Mitoxantrone
in MS
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.
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
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5
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case of acute
promyelocytic leikaemia following mitoxantrone treatment of multiple
sclerosis.
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6
Heesen C, Bruegmann M, Gbdamosi J, Koch E, Monch A,
Buhmann C.
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multiple
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7
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8
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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
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10
Bastianello
S, Pozzilli C, D'Andrea F,
Millefiorini E, Trojano M, Morino S, Gasperini C, Bozzao A, Gallucci M,
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mitoxantrone in multiple
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11
Edan G, Miller D, Clanet M, Confavreux C,
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12
Millefiorini E, Gasperini C, Pozzilli C,
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13
van de Wyngaert FA, Beguin C, D'Hooghe MB,
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14
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15
Avasarala JR, Cross AH, Clifford DB, Singer BA, Siegel
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progressive
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16
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17
Edan
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18
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19
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20
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21
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23
Goffette S,
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24
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25
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Inserted
Revised
March