Mitoxantrone in MS

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Mitoxantrone [MIT] is used in the treatment of breast cancer and other malignancies, yielding substantial experience with this drug. It is an immunosuppressive agent, given by infusion at intervals between 3 weeks and three months to a dose generally not exceeding 100 mg/m˛ in two years – what then comes has not been invented yet.


Clinical effects in MS:

MIT is currently among the few proven method for the therapy of MS. Astounishing effects have been seen, in particular in younger patients and in 2000, the FDA approved the drug for treament of all types of MS. The question is, however, at which price in aderse effects. This evaluation demands observation for several years, i.e. for a time to come, since it as a drug for MS is a relative novelty.


Adverse effects:

Frequent side-effects are nausea (ameliorated by simultaneous infusion of 5-HT3-Antagonists) and occasionally alopecia may occur. These uncomfortable properties are, however, overshadowed by rare but serious, life-threatening effects: Severe cardiac failure may occur, and this phenomenon is dependant upon the total dose – thus, MIT has a cumulative effect and once it is in the body, some activity remains. The cardiac adverse effect can be minimized by reducing the dose and excluding patients already with signs of left ventricular failure but even then, it remains a serious, occasionally fatal side effect, also in MS-patients [1-3]. Avasarala et al. [15] found after three doses of MIT a deteriorated left ventricular function in 5 of 28 patients (18%). Various forms of leucaemia must be counted to these adverse effects. This may appear logical from the status as an immunosuppressive and perhaps illogical since it has also been used for treatment of these malignancies. One could speculate that when a patient already has one malignancy (e.g. breast cancer), the risk of getting a second is lower. The risk of getting a haematogenic malignancy is in the treatment of breast cancer with MIT estimated to be increased 20 times in relation to basic values; even then, it remains less than 2%. But who would accept such a risk for themselves?

         MIT is enjoying an astonishing popularity today. It has even been proposed for patients without any previous (interferon) therapy. In the waves of this fashion, much lower incidences are currently presented. In a recent review [16] Scott and Figgitt describes that “the incidence of drug-related acute myelogenous leukaemia was very low (0.12%)” while “evidence suggests that the risk of cardiotoxicity is low in patients with MS. After 1 year of monotherapy, 3.4% of mitoxantrone recipients had a reduction in left ventricular ejection fraction.” However, at least twelve recent case-reports (probably representing a fraction of what really occurs) makes this adverse effect a real threat [4-8,18-24]. There are good reasons to cite the risk of haematogenous malignancies to about 1.5 % and that of cardiac deterioration to 15-20 %. Severe cardiac failure may be delayed several months and is then perhaps not so rare; Goffette et al. [23] reported of three cases from 52 who received the drug. The low rates in the literature may reflect the short use of the drug in MS; more realistic evaluations are bound to occur. Therefore, the evaluation of Gonsette [25] of MIT merely as a rescue medication seems most appropriate. Similarly, Evans [17] described that these side effects “justify the fact that this drug is limited to the aggressive forms of MP.

 

Studies in humans:

Six studies have been published so far:

 

Ref.

Year

n

Dur.

Type

verum

control 1

control 2

superiority

1st author

9

1993

13

6 M

SP

MIT 72 mg/m˛

Hist.: Placebo

Hist.: CYP

None

Noseworthy

10

1994

25

12 M

RR

MIT 

Placebo

 

None

Bastianello

11

1997

42

6 M

very active disease

MIT 120 mg + MP

MP (=Placebo)

 

MIT

Edan

12

1997

51

24 M

RR

MIT 96 mg/m˛

Placebo

 

MIT

Millefiorini

13

2001

49

32 M

SP

MIT 156 mg/m˛

MP (=Placebo)

 

MIT

v d Wyngaert

14

2002

194

24 M

SP

MIT 96 mg/m˛

MIT 40 mg/m˛

Placebo

MIT

Hartung

 

The last four studies concluded that MIT is effective and it has for that reason been registered for use in secondary progressive MS [SP], but not for relapsing-remittant MS [RR].

 

Ethical aspects:

The first study utilized a historical control (Hist.) from another investigation in the same clinic whereas the other 5 studies used either placebo or methylprednisolone [MP] – which in the treatment of SP-MS can be regarded equally effective.

         Use of null-hypothesis in controlled studies: In order to use a placebo-group, similarity between the two groups must be assumed. It deserves mention that b-Interferon was registered for the treatment of SP already in 1996. After that time, you must consider that patients have been kept without treatment for a long time although something was available for their disease. Even in the so-called “note of clarification,” imposed on the last version of the Helsinki Declaration by the American FDA, it is demanded that patient in the control group should come to no harm. The study conclusion was, that harm was done! Remains to be investigated if some of the participants of the mentioned studies can even be cited for having recommended b-interferons for SP-MS. This is a juridical aspect and thus remote from the purpose of this investigation.

         It deserves mention that the patients in one of the late studies [13] were enrolled between June 1992 and December 1994.

         The question of the potential adverse effects of the therapy is less dramatical. It must be assumed that the two serious adversities have been clarified and it is also true when the incidence of them has been declared as totally unknown.

 

Conclusion:

Except for desparate cases, where the risk of serious adverse effects is acceptable on basis of a debilitating disease. For other indications, I cannot recommend MIT on the basis given. There is a considerable chance to experience adverse effects without profiting from the beneficial, attempted ones. Moreover, the drug is to be considered given in a life-time deposit, in contrast to other immune modulating drugs that can at least be cancelled at any time. The last studies published can be taken as symptomatic (and unfortunately far from unique) for the placebomania which harasses MS-studies.

 

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References:

1                  Avasarala JR, Cross AH, Clifford DB, Singer BA, Siegel BA, Abbey EE. Rapid onset mitoxantrone-induced cardiotoxicity in secondary progressive multiple sclerosis. Mult Scler 2003;9:59-62.

2                  De Castro S, Cartoni D, Millefiorini E, Funaro S, Gasperini C, Morino S, Tallarico D, Beni S. Noninvasive assessment of mitoxantrone cardiotoxicity in relapsing remitting multiple sclerosis. J Clin Pharmacol 1995;35:627-32.

3                  Gbadamosi J, Munchau A, Weiller C, Schafer H. Severe heart failure in a young multiple sclerosis patient. J Neurol 2003;250:241-2.

4                  Ghalie RG, Mauch E, Edan G, Hartung HP, Gonsette RE, Eisenmann S, Le Page E, Butine MD, De Goodkin DE. A study of therapy-related acute leukaemia after mitoxantrone therapy for multiple sclerosis. Mult Scler 2002;8:441-5.

5                  Cattaneo C, Almici C, Borlenghi E, Motta M, Rossi G. A case of acute promyelocytic leikaemia following mitoxantrone treatment of multiple sclerosis. Leukaemia 2003;17:985-6.

6                  Heesen C, Bruegmann M, Gbdamosi J, Koch E, Monch A, Buhmann C. Therapy-related acute myelogenous leukaemia (t-AML) in a patient with multiple sclerosis treated with mitoxantrone. Mult Scle 2003;9:213-4.

7                  Mogenet I, Simiand-Erdociain E, Canonge JM, Pris J. Acute myelogenous leukemia following mitoxantrone treatment for multiple sclerosis. Ann Pharmacother. 2003;37:747-8.

8                  Jaster JH, Niell HB, Dohan FC Jr, Smith TW. Therapy-related acute myeloblastic leukemia after mitoxantrone treatment in a patient with MS. Neurology. 2003;60:1399-400.

9                  Noseworthy JH, Hopkins MB, Vandervoort MK, Karlik SJ, Lee DH, Penman M, Rice GP, Grinwich KD, Cauvier H, Harris BJ, et al. An open-trial evaluation of mitoxantrone in the treatment of progressive MS. Neurology 1993;43:1401-6.

10             Bastianello S, Pozzilli C, D'Andrea F, Millefiorini E, Trojano M, Morino S, Gasperini C, Bozzao A, Gallucci M, Andreula C, et al. A controlled trial of mitoxantrone in multiple sclerosis: serial MRI evaluation at one year. Can J Neurol Sci 1994;21:266-70.

11             Edan G, Miller D, Clanet M, Confavreux C, Lyon-Caen O, Lubetzki C, Brochet B, Berry I, Rolland Y, Froment JC, Cabanis E, Iba-Zizen MT, Gandon JM, Lai HM, Moseley I, Sabouraud O. Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: a randomised multicentre study of active disease using MRI and clinical criteria. J Neurol Neurosurg Psychiatry 1997;62:112-8.

12             Millefiorini E, Gasperini C, Pozzilli C, D'Andrea F, Bastianello S, Trojano M, Morino S, Morra VB, Bozzao A, Calo' A, Bernini ML, Gambi D, Prencipe M. Randomized placebo-controlled trial of mitoxantrone in relapsing-remitting multiple sclerosis: 24-month clinical and MRI outcome. : J Neurol 1997;244:153-9.

13             van de Wyngaert FA, Beguin C, D'Hooghe MB, Dooms G, Lissoir F, Carton H, Sindic CJ. A double-blind clinical trial of mitoxantrone versus methylprednisolone in relapsing, secondary progressive multiple sclerosis. Acta Neurol Belg 2001;101:210-6.

14             Hartung HP, Gonsette R, Konig N, Kwiecinski H, Guseo A, Morrissey SP, Krapf H, Zwingers T; Mitoxantrone in Multiple Sclerosis Study Group (MIMS). Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet 2002;360:2018-25.

15             Avasarala JR, Cross AH, Clifford DB, Singer BA, Siegel BA, Abbey EE. Rapid onset mitoxantrone-induced cardiotoxicity in secondary progressive multiple sclerosis. Mult Scler 2003;9:59-62.

16             Scott LJ, Figgitt DP. Mitoxantrone: A Review of its Use in Multiple Sclerosis. CNS Drugs 2004;18:379-396.

17             Edan G. Sclerose en plaques agressive. Definition et indication therapeutique particuliere [Aggressive multiple sclerosis. Definition and specific therapeutic indication] Presse Med 2004;33:187-91.

18             Delisse B, de Seze J, Mackowiak A, N'Kendjuo JB, Verier A, Derepeer O, Boisselier C, Devos P, Hautecoeur P, Vermersch P; G-SEP. Therapy related acute myeloblastic leukaemia after mitoxantrone treatment in a patient with multiple sclerosis. Mult Scler 2004;10:92.

19             Nagele H, Castel MA, Deutsch O, Wagner FM, Reichenspurner H. Heart transplantation in a patient with multiple sclerosis and mitoxantrone-induced cardiomyopathy. J Heart Lung Transplant 2004;23:641-3.

20             Voltz R, Starck M, Zingler V, Strupp M, Kolb HJ. Mitoxantrone therapy in multiple sclerosis and acute leukaemia: a case report out of 644 treated patients. Mult Scler 2004;10:472-4. 

21             Tanasescu R, Debouverie M, Pittion S, Anxionnat R, Vespignani H. Acute myeloid leukaemia induced by mitoxantrone in a multiple sclerosis patient. J Neurol 2004;251:762-3.

22             Novoselac AV, Reddy S, Sanmugarajah J. Acute promyelocytic leukemia in a patient with multiple sclerosis following treatment with mitoxantrone. Leukemia 2004;18:1561-2.

23             Goffette S, van Pesch V, Vanoverschelde JL, Morandini E, Sindic CJ. Severe delayed heart failure in three multiple sclerosis patients previously treated with mitoxantrone. J Neurol 2005;252:1217-22.

24             Arruda WO, Montu MB, de Oliveira Mde S, Ramina R. Acute myeloid leukaemia induced by mitoxantrone: case report. Arq Neuropsiquiatr 2005;63:327-9.

25             Gonsette RE. A comparison of the benefits of mitoxantrone and other recent therapeutic approaches in multiple sclerosis. Expert Opin Pharmacother 2004;5:747-65.

 

 

Inserted October  21, 2003

Revised March 30, 2006

 

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