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      Progressive Multifocal Leukoencephalopathy with Negative JC Virus PCR following Treatment of Follicular Lymphoma: Implications for Biologics in the Era of Targeted Cancer Therapy

      case-report
      1 , 2 , *
      Case Reports in Oncological Medicine
      Hindawi Publishing Corporation

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          Abstract

          Anticancer therapy predisposes patients to infections by the immunosuppression that results from treatment. Although 85% of patients with progressive multifocal leukoencephalopathy (PML) have concurrent HIV/AIDS, PML can also develop in patients after they receive chemotherapy for cancer. The case herein describes a 69-year-old man with history of follicular lymphoma who presented with progressive dysarthria and right-sided paralysis. He received rituximab one year prior to presentation. PET scan suggested no recurrence of lymphoma. Cerebrospinal fluid (CSF) analysis was negative and showed fewer than 500 copies/mL of JC virus. However, brain biopsy showed chromatin margination and viropathic change within oligodendrocytes, confirming PML. He was started on mirtazapine and mefloquine with some clinical improvement. To our knowledge, this is the first case of rituximab-associated PML in a patient with negative JC virus PCR from the CSF. Recognition of PML in the differential of oncology patients with CNS symptoms is an important consideration as we enter the era of targeted therapy and personalized cancer medicine involving biologics. Furthermore, screening of patients for presence of subclinical JC viremia prior to the use of biologics may be an important component of assessing patient candidacy for these agents.

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          Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project.

          Rituximab improves outcomes for persons with lymphoproliferative disorders and is increasingly used to treat immune-mediated illnesses. Recent reports describe 2 patients with systemic lupus erythematosus and 1 with rheumatoid arthritis who developed progressive multifocal leukoencephalopathy (PML) after rituximab treatment. We reviewed PML case descriptions among patients treated with rituximab from the Food and Drug Administration, the manufacturer, physicians, and a literature review from 1997 to 2008. Overall, 52 patients with lymphoproliferative disorders, 2 patients with systemic lupus erythematosus, 1 patient with rheumatoid arthritis, 1 patient with an idiopathic autoimmune pancytopenia, and 1 patient with immune thrombocytopenia developed PML after treatment with rituximab and other agents. Other treatments included hematopoietic stem cell transplantation (7 patients), purine analogs (26 patients), or alkylating agents (39 patients). One patient with an autoimmune hemolytic anemia developed PML after treatment with corticosteroids and rituximab, and 1 patient with an autoimmune pancytopenia developed PML after treatment with corticosteroids, azathioprine, and rituximab. Median time from last rituximab dose to PML diagnosis was 5.5 months. Median time to death after PML diagnosis was 2.0 months. The case-fatality rate was 90%. Awareness is needed of the potential for PML among rituximab-treated persons.
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            Identification and characterization of mefloquine efficacy against JC virus in vitro.

            Progressive multifocal leukoencephalopathy (PML) is a rare but frequently fatal disease caused by the uncontrolled replication of JC virus (JCV), a polyomavirus, in the brains of some immunocompromised individuals. Currently, no effective antiviral treatment for this disease has been identified. As a first step in the identification of such therapy, we screened the Spectrum collection of 2,000 approved drugs and biologically active molecules for their anti-JCV activities in an in vitro infection assay. We identified a number of different drugs and compounds that had significant anti-JCV activities at micromolar concentrations and lacked cellular toxicity. Of the compounds with anti-JCV activities, only mefloquine, an antimalarial agent, has been reported to show sufficiently high penetration into the central nervous system such that it would be predicted to achieve efficacious concentrations in the brain. Additional in vitro experiments demonstrated that mefloquine inhibits the viral infection rates of three different JCV isolates, JCV(Mad1), JCV(Mad4), and JCV(M1/SVEDelta), and does so in three different cell types, transformed human glial (SVG-A) cells, primary human fetal glial cells, and primary human astrocytes. Using quantitative PCR to quantify the number of viral copies in cultured cells, we have also shown that mefloquine inhibits viral DNA replication. Finally, we demonstrated that mefloquine does not block viral cell entry; rather, it inhibits viral replication in cells after viral entry. Although no suitable animal model of PML or JCV infection is available for the testing of mefloquine in vivo, our in vitro results, combined with biodistribution data published in the literature, suggest that mefloquine could be an effective therapy for PML.
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              Prognostic significance of JC virus DNA levels in cerebrospinal fluid of patients with HIV-associated progressive multifocal leukoencephalopathy.

              Progressive multifocal leukoencephalopathy (PML) remains a frequent and life-threatening complication of human immunodeficiency virus (HIV) infection in the era of highly active antiretroviral therapy (HAART). Although one-half of patients with this disease will survive, the outcome is unpredictable at diagnosis, and prognostic markers are needed. JC virus (JCV) DNA levels were measured in cerebrospinal fluid (CSF) samples obtained from 61 HIV-infected patients with PML, including 38 patients who were treated with HAART and 23 patients who did not receive HAART, with use of real-time polymerase chain reaction. The diagnostic reliability of the assay was evaluated by comparing CSF findings with histopathological findings in patients with PML or other HIV-related diseases of the central nervous system. The prognostic value was assessed by comparing JCV DNA levels with survival and other patient variables. The assay had a diagnostic sensitivity of 76% and specificity of 100%. In the first CSF sample obtained after onset of PML symptoms, JCV DNA values ranged from undetectable to 7.71 log copies/mL (median, 3.64 log copies/mL). JCV DNA levels >3.64 log copies/mL correlated significantly with shorter survival and lower CD4+ cell counts in patients not receiving HAART. However, neither relationship was found in patients who were treated with HAART. The analysis of sequential CSF samples obtained from 24 patients demonstrated a marked decrease in JCV DNA levels over time in HAART-treated patients showing PML stabilization, but not in untreated or HAART-treated patients with progressively fatal disease. Measurement of JCV DNA levels in CSF samples may be a useful virological marker for management of PML in patients receiving HAART.
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                Author and article information

                Journal
                Case Rep Oncol Med
                Case Rep Oncol Med
                CRIONM
                Case Reports in Oncological Medicine
                Hindawi Publishing Corporation
                2090-6706
                2090-6714
                2015
                15 December 2015
                : 2015
                : 534529
                Affiliations
                1Department of Gynecologic Oncology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), 550 16th Street, San Francisco, CA 94158, USA
                2Department of Medicine, Stanford University Medical Center, 300 Pasteur Drive, Stanford, CA 94305, USA
                Author notes

                Academic Editor: Jose I. Mayordomo

                Article
                10.1155/2015/534529
                4693014
                26788389
                e237342a-41bd-4122-b309-4ebced2ef491
                Copyright © 2015 K. A. Silverio and S. A. Patel.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 12 October 2015
                : 4 December 2015
                : 6 December 2015
                Categories
                Case Report

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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