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Patient affected by advanced Follicular Lymphoma undergoing front-line immunochemotherapy and antiCD-20 maintenance in the FIL_FOLL19 trial

Evaluation of cellular immunity vs SARS-CoV-2 by ELISpot assay

Cellular immunity vs SARS-CoV-2

Evaluation of Humoral immunity vs SARS-CoV-2 by ELISA assay (IgG anti-RBD and anti-N)

Humoral immunity vs SARS-CoV-2

Evaluation of cellular immunity vs VZV by Enzyme-Linked immunoSPOT (ELISPOT) assay

Cellular immunity vs Varicella Zoster Virus

Evaluation of humoral immunity vs VZV by ELISA (VZV gE-binding IgG)

Humoral immunity vs Varicella Zoster Virus

Evaluation of diphtheria toxin-binding IgG by ELISA assay

Diphtheria toxin-binding IgG

Evaluation of tetanus toxoid-binding IgG by ELISA assay

Tetanus toxoid-binding IgG

Characterization of T-cell populations and markers by flow cytometry

T-cell populations and markers characterization

Uffici Studi FIL

Gioacchino Catania, MD

Annarita Conconi, MD

Erika Meli, MD

Alessandro Noto, MD

Gloria Margiotta Casaluci, MD

Luca Arcaini, MD

Patrizia Bernuzzi, MD

Federica Cavallo, MD

Carola Boccomini, MD

Benedetta Bianchi, MD

Antonella Anastasia, MD

Benedetta Sordi, MD

Stefano Luminari, MD

Emanuele Cencini, MD

Michele Merli, MD

This is a prospective biological study evaluating the persistence of COVID-19 vaccine and other vaccines' (zoster, diphtheria and tetanus)-induced immunity in a subgroup patient affected by Follicular Lymphoma requiring treatment undergoing frontline induction immuno-chemotherapy and anti-CD20 maintenance within the prospective FIL_FOLL19 study (NCT05058404).

Blood samples from patients will be collected before and at planned timepoints during treatment to evaluate humoral and cellular immunity against SARS-COV-2, VZV, tetanus and diphtheria and T-cell markers characterization.

Patients (pts) with follicular lymphoma (FL) were reported to be at high risk for hospitalization and death from COVID-19 infection, especially if exposed to anti-CD20 monoclonal antibodies (mAbs)-based therapy. A large amount of studies unequivocally demonstrated that anti-CD20 mAbs-containing therapies typically impair the development of protective levels of neutralizing anti-spike antibodies after immunization with full course of approved mRNA-based COVID-19 vaccines (up to 12 months after last anti-CD20 infusion). Moreover, booster doses seem to induce seroconversion only in a minority of such pts. On the contrary, preliminary findings seem to suggest that a substantial proportion of vaccinated pts with B-cell lymphoma (B-NHL) mount detectable SARS-CoV-2-specific T-cell responses (as measured by assays evaluating IFN-Y secretion after stimulation with SARS-CoV-2 peptides), independently from humoral response status.

For newly diagnosed FL pts current guidelines suggest to complete the vaccination with booster dose(s) before treatment initiation, as anti-CD20 mAbs seems to spare pre-established humoral immunity to COVID-19 vaccine, although data supporting this finding are scanty.5 Furthermore, data about long term persistence of pre-established cellular immunity in this setting are lacking, although preliminary findings in unselected immunosuppressed pts suggest that it decline over time without significant difference with respect to the general population.

The novel adjuvanted recombinant zoster vaccine demonstrated lower humoral immune response in pts with B-NHL with respect to other pts, probably due to anti-CD20 therapy, while cellular immunity was not affected, although the small number of pts requires further investigation.

Very few data concerning persistence of immunity to childhood vaccines after anti-CD20-based therapy are available and suggest that humoral immunity to diphtheria and tetanus may be significantly impaired after therapy.

This is a prospective biological study evaluating the persistence of COVID-19 vaccine and other vaccines' (zoster, diphtheria and tetanus)-induced immunity in a subgroup of FL patients undergoing frontline induction immuno-chemotherapy and anti-CD20 maintenance within the prospective FIL_FOLL19 study (NCT05058404).

After the signature of a specific informed consent, eligible patients will receive a questionnaire evaluating vaccination history, past infection history and treatment, and passive immune prophylaxis (e.g. tixagevimab/cilgavimab administration). A baseline blood sample will be collected before the initiation of treatment and will be sent to the central laboratory, where specific analyses evaluating vaccine-induced cellular and/or humoral immunity against COVID-19, VZV, diphtheria and tetanus will be performed.

COVID-19 cellular and humoral immunity will be evaluated in all patients at all available timepoints.

Humoral and cellular immunity for VZV will be evaluated for all patients at study entry. In the subgroup of patients with a detectable serologic response at study entry, humoral and cellular immunity will be also evaluated at all available later timepoints.

Humoral immunity for diphtheria and tetanus will be evaluated for all patients at study entry. In the subgroup of patients with a detectable serologic response at study entry, humoral immunity will be also evaluated at all available later timepoints.

T-cell immunological parameters will be evaluated at study entry and 12 months after EOI (or early withdrawal).

Prospective Biological Study to Evaluate the Persistence of COVID-19 Vaccine and Other Vaccines'-Induced Immune Responses in Follicular Lymphoma Patients Undergoing Frontline Induction Immuno-chemotherapy and Anti-CD20 Maintenance

Proportion of patients with laboratory parameters of vaccine-induced cellular immunity against SARS-CoV-2 (by ELISpot assay) at EOI (after induction immuno-chemotherapy) vs proportion at baseline

Proportion of patients with laboratory parameters of vaccine-induced cellular immunity against SARS-CoV-2 (by ELISpot assay) during anti-CD20 maintenance (+12 months after EOI) vs proportion at baseline

Proportion of patients with laboratory parameters of vaccine-induced humoral immunity against SARS-CoV-2 (by ELISA assay detecting anti-receptor binding domain \[RBD\] and anti-nucleocapsid \[N\] IgG antibodies) after standard induction immuno-chemotherapy (EOI) and during anti-CD20 maintenance (+12 months after EOI) vs proportion at baseline (excluding patients who received pre-exposure tixagevimab/cilgavimab or other monoclonal antibodies).

Proportion of patients with laboratory parameters of vaccine-induced humoral (by ELISA assay detecting anti-glycoprotein E IgG antibodies) and/or cellular immunity (by ELISpot assay) against VZV at EOI and during anti-CD20 maintenance (+12 months after EOI) vs proportion at first detection after vaccination (in the subgroup of patients with a detectable serologic response at study entry).

Proportion of patients with laboratory parameters of vaccine-induced humoral immunity against diphtheria and tetanus (by ELISA assay detecting diphtheria toxin-binding IgG and tetanus toxoid-binding IgG) at EOI and during anti-CD20 maintenance (+12 months after EOI) vs proportion at baseline (in the subgroup of patients with a detectable serologic response at study entry).

Incidence of COVID-19 infections and their severity in vaccinated patients undergoing induction immuno-chemotherapy and maintenance and correlation with the level of immunity as measured by humoral and/or cellular immune parameters at the time point before the event as well as with eventual tixagevimab/cilgavimab administration (or prophylaxis with other monoclonal antibodies) and with dominant SARS-CoV-2 variant/subvariant at the time of infection

Incidence of zoster infections and their severity in vaccinated patients undergoing induction immuno-chemotherapy and maintenance and correlation with the level of immunity as measured by humoral and/or cellular immune parameters at the time point before the event.

Description in the study population at study entry and at the latest timepoint of the percentage and absolute number of T lymphocytes populations and their subset distribution, expression of markers of activation and of functional exhaustion and immune checkpoints on T lymphocytes and T helper (Th) polarization of the CD4+ T-cell population by flow cytometry

Spots Global Cancer Trial Database for humoral immunity vs varicella zoster virus