Relapsing-remitting multiple sclerosis (MS) patients who experienced breakthrough disease despite treatment with interferon beta-1a required less acute corticosteroids during relapses and had better responses on several MRI outcomes with the addition of fludarabine, compared with monthly methylprednisolone, in a small, prospective, randomized, open-label study.
Investigators led by Dr. Steven J. Greenberg of AbbVie, North Chicago, chose to test fludarabine in the proof-of-concept, pilot study because of its immunosuppressive properties and effectiveness in treating disorders involving immune dysregulation, most notably lymphoproliferative disorders and hematologic malignancies.
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Fludarabine is a purine nucleoside analog prodrug that upon phosphorylation is toxic to dividing and quiescent lymphocytes and monocytes, according to the researchers, and exerts its effects through DNA synthesis interference and apoptosis. Methylprednisolone was used as an add-on comparator because of its common use in multiple sclerosis.
In addition to weekly intramuscular interferon beta-1a (Avonex), all 18 patients in the study initially received IV methylprednisolone 1 g once daily for 3 consecutive days, and then 1 week later were randomized to receive fludarabine 25 mg/m2 IV once daily for 5 consecutive days per 4-week cycle for 3 consecutive cycles or methylprednisolone 1 g IV 1 day per 4-week cycle for 3 consecutive cycles (Ther Adv Neurol Disord. 2016 Jan 21. doi: 10.1177/1756285615626049).
Treatment-emergent adverse events occurred with similar frequency in each group over 12 months of follow-up, with infection being the most common AE (three with fludarabine and two with methylprednisolone). Grade 3 or grade 2 leukopenia that had not normalized within 28 days after treatment occurred in three fludarabine patients and one methylprednisolone patient, and took significantly longer resolve for those taking fludarabine (3.75 months vs. 0.17 months).
Over 12 months of follow-up, fludarabine-treated patients experienced numerically, but not significantly, fewer mean relapses (0.5 vs. 0.8) and longer median time to relapse (10.5 months vs. 8.5 months). However, fludarabine led to significantly fewer mean cycles of corticosteroids (0.5 vs. 0.8).
Expanded Disability Status Scale scores declined from baseline to 12 months by a mean of –0.2 in the fludarabine group but increased in the methylprednisolone group by 0.5. Both groups achieved slight improvements in MS Functional Composite scores.
Fludarabine-treated patients had significant declines from baseline to 12 months in gadolinium-positive lesion volume (–98.3%) and number (–93.3%), but no significant differences were recorded in either group for changes in FLAIR lesion volume, T1-hypointense lesion volume or number, or brain parenchymal fraction.
Two outlier patients in the fludarabine group who had 21 and 17 gadolinium-positive lesions, respectively, at baseline were examined in separate analyses and results for the fludarabine group were analyzed both with and without them. None of the results appreciably changed when they were included or excluded, except for gadolinium-positive lesion volume and number, which were not significantly changed without the two patients. The two outlier patients had 100% mean reductions in gadolinium-positive lesion number and volume and a 19.4% mean reduction in FLAIR lesion volume.
The investigators cautioned that “the long-term safety of repetitive use has not been established by this study, which is a critical consideration for a chronic disease like MS. We emphasize that our results should be considered preliminary and would await confirmation in a larger-scale trial.”
This study was supported in part by an investigator-initiated study grant provided by Biogen. Berlex Laboratories provided fludarabine. Dr. Greenberg is an employee of AbbVie, and two coauthors reported financial ties to companies marketing MS drugs.