Safety and Efficacy of Sars-Cov-2 Vaccines in Hodgkin Lymphoma Patients Receiving PD-1 Inhibitors

Background: Patients (pts) with cancer are at higher risk for complications and mortality related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although mRNA vaccines have been granted Food and Drug Administration emergency use authorization (EUA) for prevention of COVID-19, the pivotal trials largely excluded pts with active cancer. Emerging data suggests suboptimal efficacy of these vaccines in pts with hematologic malignancies. There are also theoretical concerns that programmed cell death protein 1 inhibitors (PD-1i) could potentiate vaccine-related adverse events (AEs); conversely, these vaccines could activate the immune system, increasing the risk for immune-related reactions (IRRs) after PD-1i treatment. Pts with classic Hodgkin lymphoma (cHL) receiving PD-1i represent a unique cohort and should be investigated for safety and efficacy issues with SARS-CoV-2 vaccines.

Methods: We conducted a retrospective analysis of pts with cHL who were treated with PD-1i within the past 12 months. Our primary objective was to determine the frequency of vaccine-related AEs and also subsequent IRRs to PD-1i after vaccination as reported in the medical records. Our secondary objective was to determine efficacy based on post-vaccine COVID-19 infection rates and by presence of adequate receptor binding domain (RBD) IgG antibody level to the SARS-CoV-2 spike protein. This assay was a clinically available institutional assay developed under EUA. While the level of antibody that is associated with immune protection has not yet been defined, we used RBD IgG > 0.700 AU as positive since it was previously correlated with virus neutralization titer in vitro.

Results: From July 1, 2020 through June 31, 2021, we identified 27 pts who received PD-1i for cHL and were seen at the University of Pennsylvania. Seventeen (63%) pts received nivolumab and 10 (37%) received pembrolizumab. The median age was 42 years (23-86), median number of therapies was 4 (2-15), and 7 (26%) had prior history of COVID-19 infection (none required hospitalization). Twenty-three pts (85% of total) were vaccinated: 17 (74%) received Pfizer-BioNTech BNT162b2 and 6 (26%) had Moderna mRNA-1273 formulations. Of 19 (83%) pts who received at least one dose of PD-1i prior vaccine, the median time between last PD-1i infusion and first vaccine administration was 20 days (2-157). Of 19 (83%) pts who received any PD-1i after vaccine, the median time to infusion was 18 days (4-89). In pts who had prior COVID-19 infection, the median time between the prior infection and vaccine was 91 days (range 78-350). There were no unexpected toxicities noted and no severe adverse events or hospitalizations directly related to vaccination. No patient discontinued the vaccination series due to side effects. In 12 vaccinated pts who had vaccine-related AEs solicited by the medical provider, 7 (58%) developed injection site reaction/pain: grade 1 (6/12) and grade 2 (1/12). Six (50%) pts had systemic AEs: grade 1 fatigue (4/12), grade 2 fatigue (1/12), transient generalized lymphadenopathy (1/12), fever (1/12). No new IRRs occurred in pts receiving subsequent PD-1i after vaccination. Two weeks after second vaccination, 1 patient developed worsening cough with imaging suggestive of pneumonitis but improved with antibiotics. There were no post-vaccine COVID-19 infections noted. RBD IgG antibody levels were available in 12/23 (52%) of all vaccinated pts; 11/12 (92%) pts had positive antibody titers. The only patient who did not mount positive RBD IgG antibody titers received brentuximab vedotin concurrently with PD-1i prior to vaccination. There were insufficient events to correlate pre-vaccine factors with AEs or efficacy.

Conclusion: Pts with relapsed/refractory cHL on PD-1i who received SARS-CoV-2 vaccines had no unexpected toxicities and tolerated subsequent PD-1i without new IRRs. The efficacy based on post-vaccination COVID-19 rates and RBD IgG levels is encouraging in these heavily pretreated pts. We plan an additional prospective component of this study using patient reported outcomes and long-term safety and efficacy follow-up.