Natalizumab-Associated T Cell Complications: First Case of Peripheral T Cell Lymphoma and Second Case with PML-IRIS and Clonal T Cell Production
Jeffrey T Schowinsky, John R Corboy, Timothy L Vollmer, BK Kleinschmidt-DeMasters. U. Colorado SOM, Aurora, CO
Background: Natalizumab (NTZ) is a therapeutic monoclonal antibody approved in 2004 for treatment of patients with the relapsing form of multiple sclerosis (MS). NTZ reduces MS relapses as well as new inflammatory lesions on MRI and has significant clinical efficacy. Unfortunately, soon after approval, occurrence of progressive multifocal leukoencephalopathy (PML) due to reactivation of JC virus infection in oligodendrocytes was associated with use of NTZ (Kleinschmidt-DeMasters, Langer-Gould), and NTZ was temporarily removed from the market. Availability resumed in 2006 with monitoring programs, including serological testing for JC virus exposure. To date, >80,000 patients with MS have used NTZ and despite cautious use, PML cases continue to be reported. In patients with PML after NTZ withdrawal, an immune reconstitution inflammatory syndrome (IRIS) can occur, a condition for which there is limited histological information, particularly with long-standing IRIS and particularly at autopsy. Only a single case of lymphoma has previously been reported as a complication of NTZ (primary CNS B cell).
Design: We report two MS patients with NTZ use who developed T cell abnormalities.
Results: The first is a 39yo woman who developed a symptomatic skull mass in 2010 that proved to be peripheral T cell lymphoma, NOS (CD3+, CD4-, CD8-). Subsequent marrow and vertebral body biopsies have remained positive despite aggressive therapy; she remains alive but doing poorly. The second patient was a 56yo woman with relapsing remitting MS, treated for 4 years with NTZ, who discontinued drug in the summer of 2010 after diagnosis of PML. CSF analysis in November 2010 showed normal results by flow cytometry and cytology; CSF protein was 50 mg/dl; with 26 WBCs: 91% lymphocytes, 9% monocytes. JC virus was <100 and HHV-6 <250. PML versus IRIS was diagnosed; comfort care was instituted but demise did not occur until a year after NTZ withdrawal. Autopsy showed massive cavitary brain lesions far more destructive than with previously reported PML-natalizumab or PML-IRIS cases, with abundant perivascular and parenchymal CD8+ T cell infiltrates; Monoclonal T cell populations were detected in both marrow and spleen, suggesting emergence of a pre-lymphomatous population, but no overt lymphoma was seen histologically. We interpret this case as prolonged severe PML-IRIS with overstimulation of T cells.
Conclusions: Complications of NTZ have largely been centered on PML, but these two cases suggest T cell abnormalities can occur. We report the first example of peripheral T cell lymphoma with NTZ use.
Tuesday, March 20, 2012 1:00 PM
Poster Session IV # 264, Tuesday Afternoon