`
`THE LANCET
`
`Cladribine in treatment of chronic progressive multiple sclerosis
`
`JC Sipe, J S Romine, J A Koziol, R McMillan, J Zyroff, E Beutler
`
`
`Introduction
`
`Although the primary cause of multiple sclerosis (MS)is
`unknown,there is circumstantial evidence to indicate that
`autoimmune mechanismsplay a majorpart in the attack of
`the body’s own immunocytes on central nervous system
`myelin to cause the symptoms in MS.
`Carson and colleagues’? developed cladribine (2-
`chlorodeoxyadenosine) as a highly specific antilymphocyte
`agent that mimics the accumulation of deoxynucleotides in
`adenosine deaminase deficiency. This drug has been found
`to cause death of lymphocytes by apoptosis and to have
`relatively low toxicity toward other tissues. Unlike most
`other antilymphocyte drugs, it is equally effective against
`resting and dividingcells.
`Theuse of cladribine in chronic MS wasconsideredafter
`extensive experience had been obtained with the drugin the
`successful treatmentof lymphoid leukaemias, notably hairy
`cell leukaemia and lymphomas, and some success in the
`treatment of autoimmune haemolytic anaemia.?* Because
`of its relative safety and the long-lasting lymphopenia
`observed during its administration, we undertook a pilot
`study,treating 4 patients with chronic progressive MS with
`cladribine in 1990. Results were sufficiently encouraging
`for us to conduct a more extensive randomised, double-
`blind, placebo-controlled study in 51 patients with chronic
`progressive MS.
`
`Patients and methods
`
`51 patients, all of whom had clinically definite or laboratory-
`supported definite chronic progressive MS° for more than 2 years,
`were entered into the study. These patients had been followed at
`Scripps Clinic by the neurology group for between 6 months and 10
`years. The study plan,risks, and potential benefits were explained
`to each patientin detail, and all patients gave informed consent.
`Patients were matched according to age, sex, and severity of
`disease and 24 pairs of patients were identified. Each pair was
`randomised by thestatistician (JAK) using random numbertables”
`so that one patient was assigned to the groupinitially receiving
`cladribine and the otherto the grouporiginally receiving placebo.1
`other patient, for whom no suitable match was identified, was
`started on cladribine; this individual left the study after 8 months
`on protocol, 2 patients, both initially assigned to cladribine, were
`lost at 2. and 3 months: as discussed below, | patient died of acute
`fulminating hepatitis B during her second month on protocol and
`the other patient dropped outof the study at 3 monthsbecauseof a
`traumatic hip fracture. The loss of these 2 patients seemed
`unattributable to cladribine so we recruited 2 additional matched
`patients as replacements and assigned them to cladribine. 1 patient
`receiving placebo withdrew from the study after 4 months on
`protocol for reasons unrelated to treatment, so we chose not to
`replace this patient. The analyses reported here refer to the 24
`matched pairs of patients (table 1), and exclude the 3 patients on
`cladribine who did not complete a full year of the study.
`Participants were permitted to continue medications to treat
`troublesome symptoms of MS—eg,
`spasticity treated with
`baclofen or bladder dysfunction with oxybutynin. Candidate
`Merck 2004
`ieMCECK20048.
`TWi v Merck
`Vol 344 * July 2, 1994
`TWiv Merck
`9
`IPR2023-00049
`IPR2023-00049
`
`Summary
`is a severely
`Chronic progressive multiple sclerosis (MS)
`disabling demyelinating disease in which autoimmune
`processes seem to have a major role. The nucleoside drug
`cladribine is a potent lympholytic agent with few side-effects.
`We have studied its efficacy and safety in a randomised
`double-blind trial.
`51 patients (48 entered as matched pairs) received four
`monthly courses of 0-7 mg/kg cladribine or placebo (saline)
`given througha surgically implanted central line. Neurologists
`with no knowledge of which medication the patient was
`receiving examined the patients monthly and noted two rating
`scale scores (Kurtzke and Scripps). Cerebrospinal fluid and
`brain magnetic resonance imaging (MRI) examinations were
`done at 6 and 12 months. Average neurological scores,
`demyelinated volumes on MRI, and concentrations of
`oligocional bands in cerebrospinal
`fluid were stable or
`improvedin the patients receiving cladrabine but continued to
`deteriorate in patients on placebo. Mean paired (placebo
`minus matched cladribine) differences at 12 monthsrelative
`to baseline were 1-0 (SE 0-4) for the Kurtzke scores, -13-9
`(2-3) forthe Scripps scores, 4 57 (1-17) mL fordemyelinated
`volumes, and 7:3 (3:3) arbitrary units for concentrations of
`oligocional bands.
`tolerated and clinically
`Cladribine was generally well
`significant toxicity occurred in only 1 patient, in whom severe
`marrow suppression developed with complete recovery after
`several months. 1 patient died of newly acquired hepatitis B,
`an event unlikely to be related to cladribine. We conclude that
`the immunosuppressive drug cladribine influences favourably
`the course of chronic progressive MS.
`Lancet 1994; 344: 9-13
`
`
`
`
`
`Department of Molecular and Experlmental Medicine, Scripps
`ResearchInstitute (J C Sipe mp, J S Romine mo,Prof J A Koziol pno,
`Prof R McMillan mo, Prof E Beutier mo); and Division of Neurology and
`Department of Radiology, Scripps Clinic and Research Foundation
`(JC Sipe, J S Romine,J Zyroff mo), La Jolla, Callfornla, USA
`Correspondence to: Prof Ernest Beutler, Department of Molecular
`and Experimental Medicine (SBR-3), Scripps ResearchInstitute,
`10666 North Torrey Pines Road, La Jolla, CA 92037,USA
`
`

`

`THE LANCET
`
`
`Time
`Score
`Placebo
`
`Cladribine
`
`Epss
`Baseline
`6 mo
`12.mo
`
`SNRS
`69 5(2 2)
`69 5(2 1)
`Baseline
`73 7(27)
`65 3(2 3)
`6 mo
`
`
`62 6 (2 3)12mo 74 B(2 1)
`
`47(03)
`45(04)
`44(04)
`
`46(03)
`5 0(03)
`56(03)
`
`Table 2: Summary statistics from neurological examinations
`
`analysis and complete blood count. The unblinded investigators
`decided, on the basis of the blood count, whether it was safe to
`proceed with the next dose of test medication. If these observers
`judged that the drug could be given safely, cladribine (or placebo)
`was administered by continuous 7-day intravenousinfusion at the
`rate of0-1 mg/kg daily. Ifnot, the counts were repeated periodically
`and the decision whether or not to continue was made; planned
`infusions were delayed in 4 patients receiving the drug and in 2
`patients on placebo.
`In the original protocol six monthly doses were planned butthis
`was modified to four courses after the study began because the
`thrombocytopenia was more profound than expected in some
`patients.
`] patient had already received five courses before the
`decision to reduce dosage had been made.| patient received only
`two courses and 2 patients only three because ofthrombocytopenia.
`All other patients were given four courses.
`
`Magnetic resonance imaging
`Magnetic resonance imaging (MRI) was performed on a 1-5 T
`General Electric Signa scanner. T2 and proton density weighted
`images were obtained using a conventional spin-echo sequence
`with repetition times of 2500 ms and echo delay times of 30 and 90
`ms. Sections were 4 mm thick with a 1 mm interslice gap. Tl
`weighted scans were obtained in the sagittal and axial planes. Axial
`scans of3 mm thickness and 0 interslice gap were done about 10 min
`after
`gadopentetate
`dimeglumine
`(Magnevist;
`Berlex
`Laboratories, Wayne, New Jersey, USA) injection to ensure
`optimal time for transmigration of the contrast agent across the
`blood-brain barrier. Special attention was given to careful
`repositioning of patients to guarantee reproducible slice positions.
`Regions of demyelination on proton density weighted scans and
`contrast enhancement on T] weighted scans were outlined by hand
`SNRS
`
`78
`
`@ Cladribine
`
`O Placebo 75
`
`72
`
`69
`
`Score 66
`
`63
`
`60
`
`Placebo
`
`Cladribine
`
`16/8
`16/8
`Sex (F/M)
`24/0
`22/2
`Race (white/other)
`43 0 (28-53)
`42 7 (21-54)
`Meanage (yr) (and range)
`
`Mean duration ofclinical symptoms of MS(yr) (and range) 10 5 (2-31) 12 7 (4-24)
`
`Table 1: Demographic characteristics of paired patients at
`study entry
`
`patients were excluded if the serum creatinine was above 132
`pmol/L or if the calculated creatinine clearance was less than 80°,
`of the age-adjusted normalvalue;ifserum transaminasesor hepatic
`alkaline phosphatase were more than twice the upper limit of
`normal; or if the neutrophil count was below 1600/pL or platelet
`count was less than 130 000/uL. No woman not taking adequate
`birth control measures or man planning to father a child for the
`duration of the study was included. Patients who weretreated with
`corticosteroids or other immunosuppressive medications such as
`cyclophosphamide, azathioprine, or cyclosporin within the
`previous 6 months or who appeared to have decreased marrow
`reserve as manifested by leukopenia or thrombocytopenia for more
`than
`6 weeks
`after
`conclusion
`of
`treatment with
`immunosuppressive agents were excluded. All patients had a
`central venous access device implanted for drug or placebo
`administration.
`
`Study design
`The investigation was designed as a 2-year double-blind crossover
`study. This design was ethically necessary because of the need for
`surgically implanted central venous lines. However, the protocol
`stipulated analysis as a parallel study after 1 year, crossover being
`decided at that me. The primary endpoint was neurological
`improvement, and since significant improvement was achieved at
`the end of | year this portion of the study was concluded at that
`time.
`
`Evaluation
`The examining neurologists, nurses, and patients were blinded to
`the treatmentassignments. An unblinded investigator (EB or RM)
`monitored all the laboratory studies and patients’ complaints and
`illnesses, if any. Every patient was examined monthly by the same
`neurologist for the first year of the study. Two neurological
`assessments, the Scripps Neurologic Rating Scale (SNRS)* and the
`Kurtzke Expanded Disability Status Scale (EDSS),’ were scored at
`every examination, and at each visit blood was taken for chemical
`EDSS
`
`@ Cladribine
`a O Placebo
`
`4.5
`
`5.0
`
`23
`
`5.5
`
`—_--
`9
`2
`4
`6
`8
`10
`12
`Month
`
`Figure 1: ChangesIn the Kurtzke (EDSS) and Scripps (SNRS)rating scores
`Mean (SE bars) shown.
`
`
`10
`
`Vol 344 » July 2, 1994
`
`

`

`EDSS
`
`0.5
`
`
`
`
`
`Paireddifferences(placebo—cladribine)
`
`0.5
`
`1.0
`
`15
`
`THE LANCET
`
`SNRS
`
`°o
`
`w
`
`a
`
`©
`
`“12
`
`“15
`
`0
`
`2
`
`4
`
`6
`Month
`
`8
`
`10
`
`12
`
`0
`
`2
`
`4
`
`6
`Month
`
`8
`
`10
`
`12
`
`Figure 2: Differences between Kurtzke (EDSS) and Scripps (SNRS) rating scores In matched pairs (placebo minus cladribine)
`Mean paired differences (SE bars) shown. Paired differences were significantly greater than zero (EDSS p<0. 01. SNRS p<0 001).
`
`on filmed images. All scans were interpreted and marked by the
`same neuroradiologist (JZ) who had no knowledge of treatment
`protocols. ‘These were then duplicated by a technologist using the
`taped raw data and a computer work station (CEMAX,Santa
`Clara, California). Pixel counts for each slice were converted into
`volumes by a volume rendering software program. All
`the
`volumetric analyses were done by the same technologist.
`
`Cerebrospinal fluid (CSF) examination
`CSF was
`tested
`for
`total protein and immunoglobulin
`concentration, and samples were frozen for assessment of changes
`in oligoclonal bands. At the end of one year the baseline and 6 and
`12 month samples of CSF were labelled with ‘*I-albumin and
`concentrated 40-fold in a Centricon-10 (Amicon) centrifugal
`concentrators, and electrophoresis was performed on Corning high
`resolution protein agarose plates. After staining with acid violet,
`the strips were scanned with a Zeineh soft
`laser scanning
`densitometer (Biomed Instruments, Fullerton, California). The
`height of oligoclonal bands was measured in millimetres as
`arbitrary units by a technician with no knowledgeof the treatment.
`‘The radioactivity of the albumin band was determined to correct
`for
`inter-sample differences
`in concentration and sample
`application. When the concentration of any sample in a series was
`150°, or more of any other sample electrophoresis was repeated,
`the volumes applied being changed so that nearly the same amounts
`of each original CSF was applied to the gel. A reliability
`experiment, on 12 random samples run on three different gels,
`yielded an intra-class correlation coefficient’® of 0-95 for the
`replicates across the gels.
`
`Statistical methods
`The design was a double-blind crossover trial, with one planned
`interim analysis at 12 months, before crossover. Our primary
`endpoint was neurological improvement as assessed by the two
`rating scales. Our pilot study suggested that, relative to placebo,
`cladribine would improve the status of patients with chronic
`progressive MS. We estimated that a sample size of 44 patients (22
`per arm) would besufficient to detect a 15% SNRS improvement
`in patients on cladribine if there was no improvement on placebo,
`with a statistical power of 0-90 and a one-sided statistical test at
`conventional alpha level 0-05. Our stopping rule at 12 months was
`
`significant improvement in the SNRSfor the cladribine group
`comparedwith the placebo arm,at an alpha level of 0-01. Since this
`improvementwasachieved,thestatistical analysis was done as fora
`conventional randomised parallel design.
`Comparisons between treatment arms were based on the
`underlying matching of 24 pairs of patients; the last available
`observations were carried forward for the patient who had not
`completed 12 monthsin the study. Similar analyses were done in
`which these missing data remained missing and in which they were
`modelled under the representation that
`they were missing at
`random. Also, an unpaired, intent-to-treat analysis was done on
`data from all 51 patients; and a paired analysis incorporating data
`from the 2 cladribine patients lost by month 3 wasalso undertaken.
`All additional analyses yielded results similar to those reported
`here.
`Summary statistics are based on the 24 matchedpairs of patients
`and are reported as mean (and standard error, SEM). The paired
`differences in neurological scores were analysed with a non-
`parametric repeated measures analysis of variance.** Other paired
`comparisons between the treatment arms were made with both
`parametric and non-parametric one-sample procedures, with
`two-sided p values reported throughout.
`
`Results
`Neurological! examinations
`Both examining neurologists (JR and JS) participated in a
`study of inter-rater and intra-rater reliability. 20 patients
`(10 primarily followed by each neurologist) were
`independently assessed by each examiner on the same day.
`Inter-rater agreement? washigh: the weighted x coefficient
`was 0-976 for EDSS and 0-828 for SNRS. Inter-rater
`agreement on the EDSS was 100% for all sets of
`examinations when agreement was defined as a difference
`less than or equal to 1-0. This compared favourably with
`agreements reported in otherclinical trials of therapeutic
`agents in MS." Inter-rater agreement on the SNRS was
`85°, with agreementdefined as difference of no more than
`10 points. Separately, 18 patients (JR, 8, and JS, 10) were
`assessed by the same examiner twice on the same day, the
`period between examinations ranging from 135 to 240 min.
`
`Vol 344 = July 2, 1994
`
`11
`
`

`

`THE LANCET
`
`Mean (SE) volume (mL)
`Time
`Cladribine
`Placebo
`
`23 46 (4 35)
`18 32 (2 85)
`Baseline
`24 35 {4 81)
`20 91 (3 37)
`6 mo
`
`
`22 46 (3 39)12 mo 22 66 (4 32)
`
`Table 3: Total lesion volumes (MRI)
`
`Intra-rater agreement on the EDSS wasperfect; weighted k
`coefficients of agreement between the two SNRSscores
`were 0-978 (JR) and 0-998 (JS).
`SNRS and EDSS scores are shown in figure 1 with
`summary statistics in table 2. Both scores
`indicated
`progressive deterioration in patients
`randomised to
`placebo. Modest improvementin mean scores was foundin
`patients
`on
`cladribine. The
`average matched-pair
`differences (placebo minus cladribine) in scores during the
`study are shown in figure 2. A distribution-free procedure"
`was used to assess whether individual paired differences
`were consistently positive or negative. These directional
`statistics were highly significant (y?,=8-38, p<0-004 for
`EDSS, x?, = 13-26, p< 0-001 for SNRS). The mean paired
`differences in EDSS and SNRS scores at 6 monthsare 0-6
`(0-3) and —8-9 (2:2), with respective 95° confidence
`intervals of 0-1-2 and — 13-5 to — 4-3), At 12 months, the
`meanpaired differences in EDSS and SNRSscoresare 1-3
`(0-3)and — 12-5(2-0), respective 95% CIs being 0-6—2:0.and
`— 16:7 to — 8:2.
`We also analysed the numberof patients experiencing a
`change in EDSS scoreof 1 or more pointsat 1 year. Among
`the 23 patients receiving placebo who were evaluable at 12
`months the EDSS score of 7 of them had progressed by at
`least 1 point, the score had improved (decreased) at least a
`point in only 1, and 15 patients remained within 1 point of
`baseline. Among the 24 evaluable patients receiving
`cladribine, the EDSS scoreof only 1 patient had worsened
`by at least a point, the EDSS had improved (decreased) by
`at least a point in 4 patients, and 19 patients had an EDSS
`score that changed less than 1 point. These proportions are
`significantly different (p < 0-02, Terpstra-Jonckheeretest).
`
`MRI data analyses
`Summary statistics relating to demyelinated and enhancing
`volumes are given in table 3. Paired differences (placebo
`minuscladribine) of demyelinated volumesat 6 months and
`at 12 months, relative to baseline values, were different
`from zero (T?, ,,= 17-01, p< 0-002). This can be attributed
`primarily to the changes at 12 monthsrelative to baseline.
`The meanpaired difference (placebo minuscladribine) in
`demyelinated volumes at 6 monthsrelative to baseline was
`1-47 (1:32) mL (95% CI — 1-26 to 4-19); at 12 monthsthe
`mean difference was 4-42 (1-10) (95% CI 2-16-6-69).
`We dichotomised the enhancing volume findings by
`calling the elimination of enhancing volumes or their
`continued absence a favourable outcomeand labelling the
`emergence of or continued presence of enhancing volumes
`as an unfavourable outcome. A paired analysis of the
`12-month findings relative to baseline yields 13 pairs with
`jointly
`favourable outcomes,
`3 pairs with
`jointly
`unfavourable outcomes,| pair with placebo favourable and
`cladribine unfavourable, and 10 pairs with placebo
`unfavourable, cladribine favourable (p <0:001, McNemar
`test).
`
`CSF examination
`The number of oligoclonal bands did not change in any
`patient. For the cladribine group,
`relative oligoclonal
`*
`
`concentrations at baseline and at 6 months and 12 months
`averaged 29-9 (4-2), 26:5 (3-4), and 25-0 (3-3) a significant
`decline (F, ,,=5:17, P < 0-02). Corresponding valuesfor the
`placebo group were 26-2 (3-8), 29-9 (3-8), and 29-9 (4-7), a
`modest but non-significant increase (F,,,= 1°81, p=0:18).
`Amongthe matchedpairs, the placebo patients tended to
`have higher values than their counterparts on cladribine:
`The mean paired difference (placebo minus matched
`cladribine)
`in
`relative
`oligoclonal
`immunoglobulin
`concentrations at 6 months relative to baseline is 4-3 (2-0)
`(95% CI 0-1-8-5); at 12 months it was 7:3 (3-3) (95% CI
`0-5-14-1),
`
`Side-effects and complications
`In general, cladribine was well-tolerated byall patients and
`there were no untoward side-effects or symptoms in MS
`patients that could have systematically affected the double-
`blindedness of the protocol. Marrow suppression occurred
`in several patients but wasclinically significant in only l,a
`patient who wasalso taking large doses of phenytoin for
`trigeminal neuralgia. This patient’s marrow function
`recovered fully over a period of several months after
`conclusion of therapy with cladribine. Details of the
`haematological data collected in this study are summarised
`elsewhere.'*
`Two serious medical events occurred. A 40-year-old
`woman received her second dose of cladribine when her
`blood count and blood chemistry, including liver function
`tests, were normal. Hepatitis B serology had been negative
`on study entry. 3 days after the infusion, she presented with
`fever, abdominal pain, and transaminase levels exceeding
`15 000 U/mL.Peripheral blood counts were normal except
`for modest lymphopenia. There was a history of probable
`exposure to hepatitis B infection, and liver biopsy revealed
`acute necrosis that was demonstrated to be due to hepatitis
`B virus. Theclinical course was fulminant, and the patient
`died 5 days after admission. The fulminant course is
`unlikely to be related to cladribine (see Discussion). A
`second patient developed abdominal pain and low grade
`fever 2 weeks after conclusion of her second course of
`placebo, She declined hospital admission and did not attend
`for follow-up the next day. 2 days later she was admitted to
`the hospital with severe lower abdominal pain, decreased
`bowel sounds, and rebound tenderness. Surgery was
`considered, but a culture revealed Salmonella enteritidis in
`her stools, and the patient responded promptly to antibiotic
`therapy.
`2 patients who hadreceived cladribine had mild episodes
`of herpes zoster restricted to one or two dermatomes, and
`these subsided rapidly on treatmentwith oral acyclovir.
`
`Discussion
`
`Immunosuppressive therapy in MS has previously
`involved treatment primarily with cyclophosphamide,
`azathioprine,
`and cyclosporin. Evidence of modest
`efficacy!’ has been tempered by significant side-effects in
`some patients on long-term therapy. Plasmapheresis and
`lymphocytapheresis have been tried but there is no clear
`evidence of sustained clinical benefit.© Monoclonal
`antibodies directed against specific T-cell subsets have also
`been used in MS but the primary obstacle to long-term
`treatment has been the development of antibody to the
`monoclonal.'’ Although interferon beta has been found to
`be effective in relapsing-remitting MS—with significant
`reductions in exacerbationrate, in severity of exacerbations
`
`12
`
`Vol 344 + July 2, 1994
`
`

`

`THE LANCET
`
`lesions—no satisfactory
`and in accumulation of MRI
`treatment has been found for progressive MS.
`Cladribine in our study was associated with highly
`significant improvements in neurological ratings. The MS
`status of patients on placebo continued to decline, and this
`neurological deterioration was not only significant but also
`was sufficiently severe to affect the patients’ disability
`status.
`
`that the drug may be given by the much more convenient
`subcutaneous route,** and in futuretrials this is what we
`plan to use. Preliminary results suggest that a lower doseis
`less likely to produce marrow suppression andis effective.
`Cladribine may becomea useful agent for the management
`of chronic progressive MS.
`Supported by FDA grant FD-R-000280 and NIH grants NS30218 and
`RRO0833, the Sam Stein and Rose Stein Charitable Trust Fund, and a
`grant from the R W Johnson Pharmaceutical Research Institute. This
`work could not have been done without the outstanding assistance of
`Carolyn Koumaras, and otherstaff of the General Clinical Research
`Center.
`
`In a double-blind study the aim 1s for both patients and
`evaluating physicians to be blinded to the treatment being
`given but sometimesthere are clues that make blinding less
`than perfect. For example, although the studyof interferon
`was blinded'*° this agent does cause malaise, among other
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`immunosuppressive drugs seems to ameliorate the course
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`13 Goodkin DE, Cookfair D, Wende K,et al. Inter- and intrarater scoring
`of both acutely acquired and chronic hepatitis. ‘““Rebound”
`agremmentusing grades 1-0 to 3-5 of the Kurtzke Expanded Disability
`exacerbation
`of
`infection
`may
`occur
`when
`Status Scale (EDSS). Neurology 1992; 3 42: 859-63.
`immunosuppression is withdrawn?!?? but our patient had
`14 Beutler E, Koziol J, McMillan R, Sipe JC, Romine JS, Carrera CJ.
`fulminating hepatic necrosis during and immediately after
`Marrow suppression produced by repeated doses of cladribine. Acta
`the infusion of cladribine. Cladribine has no known liver
`haematol 1994; 91: 10-15.
`15 Weiner HL, Hafler DA. Immunotherapy in multiple sclerosis. Ann
`toxicity and liver-function tests of the other patients in this
`Neurol 1988; 23: 211-22.
`study revealed no difference between drug and placebo
`16 Tindall R. A closer look at plasmapheresis in multiple sclerosis: the
`patients. More than 1000 patients have received cladribine
`cons. Neurology 1988; 38: 53-56.
`at this institution, and at least 1 has developedviral hepatitis
`17 Hafler DA, Weiner HL. Immunosuppression with monoclonal
`antibodies in multiple sclerosis. Neurology 1988; 38: 42-47.
`with a benign course. Over 5000 patients have received this
`18 Duquette P, Girard M, Despault L, Dubois R,et al. Interferon
`drug worldwide and no other case of fulminant hepatitis
`beta-1b is effective in relapsing-remitting multiple sclerosis I. Clinical
`infection has been recorded.
`Indeed, a patient with
`results of a multicenter, randomized, double-blind, placebo-controlled
`trial. Neurology 1993; 43: 655-67.
`subfulminant hepatitis C from blood transfusion given 18
`19 Paty DW, Li DKB.Interferon beta-1b is effective in relapsing-
`days earlier showed rapid recovery in the face of the
`remitting multiple sclerosis II, MRI analysis results of a multicenter,
`cladribine therapy.27 We consider it unlikely that
`the
`randomized double-blind, placebo-controlled trial. Neurology 1993;;
`43: 622-67.
`fulminant course in our patient wasrelated to cladribine.
`20 Moriyama T, Guilhot $, Klopchin K,et al. Immunobiology and
`Cladribine is incorporated into DNA.' Althoughourfirst
`pathogenesis of hepatocellular injury in hepatitis B virus transgenic
`patients were treated a decade ago? most had far advanced
`mice. Science 1990; 248: 361-64.
`leukaemia or lymphomaand did not survive long enough to
`Lau JY, Bird GL, Gimson AE,Alexander GJ), Williams R. Treatment
`permit assessment of long-term toxicity or oncogenicity.
`of HBVreactivation after withdrawal of immunosuppression. Lancer
`1991; 337: 802.
`Large numbersof patients with hairy cell leukaemia have
`22 Lueg E, Heathcote J. Dangers of immunosuppression therapy in
`been treated in the past 5 years, but these generally received
`hepatitis B virus carriers. Can Med Assoc J 1992; 147: 1155-58.
`2wo
`a total dose of only 0-7 mg/kg body weight. None of the 4
`Schirmer M, Vogel W, Thaler J, et al. Subfulminant hepatitis Cina
`patient with hairy-cell leukemia during treatment with cladribine. Exp
`patients with MS wetreated with a total dose of 2-5 mg/kg 4
`Hematol 1993; 21: 1091.
`years ago in a pilot study has had adverseeffects long-term.
`24 Liliemark J, Albertioni F, Hassan M, Juliusson G, On the
`In this study surgical implantation of a catheter was
`bioavailability of oral and subcutaneous 2-chloro-2’-deoxyadenosine in
`required because no information abouttheefficacy of other
`humans:alternative routes of administration. 7 Clin Oncol 1992; 10:
`1514-18,
`routes of administration was available. We now recognise
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