Abstract
Objective
Cyclophosphamide (CYC) is an alkylating agent with immunosuppressive effect by inhibiting DNA synthesis and producing apoptosis used in many autoimmune diseases, including multiple sclerosis (MS). Here, we analyze the efficacy of CYC treatment in relapsing-remitting (RRMS) and active secondary progressive MS (SPMS) in our center with a monthly scheme.
Methods
Patients with MS treated with CYC and a follow up of at least 36 months were eligible for inclusion. All participants had received a standard CYC regimen. The EDSS score mean annualized relapse rate (ARR) and progression index (PI) were measured as efficacy outcomes at 12, 24, and 36 months. Outcomes were also analyzed comparing disease course and activity.
Results
A total of 16 patients were included (50% male, 18.75% RRMS and 81.25% SPMS). EDSS remained stable along the follow-up period, with 62.5% improving or maintaining the same EDSS score at 12 months. PI decreased 14% and 21% at 12 and 24–36 months of follow-up, respectively. ARR decreased 20% after 12 months, 19% after 24 months, and 30.23% after 36 months. Median differences in ARR were higher in patients with high relapse activity (0.60 vs 0.07, p = 0.001) and malignant course (0.60 vs 0.17, p = 0.027). PI also differed with higher mean differences in patients with high relapse activity (0.70 vs 0.03, p = 0.016) and malignant course (1.17 vs 0.03, p = 0.003).
Conclusions
CYC continues to be a valid therapeutic option, especially in regions with limited access to high-efficiency therapies particularly in patients with high relapsing activity and malignant course.
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References
Compston A, Coles A (2008) Multiple sclerosis. Lancet. 372:1502–1517. https://doi.org/10.1016/S0140-6736(08)61620-7
Thompson AJ, Baranzini SE, Geurts J, Hemmer B, Ciccarelli O (2018) Multiple sclerosis. Lancet. 391:1622–1636. https://doi.org/10.1016/S0140-6736(18)30481-1
Hartung DM (2017) Economics and cost-effectiveness of multiple sclerosis therapies in the USA. Neurotherapeutics. 14:1018–1026. https://doi.org/10.1007/s13311-017-0566-3
Ahlmann M, Hempel G (2016) The effect of cyclophosphamide on the immune system: implications for clinical cancer therapy. Cancer Chemother Pharmacol 78:661–671. https://doi.org/10.1007/s00280-016-3152-1
Awad A, Stue O (2009) Cyclophosphamide in multiple sclerosis: scientific rationale, history and novel treatment paradigms. Ther Adv Neurol Disord. https://doi.org/10.1177/1756285609344375
Weiner HL, Cohen JA (2002) Treatment of multiple sclerosis with cyclophosphamide: critical review of clinical and immunologic effects. Mult Scler 8:142–154. https://doi.org/10.1191/1352458502ms790oa
Perini P, Calabrese M, Rinaldi L, Gallo P (2007) The safety profile of cyclophosphamide in multiple sclerosis therapy. Expert Opin Drug Saf 6:183–190. https://doi.org/10.1517/14740338.6.2.183
La Mantia L, Milanese C, Mascoli N, D’Amico R, Weinstock-Guttman B (2002) Cyclophosphamide for multiple sclerosis. In: Cochrane database of systematic review. John Wiley & Sons, Ltd. https://doi.org/10.1002/14651858.cd002819
Hommes OR, Prick JJG, Lamers KJB (1975) Treatment of the chronic progressive form of multiple sclerosis with a combination of cyclophosphamide and prednisone. Clin Neurol Neurosurg 78:59–72. https://doi.org/10.1016/S0303-8467(75)80007-2
Hauser SL, Dawson DM, Lehrich JR, Beal MF, Kevy SV, Propper RD, Mills JA, Weiner HL (1983) Intensive immunosuppression in progressive multiple sclerosis. N Engl J Med 308:173–180. https://doi.org/10.1056/nejm198301273080401
Weiner HL, Mackin GA, Orav EJ, Hafler DA, Dawson DM, Lapierre Y, Herndon R, Lehrich JR, Hauser SL, Turel A, Fisher M, Birnbaum G, Mcarthur J, Butler R, Moore M, Sigsbee B, Safran A (1993) Intermittent cyclophosphamide pulse therapy in progressive multiple sclerosis: final report of the northeast cooperative multiple sclerosis treatment group. Neurology. 43:910–918. https://doi.org/10.1212/wnl.43.5.910
Noseworthy JH, Ebers GC, Vandervoort MK, Farquhar RE, Yetisir E, Roberts R (1994) The impact of blinding on the results of a randomized, placebo–controlled multiple sclerosis clinical trial. Neurology. 44:16–20. https://doi.org/10.1212/wnl.44.1.16
Likosky WH, Fireman B, Elmore R, Eno G, Gale K, Goode GB, Ikeda K, Laster J, Mosher C, Rozance J, Richmon J, Rosenberg S, Samman A, Sternbach R, Whaley J, Fehrenbacher L (1991) Intense immunosuppression in chronic progressive multiple sclerosis: the Kaiser study. J Neurol Neurosurg Psychiatry 54:1055–1060. https://doi.org/10.1136/jnnp.54.12.1055
Weinstock-Guttman B, Kinkel RP, Cohen JA, Ransohoff RM, Schwetz K, Gogol D et al (1997) Treatment of fulminant multiple sclerosis with intravenous cyclophosphamide. Neurologist 3:178–185
Hohol MJ, Olek MJ, Orav EJ, Stazzone L, Hafler DA, Khoury SJ, Dawson DM, Weiner HL (1999) Treatment of progressive multiple sclerosis with pulse cyclophosphamidel methylprednisolone: response to therapy is linked to the duration of progressive disease. Mult Scler J 5:403–409. https://doi.org/10.1177/135245859900500i606
Gobbini MI, Smith ME, Richert ND, Frank JA, McFarland HF (1999) Effect of open label pulse cyclophosphamide therapy on MRI measures of disease activity in five patients with refractory relapsing-remitting multiple sclerosis. J Neuroimmunol 99:142–149. https://doi.org/10.1016/S0165-5728(99)00039-9
Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O’Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS (2011) Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 69:292–302. https://doi.org/10.1002/ana.22366
Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sorensen PS, Thompson AJ, Wolinsky JS, Balcer LJ, Banwell B, Barkhof F, Bebo B, Calabresi PA, Clanet M, Comi G, Fox RJ, Freedman MS, Goodman AD, Inglese M, Kappos L, Kieseier BC, Lincoln JA, Lubetzki C, Miller AE, Montalban X, O’Connor PW, Petkau J, Pozzilli C, Rudick RA, Sormani MP, Stuve O, Waubant E, Polman CH (2014) Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology 83:278–286. https://doi.org/10.1212/WNL.0000000000000560
Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 33:1444–1452. https://doi.org/10.1212/wnl.33.11.1444
Poser S, Raun NE, Poser W (1982) Age at onset, initial symptomatology and the course of multiple sclerosis. Acta Neurol Scand 66:355–362. https://doi.org/10.1111/j.1600-0404.1982.tb06856.x
Jokubaitis VG, Spelman T, Kalincik T, Lorscheider J, Havrdova E, Horakova D, Duquette P, Girard M, Prat A, Izquierdo G, Grammond P, Van Pesch V, Pucci E, Grand’Maison F, Hupperts R, Granella F, Sola P, Bergamaschi R, Iuliano G, Spitaleri D, Boz C, Hodgkinson S, Olascoaga J, Verheul F, McCombe P, Petersen T, Rozsa C, Lechner-Scott J, Saladino ML, Farina D, Iaffaldano P, Paolicelli D, Butzkueven H, Lugaresi A, Trojano M (2016) Predictors of long-term disability accrual in relapse-onset multiple sclerosis. Ann. Neurol 80:89–100. https://doi.org/10.1002/ana.24682
Kieseier BC, Jeffery DR (2010) Chemotherapeutics in the treatment of multiple sclerosis. Ther Adv Neurol Disord 3:277–291. https://doi.org/10.1177/1756285610379885
Perini P, Gallo P (2003) Cyclophosphamide is effective in stabilizing rapidly deteriorating secondary progressive multiple sclerosis. J Neurol 250:834–838. https://doi.org/10.1007/s00415-003-1089-x
Khan OA, Zvartau-Hind M, Caon C, Din MU, Cochran M, Lisak D, Tselis AC, Kamholz JA, Garbern JY, Lisak RP (2001) Effect of monthly intravenous cyclophosphamide in rapidly deteriorating multiple sclerosis patients resistant to conventional therapy. Mult Scler 7:185–188. https://doi.org/10.1177/135245850100700309
Filippini G, Del Giovane C, Vacchi L, D’Amico R, Di Pietrantonj C, Beecher D, Salanti G (2013) Immunomodulators and immunosuppressants for multiple sclerosis: a network meta-analysis. Cochrane Database Syst Rev 2013. https://doi.org/10.1002/14651858.CD008933.pub2
Blank N, Lisenko K, Pavel P, Bruckner T, Ho AD, Wuchter P (2016) Low-dose cyclophosphamide effectively mobilizes peripheral blood stem cells in patients with autoimmune disease. Eur J Haematol 97:78–82. https://doi.org/10.1111/ejh.12686
Gladstone DE, Golightly MG, Brannagan TH (2007) High dose cyclophosphamide preferentially targets naïve T (CD45/CD4/RA+) cells in CIDP and MS patients. J Neuroimmunol 190:121–126. https://doi.org/10.1016/j.jneuroim.2007.07.005
La Mantia L, Eoli M, Salmaggi A, Torri V, Milanese C (1998) Cyclophosphamide in chronic progressive multiple sclerosis: a comparative study. Ital J Neurol Sci 19:32–36. https://doi.org/10.1007/BF03028809
Gladstone DE, Zamkoff KW, Krupp L, Peyster R, Sibony P, Christodoulou C, Locher E, Coyle PK (2006) High-dose cyclophosphamide for moderate to severe refractory multiple sclerosis. Arch Neurol 63:1388–1393. https://doi.org/10.1001/archneur.63.10.noc60076
Krishnan C, Kaplin AI, Brodsky RA, Drachman DB, Jones RJ, Pham DL, Richert ND, Pardo CA, Yousem DM, Hammond E, Quigg M, Trecker C, McArthur JC, Nath A, Greenberg BM, Calabresi PA, Kerr DA (2008) Reduction of disease activity and disability with high-dose cyclophosphamide in patients with aggressive multiple sclerosis. Arch Neurol 65. https://doi.org/10.1001/archneurol.65.8.noc80042
Schwartzman RJ, Simpkins N, Alexander GM, Reichenberger E, Ward K, Lindenberg N, Topolsky D, Crilley P (2009) High-dose cyclophosphamide in the treatment of multiple sclerosis. CNS Neurosci Ther 15:118–127. https://doi.org/10.1111/j.1755-5949.2008.00072.x
Patti F, Lo Fermo S (2011) Lights and shadows of cyclophosphamide in the treatment of multiple sclerosis. Autoimmune Dis 1. https://doi.org/10.4061/2011/961702
Lebrun C, Debouverie M, Vermersch P, Clavelou P, Rumbach L, de Seze J, Wiertlevski S, Defer G, Gout O, Berthier F, Danzon A (2008) Cancer risk and impact of disease-modifying treatments in patients with multiple sclerosis. Mult Scler 14:399–405. https://doi.org/10.1177/1352458507083625
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Gómez-Figueroa, E., Gutierrez-Lanz, E., Alvarado-Bolaños, A. et al. Cyclophosphamide treatment in active multiple sclerosis. Neurol Sci 42, 3775–3780 (2021). https://doi.org/10.1007/s10072-021-05052-1
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DOI: https://doi.org/10.1007/s10072-021-05052-1