Pilot Trial of Rituximab for the Prevention of Epstein Barr Virus B Cell Lymphoproliferative Disorder (EBV-LPD) Following T Cell Depleted (TCD) Unrelated or HLA-Mismatched Related Hematopoietic Stem Cell Transplantation.

The risk of developing an EBV-LPD is highest in recipients of an unrelated or HLA-mismatched related TCD HCT, with a reported incidence of 10–23%. Although treatment with anti-B cell monoclonal antibodies and/or adoptive immunotherapy can be curative, these therapies are not always effective and can cause fatal tumor lysis syndrome. We have previously shown that the risk of developing an EBV-LPD after a TCD HCT is greatest within the first 2 to 6 months post HCT, and in patients whose circulating CD4 cell counts are less than 200/ul. We therefore developed a phase I pilot trial to investigate the feasibility of 6 monthly doses of rituximab for the prevention of EBV-LPD. Eligibility included hepatitis B surface antigen negative recipients of a TCD HCT from an unrelated or HLA mismatched related donor, EBV seropositive donor and/or host, ANC of >1500 cells/ul, documentation of remission, negative EBV viremia at baseline, and lack of ongoing infection at the time of enrollment. Patients received a maximum of 6 consecutive monthly doses of rituximab (375 mg/m2/dose) starting approximately 1 month post HCT. Less than six monthly doses were given if the patient developed a circulating CD4 cell count > 200/ul sooner than 7 months post transplant. To date, 22 patients (4–68 years of age, median 19.5 years) have been enrolled on this IRB approved trial, 20 of whom have completed therapy. Rituximab was well tolerated. The main side effect potentially related to rituximab was reversible neutropenia (n=5), which resulted in cessation of treatment as per protocol after the 2^nd (n=1), 3^rd (n=1), or 4^th (n=1) dose. To date, none of the 22 patients on trial have developed an EBV-LPD compared to 10.1% of patients who received an unrelated or HLA MM-related TCD HCT during the same time interval but did not receive prophylactic rituximab. Although 2 patients had prolonged shedding of parainfluenza virus (n=1) or RSV (n=1) from the upper respiratory tract, there was no significant increase in viral or bacterial infections in patients who received rituximab prophylaxis. No patient on trial developed a fatal infection. Eighteen of 22 patients enrolled on trial are alive at a median of 14.5 months post HCT. One patient died of GVHD and 3 high risk patients succumbed to relapse. In evaluable patients, recovery of normal numbers of circulating B cells occurred between 5 and 12 months after the last dose of rituximab. This trial suggests that monthly rituximab can be safely given during the first 6 months after a TCD HCT, resulting in a decreased incidence of EBV-LPD. Larger trials investigating the optimum number and timing of Rituximab doses required to prevent this complication are needed as are studies evaluating recovery of specific B cell function in recipients of rituximab after allogeneic HCT.