Prolonged Stability of Progressive Multifocal

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Oct 1, 2010 - histologic evidence of vasculitis (fibrinoid necrosis of vascular wall) .... immunoglobulins, and leukapheresis and autotransfusion of leuko-.

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JOURNAL OF CLINICAL ONCOLOGY

Prolonged Stability of Progressive Multifocal Leukoencephalopathy in a Patient With Chronic Lymphocytic Leukemia A 72-year-old right-handed man with a medical history of chronic lymphocytic leukemia (CLL) noted progressive difficulties with handwriting. He was diagnosed 3 years prior and received chlorambucil, fludarabine, vincristine, cyclophosphamide, and rituximab. His treatments were held due to low white cell counts. He noted progressive clumsiness and weakness in the right hand over 3

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months. A magnetic resonance imaging (MRI) of the brain showed increased T2-signal and enhancement in the left postcentral gyrus, right frontal white matter, and medial frontal lobe (Fig 1). The differential diagnosis included lymphoma, primary brain tumor, or progressive multifocal leukoencephalopathy (PML). He had normal WBC counts (4,130 cells/␮L) with normal CD4 and CD4/CD8 ratio at this time. Lumbar puncture for CSF evaluation was negative for malignant cells, inflammation, or infection. A brain biopsy was done and intraoperative smear preparation showed occasional oligodendroglial cells with viral cytopathic change (ie, nuclear enlargement

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Fig 1. Journal of Clinical Oncology, Vol 28, No 28 (October 1), 2010: pp e503-e506

© 2010 by American Society of Clinical Oncology

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and evenly distributed smudgy chromatin; Fig 2A). Histologic examination showed numerous histiocytes/macrophages infiltrating the cerebral white matter (Fig 2B) as well as numerous blood vessels with chronic (lymphocytic) perivascular cuffing (Fig 2C); however, no histologic evidence of vasculitis (fibrinoid necrosis of vascular wall) was present. Higher magnification (Fig 2D) shows vacuolated white matter with numerous histiocytes/macrophages and occasional abnormal cells showing viral cytopathic change (enlarged hyperchromatic nucleus with smudgy chromatin). Immunohistochemistry with antibodies against polyoma virus (including JC virus; clone: PAb416; Sigma-Aldrich, St Louis, MO) showed scattered positive cells of oligodendroglial phenotype. These histologic features were diagnostic of PML. CSF studies were subsequently positive for JC virus DNA. After the biopsy, the patient was started on decadron and mirtazapine at 15-mg daily, a 5-HT2A receptor antagonist. The dose of mirtazapine was gradually increased to 45 mg daily while the decadron was tapered off. The patient improved clinically, and imaging studies showed stable T2 changes without enhancement and improving edema. Approximately 2 years later, he started chemotherapy (CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone] regimen) again for recurrent CLL. Because of chemotherapy-induced anemia, he was switched to rituximab. As a result of reports of concerns about reactivating PML, rituximab was stopped after 1 cycle although the patient remained neurologically stable. He was subsequently started on revlimid at 10 mg daily and his CLL did not progress. His neurologic status remained stable and longitudinal brain imaging over the past 4 years continues to show stable T2 changes with expected atrophy but without enhancement (Fig 3). PML is a progressive demyelinating disease usually affecting immunocompromised patients with no proven treatment. It is caused by e504

© 2010 by American Society of Clinical Oncology

a human polyoma virus (JC virus), which infects oligodendrocytes. PML occurs in immunosuppressed patients (eg, AIDS), tuberculosis, chronic neoplastic diseases (eg, M. Hodgkin’s or CLL), transplant patients, or chemotherapy (eg, cyclosporine, methotrexate, or fludarabine). Patients with PML present with a variety of neurologic symptoms, such as hemiparesis, ataxia, aphasia, or personality changes. On MRI, PML is characterized by multifocal sites of hyperintensity in the white matter on T2-weighted sequences. Enhancement on MRI is atypical and may actually represent active immune response to the virus, which is thought to be a predictor of good outcome. The diagnosis can be ensured by polymerase chain reaction detection of JC virus DNA in the CSF or by histologic changes on brain biopsy. The sensitivity of PCR is high but is not always positive in patients with true PML.1 PML is typically characterized by multifocal demyelinating lesions of varying size in the hemispheres, brainstem, cerebellum, and rarely in the spinal cord.2 The diagnosis of PML is usually based on a combination of neurologic symptoms, JC virus DNA in the CSF and typical multifocal T2 hyperintensity of the white matter. Additional brain biopsy showing abnormal oligodendrocytes and reactive, hyperchromatic astrocytes can ensure the diagnosis. PML is an uncommon disease of the elderly usually emerging on the basis of neoplasms or an immunodeficiency state caused by underlying cancer, chemotherapies, or immunosupression for transplants. The causative agent of the disease can be found in affected oligodendrocytes and is a human polyomavirus called JC virus. Although JC virus is present in approximately 70% of the adult population, an immunosuppressed state permits active replication leading to PML. PML affects approximately 5% of AIDS patients, and approximately three fourths of all PML cases are associated with AIDS. Association of PML with chronic neoplastic diseases, such as Hodgkin’s disease or JOURNAL OF CLINICAL ONCOLOGY

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Diagnosis in Oncology

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CLL as in our case, has been described in literature.3 As a result of the multifocal character of PML, presenting symptoms range from personality changes to hemiparesis, aphasia, ataxia, cortical blindness, and coma. According to the variety of presenting symptoms a large number of possible differential diagnoses exist. They include ischemic brain disease, vasculitis, neoplasms of the brain (eg, gliomas or lymphomas), CNS infections (eg, HIV encephalopathy, herpes simplex, neurosyphilis), multiple sclerosis, acute disseminated encephalomyelitis, dementia, and Creutzfeldt-Jakob disease. In HIV-positive patients, opportunistic CNS infections (eg, tuberculosis, cryptococcosis, toxoplasmosis, or cytomegalovirus) should also be considered. As described in this case, the management of patients with a chronic lymphoproliferative disease and PML is challenging, given that aggressive treatment of the neoplasm affects the cellular immune response, which is more important than the humoral response for the containment of PML. In HIV-positive patients, because of improvement of both the number of CD4 cells and their specific response, highly active antiretroviral therapy has shown to have efficacy in the treatment of www.jco.org

PML in patients with AIDS. Especially immunosuppressants including cyclosporine, methotrexate, cyclophosphamide, and mafosfamide seem to make patients more susceptible for PML by suppressing CD4 response. A strong linkage between fludarabine, a purine analog used in the treatment of CLL, and PML has been reported.4 Nucleoside analogs are known to cause low CD4 counts for years. As mentioned above, our patient has been on fludarabine before the onset of neurologic symptoms. Low T-cell count, especially the CD4 subset, is thought to promote the development of PML. Consequently, patients with CD4 lymphopenia (eg, idiopathic or associated with tuberculosis) are more often affected by this disease.5 PML is reported to usually occur in patients with CD4 counts lower than 100/␮L, but it can also affect patients with CD4 counts higher than 200/␮L as described in our case. More recent cases of PML occurring in patients treated with novel targeted therapeutics, such as natalizumab6 and rituximab,7 have been reported in neurologic, oncologic, and rheumatic diseases.8 For instance natalizumab, a new treatment option for patients with active relapsing-remitting multiple sclerosis, was highly © 2010 by American Society of Clinical Oncology

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effective and well tolerated; however, three cases of PML occurred during treatment. Rituximab depletes B cells and may also predispose patients to PML. Since there is no curative treatment, the prognosis for PML is generally poor. In HIV-negative patients, death usually occurs in 3 to 6 months from the onset of neurologic symptoms. Management should initially be focused on reducing immunosuppresion.9,10 Anecdotal success in treating PML with intrathecal and intravenous cytarabine and intravenous cidofovir has been reported.2,11 Cidofovir has been shown to be of no benefit in HIV/PML in addition to HAART.12 According to more recent evidence, serotonin receptor antagonists may help contain PML by preventing the spread of JC virus to glial cells via downregulation of serotonin receptors.13-15 Based on the fact that the antidepressant mirtazapine is a potent antagonist of 5-HT2 and 5-HT3 receptors and crosses the blood-brain barrier, several cases of efficacy of mirtazapine in treating PML have been reported.1,13,14,16 Our patient was treated with mirtazapine and his neurologic status improved, and imaging over the past 4 years continues to show improvement despite recurrence of CLL and continued systemic chemotherapy treatments. Since PML is an aggressive disease a prolonged stability over years as reported here is remarkable. It is likely that immune factors, such as the patient’s response to the virus given enhancement on MRI, likely contributed to the prolonged stability.17 Investigations into the heterogeneity of PML outcomes strongly suggest that multiple factors, especially the immune response to PML and possibly receptors such as 5-HT2A may be important prognostic determinants. Further investigations of novel treatment approaches, such as antiviral treatment, immunomodulatory therapies, hematopoietic growth factors, plasma exchange, intravenous immunoglobulins, and leukapheresis and autotransfusion of leukocytes may lead to better management of this devastating disease. As the use of targeted, immune-directed therapies becomes more common in neurologic, rheumatic, and oncologic diseases, we may well see an increase in such opportunistic diseases. Maintaining clinical vigilance allows for early suspension of such therapies in potential cases of PML, thereby increasing the opportunity for immune reconstitution, which may improve prognosis in PML.

Meng Zhang Daping Hospital, Third Military Medical University, Chongqing, China

Fumin Li South East University Medical School, Xuzhou Hospital, Jiangsu, China

Michael Rasper Dana-Farber Cancer Institute, Boston, MA; and the Technical University Munich, Munich, Germany

Santosh Kesari Dana-Farber Cancer Institute; Brigham and Women’s Hospital; and the Harvard Medical School, Boston, MA

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest. REFERENCES 1. Kesari S, Akar S, Saad A, et al: Progressive multifocal leukoencephalopathy in a patient with relapsed acute myelogenous leukemia. J Clin Oncol 26:38043807, 2008 2. Koralnik IJ: Progressive multifocal leukoencephalopathy revisited: Has the disease outgrown its name? Ann Neurol 60:162-173, 2006 3. Kiewe P, Seyfert S, Korper S, et al: Progressive multifocal leukoencephalopathy with detection of JC virus in a patient with chronic lymphocytic leukemia parallel to onset of fludarabine therapy. Leuk Lymphoma 44:1815-1818, 2003 4. Hequet O, Salles G, Espinousse D, et al: Multifocal progressive leukoencephalopathy occurring after refractory anemia and multiple infectious disorders consecutive to severe lymphopenia. Ann Hematol 81:340-342, 2002 5. Ng C, Slavin MA, Seymour JF: Progressive multifocal leukoencephalopathy complicating Waldenstrom’s macroglobulinaemia. Leuk Lymphoma 44:18191821, 2003 6. Goodin DS, Cohen BA, O’Connor P, et al: Assessment: The use of natalizumab (Tysabri) for the treatment of multiple sclerosis (an evidence-based review): Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 71:766-773, 2008 7. Hopfinger G, Plessl A, Grisold W, et al: Progressive multifocal leukoencephalopathy after rituximab in a patient with relapsed follicular lymphoma and low IgG levels and a low CD4⫹ lymphocyte count. Leuk Lymphoma 49:23672369, 2008 8. Calabrese LH, Molloy ES: Progressive multifocal leucoencephalopathy in the rheumatic diseases: Assessing the risks of biological immunosuppressive therapies. Ann Rheum Dis 67:iii64-5, 2008 (suppl 3) 9. Stuve O, Marra CM, Cravens PD, et al: Potential risk of progressive multifocal leukoencephalopathy with natalizumab therapy: Possible interventions. Arch Neurol 64:169-176, 2007 10. Kappos L, Bates D, Hartung HP, et al: Natalizumab treatment for multiple sclerosis: Recommendations for patient selection and monitoring. Lancet Neurol 6:431-441, 2007 11. Aure K, Behin A, Louillet F, et al: Dramatic improvement in non-AIDS related progressive multifocal leucoencephalopathy. J Neurol Neurosurg Psychiatry 76:1305-1306, 2005 12. Marra CM, Rajicic N, Barker DE, et al: A pilot study of cidofovir for progressive multifocal leukoencephalopathy in AIDS. AIDS 16:1791-1797, 2002 13. Focosi D, Kast RE, Maggi F, et al: 5-HT2a inhibitors for progressive multifocal leukoencephalopathy: Old drugs for an old disease. J Infect Dis 197:328, 2008; author reply 197:328-329, 2008 14. Elphick GF, Querbes W, Jordan JA, et al: The human polyomavirus, JCV, uses serotonin receptors to infect cells. Science 306:1380-1383, 2004 15. Verma S, Cikurel K, Koralnik IJ, et al: Mirtazapine in progressive multifocal leukoencephalopathy associated with polycythemia vera. J Infect Dis 196:709711, 2007 16. Owczarczyk K, Hilker R, Brunn A, et al: Progressive multifocal leucoencephalopathy in a patient with sarcoidosis–successful treatment with cidofovir and mirtazapine. Rheumatology (Oxford) 46:888-890, 2007 17. Travis J, Varma A, duPlessis D, et al: Immune reconstitution associated with progressive multifocal leukoencephalopathy in human immunodeficiency virus: A case discussion and review of the literature. Neurologist 14:321-326, 2008

Ali G. Saad Arkansas Children’s Hospital and University of Arkansas for Medical Sciences, Little Rock, AR

DOI: 10.1200/JCO.2009.26.8078; published online ahead of print at www.jco.org on June 28, 2010 ■ ■ ■

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