BTK inhibitors impair humoral and cellular responses to recombinant zoster vaccine in CLL

Abstract

Vaccinations effectively prevent infections; however, patients with chronic lymphocytic leukemia (CLL) have reduced antibody responses following vaccinations. Combined humoral and cellular immune responses to novel adjuvanted vaccines are not well characterized in CLL. In an open-label, single-arm clinical trial, we measured the humoral and cellular immunogenicity of the recombinant zoster vaccine (RZV) in CLL patients who were treatment naïve (TN) or receiving Bruton tyrosine kinase inhibitor (BTKi) therapy. The primary endpoint was antibody response to RZV (≥4-fold increase in anti glycoprotein E [gE]). Cellular response of gE-specific CD4+ T cells was assessed by flow cytometry for upregulation of ≥ 2 effector molecules. The antibody response rate was significantly higher in the TN cohort (76.8% [95% confidence interval 65.7-87.8]) compared to patients receiving a BTKi (40.0% [26.4-53.6]; P = .0002). The cellular response rate was also significantly higher in the TN cohort (70.0% [57.3-82.7]) compared to the BTKi group (41.3% [27.1-55.5]; P = .0072). A concordant positive humoral and cellular immune response was observed in 69.1% [56.9-81.3] of subjects with a humoral response, whereas 39.0% [24.1-54.0] of subjects without a humoral response attained a cellular immune response (P = .0033). Antibody titers and T cell responses were not correlated with age, absolute B and T cell counts, or serum immunoglobulin levels (all P > 0.05). RZV induced both humoral and cellular immune responses in treated and untreated CLL patients, albeit with lower response rates in patients on BTKi therapy compared to TN patients. Registered at www.clinicaltrials.gov as #NCT03702231.

Efficacy of COVID-19 Booster Vaccines in Patients with Hematologic Malignancies: Experiences in a Real-World Scenario

“…Along this line, we observed a low seroconversion rate of 43% and a significant 96% decrease of antibody titer levels in B-cell lymphoma patients treated with BTKi. The negative impact of the latter on serologic response might be attributable to the BTKi-mediated block of the B-cell receptor signaling and was comparable to the findings of others [ 18 , 19 , 26 , 50 , 51 ]. The anti-CD38 therapy results indicated a depletion of antibody-producing plasma cells and was associated with a weak or non-existent response to COVID-19 vaccines in previous trials [ 21 , 48 , 52 ].…”

Impaired serological response to COVID‐19 vaccination following anticancer therapy: A systematic review and meta‐analysis

“…34 BTKi therapy compared with treatment naïve patients. 38 BCL2i, like venetoclax, was found to be associated with decreased seroconversion rate, while the response rates were lower when combined with anti-CD20 antibodies. 22 In CLL patients with venetoclax monotherapy, some developed a positive response but with low Ab titers.…”

“… 27 , 37 A recent study evaluated the humoral and cellular response of the recombinant zoster vaccine in CLL patients, which indicated that both immune responses were attenuated in those on BTKi therapy compared with treatment naïve patients. 38 BCL2i, like venetoclax, was found to be associated with decreased seroconversion rate, while the response rates were lower when combined with anti‐CD20 antibodies. 22 In CLL patients with venetoclax monotherapy, some developed a positive response but with low Ab titers.…”

“…Previous evidence illustrated that BTKi therapy impaired humoral response to influenza and hepatitis vaccines among CLL patients 27,37 . A recent study evaluated the humoral and cellular response of the recombinant zoster vaccine in CLL patients, which indicated that both immune responses were attenuated in those on BTKi therapy compared with treatment naïve patients 38 . BCL2i, like venetoclax, was found to be associated with decreased seroconversion rate, while the response rates were lower when combined with anti‐CD20 antibodies 22 .…”

Vaccinations in hematological patients in the era of target therapies: Lesson learnt from SARS-CoV-2

“…2021 [ 26 ] CLL SARS-CoV2 vaccine 14 21% Herishanu Y, Blood 2021 [ 33 ] CLL SARS-CoV2 vaccine 50 16% 1) Age ≥ 65 years 2) Active treatment 3) Baselinge IgG levels <550 mg/dL 4) Baseline IgM levels <40 mg/dL 5) Male sex Zent C, Leukemia 2021 [ 61 ] WM + CLL rVZV vaccine 32 75% 1) Longer duration of pre-vaccination BTKi treatment Pleyer C, Blood 2021 [ 62 ] CLL HBV vaccine 26 4% Pleyer C, Blood 2021 [ 62 ] CLL rVZV revaccine 41 41% Benjamini O, Haematologica 2022 [ 21 ] CLL SARS-CoV2 vaccina 106 23% 1) Active treatment Shen Y, Br J Haematol 2022 [ 35 ] CLL SARS-CoV2 vaccine 21 15% 1) Lower baseline IgM serum levels 2) Active therapy Bacova B, Clin Exp Med. 2022 [ 28 ] B-NHL+ CLL SARS-CoV2 vaccine 16 19% Haggenburg S, Blood Adv 2022 [ 27 ] CLL SARS-CoV2 vaccine 38 27% 1) Older age 2) Low baseline IgG4 serum levels 3) Low baseline NK and B-cells counts 4) Use of rituximab, venetoclax and CD-19 directed CAR-T cells Diamantopoulos P, Ther Adv Hematol 2022[ 54 ] CLL SARS-CoV2 vaccine 7 14% Pleyer, Blood Adv 2022 [ 63 ] CLL rVZV vaccine 50 40...…”