Fatal Progressive Multifocal Leukoencephalopathy Research Articles

Progressive Multifocal Leukoencephalopathy (PML) With Anti-CD20 and Other Monoclonal Antibody (mAb) Therapies in Multiple Sclerosis (P8-3.016)

<h3>Objective:</h3> To review the incidence of progressive multifocal leukoencephalopathy (PML) associated with monoclonal antibody (mAb) therapies, specifically anti-CD20 medications used in multiple sclerosis (MS). <h3>Background:</h3> PML is an opportunistic and fatal inflammatory disease of the central nervous system, which occurs almost exclusively in immunocompromised hosts; therefore, patients receiving mAb immunotherapy become an at-risk population. B cell-depleting mAbs targeting CD20+ cells have become widely used in MS. Although their efficacy is well-known, their associated risk of PML, especially among those without previous disease-modifying therapy (DMT) exposure, has been insufficiently studied. <h3>Design/Methods:</h3> A systematic literature review of PubMed, Google Scholar, EMBASE, and Scopus was conducted by two independent researchers from June 1, 1997, to July 10, 2022. Further data was obtained from the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database and individual pharmaceutical companies (Genentech, Novartis, and TG Therapeutics). Carryover cases from prior exposure to other immunosuppressants were excluded. <h3>Results:</h3> Between 2015 and 2017, 10 cases of PML were reported in the FAERS database among 334 MS patients taking rituximab; two had previously received natalizumab, leaving eight cases in total. Rituximab-associated PML was also seen in lymphoproliferative disorders (n=52), rheumatoid arthritis (n=9), and granulomatosis with polyangiitis (n=2). Two fatal PML cases were found in MS patients taking ocrelizumab. No cases of PML were reported with ofatumumab in MS; however, 5 cases were reported in chronic lymphocytic leukemia. PML has not been observed with ublituximab, which is currently under FDA review. Among other DMTs, PML was frequently reported with natalizumab (n=884), fingolimod (n=30), dimethyl fumarate (n=12), and alemtuzumab (n=1). <h3>Conclusions:</h3> Anti-CD20 therapies are a safe class of medications with a low infectious risk for PML, especially compared to other mAbs used in MS, such as natalizumab. Nonetheless, risk stratification in susceptible individuals, as done with natalizumab, could prove beneficial with all mAb treatments. <b>Disclosure:</b> Dr. Sharma has nothing to disclose. Dr. Srivastava has nothing to disclose. Dr. JENA has nothing to disclose. Dr. Kakara has nothing to disclose. Dr. Sriwastava has nothing to disclose. Maha Daimee has nothing to disclose. Dr. Xu has nothing to disclose.

The Classic Form of Progressive Multifocal Leukoencephalopathy in Advanced Prostate Cancer: a Case Report

Progressive multifocal leukoencephalopathy (PML) is a serious and often lethal demyelinating disease of the brain that develops almost exclusively in patients with severe immunosuppression. The disease is caused by the reactivation of latent polyoma JC virus (JCV). PML occurs rarely in non-hematologic malignancies, and in this report, the authors present an uncommon case of rapidly progressing, fatal PML in a patient with advanced prostate cancer. Although uncommon, PML should be included in the differential diagnosis of white matter lesions in the oncologic population.

Exploring the role of NCCR variation on JC polyomavirus expression from dual reporter minicircles.

JC virus (JCV), a ubiquitous human polyomavirus, can cause fatal progressive multifocal leukoencephalopathy (PML) in immune compromised patients. The viral genome is composed of two conserved coding regions separated by a highly variable non-coding control region (NCCR). We analyzed the NCCR sequence from 10 PML JCV strains and found new mutations. Remarkably, the NCCR f section was mutated in most cases. We therefore explored the importance of this section in JCV expression in renal (HEK293H) and glioblastoma (U-87MG) cell lines, by adapting the emerging technology of DNA minicircles. Using bidirectional fluorescent reporters, we revealed that impaired NCCR-driven late expression in glioblastoma cells was restored by a short deletion overlapping e and f sections. This study evidenced a relevant link between JCV NCCR polymorphism and cell-type dependent expression. The use of DNA minicircles opens new insights for monitoring the impact of NCCR variation.

Natural history of GATA2 deficiency in a survey of 79 French and Belgian patients.

Heterozygous germline GATA2 mutations strongly predispose to leukemia, immunodeficiency, and/or lymphoedema. We describe a series of 79 patients (53 families) diagnosed since 2011, made up of all patients in France and Belgium, with a follow up of 2249 patients/years. Median age at first clinical symptoms was 18.6 years (range, 0-61 years). Severe infectious diseases (mycobacteria, fungus, and human papilloma virus) and hematologic malignancies were the most common first manifestations. The probability of remaining symptom-free was 8% at 40 years old. Among the 53 probands, 24 had missense mutations including 4 recurrent alleles, 21 had nonsense or frameshift mutations, 4 had a whole-gene deletion, 2 had splice defects, and 2 patients had complex mutations. There were significantly more cases of leukemia in patients with missense mutations (n=14 of 34) than in patients with nonsense or frameshift mutations (n=2 of 28). We also identify new features of the disease: acute lymphoblastic leukemia, juvenile myelomonocytic leukemia, fatal progressive multifocal leukoencephalopathy related to the JC virus, and immune/inflammatory diseases. A revised International Prognostic Scoring System (IPSS) score allowed a distinction to be made between a stable disease and hematologic transformation. Chemotherapy is of limited efficacy, and has a high toxicity with severe infectious complications. As the mortality rate is high in our cohort (up to 35% at the age of 40), hematopoietic stem cell transplantation (HSCT) remains the best choice of treatment to avoid severe infectious and/or hematologic complications. The timing of HSCT remains difficult to determine, but the earlier it is performed, the better the outcome.

Gene therapy for human glioblastoma using neurotropic JC virus-like particles as a gene delivery vector

Glioblastoma multiforme (GBM), the most common malignant brain tumor, has a short period of survival even with recent multimodality treatment. The neurotropic JC polyomavirus (JCPyV) infects glial cells and oligodendrocytes and causes fatal progressive multifocal leukoencephalopathy in patients with AIDS. In this study, a possible gene therapy strategy for GBM using JCPyV virus-like particles (VLPs) as a gene delivery vector was investigated. We found that JCPyV VLPs were able to deliver the GFP reporter gene into tumor cells (U87-MG) for expression. In an orthotopic xenograft model, nude mice implanted with U87 cells expressing the near-infrared fluorescent protein and then treated by intratumoral injection of JCPyV VLPs carrying the thymidine kinase suicide gene, combined with ganciclovir administration, exhibited significantly prolonged survival and less tumor fluorescence during the experiment compared with controls. Furthermore, JCPyV VLPs were able to protect and deliver a suicide gene to distal subcutaneously implanted U87 cells in nude mice via blood circulation and inhibit tumor growth. These findings show that metastatic brain tumors can be targeted by JCPyV VLPs carrying a therapeutic gene, thus demonstrating the potential of JCPyV VLPs to serve as a gene therapy vector for the far highly treatment-refractory GBM.

Atypical Infections in Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma Patients Treated with Ibrutinib

Ibrutinib is an oral Bruton’s tyrosine kinase inhibitor with clinical efficacy in several B cell malignancies. In a pooled analysis of clinical trials evaluating ibrutinib, grade 3-4 infections were reported in 14% of patients. We screened consecutive patients on ibrutinib therapy for chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL) for infectious complications. Patients were hospitalized with documented infections uncommon to this patient population including Legionella pneumonia, Campylobacter bacteremia and fatal progressive multifocal leukoencephalopathy (PML). All patients received prior therapies for CLL/MCL. Immunological evaluation of these patients demonstrated immunoglobulin depression and profound lymphopenia with severe depletion in both B and CD4 T cell counts, suggesting defects in both humoral and T cell mediated immunity. This data support a broader immunosuppressive effect for ibrutinib than initially anticipated. While responding patients may show later recovery of B cell function, profound immunosuppression may occur at earlier treatment time points, particularly in previously treated patients. Closer patient monitoring during the first months of ibrutinib therapy may be desirable.

Low frequencies of central memory CD4 T cells in progressive multifocal leukoencephalopathy.

Objectives:To assess alterations in the composition of peripheral immune cells in acute progressive multifocal leukoencephalopathy (PML).Methods:Fresh blood samples from 5 patients with acute PML and 10 healthy controls were analyzed by flow cytometry for naive, central memory and effector memory CD4 and CD8 T cells, B lymphocytes, plasma cells, memory B cells, plasma blasts, and natural killer (NK) cells. The frequency of central memory CD4 T cells was determined longitudinally during the course of PML in 2 patients.Results:The frequencies of naive, central memory and effector memory CD8 T cells, B cells, plasma cells, and NK cells were not altered in patients with PML. In contrast, the frequencies of naive CD4 T cells (p = 0.04) and central memory CD4 T cells (p < 0.00001) were reduced and the frequencies of effector memory CD4 T cells were increased (p = 0.01). Longitudinal analysis showed that this pattern was preserved in a patient with fatal PML outcome and restored in one patient who recovered from PML.Conclusions:These data indicate that PML is associated with reduced frequencies of peripheral central memory helper T cells but not with alterations in the frequencies of cytotoxic T cell populations, B lymphocytes, plasma cells, or NK cells.

Efficacy and side effects of natalizumab therapy in patients with multiple sclerosis.

Natalizumab (Nat) is a humanized monoclonal antibody used for the treatment of relapsing multiple sclerosis (MS). Nat inhibits lymphocyte migration via the blood brain barrier (BBB) by blockage of an integrin adhesion molecule, very late antigen 4. During the phase III clinical trials, it was shown that Nat reduces disease activity and prevents disability progression. In addition, several smaller studies indicate a positive influence of Nat on cognition, depression, fatigue, and quality of life (Qol). Therapeutic efficacy has to be weighed against the risk of developing potentially fatal progressive multifocal leukoencephalopathy (PML), an opportunistic infection by JC-virus (JCV) with an incidence of 3.4/1000 (95% CI 3.08–3.74) in Nat treated MS patients. In this review article, we will review data on the presumed mechanism of Nat action, clinical and paraclinical efficacy parameters, and adverse drug reactions with a special focus on PML.

Rituximab for the treatment of rheumatoid arthritis: an update

Rituximab is a chimeric monoclonal antibody that targets the CD20 molecule expressed on the surface of B cells. It was first used in the treatment of non-Hodgkin’s lymphoma and later approved for the treatment of rheumatoid arthritis (RA) that does not respond adequately to disease-modifying antirheumatic drugs, including the anti-tumor-necrosis-factor (TNF) biologics. Sustained efficacy in RA can be achieved by repeated courses of rituximab. However, the optimal dose and retreatment schedule of rituximab in RA remains to be established. Seropositivity, complete B cell depletion shortly after treatment, and previous failure to no more than one anti-TNF agent are three factors associated with greater clinical benefits to rituximab. Infusion reaction to the first dose of rituximab occurs in approximately 25% of RA patients, and the incidence reduces with subsequent exposure. Immunogenicity to the chimeric compound occurs in 11% of RA patients, but this does not correlate with its efficacy in B cell depletion. Extended observation of randomized controlled trials in RA does not reveal a significant increase in the incidence of serious infections related to rituximab compared to placebo groups, and the infection rate remains static over time. Repeated treatment with rituximab is associated with hypogammaglobulinemia, which may increase the risk of serious, but rarely opportunistic, infections. Reactivation of occult hepatitis B infection has been reported in RA patients receiving rituximab, but no increase in the incidence of tuberculosis was observed. Screening for baseline serum immunoglobulin G level and hepatitis B status (including occult infection) is important, especially in Asian countries where hepatitis B infection is prevalent. The rare but fatal progressive multifocal leukoencephalopathy linked to the use of rituximab has to be noted. Postmarketing surveillance and registry data, particularly in Asia, are necessary to establish the long-term efficacy and safety of rituximab in the treatment of RA.

Lessons Learned From Fatal Progressive Multifocal Leukoencephalopathy in a Patient With Multiple Sclerosis Treated With Natalizumab

To describe the clinical, radiological, and histopathological features of a fatal case of progressive multifocal leukoencephalopathy (PML) in a patient with multiple sclerosis treated with natalizumab. We will use this case to review PML risk stratification and diagnosis. Case report. Tertiary referral center hospitalized care. A 55-year-old, JC virus (JCV) antibody-positive patient with multiple sclerosis who died of PML after receiving 45 infusions of natalizumab. Brain magnetic resonance imaging and cerebrospinal fluid JCV DNA polymerase chain reaction results. The patient developed subacute onset of bilateral blindness following his 44th dose of natalizumab. Ophthalmologic examination was normal, the brain magnetic resonance imaging was not suggestive of PML, and cerebrospinal fluid analysis did not reveal the presence of JCV DNA. The patient was subsequently treated for a presumed multiple sclerosis relapse with high-dose corticosteroids. Two weeks after his 45th dose of natalizumab, he developed hemiplegia that evolved into quadriparesis. Repeated magnetic resonance imaging and cerebrospinal fluid studies were diagnostic for PML. Postmortem histopathological analysis demonstrated PML-associated white matter and cortical demyelination. The risks and benefits of natalizumab must be reassessed with continued therapy duration. When there is high clinical suspicion for PML in the setting of negative test results, close clinical vigilance is indicated, natalizumab treatment should be suspended, and JCV polymerase chain reaction testing and brain magnetic resonance imaging scans should be repeated.

Neurologic Complications in Patients with Inflammatory Bowel Disease

Extraintestinal manifestations of inflammatory bowel disease (IBD) can involve almost every organ system. Neurologic complications are not infrequent in patients with IBD, but are poorly recognized and underreported. Pathophysiologically, these may represent immune-mediated phenomenon, nonimmunologic complications due to micronutrient deficiencies, thromboembolism, or be medication-induced. Peripheral neuropathy is the most common neurologic complication of IBD and may be immune-mediated, or caused by therapy with anti-tumor necrosis factor-alpha (TNF-α) therapy or metronidazole. Multiple sclerosis occurs with a greater frequency in patients with IBD. Anti-TNF-α therapy can cause neurologic disease characterized by central demyelination that mimics multiple sclerosis. Hence, patients with a history of demyelinating diseases or with symptoms of polyneuropathy should be carefully evaluated before initiation of anti-TNF-α therapy. Natalizumab has been associated with fatal progressive multifocal leukoencephalopathy due to reactivation of JC virus, and occurs with greater frequency in patients with previous JC virus infection. Stroke secondary to venous or arterial thromboembolism can be seen in patients with active Crohn's disease. It is important for gastroenterologists to be aware of the neurologic complications in patients with IBD. Neurologic symptoms in these patients should be promptly evaluated.

Fatal PML associated with efalizumab therapy

Progressive multifocal leukoencephalopathy (PML) has become much more common with monoclonal antibody treatment for multiple sclerosis and other immune-mediated disorders. We report 2 patients with severe psoriasis and fatal PML treated for ≥3 years with efalizumab, a neutralizing antibody to αLβ2-leukointegrin (LFA-1). In one patient, we conducted serial studies of peripheral blood and CSF including analyses of leukocyte phenotypes, migration ex vivo, and CDR3 spectratypes with controls coming from HIV-infected patients with PML. Extensive pathologic and histologic analysis was done on autopsy CNS tissue of both patients. Both patients developed progressive cognitive and motor deficits, and JC virus was identified in CSF. Despite treatment including plasma exchange (PE) and signs of immune reconstitution, both died of PML 2 and 6 months after disease onset. Neuropathologic examination confirmed PML. Efalizumab treatment was associated with reduced transendothelial migration by peripheral T cells in vitro. As expression levels of LFA-1 on peripheral T cells gradually rose after PE, in vitro migration increased. Peripheral and CSF T-cell spectratyping showed CD8+ T-cell clonal expansion but blunted activation, which was restored after PE. From these data we propose that inhibition of peripheral and intrathecal T-cell activation and suppression of CNS effector-phase migration both characterize efalizumab-associated PML. LFA-1 may be a crucial factor in homeostatic JC virus control.

Comment: PML and adhesion molecule therapy

A total of 159 cases of progressive multifocal leukoencephalopathy (PML) have now been associated with natalizumab, an antibody that inhibits CNS lymphocyte entry by binding to α4 integrin.1 This study describes 2 of the 3 known fatal PML cases occurring following treatment with efalizumab, an adhesion molecule inhibitor that binds to the α subunit of LFA-1 (CD11a) and blocks its attachment to ICAM-1.2 The estimated risk of PML in patients treated with efalizumab (∼1:400) falls into the general range of that for natalizumab (∼1:600), and resulted in the removal of efalizumab from the market in 2009. A unique feature …

Granulomatous inflammation in cartilage-hair hypoplasia: Risks and benefits of anti–TNF-α mAbs

Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive disorder characterized by short-limbed skeletal dysplasia. Some patients also have defects in cell-mediated immunity and antibody production. Granulomatous inflammation has been described in patients with various forms of primary immunodeficiencies but has not been reported in patients with CHH. We sought to describe granulomatous inflammation as a novel feature in patients with CHH, assess associated immunodeficiency, and evaluate treatment options. In a retrospective observational study we collected clinical data on 21 patients with CHH to identify and further characterize patients with granulomatous inflammation. Four unrelated patients with CHH (with variable degrees of combined immunodeficiency) had epithelioid cell granulomatous inflammation in the skin and visceral organs. Anti-TNF-α mAb therapy in 3 of these patients led to significant regression of granulomas. However, 1 treated patient had fatal progressive multifocal leukoencephalopathy caused by the JC polyomavirus. In 2 patients immune reconstitution after allogeneic hematopoietic stem cell transplantation led to the complete disappearance of granulomas. To the best of our knowledge, this is the first report of granulomatous inflammation in patients with CHH. Although TNF-α antagonists can effectively suppress granulomas, the risk of severe infectious complications limits their use in immunodeficient patients.

Fatal progressive multifocal leukoencephalopathy in a patient with non-Hodgkin lymphoma treated with rituximab

We report a case of progressive multifocal leukoencephalopathy (PML) in a woman with non-Hodgkin lymphoma treated with chemotherapy in combination with rituximab. She presented with rapid deterioration of vision and subsequently cognitive decline. Magnetic resonance imaging (MRI) of the brain raised the suspicion of PML. The first PCR analysis of the cerebrospinal fluid (CSF) was negative, but a second sample was positive for JC virus DNA. Anti-viral treatment was ineffective and the patient died 7 months after debut of symptoms. Our case emphasizes the importance of the awareness of PML in patients with progressive neurological symptoms treated with antilymphocytic drugs and that consecutive CSF analyses may be needed to detect the JC virus.

Survey for the presence of BK, JC, KI, WU and Merkel cell polyomaviruses in human brain tissues

Background Recently three previously unknown polyomaviruses (KI, WU and Merkel cell polyomaviruses) have been identified from human specimens. The spectrum of clinical manifestations and their tissue tropism are currently unknown. Since a member of this virus family, JC virus, is well-known for its capacity to establish latency in human brain tissue where reactivation in immunocompromised individuals can result in fatal progressive multifocal leukoencephalopathy, we sought to examine for the presence of all the five known human polyomaviruses in a series of human brain tissues. Objectives To investigate the possibility of neuropersistence of the newly identified human polyomaviruses. Study design Autopsy brain tissues were collected from 10 different brain regions of 30 individuals who died from diseases unrelated to viral infections. Nested PCR was used to assess the presence or absence of viral DNA. Results Ten samples collected from five individuals were found to harbour JCV DNA. In contrast, none of the 300 brain tissues examined showed positive results for BK, KI, WU or Merkel cell polyomavirus. Conclusion The newly identified KI, WU and Merkel cell polyomaviruses either do not, or have a much lower neuropersistent potential compared to JCV.