Phase I Trial of Prophylactic Rituximab for the Prevention of Post Transplant Epstein-Barr Related Lymphoproliferative Disease (EBV-PTLD) Following T Cell Depleted (TCD) Unrelated or HLA-Mismatched Related Hematopoietic Cell Transplantation (HCT): Efficacy, Toxicity, and Effect on Subsequent B Cell Reconstitution
Authors: Small Trudy N , Kernan Nancy A. , Jakubowski Ann A. , Knowles Molly A , Young James W , Castro-Malaspina Hugo , Prockop Susan E , O'Reilly Richard J. , Papadopoulos Esperanza B 
Published: October 2019

Abstract
Abstract 1971
Rituximab, a chimeric IgG1 kappa monoclonal antibody against the pan-B cell marker CD20, has proven effective in treating B cell malignancies, including EBV-PTLD. To determine its potential role in prevention of EBV-PTLD, 25 patients were enrolled on a prospective IRB approved trial (11/1/03-2/1/07) of monthly rituximab (375 mg/m2/dose, maximum 6 doses), starting 30–45 days after a TCD unrelated (n=23) or HLA-mismatched HCT (n=2). Eligibility included EBV seropositive patient, negative hepatitis B surface antigen, ANC >1500 cells/uL, remission, and negative plasma EBV PCR at baseline. Per protocol, rituximab was stopped prior to 6 doses in patients who achieved a circulating CD4 count >200 cells/ul, at which time their risk of EBV-PTLD was considered minimal. The median patient age (range) was 22.0 (8.0-68.0) years. Patients underwent transplantation for acute leukemia (n=18), CML (n=2), NHL (n=2), MDS (n=2), or Fanconi anemia/AML (n=1). Only two patients developed fever and chills, without respiratory distress or hypotension, within the first hour of their initial infusions, which proved to be due to coincidental line infections for which both were treated and recovered uneventfully. Both patients refused further rituximab. Six patients received all 6 planned doses; 5 patients received fewer than 6 doses due to recovery of CD4 count >200 cells/ul before the planned 3rd (n=4) or 5th dose (n=1). The remaining 12 patients received 1 (n=2), 2 (n=4), 3 (n=2), or 4 doses (n=4), due to persistent neutropenia (<1500 cells/ul) >45d after the prior rituximab dose (n=4), recurrent disease (n=2), prolonged parainfluenza upper respiratory tract infection (n=1), secondary graft failure (n=1), abnormal LFTs of unclear etiology (n=1), GVHD requiring phase I therapy (n=1), aseptic meningitis (n=1) attributed to intravenous gammaglobulin, or pneumococcal sepsis (n=1). At a median follow-up of 5.8 (4.4-5.7) years, 16 of 25 patients are alive, 13 disease-free. Five patients died of recurrent hematologic malignancy, three of GVHD, and one of non-alcoholic steatohepatitis. Of the 25 patients accrued to the protocol, none developed EBV viremia or EBV-PTLD, compared to 23% (p<0.01) and 7%, respectively of patients (n=95) not given prophylactic rituximab following a TCD unrelated or HLA –mismatched related donor performed during the same time period. Despite recovery of normal numbers of CD20+ B cells at a median of 8.4 months post rituximab, 5 of 13 recipients of prophylactic rituximab have had prolonged hypogammaglobulinemia, a paucity of memory switched (CD27+ IgD-) B cells, and no specific antibody responses persisting at least 4 years from their last dose of rituximab. B cell dysfunction did not correlate with the number of doses of prophylactic rituximab administered. To estimate how frequently persistent B cell dysfunction occurs following rituximab treatment, serum immunoglobulin levels +/− specific antibody production was assessed in an additional 44 patients who received rituximab following TCD unrelated or HLA-mismatched related HCTs for the treatment of EBV viremia, EBV-PTLD, autoimmune cytopenias, or as prophylaxis against recurrent EBV (-) B-cell NHL, or EBV-LPD. Patients received a median of 4 doses of rituximab at a dose of 375 mg/m2 given weekly in most patients. Despite recovery of normal numbers of circulating B cells in all 44 patients, 10 patients have had prolonged hypogammaglobulinemia (>18 months), including 6 patients who remain on monthly IVIG a median of 40 (25–66) months following rituximab. In this cohort, 30 patients were immunized with a series TDAP, PCV7 or PCV13, HIB, and/or inactivated polio vaccines. Following the third vaccine, 13 patients (43%) failed to respond to any vaccine, 6 patients (20%) had incomplete responses, and 11 patients (37%) responded to all vaccines administered. Lack of vaccine response was associated with a paucity of memory switched B cells. This study demonstrates the effectiveness of rituximab in preventing EBV viremia in high risk recipients of a T cell depleted HCT. It also suggests that rituximab affects B cell function long-term, despite quantitative, but not necessarily qualitative recovery of B cells. Further studies investigating the minimal number of rituximab doses required to prevent EBV viremia/EBV-PTLD in high risk patients and the mechanism of prolonged B cell impairment following its use are needed.

Disclosures:
Off Label Use: Rituximab for the prevention of EBV-LPD post HCT. Papadopoulos:Biogen-Idec: Membership on an entity's Board of Directors or advisory committees, family member on board of Biogen-Idec who receives royalties from Hoffman La-Roche.