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637 Humoral Response to mRNA Vaccines BNT162b2 and mRNA-1273 COVID-19 in Chronic Lymphocytic Leukemia Patients

Program: Oral and Poster Abstracts
Type: Oral
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological II
Hematology Disease Topics & Pathways:
Clinically Relevant
Monday, December 13, 2021: 10:30 AM

Cristina Bagacean, MD, PhD1,2*, Rémi Letestu3*, Chadi Al Nawakil4*, Ségolène Brichler5*, Vincent Lévy4*, Nanthara Sritharan4*, Alain Delmer6, Caroline Dartigeas, MD7*, Véronique Leblond8, Damien Roos-Weil8*, Marie C Béné9*, Aline Clavert10*, Driss Chaoui11*, Philippe Genet11*, Romain Guieze12*, Kamel Laribi, MD13*, Yamina Touileb13*, Bernard Drenou14*, Lise Willems15*, Cécile Tomowiak16*, Fatiha Merabet17*, Christian Puppink18*, Hugo Legendre19*, Xavier Troussard20, Stéphanie Malartre21*, Florence Cymbalista3* and Anne-Sophie Michallet21*

1Université Bretagne Occidentale, Inserm UMR1227, Brest, France
2Department of Hematology, CHU Brest, Brest, France
3Hematology Laboratory, Avicenne Hospital, APHP, Bobigny, France
4Department of Clinical Research, APHP, Hôpital Avicenne, Bobigny, France
5Department of Virology, APHP, Hôpital Avicenne, Bobigny, France
6Department of Hematology, CHU Reims, Reims, Cedex, France
7Department of Hematology, CHU Tours, Tours, France
8Department of Hematology, APHP, Hôpital de la Pitié Salpêtriere, Paris, France
9Laboratory of Hematology, CHU Nantes, Nantes, France
10Department of Hematology, CHU Angers, Angers, France
11Department of Hematology, CH Argenteuil, Argenteuil, France
12Department of Hematology, CHU Clermont Ferrand, Clermont Ferrand, France
13Department of Hematology, CH Le Mans, Le Mans, France
14Department of Hematology, CH Mulhouse, Mulhouse, France
15Department of Hematology, APHP, Hôpital Cochin, Paris, France
16Department of Hematology, CHU Poitiers, Poitiers, France
17Department of Hematology, CH Versailles, Le Chesnay, France
18Chronic Lymphocytic Leukemia Patients' Association (SILLC), Paris, France
19Department of Hematology, CHU Sud Réunion, Réunion, France
20Department of Hematology, CHU Caen, Caen, France
21Department of Hematology, Centre Léon Bérard, Lyon, France

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for an ongoing global pandemic. Phase III trials have demonstrated excellent efficacies of mRNA vaccines against SARS-CoV-2 in large population studies (Baden LR, NEJM, 2021; Polack FP, NEJM, 2020). Immunosuppressed individuals such as chronic lymphocytic leukemia (CLL) patients are at risk for a suboptimal response to 2 vaccine doses (Herishanu Y, Blood, 2021). The French National Authority for Health recommends the use of a third dose in immunosuppressed patients. However, seroconversion rate after the triple-dose vaccine is not yet known.

The objective of our study was to evaluate SARS-CoV-2 antibody responses after the first, second and third doses of the BNT162b2 and mRNA-1273 vaccines.

Data were collected from 17 French Innovative Leukemia Organization (FILO) investigating centers and the French CLL patients’ association (SILLC). SARS-CoV-2 IgG anti-Spike levels were measured at 4-6 weeks after each vaccine dose.

A total of 530 patients and 14 controls were included in the study. Vaccine response was evaluated post-dose 1 for 158 CLL patients, post-dose 2, for 506 patients and post-dose 3 for 66 patients. Peripheral blood lymphocyte subsets were studied post-dose 2 by flow cytometry in 80 CLL patients and 14 controls.

The median age of the patients was 71 years (range 37-93), 218 (40%) were treatment-naïve (TN), 136 (26%) had a prior CLL treatment and 176 (34%) were on therapy.

Post-dose 1, the global response rate was 27% (43/158). TN patients had a response rate of 34% (23/67), similar to those who had a prior CLL treatment (33%,12/36), and higher compared to on-therapy patients (15%, 8/55, P=0.02).

Post-dose 2, the global response rate was 52% (265/506). TN patients had the highest response rate of 72% (151/210) compared to previously treated patients, mostly by immunochemotherapy (60%, 78/130, P=0.02) and on-therapy patients (22%, 36/166, P<0.001) (Figure 1A). Among the 166 on-therapy patients, mostly receiving targeted agents, those receiving venetoclax monotherapy achieved a significantly higher response rate (52%, 12/23) than those treated with BTK inhibitors (BTKi) ibrutinib or acalabrutinib (22%, 23/104, P<0.001). Patients treated with venetoclax+anti-CD20 monoclonal antibodies (n=19) or venetoclax+BTKi (n=6) were all seronegative after the second dose of vaccine (Figure 1B). In multivariate analysis, the variables found to be significantly associated with seroconversion were age >65 years (OR 0.55, 95% CI 0.33-0.92, P=0.02), ongoing CLL treatment (OR 0.13, 95% CI 0.07-0.23, P<0.001) and gamma-globulins ≤6g/L (OR 0.41, 95% CI 0.19-0.88, P=0.03).

Flow cytometry results suggest a differential balance of the T CD4+ cell subpopulations in Binet stage A and in patients on targeted therapy compared to healthy controls.

Post-dose 2 seronegative patients were proposed a third dose and to date, 66 have been tested for the antibody response 4-6 weeks post-dose 3. The post-dose 3 response rate was 42% (28/66). TN patients and previously treated patients had a significantly higher response rate (57%, 16/28) compared to on-therapy patients (32%, 12/38, P=0.03). We further analyzed patients tested post-dose 2 with the Abbott Architect SARS-CoV-2 IgG anti-Spike assay (n=24). Those who achieved seroconversion after the third dose (n=10) had significantly higher titers post-dose 2 (median 12, IQR 3.0-40.8) compared to those who remained seronegative (n=14) (median 2.2, IQR 0.5-5.1, p<0.01), although both median values are considered below the threshold by the manufacturer.

An additional cohort of 40 CLL patients who presented a SARS-CoV-2 infection prior to vaccination participated to the study and was analyzed independently. All patients achieved seroconversion after infection and a single dose of vaccine, even though 30% (n=12) had an ongoing CLL treatment.

In conclusion, double-dose mRNA vaccination generated a humoral response in 52% of our CLL cohort and a third dose induced seroconversion in 42% of the patients who remained seronegative after the second dose. The major independent predictor of negative antibody response was ongoing treatment with BTKi. The strongest boost to immune response against the virus seems to be SARS-CoV-2 infection, as a substantial increase in anti-Spike antibodies was observed in all CLL patients with prior infection, after a single dose vaccination.

Disclosures: Letestu: Janssen: Research Funding, Speakers Bureau; Roche: Speakers Bureau; AbbVie: Research Funding, Speakers Bureau. Dartigeas: Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress. Laribi: Astellas Phama, Inc.: Other: Personal Fees; BeiGene: Other: Personal Fees; AstraZeneca: Other: Personal Fees; IQONE: Other: Personal Fees; AbbVie: Other: Personal Fees, Research Funding; Takeda: Other: Personal Fees, Research Funding; Novartis: Other: Personal Fees, Research Funding; Le Mans Hospital: Research Funding; Jansen: Research Funding. Cymbalista: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Lilly-LOXO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTRA ZENECA: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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