diphenhydramine immediately at the onset of pruritus, stopping the infusion when pruritus subsides, and then restarting the infusion at a lower rate. If a rash occurs, they administer oral hydroxyzine 50 mg three times daily, increasing the dose to 100 mg three times daily if needed.

The researchers reported data for 19 patients—eight with relapsing MS and 11 with progressive MS. The baseline relapse rate during the previous two years was a median of 1.0/year with a mean of 1.4 /year. Median Expanded Disability Status Scale (EDSS) score was 6.0, with a prior-year mean and median change of 0.5 points. Prior treatment costs were a mean of $29,000/year.

Following the single doses of alemtuzumab, the mean relapse rate decreased to 0.9/year. Three of 14 patients for whom EDSS data were available improved by 1.5 to 2.0 points, six improved by 0.5 to 1.0 point, and four had no change in EDSS score. Eight patients each rated their response to alemtuzumab as “very good” or “good,” and two reported no effect. The cost of alemtuzumab treatment was $8,000 and included two IV methylprednisolone courses.

Among adverse events that were observed, one patient developed anaphylactoid hypotension or bronchospasm, two patients had major urticaria, marked rash, mild bronchospasm, or cough, 13 patients developed minor erythematous rash or evanescent urticaria or moderate to severe headache (at a median dose of 50 mg), and three patients had mild or no complaints.

The investigators concluded that alemtuzumab “can be implemented in off-label use as a safe, cost-effective, practical, and neurologically effective therapy for treatment-refractory or poor-prognosis MS in the most common variants of relapsing and secondary progressive MS. Substantial care is required in informed consent, patient education, and treatment monitoring to avoid adverse effects.”           

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