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Mitoxantrone for multiple sclerosis

  1. Filippo Martinelli Boneschi1,*,
  2. Laura Vacchi2,
  3. Marco Rovaris3,
  4. Ruggero Capra4,
  5. Giancarlo Comi5

Editorial Group: Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group

Published Online: 31 MAY 2013

Assessed as up-to-date: 30 AUG 2012

DOI: 10.1002/14651858.CD002127.pub3


How to Cite

Martinelli Boneschi F, Vacchi L, Rovaris M, Capra R, Comi G. Mitoxantrone for multiple sclerosis. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD002127. DOI: 10.1002/14651858.CD002127.pub3.

Author Information

  1. 1

    INSPE - San Raffaele Scientific Institute, Department of Neurology, Milano, Italy

  2. 2

    Scientific Institute and University Ospedale San Raffaele, Institute of Experimental Neurology (INSPE), Milano, Italy

  3. 3

    I.R.C.S.S. S. Maria Nascente - Fondazione Don Gnocchi, U.O. Sclerosi Multipla, Milano, Italy

  4. 4

    Spedali Civili, Brescia, Italy

  5. 5

    San Raffaele Hospital, Department of Neurology, Milano, Italy

*Filippo Martinelli Boneschi, Department of Neurology, INSPE - San Raffaele Scientific Institute, Via Olgettina, 48, Milano, 20131, Italy. filippo.martinelli@hsr.it.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 31 MAY 2013

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Characteristics of included studies [ordered by study ID]
Edan 1997

MethodsRandomised controlled trial.
Central randomisation.
Intention to treat used, even if not specified in the paper.
Double blinded: but in discussion it is specified that blinding of patients is difficult for MX side effects and blinding of the physicians is difficult for the decrease in white cell count.
Treatment period: 6 months.
No follow-up.
Withdrawn criteria: not pre-specified.
Withdrawals: 5 "due to pronounced clinical worsening" (all in MP group).
Lost to follow-up: no follow-up.


Participants42 patients: 21 MX + MetylP; 21 MetylP.
6 Centres.
Sex: both.
Included: CDMS with a RR (at least 2 exacerbations with sequelae within the previous 12 months) or SP course (progression of 2 points on EDSS scale within the previous 12 months); disease duration < 10 years; age between 18 and 65 years; EDSS ≤ 6.0; at least 1 MRI enhancing lesion during the baseline period (defined as the period between 2 months before the baseline visit and the baseline visit, during which all the patients received 1 g MetylP once a month).
Excluded: coexistence of other severe illnesses; pregnancy; immunosuppressant drugs use 3 months before entry; corticotropin or corticosteroids use 1 month before entry.
Baseline characteristics:
Sex: MX+MetylP 71,4% female; MetylP 52,3 % female.
Mean Age (SD): MX+MetylP 31,4 years (8,3); MetylP 32,2 years (8,1).
Mean EDSS (SD): MX+MetylP 4.5 (1.6), MetylP 4.6 (1.7).
Mean disease duration (SD): MX+MetylP 6,9 years (3,6), MetylP 5,7 years (4).
Age at onset of MS (SD): MX+MetylP 25,1 (7); MetylP 26,6 (6,5).
Number of relapses 1 year before the inclusion (SD): MX+MetylP 3,1 (1,8); MetylP 2,4 (1,7).
Course of disease: MX+MetylP (80,9% RR; 19,1% SP); MetylP (71,4% RR; 28,6% SP).


InterventionsRx: 20 mg MX + 1 g. MetylP i.v.
Placebo: 1 g. MetylP i.v.
(Between Month -2 and baseline: MetylP 1 g. i.v. for either groups).
Administration: once a month.
Total dosage: MX 120 mg over 6 months.


OutcomesPrimary outcomes:
(1) Proportion of patients who develop new T1 enhancing lesions on serial gadolinium MRI scans during trial.
Secondary outcomes:
(1) Mean number of new enhanced lesions per month per patient; (2) Mean number of new T2 lesions between baseline and end of trial; (3) Mean EDSS difference between baseline and end of trial; (4) Mean number of exacerbations between baseline and end of trial.


NotesDefinitions: Progression of disability: Confirmed increase of 1.0 EDSS point if baseline EDSS <= 5,5, or of a 0.5 EDSS point if baseline EDSS >= 6.0, between month 0 and the end of the study (measured for two months running at the end of the study). Relapse: occurrence of symptoms of neurological disfunction lasting more than 48 hours and preceded by stability or improvement for at least 30 days.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported.

Allocation concealment (selection bias)Low risk"The allocation of the treatment at month 0 was done after inclusion by a central randomisation service by fax." Page 113

Blinding (performance bias and detection bias)
For investigator e patients
High risk"In the present study, although the allocation of treatment was performed using an unbiased randomisation service, neither the patients nor the clinical investigators were blinded during the study. Blinding of patients was not possible in this trial, as obvious side effects of mitoxantrone were experienced in almost all cases. Blinding of the physician was made difficult by the fall in white cell count that always accompanies mitoxantrone treatment. Blind clinical observers might have been appointed, but this could not be done for economic reasons. The clinical efficacy suggested in this study must therefore be regarded with caution as it was acquired unblinded.” (Page 116)
Only the two MRI observers were blinded to patients’ clinical status.

Incomplete outcome data (attrition bias)
All outcomes
High risk5 withdrawals "due to pronounced clinical worsening" (all in the methylprednisolone group) were not included in the 6 months follow-up analysis. Bias is toward a reduced efficacy of the drug, on the reduction of the disability progression since all excluded patients in the control group worsened during the study.

Selective reporting (reporting bias)Low riskProtocol not available. Outcomes were reported completely, even if the total number of relapses in the two arms was reported, but not the distribution in patients. Moreover, the two arms were not matched for baseline number of enhancing lesions.

Other biasHigh riskSustained disability progression confirmed every 2 months.
Possibility that part of the benefit reported in the mitoxantrone group came from the addition of methylprednisolone to the treatment regimen.

Notes: It's unclear if this study was sponsored.

Hartung 2002

MethodsRandomised controlled trial.
Central computer randomisation.
Intention to treat.


Participants188 patients: 63 MX 12 mg; 66 MX 5 mg; 65 Placebo.
17 centres.
Sex: both.
Included: CDMS with a SP or PR course; duration of disease not specified; progression of at least 1.0 point on EDSS scale in preceding 18 months of study entry; age between 18 and 65 years; EDSS: between 3.0 and 6.0; WBC> 4.0*10^9/L; platelet count > 100*10^9/L.
Excluded: co-existence of other severe illnesses; pregnancy; immunosuppressant/immunomodulant use before study entry; relapses or corticosteroids use in preceding 8 weeks before entry; LVEF < 50%.
Baseline characteristics:
Sex: MX 12: 46,6% female; MX 5: 60,9% female; placebo: 48,4% female.
Mean Age (SD): MX 12 40 years (6.8); MX 5 39.9 ( 8.1); placebo 40 (7.9).
Mean EDSS (SD): MX 12 4.5 (1.1), MX 5 4.6 (1.0), placebo 4.7 (0.9).
Mean disease duration (SD): MX 12 9.6 (6.9), MX 5 9 (6.2), placebo 10.3 (6.9).
Number of relapses 1 year before the inclusion (SD): MX 12 1.3 (1.1), MX 5 1.4 (1.3), placebo 1.3 (1.1).
Course of disease: MX 12 (SP 53%, PR 47%), MX 5 (SP 42%, PR 58%), placebo (SP 55%, PR 45%).


InterventionsRx: MX 12: 12 mg/m2 body surface i.v. + ondansentron 8 mg per os.
Rx MX 5: 5 mg/m2 body surface i.v. + ondansentron 8 mg per os.
Placebo: placebo solution (15 mg) + 3 mg methylene blue i.v.
+ ondansentron 16 mg per os.
Administration every 3 months over 24 months. Total dosage: MX 12, 8 dosages over 24 months (total: 96 mg/m2 body surface). MX 5: 8 dosages over 24 months (total: 40 mg/m2 body surface).

The Rx MX 5: 5 mg/m2 body surface i.v. + ondansentron 8 mg per os arm was excluded from the analyses.


OutcomesPrimary outcomes:
1) EDSS difference between final and baseline.
2) Ambulation index (AI) difference between final and baseline.
3) Number of treated relapses.
4) Time to first treated relapse.
5) Proportion of patients with confirmed EDSS progression.

Secondary outcomes:
6) Proportion of patients with deterioration of at least 1.0 EDSS point.
7) Proportion of patients with such EDSS deterioration confirmed after 3 and 6 months.
8) Time to first sustained EDSS deterioration
9) Time to first relapse.
10) Number and annualised rate of relapses.
11) Proportion of patients with no relapses.
12) Number of days of hospitalisation.
13) Use of wheelchair assistance.
14) Quality of life assessed by Stanford Health questionnaire.
15) Number and volume of gadolinium-enhancing lesions.
16) Number and volume of T-1 lesions.
17) Number and volume of T-2 scans.


NotesDefinitions:
Progression of disability: 6-months confirmed increase of at least 1.0 EDSS point.
Relapse: occurrence of new symptoms lasting for more than 48 hours with a change in functional systems of more than 2 points or deterioration of at least 1 point in either piramidal, brainstem, cerebellar or visual FS.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk“Randomisation was done by means of a computer-generated schedule prepared for each site with a block size of three, without stratification.” Page 2019

Allocation concealment (selection bias)Unclear riskNot reported.

Blinding (performance bias and detection bias)
For investigator e patients
Low riskEDSS assessor was unaware. A separate treating physician was aware of treatment assignment. Lesion load was estimated by means of a scoring system by two experienced readers, masked to treatment assignment (Page 2020).
"This physician was allowed to speak to patients only as necessary to carry out the neurological tests. Before patients were enrolled, assessing physicians completed a training session to standardise scoring on the three tests [EDSS,ambulation index and standardised neurological status scores]” Page 2019

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe authors state that "188 patients were included in the intention-to-treat analysis of efficacy at 24 months" (194 at the onset). Reasons seemed similar.

Selective reporting (reporting bias)Low riskProtocol not available. Outcomes were reported completely.

Other biasLow riskNotes: Wyeth-Lederle Benelux and Germany sponsored this trial and financially supported independent statistical analysis. Page 2021

Millefiorini 1997

MethodsRandomised controlled trial.
Central randomisation and allocation.
Intention to treat.


Participants51 patients: 27 MX 8 mg; 24 Placebo.
8 centres.
Sex: both.
Included: CDMS or LSMS with a RR course; disease duration between 1 and 10 years; at least 2 relapses in the previous 2 years; age between 18 and 45 years; EDSS: between 2.0 and 5.0; MRI criteria not specified.
Excluded: presence of previous cardiovascular disease; pregnancy; immunosuppressant drugs use 3 months before entry; relapses or corticosteroids use in preceding 3 months before entry; LVEF< 50%.
Baseline characteristics:
Sex: MX 8 (62.9 % female); placebo (75% female).
Mean Age (SD): MX 8 30.9 years (6.0); placebo 28.7 (6.5).
Mean EDSS (SD): MX 8 3.6 (0.9), placebo 3.5 (1.2).
Mean disease duration (SD): MX 8 5.7 years; placebo 5.0.
Number of relapses 2 years before the inclusion (SD): MX 8 2.8 (1.2), placebo 2.8 (1.1).
Course of disease: MX 8, RR 100%; placebo, RR 100%.


InterventionsRx: MX 8: 8 mg/m2 body surface i.v.
Placebo: placebo solution i.v.
Administration: every month over 12 months (total dosage: 96 mg/m2 body surface).


OutcomesPrimary outcomes:
(1) Proportion of patients with confirmed progression (2) Annual mean number of exacerbations and percentage of exacerbation-free patients;
(3) Change in mean EDSS from baseline to final;
(4) Mean number of new or enlarged T2-lesions performed at baseline, 12-month and 24-month.


NotesDefinitions:
Progression of disability: 3-months confirmed progression of the disease as measured by an increase of at least 1.0 point on EDSS scale.
Relapses: appearance of a new symptom or worsening of an old symptom, attributed to MS, accompanied by a documented new neurological abnormality lasting more than 48 hours and preceded by stability or improvement for at least 30 days.
MRI new lesions: lesions not present in T2 in previous scans.
MRI enlarged lesions: lesions 33% larger in size when compared with previous ones.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"When a patient became eligible, the investigators notified the relevant centre which validated the eligibility of the patient and assigned a randomisation code number. The subject was then randomly assigned to a recipient group that received either MTX or a placebo. Patients were randomised to MTX or placebo using a scheme stratified on age, sex and EDSS which resulted in eight different age/sex/EDSS strata. According to the study protocol, within each stratum the allocation of patients to treatment or placebo was balanced by using a block design of size eight." Page 154

Allocation concealment (selection bias)Low riskCentral allocation and the intravenous bag and tubing were black to ensure no differences between the treatment groups. Page 154.

Blinding (performance bias and detection bias)
For investigator e patients
Low riskThe neurologist, who evaluated the EDSS scale, was blinded. "In order to maintain blindness, the interaction of the EDSS physicians with the patient was strictly restricted to the neurological examination. The neurologist was not allowed to talk with the patient about adverse events, or any other issue which could potentially disclose the patient’s treatment.” Page 154
“MRI data were analysed by two blinded neuroradiologists” Page 155
BUT “It must be emphasized that while EDSS evaluation was performed by four blinded neurologists, the assessment of exacerbations was monitored by treating physicians not blinded to study treatment (see Patients and methods). The unblended assessment of exacerbations suggests a potential systematic bias concerning treatment efficacy (false positive, type 1 error). This type of error, however, is a crucial element when the EDSS score must be assigned, while it seems to be less relevant in recording objective neurological findings such as determining that an exacerbation has taken place.” Page 157

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll randomised patients were included in the analysis.

For MRI outcome measure, 9 out of 51 patients did not complete the MRI study for the following reasons:2 MX and 4 placebo patients felt the drug was not working, 1 MX patient did not have good compliance with his neuroradiological centre, 1 MX and 1 placebo patients withdrew for non-medical reasons.

Selective reporting (reporting bias)Low riskProtocol not available. Outcomes were reported completely, even if “The lack of a total lesion volume evaluation on T2-weighted images, which is the most appropriate measurement for long-term studies, and the use of different MRI imagers, which might be a significant source of variation for lesion measurements, appear to be the major limitations of the present study and might explain the apparent incongruity between clinical and MRI results.” Page 157-158

Other biasHigh risk"The incomplete recruitment generated an imbalance in term of sex.” Page 155
No adequate AEs monitoring (self-reported).
Notes: It is unclear if this study was sponsored.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Capra 1993Open label pilot study

Edan 2001Observational safety study

Edan 2011RCT, absence of placebo arm

Gonsette 1990Open label pilot study

Goodkin 2001Observational safety study

Hamzehloo 2007Observational study

Kappos 1990Open label pilot study

Kornhuber 1992Open label pilot study

Krapf 1995Open label pilot study. Only MRI outcome

Mauch 1999Observational efficacy and safety study

Noseworthy 1993Open label pilot study

Rees 1998Open label pilot study

Van de Wyngaert 2001RCT, mitoxantrone versus methylprednisolone; absence of placebo group.

 
Comparison 1. Mitoxantrone versus placebo: primary outcomes

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Patients with 6-month confirmed disability progression at 2 years1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

    1.1 Disability progression
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.2 Worst
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.3 Best
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.4 Likely
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Post-hoc analysis: Patients with 3- or 6-month confirmed disability progression2Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 At 1 year
151Odds Ratio (M-H, Fixed, 95% CI)0.24 [0.04, 1.33]

    2.2 At 2 years
2179Odds Ratio (M-H, Fixed, 95% CI)0.23 [0.09, 0.59]

    2.3 At 2 years - Worst Scenario
2179Odds Ratio (M-H, Fixed, 95% CI)0.36 [0.16, 0.83]

    2.4 At 2 years - Best Scenario
2179Odds Ratio (M-H, Fixed, 95% CI)0.21 [0.08, 0.55]

    2.5 At 2 years - Likely Scenario
2179Odds Ratio (M-H, Fixed, 95% CI)0.34 [0.15, 0.78]

 3 Patients who withdrew from the study because of major side effects of the drug3221Odds Ratio (M-H, Fixed, 95% CI)2.72 [0.51, 14.54]

 
Comparison 2. Mitoxantrone versus placebo: secondary outcomes

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Patients with no relapses at 6 months/1 year2Odds Ratio (M-H, Random, 95% CI)Totals not selected

    1.1 6 months
1Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.2 1 year
1Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 2 Mean change in disability (EDSS)2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    2.1 At 1 year
125Mean Difference (IV, Fixed, 95% CI)-0.35 [-0.86, 0.16]

    2.2 At 2 years
2175Mean Difference (IV, Fixed, 95% CI)-0.36 [-0.70, -0.02]

 3 Patients with no relapses at 2 years2Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Patients with no relapses
2179Odds Ratio (M-H, Fixed, 95% CI)2.82 [1.54, 5.19]

    3.2 Worst Scenario
2179Odds Ratio (M-H, Fixed, 95% CI)2.68 [1.46, 4.92]

    3.3 Best Scenario
2179Odds Ratio (M-H, Fixed, 95% CI)3.27 [1.77, 6.04]

    3.4 Likely Scenario
2179Odds Ratio (M-H, Fixed, 95% CI)3.11 [1.68, 5.72]

 4 Annualized relapse rate3Mean Difference (IV, Fixed, 95% CI)Subtotals only

    4.1 At 6 months/1 year
3217Mean Difference (IV, Fixed, 95% CI)-1.02 [-1.69, -0.35]

    4.2 At 2 years
2175Mean Difference (IV, Fixed, 95% CI)-0.85 [-1.47, -0.23]

 5 Number of MRI active lesions3Mean Difference (IV, Fixed, 95% CI)Subtotals only

    5.1 At 6 months/1 year
262Mean Difference (IV, Fixed, 95% CI)-0.79 [-1.68, 0.09]

    5.2 At 2 years
170Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 6 Number of patients with active lesions3Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 At 6 months/1 year
3132Odds Ratio (M-H, Fixed, 95% CI)0.24 [0.10, 0.57]

    6.2 At 2 years
168Odds Ratio (M-H, Fixed, 95% CI)0.09 [0.00, 1.77]

 
Comparison 3. Mitoxantrone versus placebo: adverse events

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Amenorrea3199Odds Ratio (M-H, Fixed, 95% CI)15.50 [4.15, 57.94]

    1.1 Amenorrea (general)
3117Odds Ratio (M-H, Fixed, 95% CI)22.31 [4.03, 123.47]

    1.2 Persistent Amenorrea
282Odds Ratio (M-H, Fixed, 95% CI)8.27 [1.02, 67.18]

 2 Nausea/Vomiting3219Odds Ratio (M-H, Fixed, 95% CI)14.01 [6.36, 30.85]

 3 Alopecia3219Odds Ratio (M-H, Fixed, 95% CI)4.65 [2.37, 9.12]

 4 Urinary tract Infections3219Odds Ratio (M-H, Fixed, 95% CI)3.76 [1.67, 8.46]

 5 Respiratory tract infections3219Odds Ratio (M-H, Fixed, 95% CI)1.34 [0.72, 2.50]

 6 Headhache3219Odds Ratio (M-H, Fixed, 95% CI)1.36 [0.44, 4.24]

 
Comparison 4. Mitoxantrone versus placebo: abnormal laboratory values

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Leucopenia2168Odds Ratio (M-H, Fixed, 95% CI)17.95 [2.35, 137.00]

 2 Anemia2168Odds Ratio (M-H, Fixed, 95% CI)4.51 [0.92, 22.20]

 
Table 1. Number and reasons of withdrawn or loss to follow-up in included studies

StudiesWithdrawn or Lost to follow-up on the total of patientsMajor side effectsMinor side effectsRefusalDisease progressionOthersTotal

Edan5/42 (11.9%) in placebo arm000Placebo: 50Placebo: 5

Millefiorini0/51000000

Hartung33/128 (25.8%)

- MX 12 mg/m2: 15 patients;

- Placebo: 18 patients
- MX 12 mg/m2: 5 participants (1 major depression; 1 decreased FEVS <50%; 1 repeated nausea and vomiting; 1 repeated urinary infections and 1 renal failure);

- Placebo: 2 participants (1 hepatitis; 1 myocardial infarction)
0MX 12 mg/m2: 2;

Placebo: 6
MX 12 mg/m2: 4;

Placebo: 8
MX 12 mg/m2: 4;

Placebo: 2
MX 12 mg/m2: 15;

Placebo: 18

 
Table 2. Mitoxantrone dosage adjustment

Dose to be given100%90%75%Stop

If: Leucocytes (x1000/ml)>= 43-3.992-2.99< 2

If: Granulocytes (x1000/ml)>= 21.5-1.991-1.49< 1

If: Platelets (x1000/ml)>= 10075-9950-74< 50