Evaluation of Humoral Immune Responses to Vaccination with Tetanus Toxoid and KLH in Rituximab-Treated Follicular Non-Hodgkin’s Lymphoma Patients Compared to Healthy Volunteers

Abstract

Introduction: Since rituximab is known to rapidly deplete B lymphocytes in the blood for 6–12 months after administration, there has been interest in determining whether this results in a clinically significant impact on humoral responses to common vaccines. Therefore, we designed a trial in patients with lymphoma to study vaccination response to recall and novel antigens and to document any changes in antibody titers to specific common antigens following rituximab treatment. Vaccination of healthy control subjects served as a control for vaccine effectiveness. Design: The trial evaluated responses to neoantigen (keyhole limpet hemocyanin, KLH) as well as a recall antigen (tetanus) in 2 groups: rituximab-treated subjects with relapsed/refractory indolent non-Hodgkin’s lymphoma (NHL) and an age-matched control group of untreated healthy volunteers. Rituximab was dosed at 375 mg/m2 weekly × 4 in the NHL group, and immunization occurred 36 weeks later (or immediately in the control subjects) with tetanus (0.5 mg single dose) and KLH (1 mg weekly × 2). Titers were evaluated 28 days after the start of vaccination in all subjects. In addition, titers to a selected panel of bacterial and viral antigens were measured in the NHL subjects from pre-treatment through 40 weeks follow-up. Endpoints: Primary-- the proportion of subjects in each group with either a doubling of titers to tetanus toxoid from baseline, or if the baseline was <0.1 IU/ml, a titer of ≥0.2. Secondary-- descriptive analyses of KLH titer changes; maintenance of pre-existing titers to S. pneumoniae, influenza A, mumps, rubella, and varicella during the trial; human anti-chimeric antibody development (HACA); and adverse event rates. Results: 173 NHL and 103 control subjects were enrolled at 37 study sites; 110 and 84 subjects, respectively, satisfied the per-protocol criteria (received all rituxmab and vaccinations, had all follow-up antibody titers drawn, and did not require subsequent lymphoma therapy during the study). NHL subjects had a median of 2 prior treatments (range 1–9). Eighteen of 110 (16%) NHL subjects and 68 of 84 (81%) control subjects were classified as responders to tetanus. There was a −0.65 difference in proportions between the groups with a 95% CI of −0.77 to −0.53; therefore, it was concluded that these groups do not respond similarly to tetanus. For KLH, 4 of 108 (4%) subjects in the NHL group had a doubling of antibody titer compared to 58 of 84 (69%) control subjects. In both groups, the mean antibody titers to S. pneumoniae, influenza A, mumps, rubella, and varicella over the course of the study remained stable. No unexpected toxicities were seen during the trial, including no adverse events related to vaccination. HACA testing was positive for 1 of 170 (1%) subjects at screening and 4 of 130 (3%) at end of study. Conclusions: Compared to a control population of healthy volunteers, patients with relapsed/refractory low-grade NHL treated with rituximab had a blunted response to vaccination but no change in titers to ubiquitous environmental antigens. However, the study was not designed to determine whether the poor responses to antigen were due to the presence of NHL, immunosuppression from prior therapies, administration of rituximab, or some other factor.

In vivo human keyhole limpet hemocyanin challenge in early phase drug development: A systematic review

“…Six of the 42 studies (14%) described application of KLH challenge to assess the activity of drugs in late‐phase clinical trials and observational studies. Collectively these studies attest to suppression of the humoral immune response to KLH by anti‐CD20 agents (rituximab and ocrelizumab), 48,49 S1PR modulation (fingolimod), 50 IMPDH inhibition (mycophenolic acid), 51 and lack of effect of an anti‐α4‐integrin mAb (natalizumab) 52 . In one observational study of patients who underwent renal transplantation receiving prednisolone and cyclosporine, the use of everolimus as a third agent was associated with retention of primary humoral immune response to KLH, in contrast to complete suppression of response seen with mycophenolic acid as a third agent 53 …”