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Predictors of hematological abnormalities in multiple sclerosis patients treated with fingolimod and dimethyl fumarate and impact of treatment switch on lymphocyte and leukocyte count

Published:December 13, 2017DOI:https://doi.org/10.1016/j.msard.2017.12.003

      Highlights

      • Lymphocyte subset profiles in lymphopenic and non lymphopenic patients on dimethyl fumarate (DMF) and fingolimod were studied.
      • Female sex and prior exposure to natalizumab increased the probability of lymphopenia on fingolimod.
      • Older age was associated with increased risk of lymphopenia in patients treated with DMF.
      • Parallel switch did not lead to recovery from hematological abnormalities.
      • Reduced dose regimen of fingolimod led to modest increase in lymphocyte count but increased disease activity.

      Abstract

      Background

      There is limited data regarding the predictors of hematological abnormalities in multiple sclerosis (MS) patients treated with dimethyl fumarate (DMF) or fingolimod (FNG), and the impact of treatment switch on lymphocyte and leukocyte count

      Methods

      We identified 405 patients on DMF and 300 patients on FNG (treatment duration: at least 12 month) within a large prospective study of MS patients conducted at the Partners MS Center, Brigham and Women's Hospital (CLIMB study) between Jan 2011 to Feb 2016. Patients had complete blood counts with differentials at baseline and every 6 months while on treatment. Most participants had a clinical visit with complete neurologic examinations every 6 months and brain MRI scan every 12 months. T cell subset profile was available for subgroup of patients (n = 116).

      Results

      In the FNG group, the risk of developing lymphopenia grade 4 (< 200) was higher in female patients (p = 0.0117) and those who were previously treated with natalizumab (p = 0.0116), while the risk of lymphopenia grade 3b+4 (< 350) was higher in female patients (p = 0.0009). DMF treated patients with lower baseline lymphocyte count had a higher chance of developing lymphopenia grade 2 (< 800) (p < 0.0001) or 2+3 (< 500) (p < 0.0001). We examined the effect of treatment switch between DMF and FNG. No significant recovery in lymphocyte and leukocyte count was observed after treatment switches. Reduced dosing of FNG in patients with lymphopenia led to increase in lymphocyte count but also increased disease activity in 25% of patients.

      Conclusion

      Female sex and prior exposure to natalizumab increased the probability of lymphopenia on FNG, while low absolute lymphocyte count was associated with increased risk of lymphopenia on DMF. Parallel switch did not lead to recovery from hematological abnormalities. Long-term studies with larger number of patients are required to confirm our findings and to establish guidelines for prediction and management of hematological abnormalities.

      Keywords

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      References

        • Achtnichts L.
        • Obreja O.
        • Conen A.
        • Fux C.A.
        • Nedeltchev K.
        Cryptococcal meningoencephalitis in a patient with multiple sclerosis treated with fingolimod.
        JAMA Neurol. 2015; 72: 1203-1205
        • Baharnoori M.
        • Lyons J.
        • Dastagir A.
        • Koralnik I.
        • Stankiewicz J.M.
        Nonfatal PML in a patient with multiple sclerosis treated with dimethyl fumarate.
        Neurol. Neuroimmunol. Neuroinflamm. 2016; 3: e274
        • Bartsch T.
        • Rempe T.
        • Wrede A.
        • et al.
        Progressive neurologic dysfunction in a psoriasis patient treated with dimethyl fumarate.
        Ann. Neurol. 2015; 78: 501-514
        • Cohen J.A.
        • Barkhof F.
        • Comi G.
        • et al.
        Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis.
        N. Engl. J. Med. 2010; 362: 402-415
        • Forrestel A.K.
        • Modi B.G.
        • Longworth S.
        • Wilck M.B.
        • Micheletti R.G.
        Primary cutaneous cryptococcus in a patient with multiple sclerosis treated with fingolimod.
        JAMA Neurol. 2016; 73: 355-356
        • Fox R.J.
        • Miller D.H.
        • Phillips J.T.
        • et al.
        Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis.
        N. Engl. J. Med. 2012; 367: 1087-1097
        • Fox R.J.
        • Chan A.
        • Gold R.
        • et al.
        Characterizing absolute lymphocyte count profiles in dimethyl fumarate-treated patients with MS: patient management considerations.
        Neurol. Clin. Pract. 2016; 6: 220-229
        • Ghadiri M.
        • Rezk A.
        • Li R.
        • et al.
        Dimethyl fumarate-induced lymphopenia in MS due to differential T-cell subset apoptosis.
        Neurol. Neuroimmunol. Neuroinflamm. 2017; 4: e340
        • Gillard G.O.
        • Collette B.
        • Anderson J.
        • et al.
        DMF, but not other fumarates, inhibits NF-kappab activity in vitro in an Nrf2-independent manner.
        J. Neuroimmunol. 2015; 283: 74-85
        • Gold R.
        • Kappos L.
        • Arnold D.L.
        • et al.
        Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis.
        N. Engl. J. Med. 2012; 367: 1098-1107
        • Grebenciucova E.
        • Reder A.T.
        • Bernard J.T.
        Immunologic mechanisms of fingolimod and the role of immunosenescence in the risk of cryptococcal infection: a case report and review of literature.
        Mult. Scler. Relat. Disord. 2016; 9: 158-162
        • Gyang T.V.
        • Hamel J.
        • Goodman A.D.
        • Gross R.A.
        • Samkoff L.
        Fingolimod-associated PML in a patient with prior immunosuppression.
        Neurology. 2016; 86: 1843-1845
        • Han G.
        • Zhou Q.
        Dimethylfumarate induces cell cycle arrest and apoptosis via regulating intracellular redox systems in HeLa cells.
        In Vitro Cell Dev. Biol. Anim. 2016; 52: 1034-1041
        • Henault D.
        • Galleguillos L.
        • Moore C.
        • Johnson T.
        • Bar-Or A.
        • Antel J.
        Basis for fluctuations in lymphocyte counts in fingolimod-treated patients with multiple sclerosis.
        Neurology. 2013; 81: 1768-1772
        • Huang D.
        Disseminated cryptococcosis in a patient with multiple sclerosis treated with fingolimod.
        Neurology. 2015; 85: 1001-1003
        • Kappos L.
        • Radue E.W.
        • O'Connor P.
        • et al.
        A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis.
        N. Engl. J. Med. 2010; 362: 387-401
        • Khatri B.O.
        • Garland J.
        • Berger J.
        • et al.
        The effect of dimethyl fumarate (Tecfidera) on lymphocyte counts: a potential contributor to progressive multifocal leukoencephalopathy risk.
        Mult. Scler. Relat. Disord. 2015; 4: 377-379
        • Lehmann-Horn K.
        • Penkert H.
        • Grein P.
        • et al.
        PML during dimethyl fumarate treatment of multiple sclerosis: how does lymphopenia matter?.
        Neurology. 2016; 87: 440-441
        • Linker R.A.
        • Lee D.H.
        • Ryan S.
        • et al.
        Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway.
        Brain. 2011; 134: 678-692
        • Longbrake E.E.
        • Cross A.H.
        Dimethyl fumarate associated lymphopenia in clinical practice.
        Mult. Scler. 2015; 21: 796-797
        • Longbrake E.E.
        • Ramsbottom M.J.
        • Cantoni C.
        • Ghezzi L.
        • Cross A.H.
        • Piccio L.
        Dimethyl fumarate selectively reduces memory T cells in multiple sclerosis patients.
        Mult. Scler. 2015;
        • Longbrake E.E.
        • Naismith R.T.
        • Parks B.J.
        • Wu G.F.
        • Cross A.H.
        Dimethyl fumarate-associated lymphopenia: risk factors and clinical significance.
        Mult. Scler. J. Exp. Transl. Clin. 2015; : 1
        • Luo Z.J.
        • Tanaka T.
        • Kimura F.
        • Miyasaka M.
        Analysis of the mode of action of a novel immunosuppressant FTY720 in mice.
        Immunopharmacology. 1999; 41: 199-207
        • Mandala S.
        • Hajdu R.
        • Bergstrom J.
        • et al.
        Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists.
        Science. 2002; 296: 346-349
        • Matloubian M.
        • Lo C.G.
        • Cinamon G.
        • et al.
        Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1.
        Nature. 2004; 427: 355-360
        • Mehling M.
        • Brinkmann V.
        • Antel J.
        • et al.
        FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis.
        Neurology. 2008; 71: 1261-1267
        • Nieuwkamp D.J.
        • Murk J.L.
        • van Oosten B.W.
        • et al.
        PML in a patient without severe lymphocytopenia receiving dimethyl fumarate.
        N. Engl. J. Med. 2015; 372: 1474-1476
        • Rosenkranz T.
        • Novas M.
        • Terborg C.
        PML in a patient with lymphocytopenia treated with dimethyl fumarate.
        N. Engl. J. Med. 2015; 372: 1476-1478
        • Scannevin R.H.
        • Chollate S.
        • Jung M.Y.
        • et al.
        Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway.
        J. Pharmacol. Exp. Ther. 2012; 341: 274-284
        • Seto H.
        • Nishimura M.
        • Minamiji K.
        • et al.
        Disseminated cryptococcosis in a 63-year-old patient with multiple sclerosis treated with fingolimod.
        Intern. Med. 2016; 55: 3383-3386
        • Spencer C.M.
        • Crabtree-Hartman E.C.
        • Lehmann-Horn K.
        • Cree B.A.
        • Zamvil S.S.
        Reduction of CD8(+) T lymphocytes in multiple sclerosis patients treated with dimethyl fumarate.
        Neurol. Neuroimmunol. Neuroinflamm. 2015; 2: e76
        • Stuve O.
        • Marra C.M.
        • Jerome K.R.
        • et al.
        Immune surveillance in multiple sclerosis patients treated with natalizumab.
        Ann. Neurol. 2006; 59: 743-747
        • Stuve O.
        • Marra C.M.
        • Bar-Or A.
        • et al.
        Altered CD4+/CD8+ T-cell ratios in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis.
        Arch. Neurol. 2006; 63: 1383-1387
        • Stuve O.
        • Cravens P.D.
        • Frohman E.M.
        • et al.
        Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy.
        Neurology. 2009; 72: 396-401
        • Tanaka M.
        • Park K.
        • Tanaka K.
        Reduced fingolimod dosage treatment for patients with multiple sclerosis and lymphopenia or neutropenia.
        Mult. Scler. 2013; 19: 1244-1245
        • Treumer F.
        • Zhu K.
        • Glaser R.
        • Mrowietz U.
        Dimethylfumarate is a potent inducer of apoptosis in human T cells.
        J. Investig. Dermatol. 2003; 121: 1383-1388
        • Warnke C.
        • Dehmel T.
        • Ramanujam R.
        • et al.
        Initial lymphocyte count and low BMI may affect fingolimod-induced lymphopenia.
        Neurology. 2014; 83: 2153-2157
        • Williamson E.M.
        • Berger J.R.
        Central nervous system infections with immunomodulatory therapies.
        Continuum. 2015; 21: 1577-1598
        • Yamout B.I.
        • Zeineddine M.M.
        • Sawaya R.A.
        • Khoury S.J.
        Safety and efficacy of reduced FNG dosage treatment.
        J. Neuroimmunol. 2015; 285: 13-15
        • Zhu K.
        • Mrowietz U.
        Inhibition of dendritic cell differentiation by fumaric acid esters.
        J. Investig. Dermatol. 2001; 116: 203-208