Booster and Btki Interruption Improve Response to Sars-Cov-2 Vaccine in Patients with CLL

Abstract

Introduction: Patients with chronic lymphocytic leukemia (CLL) have inadequate responses to vaccination, including SARS-CoV-2 mRNA vaccines. Treatment with anti-B cell therapies, such as anti-CD20 monoclonal antibodies (mAb) and Bruton's tyrosine kinase inhibitors (BTKi), further suppress the antibody (Ab) response to vaccines. We investigated whether BTKi interruption around the time of a booster injection could enhance vaccine response. Methods: A single-institution retrospective cohort study of patients with CLL was conducted at the National Institutes of Health from 2020-2022. Treatment naïve (TN) patients as well as those receiving treatment with a BTKi or venetoclax (VEN) were included. Patients who received IVIG, anti-SARS-CoV-2 mAb, or convalescent plasma within three months of vaccination were excluded. Anti-spike Ab titers were measured after completion of the primary series (2 doses of Pfizer-BioNTech/Moderna vaccines or 1 dose of Janssen vaccine) and the first booster. Ab titers were measured using the Roche Elecsys® immunoassay and categorized as no response (<0.8 U/mL), weak response (0.8-50 U/mL), or strong response (>50 U/mL). Ultra-deep TCRβ sequencing (Adaptive Biotechnologies) was performed before and after the primary series to identify and track spike-specific clonotypes. A T-cell vaccine response was defined as significant expansion of ≥1 spike-specific clonotype. Results: We studied Ab response in 86 patients (54 on BTKi, 14 on VEN, and 18 TN). The median age was 68.0 (range 66-69) and 97.7% of patients received mRNA vaccine. After the primary series, seroconversion (anti-spike Ab ≥0.8 U/mL) was detected in 53% of BTKi-treated patients, 57% of patients on single-agent VEN, and 67% of TN patients. After booster, anti-spike Ab was detected in 87% of BTKi-treated patients, 50% of patients on single-agent VEN, and 83% of TN patients. No patients who received anti-CD20 mAb within 12 months of vaccination (in combination with VEN) responded to the primary series or booster. All patients with seroconversion post primary series also had detectable anti-spike Ab post booster. Anti-spike Ab increased after booster in 90% of patients who responded to the primary series. Of the patients who did not respond to the primary series, 57% seroconverted post booster. Seroconversion was associated with higher serum IgM after the primary series (median 37g/L (IQR 24-63) vs. 26g/L (IQR 9-37), p=0.02) as well as higher serum IgG (median 848g/L (IQR 620-920) vs. 611g/L (IQR 395-782), p=0.02). Patients with detectable anti-spike Ab after booster had higher IgM (median 35g/L (IQR 22-65) vs. 9g/L (IQR 5-437), p=0.04) as well as higher IgA (median 88g/L (IQR 65-112) vs. 41g/L (IQR14-84), p=0.01). Of patients on BTKi, 21/40 (52%) had seroconversion after the primary series, albeit with mostly weak responses (62%). After booster, 34/40 (85%) had detectable anti-spike Ab. Of BTKi-treated patients with a weak response to the primary series, 10/13 (77%) mounted a strong response to booster. Twelve patients interrupted BTKi for a median of 21 days (range 8-22) around the time of booster. Patients who interrupted BTKi had higher anti-spike Ab (median 7,149 U/mL, IQR 1109-19900) than those who continued therapy (median 1,198 U/mL, IQR 2.05-2985, p=0.02). Three patients experienced lymph node pain and swelling during BTKi interruption and resumed BTKi earlier than intended. Longitudinal analysis of Ab titers post-booster among BTKi patients demonstrated a decline in anti-spike Ab of 0.45% per day, which denotes a 50% decline in 111 days. No difference in the rate of decline was observed between patients who interrupted BTKi and those who continued BTKi. T-cell response to the primary series was observed in 7/15 (47%) of BTKi-treated patients. No significant difference in T-cell response was found between patients on ibrutinib and those on acalabrutinib (p=0.6). T-cell response after the primary series was not predictive of Ab response post-booster (p=0.3). Conclusion: Increasing anti-spike Ab with subsequent vaccinations support additional boosters in patients with CLL. BTKi interruption at the time of vaccination results in a more robust Ab response.