New Opportunistic Infection With Alemtuzumab

April 07, 2016

A new opportunistic infection — cerebral nocardiosis — associated with the multiple sclerosis (MS) drug alemtuzumab (Lemtrada, Genzyme) has been reported.

The case report, published online in JAMA Neurology on April 4, describes a woman in her late 40s in whom cerebral nocardiosis was diagnosed 5 months after initiation of alemtuzumab therapy.

The authors, led by Horst Penkert, MD, Technische Universität München, Germany, report that the patient had a medical history that included hypothyroidism, recurrent infections, and an anorectic disorder (body mass index of 14 kg/m2 on admission).

They suggest that her low body mass index may have contributed to a preexisting immunodeficient state and that physicians should be cautious when considering alemtuzumab in patients with MS and suspected altered cellular immunity of any origin, including a low body mass index.

Coauthor of an accompanying editorial, Reinhard Hohlfeld, MD, Institute of Clinical Neuroimmunology, Klinikum der LMU München, Germany, told Medscape Medical News that this appears to be the first report of nocardiosis with alemtuzumab in a patient who was not considered to be immunocompromised before treatment.

But because the patient was anorectic, which has been associated with immunologic changes, Dr Hohlfeld does not think this one case report should affect general recommendations on use of alemtuzumab. "I would view it more as a note of caution when considering treating patients who are very underweight or immunocompromised in other ways," he said.

Dr Penkert and coauthors note that the patient had previously received 80 infusions of natalizumab, which was stopped because of intermittent relapses and seroconversion to positive JC virus status. Alemtuzumab was started 18 weeks after the last natalizumab dose, at which time all mononuclear cell subsets that can be affected by natalizumab in the patient's peripheral blood were normal.

In their editorial, Dr Hohlfeld and coauthor Tania Kümpfel, MD, also from the Institute of Clinical Neuroimmunology, point out that an interval of up to 6 months is recommended between discontinuation of natalizumab and starting alemtuzumab but that any "safety interval" longer than 3 months carries a definite risk for recurrence of MS activity.

Dr Penkert and colleagues note that nocardia infects the lungs and spreads from there, with potential damage to the central nervous system when intraepithelial and systemic cellular immunity fails. They point out that previous cases of pulmonary and disseminated nocardiosis have been associated with alemtuzumab treatment, but only in patients with preexisting conditions that compromise immunity, including non-Hodgkin's lymphoma, B cell lymphocytic leukemia, and organ transplantation.

Dr Hohlfeld explained that alemtuzumab works by binding to CD52 expressed by many types of immune cells, including T lymphocytes, B lymphocytes, monocytes, macrophages, and eosinophils, which are then cleared from the blood and are gradually replaced at different rates.

Dr Penkert and coauthors report that the current patient had no signs of lymphocyte reconstitution at 5 months after alemtuzumab treatment, suggesting that she experienced prolonged immunodeficiency. They propose that the regular dose of alemtuzumab (12 mg/d for 5 days) might have been excessive in this case because of the patient's low body mass. "Besides eliminating circulating mononuclear cell subsets, alemtuzumab might have depleted lymphocytes in compartments (eg, intraepithelial lymphocytes) that are normally spared," they suggest.

The editorialists agree that the prolonged lymphocyte depletion in this case may indicate that the regular dose of alemtuzumab is too high for a person with a very low body mass index. "Therefore, a body weight–adapted dose regimen may be more appropriate for patients with very low body mass indices."

However, Dr Hohlfeld told Medscape Medical News that there are no data on lower doses of alemtuzumab and it is not clear whether lower doses would be effective.

"Cerebral nocardiosis should be added to the list of differential diagnoses when neurologic complications arise during alemtuzumab treatment," the editorialists conclude.

"[S]pecial caution is required in possibly immunocompromised patients because their health may be generally impaired or they may be frail. In particular, a strongly reduced body mass index, as seen in patients with anorexia nervosa, may be accompanied by a functionally immunocompromised state despite normal lymphocyte counts."

They add that this case highlights the lack of reliable tests for assessing functional immune competence and "should raise vigilance against alemtuzumab-associated opportunistic infections, which will undoubtedly continue."

Coauthor Thomas Korn, MD, reported having received a research grant for preclinical research from Biogen Idec Inc and support from the German Research Council and the European Research Council. The other authors have disclosed no relevant financial relationships. Editorialist Dr Hohlfeld reported having received grants from Bayer, Biogen, Genzyme-Sanofi, Merck-Serono, Novartis, and Teva and personal fees from Actelion, Bayer, Biogen, Genzyme-Sanofi, Medday, Merck-Serono, Novartis, Roche, and Teva. Dr Kümpfel reported having received grants from Bayer and Novartis and personal fees from Bayer, Biogen, Genzyme-Sanofi, Merck-Serono, Novartis, and Teva.

JAMA Neurol. Published online April 4, 2016. Abstract Editorial

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