Long-Term Follow-Up of Pediatric Patients Treated with Mitoxantrone for Multiple Sclerosis

Abstract

The chemotherapeutic agent mitoxantrone is approved for the treatment of aggressive multiple sclerosis (MS) in adults. Its use, however, is limited by the risk of severe adverse events including cardiotoxicity, myelosuppression, liver toxicity and secondary leukemia. The aim of this retrospective study is to present data on the safety, tolerability and efficacy of mitoxantrone in a small cohort of children with MS.

4 pediatric MS patients with a high relapse rate or severe, disabling relapses were treated with mitoxantrone and followed for 3.8–18 years. The cumulative dose of mitoxantrone was 36, 68, 84 and 120 mg/m², respectively. The frequency and severity of relapses as well as disability scores, decreased in the year after treatment onset. Short-term adverse events were transient in all cases. Cardiac monitoring by transthoracic echocardiography (TTE) showed asymptomatic left ventricular dysfunction during treatment in 1 patient, which was again normal at the next assessment. Long-term adverse events, including late-onset mitoxantrone-induced cardiotoxicity or secondary leukemia did not occur during the follow-up period.

In our cohort of pediatric MS patients, mitoxantrone showed short-term reduction of disease activity and no long-term adverse events on follow-up. However, the risk of mitoxantrone-induced cardiotoxicity or toxic leukemia remains a life-long threat.

Key words

multiple sclerosis - children - mitoxantrone

References

• 1 Boggild M. Immunosuppression followed by immunomodulation.  J Neurol Sci. 2009;  277 (S 01) S50-S54
• 2 Boiko A, Vorobeychik G, Paty D. et al and the UBC MS Clinic Neurologists Early onset multiple sclerosis: A longitudinal study.  Neurology. 2002;  59 1006-1010
• 3 Comi G. Treatment of multiple sclerosis: role of natalizumab.  Neurol Sci. 2009;  30 S155-S158
• 4 Dörr J, Bitsch A, Schmailzl KJ. et al . Severe cardiac failure in a patient with multiple sclerosis following low-dose mitoxantrone treatment.  Neurology. 2009;  73 991-993
• 5 Gatta G, Capocaccia R, Coleman MP. et al . Childhood cancer survival in Europe and the United States.  Cancer. 2002;  95 1767-1772
• 6 Ghezzi A, Banwell B, Boiko A. et al . The management of MS in children. A European view.  Mult Scler. 2010;  Aug 4. Epub ahead of print
• 7 Ghezzi A, Pozzilli C, Grimaldi LME. et al . Safety and efficacy of natalizumab in children with multiple sclerosis.  Neurology. 2010;  75 912-917
• 8 Goffette S, van Pesch V, Vanoverschelde JL. et al . Severe delayed heart failure in three multiple sclerosis patients previously treated with mitoxantrone.  J Neurol. 2005;  252 1217-1222
• 9 Gonsette RE, Demonty L. Immunosuppression with mitoxantrone in multiple sclerosis: a pilot study for two years.  Neurology. 1990;  40 (S 01) S261
• 10 Gorman M, Healy B, Polgar-Turcsanyi M. et al . Increased relapse rate in pediatric-onset compared to adult-onset multiple sclerosis.  Arch Neurol. 2009;  66 54-59
• 11 Hartung HP, Gonsette R, König N. et al and the Mitoxantrone in Multiple Sclerosis Study Group (MIMS) Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial.  Lancet. 2002;  360 2018-2025
• 12 Huppke P, Stark W, Zürcher C. et al . Natalizumab use in pediatric multiple sclerosis.  Arch Neurol. 2008;  65 1655-1658
• 13 Kappos L, Gold R, Künstler E. Mitoxantrone (Mx) in the treatment of rapidly progressive MS: a pilot study with serial gadolinium (Gd)-enhanced MRI.  Neurology. 1990;  40 (S 01) S261
• 14 Kingwell E, Koch M, Leung B. et al . Cardiotoxicity and other adverse events associated with mitoxantrone treatment for MS.  Neurology. 2010;  74 1-5
• 15 Kremer LCM, Bastiaansen BAJ, Offringa M. et al . Troponin T in the first 24 h after the administration of chemotherapy and the detection of myocardial damage in children.  Eur J Cancer. 2002;  38 686-689
• 16 Krupp LB, Banwell B, Tenembaum S. Consensus definitions proposed for pediatric multiple sclerosis and related disorders.  Neurology. 2007;  68 S7-S12
• 17 Kuntz NL, Chabas D, Weinstock-Guttman B. et al . Treatment of multiple sclerosis in children and adolescents.  Expert Opin Pharmacother. 2010;  11 505-520
• 18 Kurztke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS).  Neurology. 1983;  33 1444-1452
• 19 Makhani N, Gorman MP, Branson HM. et al . Cyclophosphamide therapy in pediatric multiple sclerosis.  Neurology. 2009;  72 2076-2082
• 20 Marriott JJ, Miyasaki JM, Gronseth G. et al . Evidence report: The efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.  Neurology. 2010;  74 1463-1470
• 21 Mullen JT, Vartanian TK, Atkins MB. Melanoma complicating treatment with natalizumab for multiple sclerosis.  N Engl J Med. 2008;  358 647-648
• 22 Multiple sclerosis therapy consensus group (MSTCG), . Wiendl H, Toyka K, Rieckmann P. et al . Basic and escalating immunomodulatory treatments in multiple sclerosis: current therapeutic recommendations.  J Neurol. 2008;  255 1449-63
• 23 Neuhaus O, Kieseier BC, Hartung HP. Therapeutic role of mitoxantrone in multiple sclerosis.  Pharmacol Therap. 2006;  109 198-209
• 24 Ness JM, Chabas D, Sadovnick AD. et al International pediatric MS study group Clinical features of children and adolescents with multiple sclerosis.  Neurology. 2007;  68 S37-S45
• 25 Pascual AM, Téllez N, Boscá I. et al . Revision of the risk of secondary leukaemia after mitoxantrone in multiple sclerosis populations is required.  Mult Scler. 2009;  15 1303-1310
• 26 Pattoneri P, Sozzi F, Pela G. et al . Assessment of mitoxantrone-induced cardiotoxicity in patients with multiple sclerosis: a tissue Doppler echocardiographic analysis.  Echocardiography. 2009;  26 397-402
• 27 Pohl D, Waubant E, Banwell B. et al . International pediatric MS study group. Treatment of pediatric multiple sclerosis and variants.  Neurology. 2007;  68 S54-S65
• 28 Polman CH, O’Connor PW, Havrdova E. et al . A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis.  N Engl J Med. 2006;  354 899-910
• 29 Ramtahal J, Jacob A, Das K. et al . Sequential maintenance treatment with glatiramer acetate after mitoxantrone is safe and can limit exposure to immunosuppression in very active, relapsing-remitting multiple sclerosis.  J Neurol. 2006;  253 1160-1164
• 30 Renoux C, Vukusic S, Mikaeloff Y. et al for the Adult Neurology Departments KIDMUS Study Group Natural history of multiple sclerosis with childhood onset.  N Engl J Med. 2007;  356 2603-2613
• 31 Rieckmann P, Toyka KV, Bassetti C. et al Multiple Sclerosis Therapy Consensus Group (MSTCG) Escalating immunotherapy of multiple sclerosis. New aspects and practical application.  J Neurol. 2004;  251 1329-1339
• 32 Shenkenberg TD, van Hoff DD. Mitoxantrone: a new anticancer drug with significant clinical activity.  Ann Intern Med. 1986;  105 76-81 [Review]
• 33 Simone IL, Carrara D, Tortorella C. et al . Course and prognosis in early-onset MS: comparison with adult-onset forms.  Neurology. 2002;  59 1922-1928
• 34 Steinherz LJ, Graham T, Hurwitz R. et al . Guidelines for cardiac monitoring of children during and after anthracycline therapy: report of the Cardiology Committee of the Childrens Cancer study Group.  Pediatrics. 1992;  89 942-949
• 35 Steinherz LJ, Steinherz PG, Tan C. Cardiac failure and dysrhythmias 6–19 years after anthracycline therapy: a series of 15 patients.  Med Pediatr Oncol. 1995;  24 352-361
• 36 US Department of Health and Human Services, National Institutes of Health, National Cancer Institute . Common Terminology Criteria for Adverse Events (CTCAE) Version 4.  Available at: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.02_2009-09-15_QuickReference_8.5x11.pdf Accessed May 14 2010; 
• 37 Van Dalen EC, van der Pal HJH, Bakker PJM. et al . Cumulative incidence and risk factors of mitoxantrone-induced cardiotoxicity in children: a systematic review.  Eur J Cancer. 2004;  40 463-652
• 38 Van Dalen EC, van der Pal HJH, Kok WEM. et al . Clinical heart failure in a cohort of children treated with anthracyclines: A long-term follow-up study.  Eur J Cancer. 2006;  42 3191-3189
• 39 Weinshenker BG, O’Brien PC, Petterson TM. et al . A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease.  Ann Neurol. 1999;  46 878-886
• 40 West TW, Cree TA. Natalizumab dosage suspension: are we helping or hurting?.  Ann Neurol. 2010;  68 395-399

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