Fingolimod inducing low white blood cell levels but saving brain

What are the consequences of having a low lymphocyte count when starting fingolimod?

Ohtani R, Mori M, Uchida T, Uzawa A, Masuda H, Liu J, Kuwabara S. Risk factors for fingolimod-induced lymphopenia in multiple sclerosis.Mult Scler J Exp Transl Clin. 2018 Feb 20;4(1):2055217318759692. 

BACKGROUND:Lymphopenia is a well-known adverse event of fingolimod, a disease-modifying drug for multiple sclerosis (MS).
OBJECTIVES: The objective of this paper is to investigate risk factors for predicting fingolimod-induced lymphopenia in MS by frequent hematological monitoring.
METHODS:We retrospectively reviewed data of fingolimod-treated MS patients. Data assessed were sex, age, disease duration, medication history, body mass index, all attacks, Kurtzke’s Expanded Disability Status Scale score, and absolute lymphocyte count (ALC) within two days before initiating fingolimod (baseline), on the day after first administration (day 2), and at least every other month after initiating fingolimod therapy.
RESULTS: Of 41 MS patients, marked lymphopenia (ALC <200/µl) was confirmed in 12 patients (lymphopenia group) within one year. A significantly more frequent history of treatment with any interferon-beta and lower median baseline ALC was observed in the lymphopenia group than in the non-lymphopenia group (n = 29) (91.7% vs. 44.8%; p = 0.006 and 1469/µl vs. 1879/µl; p = 0.005). An ALC of ≤952/μl on day 2 was the most responsible risk factor for predicting marked lymphopenia (sensitivity, 92%; specificity, 76%; area under the curve, 0.823; p < 0.001).
CONCLUSIONS: Low baseline ALC and treatment history with any interferon-beta were risk factors for fingolimod-induced lymphopenia, possibly predicted from ALC on day 2.

Low white blood cells count is part of the mechanism of many MS drugs, but if the counts stay low for too low then it exposes you risk like infection. Persistent lymphopenia occurs with DMF and as reported here with fingolimod also. This study looked for predictors of low white blood count and found that a low white cell count was a predictor

Gaetano L, Häring DA, Radue EW, Mueller-Lenke N, Thakur A, Tomic D, Kappos L, Sprenger T.Fingolimod effect on gray matter, thalamus, and white matter in patients with multiple sclerosis. Neurology. 2018 Mar 14. pii: 10.1212/WNL.0000000000005292.

OBJECTIVE: To study the effect of fingolimod on deep gray matter (GM), thalamus, cortical GM, white matter (WM), and ventricular volume (VV) in patients with relapsing-remitting multiple sclerosis (RRMS).
METHODS: Data were pooled from 2 phase III studies. A total of 2,064 of 2,355 (88%) contributed to the analysis: fingolimod 0.5 mg n = 783, fingolimod 1.25 mg n = 799, or placebo n = 773. Percentage change from baseline in dGM and thalamic volumes was evaluated; WM, cortical GM, and VV were evaluated using normalization of atrophy at months 12 and 24.
 For placebo, volume reductions were most pronounced in cGM, and relative changes from baseline were strongest in deep GM. Over 24 months, there were significant reductions with fingolimod vs placebo for deep GM (0.5 mg -14.5%, p = 0.017; 1.25 mg -26.6%, p < 0.01) and thalamus (0.5 mg -26.1%, p = 0.006; 1.25 mg -49.7%, p < 0.001). Reduction of cortical GM volume loss was not significant. Significantly less WM loss and VV enlargement were seen with fingolimod vs placebo (all p < 0.001). A high T2 lesion volume at baseline predicted on-study cortical and deep GM and thalamic volume loss (p < 0.0001) but not WM loss. Patients taking placebo with high deep GM (hazard ratio [HR] 0.54, p = 0.0323) or thalamic (HR 0.58, p = 0.0663) volume at baseline were less likely to show future disability worsening.

CONCLUSIONS: Fingolimod significantly reduced deep GM volume loss (including thalamus) vs placebo in patients with RRMS. Reducing deep GM and thalamic volume loss might improve long-term outcome

However if grey matter volume loss was inhibited , how come fingolimod failed to inhibit progressive MS. Is it poor tiral design or a small biological effect.

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