Eur Neurol 2000;43:186-187
`
`Escalating Immunotherapy with Mitoxantronein
`Patients with Very Active Relapsing-Remitting or
`Progressive Multiple Sclerosis
`SimoneCursiefen, Peter Flachenecker, Klaus Victor Toyka,
`Peter Rieckmann
`
`Departmentof Neurology, University of Wurzburg, Germany
`
`In patients with very active relapsing-remitting or secondary pro-
`gressive multiple sclerosis (VARRMS), the cytotoxic drug mitoxan-
`trone, an anthracenedione derivative, is a promising new treatment
`[1]. Experimental data have demonstrated the efficacy of mitoxan-
`trone in models of experimentalallergic encephalomyelitis [1]. The
`immunomodulating mechanismsincludeinhibition of B-cell activity
`and enhancementof T-cell suppressor function while T-cell helper
`activity was reduced[1].
`Three prospective, randomized, double-blind (except the clinical
`analysis of the trial of Edan etal. [3]) and placebo-controlled trials
`have shown recently that mitoxantroneis effective in ameliorating
`disease activity in terms ofrelapse rate, progression of disability and
`magnetic resonance imaging (MRI) parameters in patients with
`severe MS [2-5]. Mitoxantrone waswell tolerated, with manageable
`side effects like nausea, vomiting, transient alopecia and amenor-
`rhea. With a cumulative dose less than 200 mg, no cardiotoxicity was
`detected.
`Here wereport on 7 patients with VARRMS whodeteriorated
`despite different treatment regimens(table 1). These patients were
`notparticipating in a therapeutic drugtrial. Only | patient (patient 1)
`suffered from a deterioration of the disease related to a urinary tract
`infection at the time treatmentwasstarted; all other patients had no
`relapses when mitoxantronewasinitiated. A single dose of 10 mg/m?
`mitoxantrone together with antiemetic drugs (granisetrone/tropise-
`
`trone) was given monthlyforthe first 3 months and thereafter every 3
`monthsupto a total dose of 150 + 45 mg and 20 + 6 months dura-
`tion. During treatment, disease activity could be reduced in all
`patients; the relapse rate declined from 2.5 + 1.5 per year before
`mitoxantrone to 0.5 + 0.5 per year during therapy, and no further
`disease progression was detected as measured by the Expanded Dis-
`ability Status Scale (EDSS). Brain MRI was not performed under
`controlled conditions before and after treatment.
`It is generally accepted that a 1-point change on the EDSS below
`6.0 (and a 0.5-point change above6.0) is considered clinically mean-
`ingful [2-5]. Applying these criteria to our patients, 3 patients
`improved,4 patients were stable and noneofourpatients deteriorat-
`ed during mitoxantrone therapy(table 1).
`Overall, mitoxantrone was well tolerated and only minorside
`effects occurred (nausea in 5, vomiting in | and mild alopecia in 2
`patients). Echocardiography was performed at the beginning and
`after 1 year of therapy showing normal quantitative cardiac func-
`tion.
`These data confirm and extendtheresults of previoustrials [2-5]
`showing that mitoxantroneis effective in stabilizing or even improv-
`ing the course of severe relapsing-remitting and rapidly progressive
`MS.
`In our small open-label
`trial of pretreated patients with
`VARRMS ourobservation led us to suggest that mitoxantrone may
`be used in the frameworkof an escalating immunotherapy.Presently
`it is recommendedthat treatment is stopped oncea total dose of
`200 mgis reached to avoid possible cardiotoxicsideeffects, especial-
`ly irreversible congestive heart failure [1]. This would allowfora total
`treatment duration of approximately 24 months.It is suggested that
`the therapeutic efficacy of mitoxantrone may be maintained for
`another 6-12 monthseven after discontinuation of mitoxantrone[1];
`therefore the need to initiate another treatment regimen might fur-
`ther be delayed. With moreefficacious drugs available, study proto-
`cols for escalating immunotherapies in MS are warranted.
`
`Table 1. Baseline characteristics and clinical data of 7 patients before and during mitoxantrone therapy
`
`No.
`
`Gender Age
`years
`
`Course
`
`Duration Treatment
`of MS
`before MX
`years
`
`Duration
`of previous
`treatment
`
`ARR
`ARR
`during
`1 year
`before MX MX
`
`EDSS
`EDSS
`EDSS
`after
`at
`1 year
`before MX baseline MX
`
`Duration
`Cumu-
`of MX
`lative
`dose, mg months
`
`1
`2
`3
`4
`5
`6
`
`7
`
`F
`F
`M
`M
`F
`F
`
`F
`
`22
`30
`43
`48
`27
`35
`
`37
`
`RR
`RR
`RR
`RR
`RR
`SP
`
`SP
`
`3
`7
`4
`12
`6
`13
`
`19
`
`Aza
`Aza
`Aza
`Aza
`IFN 1b
`Aza
`MTX
`Aza
`MTX
`
`4 months
`1 year
`4 months
`4 months
`18 months
`9 years
`2 years
`15 years
`8 months
`
`4
`4
`2
`2
`4
`
`1
`3
`1
`
`1
`0
`1
`0
`1
`
`0
`0
`0
`
`3
`3
`2
`n.d.
`n.d.
`
`6
`n.d.
`4.5
`
`3.5
`6.5
`3.5
`3
`6
`
`6.5
`5.5
`6
`
`3
`5
`4
`2.5
`5.5
`
`6
`4
`6
`
`66
`198
`198
`132
`160
`
`154
`52
`92.5
`
`13
`26
`28
`13
`23
`
`21
`3
`13
`
`MX= Mitoxantrone; Aza = azathioprine; MTX = methotrexate; IFN 1b = interferon B 1b; EDSS = Expanded Disability Status Scale;
`RR = relapsing-remitting MS; SP = secondary progressive MS; ARR = annualrelapse rate; n.d. = not documented.
`
`186
`
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