Natalizumab, MultipleSclerosis, and PrimaryCentral Nervous SystemLymphoma: Enigma,Wrapped in Mystery,Enclosed in Conundrum

It is relatively unusual for a case report to merit edito-rial comment. The case in point, contributed bySchweikert and colleagues,1 is notable for several rea-sons. This case documents the first primary central ner-vous system lymphoma (PCNSL) in a subject receivingnatalizumab. As such, it raises scientific and clinicalquestions. Pertinent issues relate to the possible associ-ation of multiple sclerosis (MS) with PCNSL, whetherimmune modulation with natalizumab could contrib-ute to PCNSL, and how to integrate this case into therisk/benefit calculus for clinicians considering natali-zumab therapy for their MS patients.

PCNSL is an uncommon tumor representing �5%of primary central nervous system (CNS) neoplasms.2

Among the non-Hodgkin lymphomas, PCNSL carriesa poor prognosis, which is attributed mainly to itssequestration behind the blood-brain barrier, isolatedfrom access by chemotherapeutic agents and with ra-diotherapy limited by CNS toxicity. PCNSL is almostalways a B-cell tumor, characterized as a CD20� dif-fuse large B-cell lymphoma. The histological appear-ance is angiocentric, and occasionally appears vascu-litic, with invasion of the vessel wall. Two distinctclinical settings are recognized: in the immunodefi-cient, typified by transplant recipients and patientswith human immunodeficiency virus/acquired immu-nodeficiency syndrome (AIDS), PCNSL occurs at ayounger age (40s and 50s) and shows a more progres-sive course, with virtually all tumor cells in AIDS pa-tients being positive for Epstein-Barr virus (EBV) ge-nome; in the immunocompetent, the age of onset issomewhat older (median about 55 years old), tumorsmay show less aggressive histological character, anddetection of EBV genome is less common.3

The pathogenesis of PCNS in immunodeficiency isbelieved to stem from loss of control over tumorigenicEBV-immortalized B cells.3 Among the immunodefi-cient, the incidence of PCNSL rose rapidly during theAIDS pandemic, before the introduction of highly ac-tive antiretroviral therapy. For uncertain reasons, thefrequency of PCNSL among the immunocompetenthas also increased steadily over the past 40 years. Plau-

sible explanations such as improved case identification,altered population age structure, and behavioral or en-vironmental causes all seem unlikely, leaving this phe-nomenon one among many conundrums related to thismysterious disease.2 In fact, how PCNSL develops inthe immunocompetent is entirely shrouded in obscur-ity.4 There are salient weaknesses in all potential expla-nations. For example, if PCNSL arises in peripheral tis-sues and seeds the CNS, taking sanctuary there, whyare no tumor cells found elsewhere? If a local inflam-matory process (secondary to viral infection or trauma,for example) attracts lymphocytes to the CNS, whereantigenic stimulus drives expansion of a neoplasticclone, why do CNS T-cell lymphomas comprise �1%of all PCNSL? It is possible to imagine that lympho-cyte homing molecules, such as chemokines, chemo-kine receptors, and adhesion molecules, help to guidethe progenitors of PCNSL into the CNS and that theintrathecal microenvironment supports their persis-tence there.5 However, there are no data to addresswhether the invading cells are neoplastic before theirentry into the CNS or transform therein.

For understanding the present case, a further attributeof PCNSL must be considered: the occurrence of pre-monitory inflammatory demyelinating sentinel lesions ina small but fascinating subset of PCNSL cases. Sentinellesions usually present as solitary symptomatic masses,often with contrast enhancement, in the immunocom-petent.6 The differential diagnostic considerations are tu-mefactive MS,7 glioma, or PCNSL. Biopsy often showsinflammatory demyelination, and careful histopatholog-ical evaluation fails to disclose evidence of neoplasia, asin the present case. It is common for these lesions toregress markedly following treatment with corticoste-roids. In 1 series of 4 cases, recurrence led to definitivediagnosis of PCNSL by repeat biopsy within 12months.6 However, 4- or 5-year intervals between firstappearance of a sentinel lesion and onset of unambigu-ous PCNSL, which then typically progresses quickly,have been reported.8–10 The case reported by Schweikertand colleagues1 carries unusual features for any of thereasonable diagnostic possibilities. It is atypical for MS(but not for PCNSL) to present with seizures.11,12 Con-versely, oligoclonal bands are not routinely detected incerebrospinal fluid (CSF) of PCNSL cases.12 Spinal cordPCNSL lesions have been reported but are uncommon.However, the diagnosis of MS in the current patient wasclearly worrisome to his clinicians, who acceded to therequest for brain biopsy. The findings at biopsy (as iscommon) were not sufficient to discriminate PCNSLfrom MS. In the present case, the interval from onset ofneurological disease to PCNSL diagnosis was 3.5 years,which would be unusual for sentinel demyelination butnot unprecedented. EBV analysis by polymerase chainreaction and in situ hybridization were negative, consis-tent with immunocompetence,3 but histological features

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were suggestive of the more aggressive lesions seen inimmunodeficient patients. Although the patient was to-ward the younger end of the spectrum for PCNSL inthe immunocompetent, his age was not unusual for pa-tients with prolonged intervals between sentinel demy-elination and explicit PCNSL.8–10 In summary, the cur-rent patient represented an extremely difficult andintricate medical problem. He unquestionably met clin-ical, neuropathological, and radiographic criteria for di-agnosis of MS and was treated appropriately. Further-more, it has been proposed that MS itself couldrepresent a risk circumstance for PCNSL. In retrospect,it is impossible to exclude sentinel demyelination pre-ceding PCNSL in the present case.

Given this complexity, how can one incorporate thiscase into our understanding of MS, PCNSL, and na-talizumab? What if any are the take-home messages?Natalizumab has emerged as an interesting novel treat-ment for MS, where for the first time serious risk-benefit considerations apply to a relatively broad swathof the MS patient population.14 Balancing its demon-strated efficacy, 2 categories of infectious complicationshave challenged clinicians and their patients in makingdecisions on whether to use natalizumab: progressivemultifocal leukoencephalopathy (PML) in 11 cases todate of about 50,000 persons under treatment (http://phx.corporate-ir.net/External.File?item�UGFyZW50SUQ9MTEwODd8Q2hpbGRJRD0tMXxUeXBlPTM�&t�1); and uncommon CNS or peripheral infections,such as ocular toxoplasmosis.14 Neoplastic complicationsof natalizumab have been limited so far to melanoma,15

and it is uncertain whether the incidence of this diseaseis increased in recipients. The pathogenesis of melanomain natalizumab-treated patients is also proposed to bequite unusual, involving a direct interaction between thetherapeutic agent and the tumor cell.15

It is not easy to think of a role for natalizumab inprimary pathogenesis of PCNSL; the current patientwas under treatment with natalizumab for 21 monthsof the 41 months between onset of CNS disease anddiagnosis of full-blown PCNSL. During that time,the entry of circulating lymphocytes into the CNS(both CNS parenchyma and CSF16) would have beenseverely restricted, and this limitation would applyequally to neoplastic lymphocytes. On the otherhand, if the disease were already incubating (as senti-nel demyelination), then perhaps reduced CNS im-munosurveillance could, as proposed by the authors,have contributed to disease expression. Strangelythen, natalizumab would be most likely to contributeto PCNSL if the initial diagnosisi were not MS. Ul-timately, we do not have sufficient understanding ofnatalizumab, MS, or PCNSL to establish causality inthis case, as noted by Schweikert et al.1 The take-home message must therefore be precisely as stated bythe authors: unusual clinical or radiographic manifes-

tations in patients receiving natalizumab must be rap-idly and comprehensively evaluated. Only in this waywill case reports become knowledge rather than anec-dote. Additionally this case underlines yet again howcareful one must be in case selection for natalizumab.It seems likely that natalizumab has much to teach usabout the pathogenesis of CNS diseases, certainly in-cluding, but not necessarily limited to, MS and PML.

Richard M. Ransohoff, MD

Neuroinflammation Research Center, Lerner ResearchInstitute

Mellen Center for MS Treatment and Research,Neurological Institute

Cleveland ClinicCleveland, OH

Potential conflict: Dr. Ransohoff has received fees forconsulting with Biogenidec, the manufacturer ofnatalizumab.

References1. Schweikert A, Kremer M, Ringel F, et al. Primary central ner-

vous system lymphoma in a patient treated with natalizumab.Ann Neurol 2009;66:403–407.

2. Bhagavathi S, Wilson JD. Primary central nervous system lym-phoma. Arch Pathol Lab Med 2008;132:1830–1834.

3. Deangelis LM, Wong E, Rosenblum M, et al. Epstein-Barr vi-rus in acquired immune deficiency syndrome (AIDS) and non-AIDS primary central nervous system lymphoma. Cancer 1992;70:1607–1611.

4. Nakamura M, Shimada K, Ishida E, et al. Histopathology,pathogenesis and molecular genetics in primary central nervoussystem lymphomas. Histol Histopathol 2004;19:211–219.

5. Brunn A, Montesinos-Rongen M, Strack A, et al. Expressionpattern and cellular sources of chemokines in primary centralnervous system lymphoma. Acta Neuropathol 2007;114:271–276.

6. Alderson L, Fetell MR, Sisti M, et al. Sentinel lesions of pri-mary CNS lymphoma. J Neurol Neurosurg Psychiatry 1996;60:102–105.

7. Deangelis LM. Primary central nervous system lymphoma imi-tates multiple sclerosis. J Neurooncol 1990;9:177–181.

8. Ng S, Butzkueven H, Kalnins R, et al. Prolonged interval be-tween sentinel pseudotumoral demyelination and developmentof primary CNS lymphoma. J Clin Neurosci 2007;14:1126–1129.

9. Brecher K, Hochberg FH, Louis DN, et al. Case report of un-usual leukoencephalopathy preceding primary CNS lymphoma.J Neurol Neurosurg Psychiatry 1998;65:917–920.

10. Hochberg FH, Baehring JM, Hochberg EP. Primary CNS lym-phoma. Nat Clin Pract Neurol 2007;3:24–35.

11. Poser CM, Brinar VV. Epilepsy and multiple sclerosis. EpilepsyBehav 2003;4:6–12.

12. Herrlinger U, Schabet M, Bitzer M, et al. Primary central ner-vous system lymphoma: from clinical presentation to diagnosis.J Neurooncol 1999;43:219–226.

13. Ransohoff RM. Natalizumab for multiple sclerosis. N EnglJ Med 2007;356:2622–2629.

14. Zecca C, Nessi F, Bernasconi E, Gobbi C. Ocular toxoplasmo-sis during natalizumab treatment. Neurology 73: ePub Septem-ber 23, 2009.

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15. Mullen JT, Vartanian TK, Atkins MB. Melanoma complicatingtreatment with natalizumab for multiple sclerosis. N EnglJ Med 2008;358:647–648.

16. Stuve O, Marra CM, Jerome KR, et al. Immune surveillance inmultiple sclerosis patients treated with natalizumab. Ann Neu-rol 2006;59:743–747.

DOI: 10.1002/ana.21850

Natalizumab and CentralNervous System Lymphoma:No Clear Association

Schweikert et al1 report a single case of primary centralnervous system lymphoma (PCNSL) in a multiple scle-rosis (MS) patient who received 21 infusions of natali-zumab.1 Details from the Schweikert et al case, as wellas data from preclinical studies, controlled clinical tri-als, and postmarketing surveillance, suggest that thiscase of PCNSL is not causally related to natalizumabtherapy.

There was an absence of Epstein-Barr virus (EBV)staining by in situ hybridization of the PCNSL in thecase reported by Schweikert et al.1 Studies indicate thatlatent EBV infection is strongly implicated in the on-cogenesis of immunosuppression-related lymphoprolif-erative disease.2,3 EBV genomic material is identified intissue from �90% of immunocompromised patientswith PCNSL, and is usually seen in the setting of pa-tients with human immunodeficiency virus-acquiredimmunodeficiency syndrome, or in patients receivingimmunosuppressant drugs for organ transplantation orautoimmune disease.2,4–6 Hence, the absence of EBVis evidence against an immunosuppression-related lym-phoproliferative disease in this patient.

Data from preclinical and clinical studies, as well aspostmarketing experience, show no signal for PCNSLrelated to natalizumab therapy. In natalizumab pre-clinical toxicology studies, there was no evidence ofimmunosuppression-related lymphoproliferative dis-ease at any dose in nonhuman primates, includingdoses 10� greater than the therapeutic dose. In thenatalizumab phase 3 clinical studies, one Crohn’s dis-ease (CD) patient developed a peripheral nodal B-celllymphoma following 6 doses of natalizumab. ThisCD patient had multiple risk factors (including con-current treatment with long-standing immunosup-pressive therapies and a 1-year history of lymphade-nopathy prior to the start of natalizumab therapy),and the lymphoma was considered unlikely to be re-

lated to natalizumab. In the cumulative clinical trialexperience, no other cases of lymphoma, includingPCNSL, have been reported in �4,400 natalizumab-treated patients, comprising 7500 person-years of na-talizumab exposure.

In postmarketing experience, there have been noEBV-positive lymphomas or lymphomas suggestive ofimmunosuppression-related lymphoproliferative disease.As of the end of June 2009, 2 cases of PCNSL havebeen reported in approximately 56,500 patients, com-prising approximately 63,900 person-years of natali-zumab exposure, which is consistent with the expectedbackground rate in the general US population.7 One ofthe 2 cases is the case reported by Schweikert et al1; wewere informed of this case over a year ago and reportedit to regulatory authorities at that time. The other caseoccurred in a 44-year-old woman who was diagnosedwith PCNSL after approximately 3 infusions of natali-zumab. Histologic type and EBV staining results werenot available for this case; however, the patient’s briefexposure to natalizumab makes it unlikely that the lym-phoma was related to the drug. Indeed, it is possible thatthis patient had PCNSL even prior to initiating natali-zumab therapy. Diagnostic uncertainty may occur be-tween early PCNSL and MS, with neurologic manifes-tations presenting years before the diagnosis of PCNSL.8

Natalizumab has demonstrated compelling efficacyin the treatment of MS and continues to be an im-portant treatment option for many patients. In thepivotal phase 3 study, natalizumab reduced the annu-alized relapse rate by 68% and the cumulative prob-ability of sustained progression of disability by 42%to 54% over 2 years compared with placebo.9 Fur-thermore, natalizumab has shown efficacy in a broadrange of outcomes, including significant improve-ments in visual function and health-related quality oflife.10,11 More recently published data indicate that ahigher proportion of patients treated with natali-zumab are free of both clinical and radiological evi-dence of disease activity compared with placebo-treated patients (37% vs 7%).12

Data regarding the risks of natalizumab are impor-tant to physicians and patients who need to make in-formed benefit-risk decisions. However, risk shouldbe systematically investigated in carefully conductedand rigorous postmarketing programs. To that end,natalizumab remains one of the most extensivelymonitored drugs to date for the treatment of neuro-logical disease, and the risk-management program isone of the most rigorous ever designed. We closelymonitor the safety of natalizumab and are in imme-diate contact with regulators regarding any adverseevents that may signal a potential safety issue. In thiscontext, based on available data, we believe at thistime that there is no evidence that natalizumab iscausally associated with the development of PCNSL.

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