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Natalizumab A double-edged sword.

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Carmen Bozic, MD
Julia LaGuette, MD, MPH
Michael A. Panzara, MD, MPH
and Alfred W. Sandrock, MD, PhD
Natalizumab: A DoubleEdged Sword?
Biogen Idec, Inc.
Cambridge, MA
Potential conflict of interest: Nothing to report.
1. Schweikert A, Kremer M, Ringel F, et al. Primary central nervous system lymphoma in a patient treated with natalizumab.
Ann Neurol 2009;66:403– 407.
2. Rezk SA, Weiss LM. Epstein-Barr virus-associated lymphoproliferative disorders. Human Pathol 2007;38:1293–1304.
3. Bashir R, McManus B, Cunningham C, et al. Detection of
Eber-1 RNA in primary brain lymphomas in immunocompetent and immunocompromised patients. J Neurooncol 1994;
4. Harris NL, Swedlow SH, Frizzera G, Knowles DM. Post transplant lymphoproliterative disorders. In: Jaffe ES, Harris NL,
Stein H, Vardiman JW, eds. World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of the
Hematopoietic and Lymphoid Tissues. Lyon, France: IARC
Press; 2001:264 –270.
5. Hochberg FH, Baehring JM, Hochberg EP. Primary CNS lymphoma. Nat Clin Pract 2007;3:24 –35.
6. Kleinschmidt-DeMasters BK, Damek DM, Lillehei KO, et al.
Epstein Barr virus-associated primary CNS lymphomas in elderly patients on immunosuppressive medications. J Neuropathol Exp Neurol 2008;67:1103–1111.
7. Olson JE, Janney CA, Rao RD, et al. The continuing increase
in the incidence of primary central nervous system nonHodgkin lymphoma: a surveillance, epidemiology, and end results analysis. Cancer 2002;95:1504 –1510.
8. DeAngelis LM. Primary central nervous system lymphoma imitates multiple sclerosis. J Neurooncol 1990;9:177–181.
9. Polman CH, O’Connor PW, Havrdova E, et al. A randomized,
placebo-controlled trial of natalizumab for relapsing multiple
sclerosis. N Engl J Med 2006;354:899 –910.
10. Balcer LJ, Galetta SL, Calabresi PA, et al. Natalizumab reduces
visual loss in patients with relapsing multiple sclerosis. Neurology 2007;68:1299 –1304.
11. Rudick RA, Miller D, Hass S, et al. Health-related quality of
life in multiple sclerosis: effects of natalizumab. Ann Neurol
12. Havrdova E, Galetta S, Hutchinson M, et al. Effect of
natalizumab on clinical and radiological disease activity
in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study. Lancet Neurol 2009;8:
254 –260.
DOI: 10.1002/ana.21835
Annals of Neurology
Vol 66
No 3
September 2009
In this issue of the Annals, Schweikert et al.1 report a
potentially worrisome development of a primary central
nervous system lymphoma (PCNSL) in a patient with
multiple sclerosis (MS) treated with natalizumab. Natalizumab, a monoclonal antibody, targets the alpha-4 subunit of integrins on the surface of leukocytes, and prevents their transmigration across the endothelium into
the brain. This reduces the inflammatory component of
MS and decreases the number and severity of relapses.
However, the integrins also play an important role in
immune surveillance, and reduction of lymphocyte trafficking into the central nervous system (CNS) is believed
responsible for the increased risk of progressive multifocal
leukoencephalopathy associated with natalizumab use.
The very important question is whether the development of PCNSL in the Schweikert et al.1 patient represents another example of reduced immunity leading
to the development of a life-threatening complication,
or is just a coincidence. PCNSL is markedly increased
in patients with acquired or inherited immunodeficiency. The best example is human immunodeficiency
virus (HIV)-infected individuals. Such individuals once
had a marked risk of PCNSL but restoration of immunity by effective antiretroviral therapy has dramatically
reduced the incidence.2 PCNSL is also associated with
iatrogenic immunosuppression, particularly with agents
such as mycophenolate mofetil, a drug used for a variety of conditions, including neurologic diseases such as
myasthenia gravis.3 However, the PCNSL associated
with HIV and most other immunosuppressed states is
virtually always associated with the Epstein-Barr virus
(EBV) whereas PCNSL in the immunocompetent host
is almost never associated with EBV.4,5 In immunocompromised patients PCNSL develops as a consequence of the uncontrolled growth of latently-infected
and immortalized B-cells within an immune-privileged
nervous system. This uncontrolled growth leads to additional genetic changes which transform the B-cells
into a malignancy. T-cells keep growth of this latently
infected B-cell population under control. The loss of
T-cell control due to immunosuppression appears to be
responsible for the increased incidence of PCNSL in
this setting. While this explanation is potentially satisfying, it is undoubtedly too simplistic, particularly as
we recognize that immune surveillance within the CNS
is more robust than previously believed. The patient
described in this report has an otherwise typical PCNSL but it is EBV-negative. Does this mean the tumor
is unrelated to the natalizumab-induced immunosuppression?
One issue is whether the patient actually had MS and
not PCNSL from the beginning because the two have
been confused with one another.6 The authors adequately address this issue and I do not think there is any
question that the young man described here had MS. A
brain biopsy was even performed and was said to show
no evidence of lymphoma, although the authors do not
comment on whether the patient was taking steroids at
the time of biopsy. While others have suggested that steroids do not interfere with the diagnosis of lymphoma,
we have seen many patients with a negative biopsy after
a course of steroids who had a subsequent biopsy demonstrating lymphoma.7 Nor is there any question his
MS was not responding to conventional therapies before
natalizumab was begun. Therefore, it would appear that
the development of PCNSL was truly a late complication of the patient’s 3.5-year course of MS, having been
treated with numerous courses of pulse corticosteroids,
interferon beta 1a, azathioprine, and 21 infusions of natalizumab over 80 weeks.
How important is the negative EBV? EBV-induced systemic lymphomas have been linked to several autoimmune diseases, even without immunosuppressive drugs,
but the incidence appears to increase when patients are
exposed to immunosuppressive therapies.8,9 In one study
only 26% of systemic lymphomas in patients with rheumatoid arthritis and 16% in patients with primary
Sjogren’s syndrome had detectable EBV.9 This suggests
that either EBV is nonessential for lymphoma to develop
in immunosuppressed patients or that it was a coincidence
in the majority. There has not been a comparable large
study done of PCNSLs in these patients, likely because
PCNSL is so rare; however, most case reports document
EBV within PCNSL tissue. It may be that EBV-negative
brain lymphomas are not reported because they are assumed to be unrelated to the underlying immunosuppression. Technical issues aside, detection of EBV is likely not
the only criteria necessary to determine whether a lymphoma developed as a consequence of host immunosuppression.
The major clinical questions are to what extent is natalizumab responsible for PCNSL and how worried
should we be about possible future cases? It is impossible
to attribute direct causative effect of PCNSL in this patient to the natalizumab, but this remains a worrisome
report and certainly bears close scrutiny as larger numbers of patients with MS begin to receive natalizumab. A
recent report of melanoma developing in two patients
with MS treated with natalizumab also suggest that use
of this agent may predispose to the development of solid
tumors.10 Melanoma is known to occur with increased
frequency in immunocompromised patients and, parenthetically, one patient reported with EBV-positive PCNSL due to prolonged immunosuppression for treat-
ment of a polyneuropathy went on to die from
metastatic melanoma that appeared a few months after
his PCNSL went into remission.5
A single case report does not make for a firm causative
relationship. Time will tell if natalizumab predisposes to
PCNSL, EBV-positive or not, as increasing numbers of
patients receive this effective agent. Ironically, agents targeting the integrin pathway are also being explored as
potential therapy for lymphoma to reduce cell migration
and metastatic spread.11 Unfortunately, we do not yet
have the ability to adjust the immune response to depress unwanted activity while maintaining its critically
important normal functions.
Lisa M. DeAngelis, MD
Department of Neurology
Memorial-Sloan Kettering Cancer Center
New York, NY
Potential conflict: Nothing to report.
1. Schweikert A, Kremer M, Ringel F, et al. Primary central nervous system lymphoma in a patient treated with natalizumab.
Ann Neurol 2009;66:403– 407.
2. Chow KU, Mitrou PS, Geduldig K, et al. Changing incidence
and survival in patients with AIDS-related non-Hodgkin’s lymphomas in the era of highly active antiretroviral therapy
(HAART). Leuk Lymphoma 2001;41:105–116.
3. O’Neill BP, Vernino S, Dogan A, Giannini C. EBV-associated
lymphoproliferative disorder of CNS associated with the use of
mycophenolate mofetil. Neuro Oncol 2007;9:364 –369.
4. Cingolani A, Fratino L, Scoppettuolo G, Antinori A. Changing
pattern of primary cerebral lymphoma in the highly active antiretroviral therapy era. J Neurovirol 2005;11:38 – 44.
5. Kleinschmidt-DeMasters BK, Damek DM, Lillehei KO, et al.
Epstein-Barr virus-associated primary CNS lymphomas in elderly patients on immunosuppressive medications. J Neuropathol Exp Neurol 2008;67:1103–1111.
6. DeAngelis LM. Primary central nervous system lymphoma imitates multiple sclerosis. J Neurooncol 1990;9:177–181.
7. Porter B, Giannini C, Kaufmann T, et al. Primary central nervous system lymphoma can be histologically diagnosed after
previously corticosteroid use: a pilot study to determine
whether corticosteroids prevent the diagnosis of primary central
nervous system lymphoma. Ann Neurol 2008;63:662– 667.
8. Knight JS, Tsodikov A, Cibrik DM, et al. Lymphoma after solid
organ transplantation: risk, response to therapy, and survival at a
transplantation center. J Clin Oncol 2009;27:3354 –3362.
9. Dawson TM, Starkebaum G, Wood BL, et al. Epstein-Barr virus, methotrexate, and lymphoma in patients with rheumatoid
arthritis and primary Sjögren’s syndrome: case series. J Rheumatol 2001;28:47–53.
10. Mullen JT, Vartanian TK, Atkins MB. Melanoma complicating
treatment with natalizumab for multiple sclerosis. N Engl
J Med 2008;358:647– 648.
11. Sato T, Yamochi T, Yamochi T, et al. CD26 regulates p38
mitogen-activated protein kinase-dependent phosphorylation of
integrin beta1, adhesion to extracellular matrix, and tumorigenicity of T-anaplastic large cell lymphoma Karpas 299. Cancer
Res 2005;65:6950 – 6956.
DOI: 10.1002/ana.21813
Goebels and Kappos: Natalizumab Treatment Complication
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