FROM NEUROLOGY: NEUROIMMUNOLOGY AND NEUROINFLAMMATION
Nine relapsing multiple sclerosis patients had significant and unexpected disease activity within 12 months of switching from fingolimod to alemtuzumab, according to a report from six European neuroscience centers.
The centers treated 174 patients with alemtuzumab (Lemtrada); 36 had been on fingolimod (Gilenya) beforehand. “Therefore, these nine patients … represent 25% of the fingolimod-alemtuzumab cohort,” said investigators led by Mark Willis, MBBCh, a clinical research fellow at Cardiff University, Wales (Neurol Neuroimmunol Neuroinflamm. 2017 Jan 10. doi: 10.1212/NXI.0000000000000320 ).
The team speculated that prolonged sequestration of autoreactive lymphocytes following fingolimod withdrawal allowed “these cells to be concealed from the usual biological effect of alemtuzumab. Subsequent lymphocyte egress then provoke[d] disease reactivation … This may have important implications for sequential drug selection and washout periods in a subset of patients who switch from fingolimod or drugs with similar biological mechanisms,” they said.
“Careful consideration needs to be given to mode of action of individual therapies and sequential treatment effects,” the team concluded.
The nine patients were on fingolimod for 5-33 months, but it wasn’t working well so they were started on alemtuzumab following a median fingolimod washout period of 6 weeks. Eight patients had at least one clinical relapse within 12 months of the first alemtuzumab infusion cycle; the median time to relapse following alemtuzumab induction was 4.5 months. All nine patients had radiologic evidence of new disease activity.
Five patients had lymphocyte counts below normal when started on alemtuzumab.
Fingolimod has a half-life of 6-9 days, so “lymphocytes would be expected to normalize 2-4 weeks after discontinuation. However, there are case reports of prolonged lymphopenia following prolonged drug exposure, up to 37 months after discontinuation.” It has “been suggested that patients continue on an alternative [disease-modifying treatment] after fingolimod discontinuation, preferably until peripheral lymphocyte counts have normalized.” However, “there is currently no consensus as to which subsequent therapeutic agent is optimal,” the investigators said.
Despite the presence of disease activity in the first 12 months, all nine patients went on to the second planned infusion of alemtuzumab; eight were relapse free during a mean follow-up of 6 months after the second treatment cycle. Four of seven were radiologically stable, but three had new T2 lesions and one with a single new gadolinium-enhancing lesion.
Even so, the findings offers “some support to the hypothesis that, after a period, sequestrated lymphocytes eventually become available for depletion by alemtuzumab,” the researchers noted.
The mean age of the patients when diagnosed with MS was 21 years. The median disease duration to alemtuzumab treatment was 94 months.
There was no external funding. Dr. Willis had no disclosures. Other researchers reported ties to a number of companies, including Genzyme, maker of alemtuzumab, and Novartis, fingolimod’s maker.