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Journal of Clinical Oncology, Vol 26, No 22 (August 1), 2008: pp. 3804-3807 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.17.3047
Progressive Multifocal Leukoencephalopathy in a Patient With Relapsed Acute Myelogenous LeukemiaDana-Farber/Brigham and Women's Cancer Center, Center for Neuro-Oncology; Department of Neurology, Brigham and Women's Hospital; Department of Medical Oncology, Dana-Farber Cancer Institute; Harvard Medical School, Boston, MA
Dana-Farber/Brigham and Women's Cancer Center, Center for Neuro-Oncology, Boston, MA; Hacettepe University School of Medicine, Ankara, Turkey
Division of Neuropathology, Department of Pathology, Brigham and Women's Hospital; Harvard Medical School, Boston, MA
Dana-Farber/Brigham and Women's Cancer Center, Center for Neuro-Oncology; Department of Neurology, Brigham and Women's Hospital; Department of Medical Oncology, Dana-Farber Cancer Institute; Harvard Medical School, Boston, MA
Harvard Medical School; Division of Viral Pathogenesis, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA
Department of Medical Oncology, Dana-Farber Cancer Institute; Harvard Medical School, Boston, MA A 69-year-old right-handed woman with a history of relapsed acute myelogenous leukemia, presented with dysarthria and left facial weakness. The initial diagnosis of acute myeloblastic leukemia (AML), subtype M1 according to the French-American-British classification, was made 5 years prior. Cytogenetic analysis at the time of her diagnosis revealed trisomy for chromosome 8. The patient achieved complete remission to induction treatment with daunorubicin, etoposide, and cytarabine, and received one more cycle of the same as consolidation therapy. Three years later, she developed mild pancytopenia. Her leukocyte count had gradually declined from 5,500/µL to 3,500/µL within 6 months. A bone marrow biopsy revealed relapsed AML. She was reinducted with bortezomib, idarubicin, and cytarabine on a phase I clinical trial followed by consolidation therapy with idarubicin and cytarabine. Two years later she presented with decreased sensation on the left side. She had normal WBC count (7,790/µL) and differential. A repeat bone marrow examination confirmed complete remission. The CD4 count was within normal range (698/µL). CD4/CD8 ratio was also within normal limits (4.36; normal range, 1.2 to 5.3). A magnetic resonance imaging (MRI) showed an area of increased signal on T2-weighted and fluid attentuated inversion recovery (FLAIR) images within the right parietal white matter suggestive of stroke. Her symptoms progressed, and she developed left arm weakness and subsequent left foot paresis. She was able to stand, but walking was difficult. A repeat brain MRI 1 month later showed faint and patchy enhancement of the lesion on T1-weighted images after administration of gadolinium (Figs 1A to 1B) and progression of the hyperintensity in FLAIR images in the right parietal white matter (Figs 1C to 1D) that now also involved the gray matter (Fig 1D) and had central areas of T2 hypointensity. This area was bright on diffusion-weighted imaging (Figs 1E to 1F), suggesting a hypercellular region concerning for tumor. Lumbar puncture was negative for malignant cells, inflammation, or infection, and a stereotactic brain biopsy of the enhancing area was performed. Pathology showed fragments of white and gray matter with mild perivascular lymphocytic inflammation, but no involvement of the vascular wall ruling out vasculitis (Fig 2A; arrow: vessel; star: inflammatory area). Higher magnification showed vacuolated neuropil with occasional oligodendroglial cells with viral cytopathic changes including nuclear enlargement and smudgy chromatin (Fig 2B; arrow: enlarged oligodendrocyte; arrowheads: vacuolated neuropil). Luxol fast blue (myelin stain) showed multiple foci of demyelination with gradual transition into normally myelinated white matter (Fig 2C). Immunohistochemistry with antibodies against polyoma virus (including JC virus [JCV]) showed scattered positive oligodendroglial cells (Fig 2D; arrows-positive cells). These histologic features were diagnostic of progressive multifocal leukoencephalopathy (PML). Intraoperatively, she developed hemorrhage and worsening left-sided weakness. She was started on mirtazapine, a 5-HT2a receptor antagonist, at 15 mg daily. She underwent rehabilitation, and her symptoms remained stable. With continued physical therapy and a gradual increase in the dose of mirtazapine to 45 mg daily, she experienced a dramatic resolution of her symptoms, with improvement in her speech, ability to walk, and left-sided strength. Follow-up imaging also showed improvement in the hemorrhagic lesion and no increase in the size of the PML lesions. She remained neurologically stable for 28 months after the diagnosis of PML; however, her AML recurred, and she declined further treatment. An autopsy was performed and confirmed recurrent AML in bone marrow. Polymoma virus staining was negative in the histological affected areas of the brain.
PML is a rare CNS infection caused by JCV.1 It is a subacute demyelinating disease, almost exclusively described in the setting of profound immunosuppression. PML can develop as a primary infection or by reactivation of the virus after a latent infection. JCV antibodies are found in a majority (65% to 92%) of adults who often acquire the virus early in life. PML is most commonly seen in AIDS and less frequently reported after treatment with immunosuppressants, including cyclosporine, methotrexate, cyclophosphamide, and mafosfamide in patients with chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, and patients undergoing organ and bone marrow transplantation.2,3 PML is also associated with iatrogenic immunosuppression in patients with autoimmune disorders such as sarcoidosis, systemic lupus erythematosus, multiple sclerosis, and Crohn's disease.4 The majority of PML cases are associated with lymphoproliferative diseases such as CLL, chronic myelogenous leukemia, and lymphoma, and only rarely associated with in AML.5 PML is characterized by diffuse and asymmetric demyelination affecting predominantly the cerebral hemispheres but can also involve the cerebellum, brainstem, and, rarely, the spinal cord.6 Patients with PML often present with subacute neurological deficits affecting motor, sensory, visual, verbal, and cognitive functions. Patients may eventually progress to coma or dementia. On MRI, PML lesions are generally seen as single or multiple regions of white matter T2 hyperintensity, commonly localized within the periventricular region, centrum semiovale, or cerebellum. Usually, no gadolinium enhancement is observed. Brain biopsy, showing the virus and abnormal oligodendrocytes, as well as the distinguishing massive astrocytes with hyperchromatic nuclei, represents diagnostic features of PML. As a biopsy is often difficult to obtain, the detection of JC viral DNA by polymerase chain reaction (PCR) of the CSF in the presence of neurological symptoms and typical white matter T2 abnormalities is sufficient to make a diagnosis of PML. The results of CSF PCR correlate well with brain biopsy in showing degree of active disease. However, this patient did have a negative JCV PCR by testing in a commercial laboratory but subsequent testing in our research laboratory showed a JCV CSF viral load of 1,350 cps/mL. Low T-cell count, especially the CD4 subset, is thought to promote the development of PML.7 PML is seen in a number of patients with idiopathic CD4 lymphopenia.8 A close relationship is thought to exist between PML and tuberculosis, a disease known to be activated by CD4 lymphopenia. PML was reported in the setting of lymph node tuberculosis in a patient with idiopathic CD4 lymphopenia. PML is strongly linked with the use of fludarabine, a purine analog that is applied in the treatment of CLL.7 Nucleoside analogs are associated with prolonged CD4 lymphopenia for several years. Alemtuzumab, a monoclonal antibody, which can lead to a sharp decrease in T-cell counts, has recently been recognized to be predisposing to a number of infections including PML.9 CD4 lymphopenia can be observed in patients with AML who are pancytopenic and in complete remission. Our patient suffered prolonged pancytopenia after chemotherapy. Her CD4 count, however, was normal at the time of presentation with neurological symptoms. Although PML is generally reported with CD4 counts lower than 100/µL, it may occur in patients whose CD4 counts are higher than 200/µL. Our patient's CD4 count was actually normal, and the percentage of CD4 subset was above normal range. Cases of PML in immunocompetent hosts without AIDS have been reported.7,10,11 Immunological investigations into the role of the CD4 subtype in the emergence of PML have indicated that JCV-specific CD4 cell responses are crucial for impeding disease progression in PML.10 Thus, it has been suggested that impairment in CD4 function is more significant than decrease in CD4 count, in contributing to activation of the infection. In HIV-infected individuals, a specific T-cell response against JCV can be improved by immune recovery associated with the use of highly active antiretroviral therapy, which may explain the relative efficacy of the drug in the treatment of PML in HIV-positive patients. Recently, reports of natalizumab, administered for Crohn's disease and multiple sclerosis, have revealed that it may lead to a specific propensity for JCV infection among other infections.12 Investigations into the exact mechanisms of this drug, known for acting against alpha integrins, may be valuable for elucidating the etiology of PML. PML has been reported in patients with untreated CLL,13 implying either abnormalities in B cells or that CLL and possibly hematological malignancies in general can be inherently linked to PML, regardless of the treatment modality employed. Success in the treatment of PML has been reported with intrathecal and intravenous cytarabine and intravenous cidofovir.1,10 Cidofovir has been shown of being of no benefit in HIV/PML in addition to highly active antiretroviral therapy.14 According to more recent evidence, serotonin receptor antagonists may help contain PML by preventing the spread of JCV to glial cells via downregulation of serotonin receptors.15-17 Most patients with HIV-negative PML have a fatal outcome within 1 year of disease onset despite receiving treatments.18 Our patient was treated with mirtazapine, a serotonin receptor antagonist, and she was clinically and radiologically stable for 28 months. She eventually developed a second relapse of her AML and declined further therapy. She passed away due to complications of progressive AML. Although rare, PML should be considered in patients with AML who present with neurological symptoms. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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