Differential Antiviral IgG Titer Decay Rates after Frontline Chemoimmunotherapy in Patients with Aggressive B Cell Lymphoma
Authors: Chang Andres , Leal Alyssa , Churnetski Michael , Lai Lilin , Linderman Susanne , Ahmed Hasan , O'Leary Colin B , Antia Rustom , Dhodapkar Madhav V. , Suthar Mehul , Koff Jean L. , Cohen Jonathon B , Ahmed Rafi 
Published: December 2024

Introduction
Patients with B cell malignancies remain at high risk of morbidity and mortality from respiratory viruses like SARS-CoV-2. These patients often receive B cell-depleting agents in combination with chemotherapy as part of their cancer treatment, impairing their subsequent capacity to generate antibody responses to infection and vaccination. However, less is known about the effects of these aggressive treatments on already acquired humoral immunity in this population.
Objective
To determine the effect of frontline chemoimmunotherapy with anti-CD20 antibodies on established antibody titers against SARS-CoV-2, measles, and rubella over time in patients with newly diagnosed aggressive B cell non-Hodgkin lymphoma (aNHL).
Methods
Patients with a new diagnosis of aNHL were enrolled after informed consent. Serial blood samples were obtained before, during, and up to 1 year after treatment with regimens containing an anti-CD20 antibody + multiagent chemotherapy. IgG binding titers against the SARS-CoV-2 nucleocapsid (N) protein and the spike protein of several SARS-CoV-2 variants were measured with a multiplex assay. Live virus neutralization titers against SARS-CoV-2 variants over time were also measured. IgG titers against measles and rubella were measured by ELISA. Antibody decay half-lives were calculated using exponential model. Clinical information was abstracted from the electronic medical record and correlated with antibody responses.
Results
A total of 42 individuals were enrolled (33 with aNHL, 9 healthy donor controls). For the aNHL group, mean age was 59.7, 51.5% were male, and 39.4% non-white. Mean number of vaccine doses was 3 with a mean of 199 days between last vaccine and cycle 1 of lymphoma-directed therapy. All patients received rituximab as their anti-CD20 antibody and only 2 patients did not receive an anthracycline. Before treatment (baseline), 56.5% of aNHL patients did not show anti-N antibodies to indicate prior infection. Greater variability in IgG binding titers against wild-type (WT) spike protein and significantly lower neutralization titers were observed in aNHL at baseline vs controls (mean titer 1227 vs 1822 AU/mL, p&lt;0.05). Median binding titers against BA.5 and XBB.1.5 spike was 5.3- and 8.3-fold lower than WT, respectively (vs 4.0- and 7.2-fold in control, respectively).
Median anti-WT spike binding titers decreased by 2.5-, 3.4-, and 6.1-fold after 3-, 9- , and 12-months from initiation of chemoimmunotherapy, respectively while titers in controls decreased 1.1-fold over a similar period. After excluding 2 patients with very low anti-WT spike titers before aNHL treatment, the half-life for anti-WT spike was 192 days in aNHL patients vs 444 days in controls (p&lt;0.001). No statistically significant increase in anti-spike titers was seen in the 16 patients who received an additional SARS-CoV-2 vaccine within the first year of treatment initiation. Multivariable analyses for factors associated with more rapid decay will be presented.
Antibody titers vs SARS-CoV-2 are known to wane over time. Thus, to determine the effect of aNHL treatment on long-term humoral immunity, IgG titers against measles and rubella were measured, as these antibodies show remarkable stability over time in healthy individuals, and the likelihood of infection while on study was low. Baseline titers against measles and rubella did not differ significantly between controls and aNHL patients. Anti-measles and rubella titers showed &lt;2-fold decrease during the study period in aNHL patients and no decline in control.
Conclusion
In patients with newly diagnosed aNHL, preexisting antibody titers vs SARS-CoV-2, measles, and rubella, were largely preserved during lymphoma-directed treatment. However, an accelerated rate of decay was observed for anti-spike IgG during the first year after completion of aNHL therapy. Neutralization activity against newer SARS-CoV-2 variants was low throughout the study period. Our data highlight the need for new mechanisms to protect these immunocompromised patients against current and emerging SARS-CoV-2 strains.