(cid:21)(cid:30)(cid:30)(cid:27)(cid:29)(cid:11)(cid:3)(cid:3)(cid:18)(cid:26)(cid:22)(cid:2)(cid:26)(cid:28)(cid:20)(cid:3)(cid:5)(cid:4)(cid:2)(cid:5)(cid:4)(cid:5)(cid:10)(cid:3)(cid:14)(cid:4)(cid:7)(cid:5)(cid:10)(cid:5)(cid:9)(cid:10)(cid:5)(cid:4)(cid:4)(cid:4)(cid:7)(cid:8)(cid:7)(cid:4)(cid:6)(cid:1)(cid:13)(cid:31)(cid:17)(cid:23)(cid:22)(cid:29)(cid:21)(cid:19)(cid:18)(cid:1)(cid:26)(cid:25)(cid:23)(cid:22)(cid:25)(cid:19)(cid:1)(cid:17)(cid:33)(cid:1)(cid:12)(cid:16)(cid:24)(cid:17)(cid:28)(cid:22)(cid:18)(cid:20)(cid:19)(cid:1)(cid:15)(cid:25)(cid:22)(cid:32)(cid:19)(cid:28)(cid:29)(cid:22)(cid:30)(cid:33)(cid:1)(cid:13)(cid:28)(cid:19)(cid:29)(cid:29)
`
`Hopewell EX1047
`
`1
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`

`THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES
`
`along with abnormal MHCclassII expression.!? In experimental
`allergic encephalomyelitis (EAE), injection of myelin basic pro-
`tein (MBP) and other myelin proteins results in T-cell infiltration
`into the CNS, accompanied by CNSlesions similar to those seen
`in MS.3 T lymphocytes specific to such myelin antigens have
`been shownto induce CNSinflammation in several mammalian
`species.4 T lymphocyte clones reactive to MBP have also been
`found in the blood of patients with MS.° Despite these observa-
`tions the exact mechanismsof demyelination are unclear.
`Beta interferons have been shown to reduce the frequency
`and severity of exacerbations in the relapsing remitting form of
`MS.° However,little progress has been made in altering the nat-
`ural history of the disease particularly in patients with chronic
`progressive MS. Despite early encouraging results, immunosup-
`pressive agents such as cyclophosphamide, azathioprine, and
`cyclosporin have demonstrated, at best, only marginal activity in
`double blind controlledtrials.”*°
`Cladribine (2 - chlorodeoxyadenosine) is a purine analog
`which is incorporated into DNAandis resistant to the enzyme
`adenosine deaminase.'° [t has demonstrated considerable anti-
`neoplastic activity in hairy cell leukemia, chronic lymphocytic
`leukemia and certain forms of non-Hodgkin’s lymphoma."!'* It
`has significant immunosuppressive effects, with reduction in the
`numbers of CD4 and CD8 lymphocytes!™!3 which persist for 6-
`12 months or more after a course of therapy. The drug is gener-
`ally well
`tolerated with the major
`toxicity being
`myelosuppression.!0!5
`Recently a small (n = 51), randomized, double-blind, placebo
`controlled, cross-over trial was reported using intravenous
`cladribine in patients with CPMS.'® 48 patients entered as
`matched pairs and the trial was stopped after one yearoftreat-
`ment before the cross-over occurred. Treatment consisted of
`four monthly cycles of 0.7 mg/kg cladribine given through a
`central line. Cladribine appeared to favourably influence the
`course of CPMS, with improvementorstabilization in neurolog-
`ical scores, lesion volumes on MRI, and concentrationsof oligo-
`clonal bands in cerebrospinal fluid in treated patients, compared
`to placebo. However, although the treatment was generally well
`tolerated, significant hematologic toxicity was reported, in addi-
`tion to several viral infections. !°
`Subcutaneous cladribine has shown goodbioavailability
`compared to the intravenous route, with a similar pharmacoki-
`netic profile.4 Our objective was to evaluate the safety andtol-
`erability of subcutaneous cladribine therapy in patients with
`chronic progressive multiple sclerosis, and to assess if lower
`doses than those previously used would be immunosuppressive
`with less myelosuppression.
`
`PATIENTS AND METHODS
`
`19 patients (13 females and 6 males) with chronic progres-
`sive MS (CPMS)attending the MS Clinic at St. Michael’s Hos-
`pital in Toronto were treated. EDSS scores ranged from 5.5 to 8,
`and ages from 31 to 60 years (mean age 43). Patients were
`selected for treatment on compassionate grounds based primari-
`ly on rapid progression in the two yearsprior to therapy.
`The average disease duration in these patients was 12.6
`years. 15 patients had no comorbid medical conditions. The fol-
`lowing conditions were found in one patient each: asthma,
`insulin-dependent diabetes mellitus (IDDM), depression, and
`
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`
`IDDM with depression. Most patients had at some pointin their
`disease been treated with short term high dose corticosteroids
`for MS exacerbations. Apart from brief courses of corticos-
`teroids, no patient had received immunosuppressive therapy in
`the year prior to the study. No patient received concomitantcor-
`ticosteroid or other immunosuppressive therapy while on
`cladribine. Cladribine (Leustatin7®, Ortho-Biotech) was admin-
`istered at a dose of 0.07 mg/kg/day by subcutaneous injection
`for 5 days per cycle, or 0.35 mg/kg/cycle, repeated every 4
`weeks for 6 cycles in total. Complete blood count (CBC) and
`differential, as well as clinical assessment, were done prior to
`each treatment cycle; CBC wasrepeated at day 14 following at
`least the first cycle to assess the nadir counts. Total lymphocyte
`counts and CD4, CD8 and CD19 positive lymphocyte subsets
`were determinedpriorto initiation of treatment, then at Cycle 3
`and 6, and (in most instances) at one year following completion
`of therapy. Lymphocyte subset analysis was done by
`immunophenotyping using a FACScan flow cytometer. The nor-
`mal reference ranges for total lymphocyte count, CD4, CD8 and
`CD19 subsets were 1500 - 2900, 535 — 1125, 300 — 810 and 135
`— 447 x 10°/L respectively.
`Neurologic assessments and EDSSscores were performed by
`neurologists at the MS clinic at baseline, during therapy, after
`completion of the 6 cycles, and in follow-up over the next 21
`months. Because ofdifficulties involved in getting significantly
`disabled patients to return for follow-up, the exact timing of the
`EDSSassessment varied somewhat.
`Data are presented as mean “+ standard deviation. The Stu-
`dent’s t-test for paired data was used to compare observations; a
`significancelevel of 0.05 was used to indicate statistical signifi-
`cance.
`
`RESULTS
`
`Of the 19 treated patients, 13 received all six cycles of
`cladribine. Six patients chose not to complete therapy, 2 patients
`after 5 cycles, 3 after 4 cycles and 1 after 3 cycles. The primary
`reasons patients gave for not completing therapy were perceived
`lack of efficacy together with the medication cost. Toxicity did
`not limit treatment in any of the cases.
`Laboratory data from 4 patients (patients 2, 8, 10 and 13 on
`Table 3) were excluded from analysis because of absent baseline
`lymphocyte subset data in two cases, and insufficient follow-up
`data in the other two. The total lymphocyte count and CD4,
`CD8 and CD19 lymphocyte subsets at baseline (priorto the start
`
`Table 1: Lymphocyte subset analysis during therapy (n = 15).
`
`Baseline
`
`3Months
`
`pvalue*
`
`6months
`
`p value**
`
`Lymphocyte
`count
`CD4count
`
`1697 +570¢ 8014350
`8654313
`411+170
`
`0.0000007
`0.000005
`
`463+207 0.000012
`187494
` 0.0000008
`
`CD8 count
`
`418170
`
`2484145
`
`0.00002
`
`165 +127 0.005
`
`CD19 count 197+104
`
`25427
`
`0.000002
`
`26416
`
`0.4
`
`P value derived from Student’s t test for paired data
`*Baseline vs. 3 months
`**3 months vs. 6 months
`
`All values expressed as mean + standard deviation, x 10®/L.
`
`2
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`

`

`LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES
`
`of cladribine therapy), and at 3 and 6 months on therapy in the
`15 evaluable patients are summarized in Table 1. As shown,sig-
`nificant decreases in total lymphocyte counts as well as in
`helper (CD4+) and cytotoxic/suppressor (CD8+) lymphocyte
`subsets were seen during cladribine therapy. There was a contin-
`uing decline in T lymphocyte subsets from 3 to 6 months; this
`wasparticularly true for the CD4 subset. Highly significant
`decreases in the B lymphocyte (CD19+) subset was also seen
`with trough values attained at 3 months.
`Follow up laboratory data, one year after completion of
`cladribine, were available on 12 of these 15 patients and are
`summarized in Table 2. The mean total lymphocyte, CD4 and
`CD 8 counts had shown some recovery compared to the values
`at the end of therapy, but werestill significantly below baseline
`level. The mean CD19 count had recovered to normallevels.
`
`Table 2: Lymphocyte subset analysis following completion of therapy
`(n=12).
`
`6 Months
`
`l year post
`therapy
`
`p value*
`
`Total Lymphocyte count
`CD4 count
`
`475+200¢
`199 + 97
`
`895+367
`302+133
`
`0.0003
`0.018
`
`There were no opportunistic infections seen either during
`cladribine therapy or in the following year. The hemoglobin,
`granulocyte and platelet counts were within normal reference
`ranges throughout the duration of cladribine therapy. One
`female patient developed a borderline anemia with a
`hemoglobin of 117 g/L while on cladribine which recovered to
`normal post therapy. Another patient had a mild thrombocytope-
`nia with a platelet count of 136 x10°/L, after one cycle of
`cladribine which returned to normal by the subsequent2 cycles.
`No definite nonhematologic toxicity was reported or
`observed. No patient required a reduction of cladribine dose or
`treatment delay secondary to adverseeffects.
`Details of EDSS scores are in Table 3. A significant change
`in EDSS score was defined as a change of one-half point or
`more measured at the first post therapy visit and compared to
`baseline. Follow-up data are available in all patients, at times
`varying from 6-21 months after completion of therapy. Ofthese,
`8 patients had an EDSSscore that increased significantly as
`compared to baseline, while 11 were unchanged. None had a
`significantly lower EDSS. Patient global rating scores obtained
`approximately 1 year after therapy indicated that 5 patients felt
`they were doing better, 3 were unchanged and 9 worse; the
`remaining 2 were uncertain.
`
`CD8 count
`
`CD19 count
`
`156 + 91
`
`227+142
`
`0.047
`
`28 + 16
`
`179+110
`
`0.00014
`
`DISCUSSION
`
`*P value derived from Student’st test for paired data
`tAll values expressed as mean + standard deviation, x 10°/L.
`
`Table 3: Summary of EDSS scores obtained on cladribine therapy; 0
`months represents baseline (n = 19).
`
`Pt. # cycles
`0
`
`Monthsfrom start of therapy
`6
`9
`12
`15
`18
`
`21
`
`3
`
`24
`
`27
`
`16=«75 8.5
`
`7
`
`2.6 #7
`
`3.
`
`4.
`
`5.
`
`6
`
`6
`
`6
`
`6 6
`
`7 6
`
`6
`
`8
`
`8
`
`65
`
`65
`
`8
`
`65
`
`65
`
`6
`
`6
`
`8.5
`
`8.5
`
`8.5
`
`65 65
`
`65
`
`7
`
`7
`
`65
`
`
`
`65
`
`7
`
`6.5
`
`75
`
`7
`
`6.5
`
`6
`
`7
`
`7
`
`7
`
`7
`
`7
`
`8.5
`
`7
`
`Cladribine is recognized to have significant immunosuppres-
`sive effects, characterized by marked reductions in T and B lym-
`phocyte subsets, when used in the treatment of hematologic
`malignancies. Myelosuppression is the major toxicity. In the
`original report of cladribine treatment in MS,a statistically sig-
`nificant drop in blood counts was observed.'> In 7 patients, the
`platelet count dropped below 80 x10°/L, while a substantial and
`sustained decrease in granulocytes was seen.'> Two patients
`developed severe and prolonged aplastic anemia requiring red
`
`cell and platelet transfusions. In one case, the patient had
`received prior therapy with carbamazepine and was receiving
`phenytoin while on cladribine. The second patient had previous-
`ly received extensive therapy with chlorambucil. Both recovered
`after several months of marrow suppression. Twopatients devel-
`oped herpes zoster which subsided rapidly on acyclovir treat-
`ment. One patient presented with acute fulminant hepatitis B
`infection 3 days after her second cladribine infusion and died 5
`days after admission. She had negative hepatitis B serology at
`start of therapy and a history of probable recent exposure.
`Ourseries of patients received a lowertotal treatment dose
`(total of 2.1 vs 2.8 mg/kg, as well as a lower treatment dose per
`cycle (0.35 mg/kg vs. 0.7 mg/kg). Using this dosing regimen,
`patients experienced no significant myelosuppression or infec-
`tious problems despite achieving profound lymphocyte suppres-
`sion. When compared to the higher dose regimen, the rate of
`decline in the CD4 count using our regimen wasless rapid,
`although the trough CD4 count at six months into treatment was
`similar.'> In contrast, the rate of decline, nadir and post-therapy
`levels of CD8 and CD19 counts were similar in the two groups.
`At approximately 1 year post-therapy, we noted a partial but
`incomplete recovery in CD4 counts, while CD4 levels remained
`severely depressed in the higher-dose study.'5 In view of the pre-
`sumed pathogenetic role of T helper cells in MS,'? the slower
`decline and earlier recovery in these cells could have implications
`
`8 6
`
`9 6
`
`10.6
`
`11.6
`
`12.6
`
`13.4
`
`14.6
`
`15.5
`
`16.5
`
`17.4
`
`18. 4
`
`193
`
`65
`
`6
`
`65
`
`6
`
`65
`
`7
`
`7
`
`7
`
`7
`
`75
`
`65
`
`55
`
`8&5
`
`65
`
`55
`
`6
`
`6
`
`6.5
`
`6.5
`
`7
`
`7
`
`6
`
`6.5
`
`7
`
`7
`
`5.5
`
`Volume 25, No. 4 — November 1998
`https://doi.org/10.1017/S0317167100034302 Published online by Cambridge University Press
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`
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`THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES
`
`
`
`Mean CD8 count Mean CD19 count
`
`
`BCyce 1
`@Cyce 3
`Cycle 6
`E11 year post therapy
`
`
`
`
`
`7i i
`
`Meantotal Lymphocyte count
`
`Mean CD4 count
`
`Figure 1: Absolute lymphocyte count and lymphocyte subsets - CD4, CD8 and CD19 at baseline, 3 months and 6 months while on Cladribine thera-
`py, and 1 year after completion of Cladribine.
`
`regarding therapeutic efficacy. However, since only a small sub-
`set of T cells is likely involved in producing MS, these implica-
`tions are unclear. Measuring T lymphocytes reactive to myelin
`basic protein’ could address this question in vitro, although only
`a randomizedtrial could accurately assess the clinical relevance
`of the effects of the different dosing regimens.
`In addition to the lower cladribine dose, none of our patients
`were On concomitant immunosuppressive or myelosuppressive
`therapy which may have contributed to the lack of toxicity. Con-
`comitant use of corticosteroids and purine analogs has been
`associated with opportunistic infections.'? Whether cladribine is
`safe to use along with or soon after medications such as beta-
`interferon, methotrexate, azathioprine or cyclophosphamideis
`unclear and requires further study. The long-term safety of
`cladribine in MSis also unknown.
`The subcutaneous route of administration has been shown to
`have a favorable pharmacokinetic profile, with 100% bioavailabil-
`ity and no local toxicity.'* Such treatment is easy to administer, not
`requiring intravenous access. Although given in our Medical Day
`Care outpatient unit, there is no reason in principle why patients
`could notbe trained in self-administration of the medication.
`Subcutaneous cladribine therapy, at the doses used in this
`study, is remarkably well tolerated in chronic progressive multi-
`ple sclerosis, with no significant toxicity despite achieving pro-
`found and long lasting immunosuppression. The degree of
`suppression of lymphocytes was similar to the higher-dose regi-
`mens,although differences were noted in the rate of decline and
`recovery of CD4 counts.
`As this was a safety and tolerability study with no control
`group, nothing meaningful can be stated regarding the observed
`EDSSchanges, given the unpredictable course of MS. Although
`no objective improvements were noted in any patient, we cannot
`exclude the possibility that cladribine may have contributed to
`
`disease stabilization in some instances. We awaitthe results of a
`large appropriately powered randomizedblindedtrial of this
`medication with interest. Although safe and easy to use, the
`therapeutic effectiveness of cladribine in chronic progressive
`MSremainsto be established.
`
`ACKNOWLEDGEMENTS
`
`We acknowledge the assistance of Janssen Ortho Inc.in partially
`defrayingthe cost of this study.
`
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`
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`
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`LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES
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`12. Juliusson G, Liliemark J. High complete remission rate from
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`
`Volume 25, No. 4 — November 1998
`https://doi.org/10.1017/S0317167100034302 Published online by Cambridge University Press
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