Progressive multifocal leukoencephalopathy after allogeneic stem cell transplantation and posttransplantation rituximab

Progressive multifocal leukoencephalopathy (PML) is a rare but fatal demyelinating disease of the brain caused by the JC papovavirus (JCV), affecting mainly immunocompromised patients. Recently, an association between PML and the application of rituximab after autologous stem cell transplantation (SCT) has been discussed (1,2). We report the first case of PML after allogeneic SCT and posttransplantation administration of rituximab. A 32-year-old man with refractory diffuse large cell lymphoma received an unmanipulated blood SCT from an HLA-identical male sibling donor after conditioning with cyclophosphamide, carmustine, and etoposide. In addition, the patient was given 10 infusions of rituximab (375 mg/m2) between days 14 and 180. Except for a grade II acute graft-versus-host disease of the skin and mild cytomegalovirus infection, the posttransplantation period proceeded without complications, and after 11 months cyclosporine A was discontinued. However, recovery of B lymphocytes was significantly delayed, requiring prolonged substitution therapy with immunoglobulins. In contrast, recovery of CD4+ and CD8+ counts was unremarkable. Seventeen months after transplantation, the patient presented with progressive bulbar speech dysfunction and subfebrile temperatures. PML was suspected after magnet resonance tomography scanning and confirmed by brain biopsy and detection of JC viral DNA in the cerebrospinal fluid. Despite therapy with interleukin 2 (106 IU/day SC) in combination with cytosine arabinoside (40 mg/week intrathecally) and cidofovir (375 mg IV every other week), the patient’s condition deteriorated continuously. He died after 3 months while still in complete remission concerning his lymphoma and without evidence of human immunodeficiency virus infection. PML arises upon JCV reactivation and has received increasing attention as a serious complication in immunocompromised subjects. In contrast to patients with human immunodeficiency virus or the cases reported recently after autologous SCT (1), CD4+ counts in our patient were normal, suggesting additional pathogenetic mechanisms in the development of PML. The onset of the first neurologic symptoms coincided with the recovery of B cells, which had been severely depressed because of rituximab administration. From recent findings concerning JCV trafficking (3) we speculate that latent JCV-bearing donor-derived B lymphocytes crossed the blood-brain barrier and transmitted JCV to brain tissue. Stimulation assays performed at the time of PML diagnosis revealed severely impaired lectin-reactive and alloreactive T-cell responses, reflecting profound suppression of cell-mediated immunity despite normal T-cell counts (Fig. 1). This is in accordance with previous reports demonstrating that functional capacities of T cells remain severely depressed for several months after autologous or allogeneic SCT (4). Figure 1: Functional assessment of T cells at the time of PML diagnosis. (A) Stimulation indices after incubation of patient’s and a healthy controls’ peripheral blood mononuclear cells with concanavalin A (ConA) at a dilution of 1:80 and stimulation with 1% phytohemagglutinin (PHA) as described previously (4). (B) Stimulation indices of patient’s and a healthy control’s peripheral blood mononuclear cells after allogeneic stimulation in a one-way mixed lymphocyte reaction as described previously (4).To date, prognosis of PML in transplant recipients is dismal, with an average survival of only a few months. Thus clinical management of PML in this group of patients needs to be improved (5). In conclusion, we report the first case of PML in the setting of posttransplantation rituximab in an allogeneic SCT recipient. This case together with other recent reports suggests that application of rituximab after SCT may result in delayed reconstitution of B cells. Prolonged SCT-associated functional T-cell defects render the patient at a high risk for late viral infections at the time of recovery of JCV-bearing autologous or donor-derived B lymphocytes. Michael Steurer1 Johannes Clausen1 Thaddaeus Gotwald2 Eberhard Gunsilius1 Guenther Stockhammer3 Guenther Gastl1 David Nachbaur1 4