P1095: COVID-19 VACCINE RESPONSES IN FOLLICULAR LYMPHOMA: DETERMINANTS OF HUMORAL AND CELLULAR IMMUNITY IN THE PETREA TRIAL OF FRONTLINE CHEMOIMMUNOTHERAPY

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Topic: 18. Indolent and mantle-cell non-Hodgkin lymphoma - Clinical Background: The COVID-19 vaccination programme offered a unique opportunity to investigate how immunological responses to vaccination are influenced by cancer and its treatment without the confounding effects of prior immunisation and/or pathogen exposure. This is particularly relevant to patients with follicular lymphoma (FL) receiving initial therapy where there is a trade-off between long-term disease control and iatrogenic immunosuppression. The NCRI phase III PETReA trial provided an ideal platform for investigating COVID-19 vaccine responses in this setting. Aims: The dual aims of the study were to quantify antibody and T-cell responses to primary COVID-19 vaccination in patients with FL undergoing frontline chemoimmunotherapy (CIT) and elucidate sources of variation in these responses. Methods: The research was configured as a substudy of the NCRI PETReA trial (EudraCT number 2016-004010-10), a multicentre non-blinded phase III randomised controlled trial for patients with previously untreated advanced-stage FL. Patients received induction therapy with the anti-CD20 monoclonal antibody rituximab and either bendamustine or cyclophosphamide, vincristine and prednisolone, with (CHOP) or without (CVP) doxorubicin, and were randomly assignment to post-induction rituximab maintenance. COVID-19 vaccines (BNT162b2 or ChAdOx1) were administered before, during or after lymphoma treatment. Blood samples obtained after the first and second vaccine doses (V1 and V2) were analysed for antibodies and T-cells reactive to the SARS-CoV-2 spike protein using the Abbott Architect platform and ELISpot assay, respectively. A cohort of healthy controls (HCs) from the PITCH study (which employed the same metholodology) was used for comparison. Independent determinants of antibody and T-cell responses in the FL cohort were identified by multivariable analysis using a backwards stepwise procedure evaluated with Akaike’s Information Criterion (AIC). A p-value of 0.05 was used throughout to determine statistical significance. Results: Antibody but not T-cell responses were significantly lower in the FL cohort (n=58) compared with HCs (n=159). High/intermediate FLIPI-2 score, low serum IgA levels, bendamustine exposure and administration of V2 during lymphoma treatment were each identified as independent determinants of a low antibody response after V2. In contrast, low serum IgA levels and administration of V2 during lymphoma treatment predicted a higher T-cell response. Both types of immune response waned between 4 weeks and 6 months. In a multivariate model that estimated vaccine-induced immune responses for different combinations of predictive variables, several clinical scenarios were identified where positive or negative antibody or T-cell responses were predicted with ≥95% confidence. Summary/Conclusion: In FL patients undergoing frontline therapy, low serum IgA levels and administration of V2 during treatment are independent determinants of a reduced antibody response and an enhanced T-cell response following primary COVID-19 vaccination, while high tumour burden and bendamustine are additional determinants of a low antibody response. Our findings, which potentially extend to other vaccines and clinical settings, suggest that DNA/RNA vaccines may confer useful, if not full, clinical protection, even when administered during therapy that depletes B cells (rituximab) and CD4+ T cells (bendamustine). Keywords: Follicular lymphoma, COVID-19, Bendamustine, Rituximab

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