`
`ELSEVIER
`
`Journal of the Neurological Sciences 176 (2000) 42-44
`
`Journal of 1be
`
`Neurological
`Sciences
`
`www.elsevier.com/ locate/jns
`
`The effect of cladribine on T 1 'black hole' changes in progressive MS
`
`M. Filippia•*, M. Rovaris\ G.P.A. Rice\ M.P. Sormani\ G. Iannucci\ L. Giacomotti\ G. Comib
`
`'Neuroimaging 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
`
`Received 3 January 2000; accepted 8 March 2000
`
`Abstract
`
`We compared the changes of the volumes of T 1 -hypointense lesions seen on the magnetic resonance imaging scans of the brain from
`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 1 -hypointense
`lesion volumes than those treated with placebo, no statistically significant effect of cladribine on T 1 -hypointense lesion accumulation was
`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. 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(cid:173)
`ribine is phosphorylated into the active triphosphate deoxy(cid:173)
`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(cid:173)
`tion) seen on enhanced magnetic resonance imaging (MRI)
`
`*Corresponding author. Tel.: + 39-0-2643-3033; fax: + 39-0-2643-
`3031.
`E-mail address: m.filippi@hsr.it (M. Filippi)
`
`scans of the brain, a modest effect on the accumulation of
`T 2 lesion volume and no effect on the accumulation of
`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(cid:173)
`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(cid:173)
`tion of irreversible disability in MS. MRI enhancing
`lesions reflect the transiently increased blood-brain barrier
`permeability and inflammation [6] and T2-weighted imag(cid:173)
`ing provides non-specific information about the pathologi(cid:173)
`cal substrate of MS lesions [7] . On the other hand,
`hypointense MS lesions on T 1-weighted scans ('black
`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-Sl0X/00 /$ - see front matter © 2000 Elsevier Science B.V. All rights reserved.
`PII: S0022-51 0X(00)00303-8
`
`Merck 2016
`TWi v. Merck
`IPR2023-00049
`
`
`
`M. Filippi et al. I 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(cid:173)
`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(cid:173)
`cluded a four-week screening phase, a one-year double(cid:173)
`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(cid:173)
`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 1 -weighted scans (five to 10 min after the
`injection of 0.1 mmol/kg gadolinium-DTPA) were ob(cid:173)
`tained from all patients. For T 1-weighted images, slices
`were axial, contiguous, 3 mm thick with a matrix size of
`256X256 mm and a field of view of 250X250 mm. We
`used T 1-weighted images obtained at study entry, at month
`12 (end of the double-blind phase) and at month 24 to
`measure the volumes of T 1-hypointense lesions. T 1-hypo(cid:173)
`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
`
`observer, unaware of the treatment regime and scan
`acquisition order, identified such lesions and marked the
`corresponding areas on transparent sheets superimposed
`over the T 1 -weighted hardcopies. Then, a trained techni(cid:173)
`cian, also unaware of the treatment regime and scan
`acquisition order, measured the T 1-hypointense lesion
`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(cid:173)
`ing have been reported previously [4].
`The effect of cladribine on the T 1-hypointense lesion
`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 1 -hypointense volumes between the two study
`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 T 2
`lesion volumes have been reported previously [4]. For the
`whole population studied, the average T 1 -hypointense
`lesion volumes were 4019 mm3 (S.D. = 6547 mm3 ) on the
`entry scans and 4104 mm3 (S.D.=6596 mm3 ) on the scans
`obtained at month 12 (mean absolute change= + 84.2 mm,
`mean percentage change= + 2.4% ). The average T 1 -hypo(cid:173)
`intense lesion volumes, the absolute and percentage vol(cid:173)
`ume difference between month 12 and study entry for the
`three treatment groups are reported in Table 1. T 1 -hypo(cid:173)
`intense lesion volumes were similar in placebo and clad(cid:173)
`ribine-treated patients on the baseline scans. Although
`patients treated with 2.1 mg/kg cladribine showed a
`
`Table 1
`Mean (SE) T 1-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
`
`T 1 -hypointense
`lesion volumes
`Entry scan (mm3)
`
`T 1 -hypointense
`lesion volumes
`Month 12 (mm3)
`
`Mean absolute
`change (SE)
`(mm')
`
`Mean percentage
`change (SE)(%)
`
`Placebo
`
`Cladribine 0.7 mg/kg
`
`Cladribine 2.1 mg/kg
`
`3980
`(1132)
`
`4371
`(1012)
`
`3711
`(754)
`
`4205
`(1184)
`
`4417
`(995)
`
`3679
`(712)
`
`+225
`(143)
`
`+45
`(126)
`
`-31
`(221)
`
`+4.2
`(4.5)
`
`+1.1
`(4.4)
`
`-1.7
`(3.4)
`
`
`
`44
`
`M. Filippi et al. I Journal of the Neurological Sciences 176 (2000) 42-44
`
`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(cid:173)
`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
`increase of T1-hypointense lesion volume 74 mm3 (SE=
`107 mm3 ) during the first phase of the study and =63
`mm3 (SE= 153 mm3 ) during the second 12 months. This
`difference was not statistically significant.
`
`4. Discussion
`
`The encouraging results of two pilot studies of clad(cid:173)
`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 2 lesion burden.
`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 2 lesions would have had a
`subsequent clinical impact. In patients with clinically
`definite MS, the correlation between changes seen on
`conventional MRI scans and the long-term clinical evolu(cid:173)
`tion of MS is modest indeed [7]. One of the main reasons
`for this finding is the poor specificity of the abnormalities
`seen on T 2-weighted and post-contrast T 1-weighted scans
`to the most destructive aspects of MS, such as severe
`demyelination and axonal loss. Recent work has shown
`that T 1-hypointense abnormalities on post-contrast scans
`correspond to areas with severe tissue damage [8], that
`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-
`
`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(cid:173)
`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
`
`Lancet
`
`(2-chlorodeoxyadenosine).
`
`Cladribine
`E.
`[1] Beutler
`1992;340:952-6.
`[2] Sipe JC, Romine JS, Koziol JA, McMillan R, Zyroff J, Beutler E.
`Cladribine in treatment of chronic progressive multiple sclerosis.
`Lancet 1994;344:9-13.
`[3] Beutler B, Sipe JC, Romine JS, Koziol JA, McMillan R, Zyroff J.
`The treatment of chronic progressive multiple sclerosis with clad(cid:173)
`ribine. Proc Natl Acad Sci USA 1996;93:1716-20.
`[4] Rice GPA for the Cladribine Clinical Study Group, Filippi M, Comi
`G for the Cladribine MRI Study Group. Cladribine and progressive
`MS. Clinical and MRI outcomes of a multicenter controlled trial.
`Neurology 2000;54:1145-55.
`[5] Rice G. Cladribine. In: Rudick RA, Goodkin DE, editors, Multiple
`sclerosis therapeutics, London: Martin Dunitz, 1999, pp. 299-308.
`[6] Katz D, Taubenberger JK, Cannella B, Mcfarlin DE, Raine CS,
`McFarland HF. Correlation between magnetic resonance imaging
`findings and
`lesion development
`in chronic, active multiple
`sclerosis. Ann Neurol 1993;34:661-9.
`[7] Filippi M, Horsfield MA, Ader HI et al. Guidelines for using
`quantitative measures of brain magnetic resonance imaging abnor(cid:173)
`malities in monitoring the treatment of multiple sclerosis. Ann
`Neurol 1998;43:449-506.
`[8] van Walderveen MAA, Kamphorst W, Scheltens P et al. Histo(cid:173)
`pathologic correlate of hypointense lesions on T 1-weighted spin(cid:173)
`echo MRI in multiple sclerosis. Neurology 1998;50:1282-8.
`[9] Truyen L, van Waesberghe JHTM, van Walderveen MAA et al.
`Accumulation of hypointense lesions ('black holes') on T 1 spin(cid:173)
`echo MRI correlates with disease progression in multiple sclerosis.
`Neurology 1996;47:1469-76.
`[10] Simon JH, Miller DE, Lull J, Sheeder J, Simonian N, Jacobs L.
`Natural history and effect oflFNl3-la (Avonex®) on T1-hypointense
`'black holes'). Neurology 1999;52(Suppl 2):378-9
`lesions (T 1
`[abstract].
`
`