Safety and Tolerabilityof Subcutaneous
`Cladribine Therapy in Progressive
`Multiple Sclerosis
`
`R.Selby, J.Brandwein and P. O'Connor
`
`ABSTRACT: Objective: To evaluate the safety and tolerability of subcutaneous (s.c.) cladribine therapy
`in patients with chronic progressive multiple sclerosis (CPMS), and to evaluate the effects on lymphocyte
`subsets. Background: Cladribine, a synthetic antineoplastic agent with immunosuppressive effects, may
`favourably affect the course of CPMS. However results of a previous reported clinical trial showed signif(cid:173)
`icant myelosuppression in some patients. Design/Methods:19 patients with severe (mean extended dis(cid:173)
`ability status score [EDSS] = 6.7) CPMS were treated on a compassionate basis with cladribine 0.07
`mg/kg/ day s.c. for 5 days per cycle, repeated every 4 weeks for a total of 6 cycles. Patients underwent
`clinical evaluation, EDSS, and hematologic analysis before, during, and following therapy. Results: The
`treatment was very well tolerated with no clinically significant side effects observed. Between baseline
`and the end of cycle 6, mean decreases were noted in absolute lymphocyte count from 1697 to 463 (p =
`0.000012), CD4 count from 865 to 187 (p = 0.0000008), CD8 from 418 to 165 (p = 0.005) and CD19
`from 197 to 26 (p = 0.000002). Platelet, granulocyte and RBC counts were unaffected. Approximately
`one year after completion of therapy, some recovery of CD4 and CD8 counts had occurred although both
`counts remained suppressed compared to baseline (302 and 227 respectively); the CD19 count had recov(cid:173)
`ered essentially to normal by one year. EDSS scores post-therapy revealed some deterioration in 8
`patients and stable scores in the remaining 11. Global patient evaluations of the treatment were mixed.
`Conclusions: Cladribine therapy, at lower doses than previously reported, was remarkably well tolerated
`in CPMS, with no significant myelosuppression. Profound effects occurred in total lymphocyte count and
`CD4, CD8 and CD19 subsets.
`
`RESUME: Securite et tolerabilite de la cladribine sous-cutanee dans le traitement de la sclerose en plaques
`progressive. But: D'evaluer la securite et la tolerabilite de la cladribine sous-cutanee (s.c.) chez les patients atteints
`de sclerose en plaques progressive chronique (SEPPC) et d'evaluer ses effets sur differentes populations lymphocy-
`taires. Introduction: La cladribine, un agent antineoplasique synthetique qui a des proprietes immunosuppressives
`peut influencer favorablement revolution de la SEPPC. Cependant, les resultats des essais therapeutiques rapportes a
`date ont montre une myelosuppression significative chez certains patients. Methodes: 19 patients atteints de SEPPC
`severe (score moyen a l'echelle d'invalidite EDSS = 6.7) ont ete traites sur une base humanitaire avec la cladribine a
`la dose de 0.07 mg/kg/jour par voie s.c. pendant 5 jours par cycle, a toutes les 4 semaines, pour un total de 6 cycles.
`Les patients ont subi une evaluation clinique, EDSS, et des analyses hematologiques avant, pendant et apres le traite(cid:173)
`ment. Resultats: Le traitement a ete tres bien tolere, sans effet secondaire cliniquement significatif. Entre la phase
`pre-traitement et la fin du sixieme cycle, des diminutions moyennes du decompte absolu des lymphocytes de 1697 a
`463 (p = 0.000012), du decompte CD4 de 865 a 187 (p = 0.0000008), du decompte CD8 de 418 a 165 (p = 0.005) et
`CD19 de 197 a 26 (p = 0.000002) ont ete observees. Le decompte des plaquettes, des granulocytes et des globules
`rouges n'etait pas atteint. Environ un an apres la fin du traitement, une recuperation du decompte CD4 et CD8 Stait
`evidente, bien que ces deux decomptes demeuraient supprimes en comparaison avec ceux de la phase pr6-traitement
`(302 et 227 respectivement); le decompte CD19 etait revenu a la normale a un an. Les scores EDSS post-traitement
`ont montre une deterioration chez 8 patients et des scores stables chez les 11 autres. L'eValuation globale du traite(cid:173)
`ment par les patients etait mixte. Conclusions: La cladribine s.c, a dose plus faible que dans les etudes rapportees
`anterieurement, a 6te remarquablement bien toleree chez les patients atteints de SEPPC, sans myelosuppression signi(cid:173)
`ficative. Des effets marques ont ete notes sur le decompte lymphocytaire total et sur les sous-populations CD4, CD8
`et CD19.
`
`Can. J. Neurol. Sci. 1998; 25: 295-299
`
`BACKGROUND
`
`There is considerable evidence that cell mediated immunity
`plays an important role in the pathogenesis of multiple sclerosis
`(MS). Helper (CD4) T lymphocytes are found in MS lesions
`
`From the Division of *Hematology, (R.S., J.B.) The Toronto Hospital and Division of
`Neurology, (P.O.) St. Michael's Hospital, University of Toronto, Toronto, Ontario,
`Canada.
`RECEIVED FEBRUARY 17, 1 9 9 8. ACCEPTED IN FINAL FORM JULY 8, 1 9 9 8.
`Reprint requests to: Dr. P. O'Connor, Division of Neurology, St. Michael's Hospital,
`30 Bond Street, Suite 3133-D, Toronto, Ontario, Canada M5B 1W8
`
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`
`along with abnormal MHC class II expression. 12 In experimental
`allergic encephalomyelitis (EAE), injection of myelin basic pro(cid:173)
`tein (MBP) and other myelin proteins results in T-cell infiltration
`into the CNS, accompanied by CNS lesions similar to those seen
`in MS.3 T lymphocytes specific to such myelin antigens have
`been shown to induce CNS inflammation in several mammalian
`species.4 T lymphocyte clones reactive to MBP have also been
`found in the blood of patients with MS.5 Despite these observa(cid:173)
`tions the exact mechanisms of demyelination are unclear.
`Beta interferons have been shown to reduce the frequency
`and severity of exacerbations in the relapsing remitting form of
`MS.6 However, little progress has been made in altering the nat(cid:173)
`ural history of the disease particularly in patients with chronic
`progressive MS. Despite early encouraging results, immunosup(cid:173)
`pressive agents such as cyclophosphamide, azathioprine, and
`cyclosporin have demonstrated, at best, only marginal activity in
`double blind controlled trials. 7,89
`Cladribine (2 - chlorodeoxyadenosine) is a purine analog
`which is incorporated into DNA and is resistant to the enzyme
`adenosine deaminase.10 It has demonstrated considerable anti(cid:173)
`neoplastic activity in hairy cell leukemia, chronic lymphocytic
`leukemia and certain forms of non-Hodgkin's lymphoma.11"14 It
`has significant immunosuppressive effects, with reduction in the
`numbers of CD4 and CD8 lymphocytes10"13 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. 10>15
`Recently a small (n = 51), randomized, double-blind, placebo
`controlled, cross-over trial was reported using intravenous
`cladribine in patients with CPMS. 16 48 patients entered as
`matched pairs and the trial was stopped after one year of treat(cid:173)
`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 improvement or stabilization in neurolog(cid:173)
`ical scores, lesion volumes on MRI, and concentrations of 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(cid:173)
`tion to several viral infections.15
`Subcutaneous cladribine has shown good bioavailability
`compared to the intravenous route, with a similar pharmacoki(cid:173)
`netic profile.14 Our objective was to evaluate the safety and tol-
`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(cid:173)
`sive MS (CPMS) attending the MS Clinic at St. Michael's Hos(cid:173)
`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(cid:173)
`ly on rapid progression in the two years prior to therapy.
`The average disease duration in these patients was 12.6
`years. 15 patients had no comorbid medical conditions. The fol(cid:173)
`lowing conditions were found in one patient each: asthma,
`insulin-dependent diabetes mellitus (IDDM), depression, and
`
`IDDM with depression. Most patients had at some point in their
`disease been treated with short term high dose corticosteroids
`for MS exacerbations. Apart from brief courses of corticos(cid:173)
`teroids, no patient had received immunosuppressive therapy in
`the year prior to the study. No patient received concomitant cor(cid:173)
`ticosteroid or other immunosuppressive therapy while on
`cladribine. Cladribine (Leustatin7®, Ortho-Biotech) was admin(cid:173)
`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 was repeated 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 determined prior to 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(cid:173)
`mal reference ranges for total lymphocyte count, CD4, CD8 and
`CD19 subsets were 1500 - 2900, 535 - 1125, 300 - 810 and 135
`- 447 x 106/L respectively.
`
`Neurologic assessments and EDSS scores 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 of difficulties involved in getting significantly
`disabled patients to return for follow-up, the exact timing of the
`EDSS assessment varied somewhat.
`Data are presented as mean "± standard deviation. The Stu(cid:173)
`dent's t-test for paired data was used to compare observations; a
`significance level of 0.05 was used to indicate statistical signifi(cid:173)
`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 (prior to the start
`
`Table 1: Lymphocyte subset analysis during therapy (n = 15).
`
`Baseline
`
`3 Months
`
`p value*
`
`6 months p value**
`
`Lymphocyte
`count
`
`1697 ± 570f 801 + 350 0.0000007 463 ±207 0.000012
`
`CD4 count
`
`865 ±313 411 ± 170 0.000005
`
`187 ±94 0.0000008
`
`CD8 count
`
`418 ±170 248 ± 145 0.00002
`
`165 ± 127 0.005
`
`0.000002
`25 + 27
`CD19 count 197 ±104
`P value derived from Student's t test for paired data
`*Baseline vs. 3 months
`**3 months vs. 6 months
`fAll values expressed as mean ± standard deviation, x 106/L.
`
`26 ± 16 0.4
`
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`of cladribine therapy), and at 3 and 6 months on therapy in the
`15 evaluable patients are summarized in Table 1. As shown, sig(cid:173)
`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(cid:173)
`uing decline in T lymphocyte subsets from 3 to 6 months; this
`was particularly 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 were still significantly below baseline
`level. The mean CD19 count had recovered to normal levels.
`
`Table 2:
`(n=12).
`
`Lymphocyte subset analysis following completion of therapy
`
`Total Lymphocyte count
`CD4 count
`CD8 count
`CD19 count
`
`6 Months
`
`475 ± 200f
`199 ± 97
`156 ± 91
`28 ±16
`
`1 year post
`therapy
`
`367
`895 ±
`133
`302 ±
`
`142
`227 ±
`
`p value*
`
`0.0003
`
`0.018
`
`0.047
`
`
`
`179 ± 110
`
`0.00014
`
`*P value derived from Student's t test for paired data
`x 10VL.
`fAll values expressed as mean ± standard deviation,
`
`Table 3: Summary of EDSS scores obtained on cladribine therapy; 0
`months represents baseline (n = 19).
`
`Pt. # cycles
`0
`
`1. 6
`
`7.5
`
`2. 6
`
`3. 6
`4. 6
`
`5. 6
`
`6. 6
`
`7. 6
`
`8. 6
`
`9. 6
`10. 6
`11. 6
`12. 6
`
`13. 4
`14. 6
`
`15. 5
`
`16. 5
`17. 4
`
`18. 4
`
`19. 3
`
`7
`
`6
`
`8
`
`8
`
`6.5
`
`6.5
`
`6.5
`
`6
`6.5
`6
`
`6.5
`7
`7
`
`7
`
`7
`
`7.5
`
`6.5
`5.5
`
`3
`
`8
`
`Months from start of therapy
`6
`9
`12
`15
`18
`21
`8.5
`
`24
`
`27
`
`7
`
`6
`
`6
`
`8.5
`
`8.5
`8.5
`
`6.5
`
`6.5
`
`6.5 6.5 6.5
`7
`
`7
`
`6.5
`
`6.5
`
`7
`
`6.5
`
`7.5
`7
`
`6.5
`
`6
`7
`
`7
`7
`7
`7
`
`8.5
`7
`
`6
`6
`6.5 6.5
`
`7
`
`7
`
`6
`6.5
`7
`7
`
`8.5
`
`6.5
`5.5
`
`5.5
`
`LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES
`
`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(cid:173)
`nia with a platelet count of 136 xl09/L, after one cycle of
`cladribine which returned to normal by the subsequent 2 cycles.
`No definite nonhematologic toxicity was reported or
`observed. No patient required a reduction of cladribine dose or
`treatment delay secondary to adverse effects.
`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. Of these,
`8 patients had an EDSS score 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.
`
`DISCUSSION
`
`Cladribine is recognized to have significant immunosuppres(cid:173)
`sive effects, characterized by marked reductions in T and B lym(cid:173)
`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(cid:173)
`nificant drop in blood counts was observed.15 In 7 patients, the
`platelet count dropped below 80 xl09/L, while a substantial and
`sustained decrease in granulocytes was seen.15 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(cid:173)
`ly received extensive therapy with chlorambucil. Both recovered
`after several months of marrow suppression. Two patients devel(cid:173)
`oped herpes zoster which subsided rapidly on acyclovir treat(cid:173)
`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.
`Our series of patients received a lower total 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(cid:173)
`tious problems despite achieving profound lymphocyte suppres(cid:173)
`sion. When compared to the higher dose regimen, the rate of
`decline in the CD4 count using our regimen was less rapid,
`although the trough CD4 count at six months into treatment was
`similar.15 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.15 In view of the pre(cid:173)
`sumed pathogenetic role of T helper cells in MS,12 the slower
`decline and earlier recovery in these cells could have implications
`
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`Mean total Lymphocyte count
`
`Mean CD4 count
`
`Mean CDS count
`
`Mean CD19 count
`
`Figure 1: Absolute lymphocyte count and lymphocyte subsets - CD4, CD8 and CD19 at baseline, 3 months and 6 months while on Cladribine thera(cid:173)
`py, and 1 year after completion of Cladribine.
`
`regarding therapeutic efficacy. However, since only a small sub(cid:173)
`set of T cells is likely involved in producing MS, these implica(cid:173)
`tions are unclear. Measuring T lymphocytes reactive to myelin
`basic protein5 could address this question in vitro, although only
`a randomized trial 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(cid:173)
`comitant use of corticosteroids and purine analogs has been
`associated with opportunistic infections. 17 Whether cladribine is
`safe to use along with or soon after medications such as beta-
`interferon, methotrexate, azathioprine or cyclophosphamide is
`unclear and requires further study. The long-term safety of
`cladribine in MS is also unknown.
`The subcutaneous route of administration has been shown to
`have a favorable pharmacokinetic profile, with 100% bioavailabil(cid:173)
`ity and no local toxicity.14 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 not be 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(cid:173)
`ple sclerosis, with no significant toxicity despite achieving pro(cid:173)
`found and long lasting immunosuppression. The degree of
`suppression of lymphocytes was similar to the higher-dose regi(cid:173)
`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
`EDSS changes, 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 await the results of a
`large appropriately powered randomized blinded trial of this
`medication with interest. Although safe and easy to use, the
`therapeutic effectiveness of cladribine in chronic progressive
`MS remains to be established.
`
`ACKNOWLEDGEMENTS
`
`We acknowledge the assistance of Janssen Ortho Inc. in partially
`defraying the cost of this study.
`
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