A Third Anti-Sars-Cov2 mRNA Dose Does Not Overcome the Pejorative Impact of Anti-CD20 Therapy and/or Low Immunoglobulin Level in CLL/Lymphoma Patients
Authors: Chbat Maureen , Kohn Milena , Merabet Fatiha , Roupie Anne-Laure , Lombion Naelle , Guemriche Amina , Marque-Juillet Stéphanie , Raggueneau Victoria , Osman Jennifer , Spentchian Marc , Delord Marc , Rigaudeau Sophie , Besson Caroline 
Published: November 2021

Abstract
Introduction: Patients with lymphoma and chronic lymphocytic leukemia (CLL) share immune-deficiencies due to the biological features of these diseases per se and to their treatments. They are at risk to develop severe and/or prolonged forms of Covid-19. The efficacy of vaccination against COVID in lymphoma/CLL patients also raises specific concerns: Antibody response to mRNA COVID-19 vaccine was shown to be negatively affected by CLL stage and its treatments, especially in case of previous administration of anti-CD20 antibodies (Herishanu et al). Therefore, the addition of a third dose of vaccine in immunosuppressed patients is currently recommended in France.
Methods: To analyse the determinants of the antibody response after anti-SARS-Cov2 mRNA vaccines (Pfizer or Moderna), we conducted a retrospective monocentric study among adults with a past or current lymphoma/CLL who underwent serology 2 weeks or more after 2 or 3 previous injections. The decision of a third dose was at the discretion of each physician. Data were extracted from the patients' medical charts on their demographics, lymphoma history and detailed treatments, vaccinations and biological parameters (immunoglobulin (Ig) G dosage, lymphocytic, B-cell and T-cell counts) and serology (Elecsys ® Anti-SARS-CoV-2 S). Statistical tests were two-tailed and p-values &lt; 0.05 were considered significant. Multivariable analysis was conducted using independent variables having univariate significance below 0.1.
This study was conducted in accordance with the Declaration of Helsinki, and approved by the ethics committee of our institution.
Results: Ninety-one patients with non-Hodgkin's lymphomas (NHL) (n=48), CLL (32) or Hodgkin's lymphoma (11) were enrolled. With a median interval since last dose of 47 days (range 15-125), 48 patients (53%) had a negative serology (Table). Gender and age were not associated with antibody response. The proportion of seronegativity was 57% among patients with B-cell NHL, and 41% among those with CLL. Among the biological variables reflecting immune deficiency, lymphocytopenia (&lt;1.5G/L), low B-cell counts (&lt;0.2G/L) and IgG levels (&lt;6g/L) were significantly associated with a higher risk of seronegativity with odds-ratios (OR, [95% confidence interval]) of 5.1 [1.8-15.3], p&lt;7x10 -4 , 15.0 [3.0-147.9], p&lt;7x10 -5, and 15.3 [3.7-93.0], p&lt;9x10 ⁻6 respectively).
Patients under watch and wait attitude and those who did not have a lymphoma/CLL treatment since at least 12 months before vaccination had a much lower risk of negative serology (OR: 0.08 [&lt;0.01 ; 0.4], p&lt; 2.10 -4). Among lymphoma/CLL therapies, chemotherapy overall or targeted therapy with BTK inhibitors or Venetoclax were not significantly associated with a lower risk of negative serology. In contrast, the administration of anti-CD20 therapy during the year before first dose of vaccine was associated with a higher risk of negative serology (OR: 4.5 [1.7; 12.1], p&lt;8.10 -4). Of note, this treatment was also significantly associated with both lymphocytopenia and low B-cell counts. There was no association between the number of vaccine doses and the risk of negative serology, 59% of the patients who received 3 doses remained seronegative.A multivariable analysis associating IgG level and treatment history showed that negative serology is significantly associated with a low level of IgG (OR: 25.74 [5.58; 201.14], p &lt; 10 -3) and anti-CD20 treatment (OR: 28.70 [4.14, 382.60], p = 3x10 -3).
Conclusion: Overall, previous anti-CD20 therapy and low IgG levels are the main independent factors associated with a lack of serological response after anti-SARS-Cov2 mRNA vaccine. Administration of a third vaccine does not overcome their pejorative impact. This should contribute to the elaboration of guidelines for the management of lymphoma/CLL patients during the Covid-19 era. In particular, in all non-critical clinical situation, SARS-CoV-2 vaccination should be proposed before the onset of lymphoma/CLL therapy. Meanwhile, individuals with CLL/lymphoma should receive the Covid-19 vaccine, be informed that they are unlikely to be protected and continue social distancing and adhere to other proven mitigation strategies. Systematic vaccination of their proxies and hospital workers should also benefit directly to patients.
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Disclosures
Rigaudeau: Takeda: Membership on an entity's Board of Directors or advisory committees.