Rituximab and progressive multifocal leukoencephalopathy: A report of 35 cases

Abstract

8531 Background: Progressive multifocal leukoencephalopathy (PML) is a demyelinating disorder of the brain caused by the reactivation of latent JC polyoma virus. PML is associated with profound immunosuppression such as: HIV, stem cell transplantation (SCT), purine analog therapy, organ transplantation, or lymphoma. Rituximab (R) is a B-cell depleting, monoclonal antibody, linked to the reactivation of hepatitis B and other viruses. We evaluated the characteristics of patients who developed PML after exposure to R, including T-cell and immunoglobulin studies, when available. Methods: Data sources included clinical observations of the authors, reports from the FDA MedWatch database, medical literature cases, and reports from the manufacturer, Genentech, that were submitted to the FDA. Reports that did not confirm PML diagnosis or were associated with known HIV were excluded. Results: Of 51 unique cases identified, 2 were excluded for HIV, and 14 for inadequate confirmation of PML. In the 35 remaining cases, survival for 1 year after PML diagnosis was reported in just three patients (9%). Diagnosis was made by brain biopsy (n=10), autopsy (n=6), or MRI of brain AND positive JC virus PCR (n=19). Indications for R were lymphoproliferative disorder (n=33) and systemic lupus erythematosus (n=2). Median age was 63 years (range 30–89), with 19 female and 16 male patients. Seven cases were seen after SCT, 5 autologous and 2 allogeneic. In the 28 remaining patients, 10 received purine analog therapy and 24 received an alkylating agent. T-cell studies were obtained on 9 patients (Table). Conclusions: Eight of 9 patients with complete T-cell studies had abnormal CD4/CD8 ratios or severe T-cell lymphopenia with CD4 count <100. This suggests that dysregulation of the cellular immune system may contribute to the development of PML after treatment with R and chemotherapy. Prospective study of T-cell changes following R administration would allow better understanding of the potential contribution of R to T-cell dysregulation and viral reactivation. T-cell and immunoglobulin studies Case Transplant Indication CD4+ (cells/μl) CD8+ (cells/μl) CD4/CD8 Ratio IgG (mg/dl) IgA (mg/dl) IgM (mg/dl) 1 Allo ALL 1059 3453 0.31 69 151 96 2 Auto Follicular NHL 234 1015 0.23 501 62 N/A 3 Auto NHL 89 41 2.17 627 58 19 4 Auto NHL 551 2596 0.21 163 17 2 5 None CLL 287 311 0.92 448 213 316 6 None DLBCL 94 243 0.39 603 41 355 7 None Mantle cell NHL 110 310 0.35 770 195 91 8 None Waldenstrom 2100 6200 0.34 N/A N/A N/A 9 None SLE 71 57 1.25 N/A N/A N/A N/A denotes not available Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech