Absence of Viral Complications When Using Rituximab to Treat TTP with Plasma Exchange

INTRODUCTION

Rituximab is widely used for the treatment of B cell lymphoma and, increasingly, for therapy in autoimmune diseases including TTP. One of the major concerns about this drug is that selectively depleting B-lymphocytes may increase the number of infections with reactivation of latent viruses such has Hepatitis B and Cytomegalovirus (CMV). Immunosuppression can result in increased susceptibility for HEV infection and chronic hepatitis. We have recently carried out a Phase II study in which Rituximab was administered to 40 TTP patients with relapsing or refractory disease. These patients received very large volumes of non-inactivated plasma (range 50 to 110 litres), so it was considered possible that infection could occur. Therefore, we determined the viral status of the patients prior to, and after treatment.

METHODS

Forty patients, 20 refractory and 20 with relapsing TTP, were recruited from 4 apheresis centres. Each received 375 mg/m² of Rituximab once a week for 4 weeks. Plasma exchange was initiated on day 0 and carried out daily for at least 7 of 10 days.  Response to therapy was measured by platelet count. Tests for viral studies for hepatitis B core antigen and hepatitis E (which we recently reported to be transmitted during PE) were carried out at our National Viral Laboratories (location province). All but 1 patient who also got SDP received either cryosupernatant plasma or FFP in combination. Blood samples were taken on day 0 and repeated at 1, 12, 24 and 52 weeks for viral studies.

RESULTS

All patients decreased their CD20 values by week 2 and recovered fully by week 24.  lgG levels were slightly decreased at week 2 in the relapsed patients but not in the refractory ones, then remained normal throughout testing. Three relapsing patients  were strongly positive for anti-HEV at presentation however, the antibodies were all IgM negative ruling out recent infection. The HEV titres did not change during the period of assessment (52 weeks). One refractory patient was positive for anti-HEV lgG at 0 but negative by 4, 12 and 52 weeks. Two patients were weakly positive for anti-HEV.  Of these, one refractory case showed a boost in titre at 24 weeks without producing lgM but no HEV RNA was found. At presentation, 3 other patients had borderline anti-HEV positive values.

None of the 36 patients tested showed anti-HBc seroconversion for Hepatitis B at any point. Four weakly positive patients became negative.

DISCUSSION

Rituximab effectively caused immunosuppression in these TTP patients however, in spite of receiving very large volumes of untreated plasma, there was no evidence of overt infection or significant seroconversion except in the one case with an increase in IgG at 6 months. 

Immunoglobulin levels remained in the normal range in these patients because of the infusion of donor plasma suggesting a protective effect of the plasma and that maintenance of normal immunoglobulin levels through the use of IVIgG may be protective in other patients receiving Rituximab.