Journal of the Neurological Sciences 176 (2000) 42–44
`
`www.elsevier.com/locate/jns
`
`The effect of cladribine on T ‘black hole’ changes in progressive MS
`1
`
`a ,
`
`*
`a
`c
`a
`a
`a
`, M. Rovaris , G.P.A. Rice , M.P. Sormani , G. Iannucci , L. Giacomotti , G. Comi
`M. Filippi
`aNeuroimaging Research Unit,Department of Neuroscience,Scientific Institute Ospedale San Raffaele,University of Milan,Milan,Italy
`bClinical Trials Unit,Department of Neuroscience,Scientific Institute Ospedale San Raffaele,University of Milan,Milan,Italy
`cUniversity Hospital,University of Western Ontario,London,Ontario,Canada
`
`b
`
`Received 3 January 2000; accepted 8 March 2000
`
`Abstract
`
`We compared the changes of the volumes of T -hypointense lesions seen on the magnetic resonance imaging scans of the brain from
`1
`159 progressive multiple sclerosis (MS) patients who were enrolled in a double-blind, placebo-controlled trial assessing the efficacy of
`two doses of cladribine. Although in patients treated with cladribine there was a tendency to have a lower increase of T -hypointense
`1
`lesion volumes than those treated with placebo, no statistically significant effect of cladribine on T -hypointense lesion accumulation was
`1
`found over the one-year double-blind phase. Furthermore, no significant treatment effect was also detected in a subset of 22 patients who
`received placebo during the double-blind phase of the study and cladribine during the subsequent one-year open-label phase. We conclude
`that cladribine does not have a major impact on the mechanisms leading to severe tissue destruction in progressive MS. © 2000 Elsevier
`Science B.V. All rights reserved.
`
`Keywords: MS; MRI; T -hypointense lesions; Cladribine
`1
`
`1. Introduction
`
`Cladribine (2-chlorodeoxyadenosine; 2-CdA) is a purine
`nucleoside analogue resistant to the action of adenosine
`deaminase, which results in preferential lymphocytoxicity.
`In cells with a high ratio of deoxycytidine kinase to
`deoxynucleotidase (e.g. lymphocytes and monocytes), clad-
`ribine is phosphorylated into the active triphosphate deoxy-
`nucleotide which damages DNA and promotes cell death
`[1]. Preliminary trials [2,3] reported that the long-lasting
`lymphocytotoxic activity of cladribine has the potential for
`modifying the evolution of progressive multiple sclerosis
`(MS). In a recent multicenter, randomized, double-blind,
`placebo-controlled trial of patients with progressive MS
`[4], it was shown that cladribine had a dramatic effect on
`the volume and number of active lesions ($90% reduc-
`tion) seen on enhanced magnetic resonance imaging (MRI)
`
`*Corresponding author. Tel.: 139-0-2643-3033; fax: 139-0-2643-
`3031.
`E-mail address: m.filippi@hsr.it (M. Filippi)
`
`scans of the brain, a modest effect on the accumulation of
`T lesion volume and no effect on the accumulation of
`2
`disability.
`As discussed in the previous paper [4,5], the discrepancy
`between the effect of cladribine on disability and MRI
`measures of MS activity and burden can be explained by
`the relatively short duration of the trial and the clinical
`characteristics of the patients studied. However, an alter-
`native explanation might be that cladribine does not
`influence factors, such as severe demyelination and axonal
`loss, which are likely to be responsible for the accumula-
`tion of
`irreversible disability in MS. MRI enhancing
`lesions reflect the transiently increased blood–brain barrier
`permeability and inflammation [6] and T -weighted imag-
`2
`ing provides non-specific information about the pathologi-
`cal substrate of MS lesions [7]. On the other hand,
`hypointense MS lesions on T -weighted scans (‘black
`1
`holes’) represent areas with severe tissue disruption [8],
`and,
`in patients with secondary progressive MS, T -1
`weighted hypointense lesion load correlate strongly with
`physical disability [9]. To investigate the effect of two
`
`0022-510X/00/$ – see front matter © 2000 Elsevier Science B.V. All rights reserved.
`PII: S0022-510X( 00 )00303-8
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`1
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`M.Filippi et al. / Journal of the Neurological Sciences 176(2000)42–44
`
`43
`
`doses of cladribine (0.7 mg/kg and 2.1 mg/kg) on the
`accumulation of
`‘black holes’
`in the same cohort of
`patients with progressive MS [4], we measured the volume
`of hypointense lesions at study entry and after one-year
`follow up. At the end of the double-blind phase, patients
`entered an open-label phase. Here we report the results of
`the analysis of ‘black hole’ changes during the double
`blind phase and the first year of the open-label phase.
`
`2. Patients and methods
`
`One hundred and fifty-nine patients with progressive MS
`were enrolled in a randomized, double-blind, parallel-
`group, placebo-controlled study to assess the safety and
`efficacy of 0.7 mg/kg and 2.1 mg/kg of cladribine
`administered by subcutaneous injection. The study in-
`cluded a four-week screening phase, a one-year double-
`blind phase, and a six-year open label phase. Patients were
`assigned to one of three parallel treatment groups (2.1
`mg/kg cladribine; 0.7 mg/kg cladribine; or placebo). After
`all patients at a study site completed the double-blind
`phase, the blind was broken, and patients who fulfilled the
`hematologic dosing criteria were permitted to receive
`open-label cladribine treatment during the extension phase,
`provided at least 12 months had elapsed since the last dose
`of cladribine and there was evidence of disease pro-
`gression. Further details about study population and design
`have been reported previously [4].
`At study entry and at months 6, 12, 18 and 24, dual-echo
`and enhanced T -weighted scans (five to 10 min after the
`1
`injection of 0.1 mmol/kg gadolinium–DTPA) were ob-
`tained from all patients. For T -weighted images, slices
`1
`were axial, contiguous, 3 mm thick with a matrix size of
`2563256 mm and a field of view of 2503250 mm. We
`used T -weighted images obtained at study entry, at month
`1
`12 (end of the double-blind phase) and at month 24 to
`measure the volumes of T -hypointense lesions. T -hypo-
`1
`1
`intense lesions were considered those areas with a signal
`intensity between that of the gray matter and that of the
`cerebro-spinal fluid and with corresponding lesions on both
`echoes of the dual-echo images. A single experienced
`
`regime and scan
`the treatment
`observer, unaware of
`acquisition order, identified such lesions and marked the
`corresponding areas on transparent sheets superimposed
`over the T -weighted hardcopies. Then, a trained techni-
`1
`cian, also unaware of the treatment regime and scan
`acquisition order, measured the T -hypointense lesion
`1
`volumes using a segmentation technique based on local
`thresholding [4] and the marked hardcopies as a reference.
`Further details regarding scan acquisition and post-process-
`ing have been reported previously [4].
`The effect of cladribine on the T -hypointense lesion
`1
`volumes during the double-blind phase was assessed using
`an ANOVA model for repeated measures including time
`(baseline and month 12 scans) as the within subjects factor
`and treatment (placebo versus 0.7 mg/kg and 2.1 mg/kg
`cladribine) as the between subjects factor. This analysis
`was also performed considering primary and secondary
`progressive MS patients separately. For patients receiving
`placebo during the double-blind phase and who then were
`treated with cladribine between months 12 and 24, the
`changes of T -hypointense volumes between the two study
`1
`periods were compared using a two-tailed Student t-test for
`paired data.
`
`3. Results
`
`Demographic and baseline characteristics of the patients
`studied as well as the effect of the two doses of cladribine
`on disability, enhancing lesion number and volume and T2
`lesion volumes have been reported previously [4]. For the
`whole population studied,
`the average T -hypointense
`1
`3
`3
`lesion volumes were 4019 mm (S.D.56547 mm ) on the
`3
`3
`entry scans and 4104 mm (S.D.56596 mm ) on the scans
`obtained at month 12 (mean absolute change5 184.2 mm,
`mean percentage change5 12.4%). The average T -hypo-
`1
`intense lesion volumes, the absolute and percentage vol-
`ume difference between month 12 and study entry for the
`three treatment groups are reported in Table 1. T -hypo-
`1
`intense lesion volumes were similar in placebo and clad-
`ribine-treated patients on the baseline scans. Although
`patients treated with 2.1 mg/kg cladribine showed a
`
`Table 1
`Mean (SE) T -hypointense lesion volumes at study entry and month 12 in patients treated with placebo, cladribine 0.7 mg/kg and cladribine 2.1 mg/kg
`1
`T -hypointense
`T -hypointense
`Mean absolute
`Mean percentage
`1
`1
`lesion volumes
`lesion volumes
`change (SE)
`change (SE) (%)
`3
`3
`3
`Entry scan (mm )
`Month 12 (mm )
`(mm )
`3980
`4205
`1225
`(1132)
`(1184)
`(143)
`
`14.2
`(4.5)
`
`Placebo
`
`Cladribine 0.7 mg/kg
`
`Cladribine 2.1 mg/kg
`
`4371
`(1012)
`
`3711
`(754)
`
`4417
`(995)
`
`3679
`(712)
`
`145
`(126)
`
`231
`(221)
`
`11.1
`(4.4)
`
`21.7
`(3.4)
`
`2
`
`

`

`44
`
`M.Filippi et al. / Journal of the Neurological Sciences 176(2000)42–44
`
`nisms leading to tissue destruction within MS lesions.
`Although cladribine (particularly when given at 2.1 mg/
`kg) reduces the amount of ‘black holes’ on follow up scans
`compared to placebo, this effect is relatively modest and
`does not reach statistical significance. One might argue
`that with a longer follow up and a larger and more
`homogeneous sample of patients, this effect might become
`statistically significant. However, our results suggest that
`the magnitude of such an effect is likely to be clinically
`unimportant and we conclude that cladribine does not have
`a major impact on the mechanisms leading to severe tissue
`destruction in lesions of progressive MS patients.
`
`Acknowledgements
`
`This study was partially supported by the R.W. Johnson
`Pharmaceutical Corporation, Raritan, NJ, USA. The au-
`thors are grateful to all the investigators of the Cladribine
`Clinical Study group (the complete list can be found in
`Ref. [4] of this paper) who acquired the MRI scans used
`for the present analysis.
`
`References
`
`modest reduction of the volume of ‘black holes’ and
`patients treated with placebo had a higher increase in the
`volume of ‘black holes’ than those treated with 0.7 mg/kg
`cladribine, no significant difference was found between the
`placebo and the treatment arms. The same was true when
`primary and secondary progressive MS patients were
`considered separately (data not shown). Twenty-two pa-
`tients who received placebo during the double-blind phase
`of the study received cladribine during the subsequent
`open-label phase. These patients had an average absolute
`3
`increase of T -hypointense lesion volume 74 mm (SE5
`1
`3
`107 mm ) during the first phase of the study and 563
`3
`3
`mm (SE5153 mm ) during the second 12 months. This
`difference was not statistically significant.
`
`4. Discussion
`
`The encouraging results of two pilot studies of clad-
`ribine in progressive and relapsing–remitting MS [2,3]
`could not be confirmed in a multicenter, randomized,
`double-blind, placebo-controlled study of 159 patients with
`either primary or secondary progressive MS [4]. On the
`one hand, cladribine dramatically reduced the number of
`enhancing lesions and had a moderate, but statistically
`significant, effect on the accumulation of T lesion burden.
`2
`On the other, however, cladribine did not have any impact
`on disability accumulation. This clinical/MRI discrepancy
`is not surprising, considering the clinical characteristics
`and the relative small size of the patients cohort studied,
`the relative short duration of the follow up period [5] and
`the much greater sensitivity of MRI-derived measures
`compared to clinical measures in detecting MS-related
`changes [7].
`However, this study [4] left unanswered the question
`whether the ability of cladribine to reduce enhancement
`and the accumulation of T lesions would have had a
`2
`subsequent clinical
`impact.
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`definite MS,
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`conventional MRI scans and the long-term clinical evolu-
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`for this finding is the poor specificity of the abnormalities
`seen on T -weighted and post-contrast T -weighted scans
`2
`1
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`1
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`their extent correlates strongly with changes in disability in
`patients with secondary progressive MS [9], and that
`treatment with interferon beta-1 a slows down the rate of
`their accumulation in patients with relapsing–remitting MS
`[10]. Therefore, we measured the volumes of ‘black holes’
`in patients with progressive MS treated with two doses of
`cladribine in a previous placebo-controlled trial [4] to
`assess whether cladribine was able to modify the mecha-
`
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