Intracerebral lymphoproliferative disorder in an MS patient treated with fingolimod

Brigit A. de Jong, Zoé L.E. van Kempen, Mike P. Wattjes, Patrick M. Smit, Laura Peferoen, Daniella Berry, Martine E.D. Chamuleau, Daphne de Jong
2018 Neurology: Neuroimmunology & Neuroinflammation  
Fingolimod, an oral sphingosine 1-phosphate (S1P) receptor modulator, is an effective oral immune therapy for treatment of relapsing-remitting MS (RRMS). 1 Development of solid malignancies was observed in large randomized phase-3 trials examining the efficacy and safety of fingolimod in patients with RRMS. 1 In this article, we present a patient who developed a primary central nervous system T-cell lymphoproliferative disorder during fingolimod treatment. Case report In January 2017, a
more » ... old man diagnosed with RRMS 3 years before presented with progressive dysarthria, vertigo, vomiting, and deficits in balance 6 months after starting fingolimod therapy. Fingolimod was initiated because of persistent disease activity after treatment with dimethyl fumarate (2014-2015) and interferon-beta 1a (2015)(2016). The patient had no significant medical history other than MS. Neurologic examination showed profound dysarthria and mild left-sided ataxia; with a normal gait. Fingolimod-induced peripheral blood lymphopenia (0.24 × 10 9 /L) was noted. MRI scan of the brain revealed new multifocal contrastenhancing lesions (figure, A) suggestive of CNS lymphoma. Fingolimod was discontinued immediately. There were no signs of systemic or ocular lymphoma involvement based on history, physical examination, and whole-body PET-CT. Six days after the MRI scan, a stereotactic biopsy of a left cerebellar lesion was performed and dexamethasone 8 mg daily was administered. Three weeks later, MRI scan of the brain revealed a decrease in the size of lesions observed in the previous scan; however, a new contrast-enhancing lesion was observed in the left frontal lobe. Shrinkage of the cerebellar lesion enabled lumbar puncture, which was contraindicated before because of compression on the fourth ventricle. Cerebrospinal fluid showed elevated protein levels (1.02 g/L) and leukocyte count (10 × 10 6 /L) without morphological or immunophenotypical abnormalities. Dexamethasone was tapered and stopped. A second follow-up MRI showed progression of left cerebellar and frontal lesions. A second stereotactic brain biopsy was performed because the first biopsy was considered inconclusive at that time. Both biopsy samples showed a lymphoproliferative process in the normal-appearing brain parenchyma, predominantly T cells with a small subpopulation of small B cells (figure, B; figure e-1, Immunohistochemical and molecular analysis supported oligoclonal proliferation of both B and T cells. However, the aberrant T-cell phenotype (CD4 + / PD1 + ) and genotype were most consistent with a reflection of dominant T-cell dysregulation, possibly with premalignant features and likely an association with a minor dysregulated B-cell proliferation (small cell, EBV negative). A diagnosis of overt malignant lymphoma was not appropriate based on these features. Considering the clinical context, a working diagnosis of T-cell primary CNS lymphoma (PCNSL) was made, despite the absence of confirmed T-cell monoclonality. Treatment with 2 induction chemotherapy cycles of MBVP (methotrexate,
doi:10.1212/nxi.0000000000000483 pmid:30027107 pmcid:PMC6047430 fatcat:xm4zphpsknh5jdizy2va74kmny