Multiple COVID-19 vaccine doses in CLL and MBL improve immune responses with progressive and high seroconversion

Abstract

Chronic lymphocytic Leukemia (CLL) and Monoclonal B-Lymphocytosis (MBL) patients have impaired response to COVID-19 vaccination. A total 258 patients (215 CLL and 43 MBL) had anti-spike levels evaluable for statistical analysis. The overall seroconversion rate for CLL was 94.2% (anti-spike ³50AU/mL Abbott Diagnostics) and for MBL 100%. After 3 doses (post-D3) in 167 CLL patients, 73.7% were seropositive, 17.4% had anti-spike levels 50-999AU/mL, and 56.3% ≥1000AU/mL with a median rise from 144.6AU/mL to 1800.7AU/mL. Of patients seronegative post-D2, 39.7% seroconverted post-D3. For those who then remained seronegative after their prior dose, seroconversion occurred in 40.6% post-D4, 46.2% post-D5, 16.7% post-D6, and 0% after D7 or D8. Following seroconversion, most had a progressive increment in anti-spike antibody level: in CLL after the latest dose, 70.2% achieved anti-spike level ≥1,000AU/mL, 48.1% ≥5,000AU/mL, and 30.3% ≥10,000AU/mL. Neutralization was associated with higher anti-spike levels, more vaccines and earlier COVID variants; 65.3% detected neutralizing antibody against early clade D614G, 52.0% against Delta, and 36.5% against Omicron. COVID-specific T-cell production of IFN-γ occurred in 73.9% and IL-2 in 60.9% of 23 tested, and more consistently with higher anti-spike levels. After multiple vaccine doses, by multivariate analysis, IgM ≥0.53g/L (OR=2.90, p=0.0314), IgG3 ≥0.22g/L (OR=3.26, p=0.0057), and lack of current CLL therapy (OR=2.48, p=0.0574) were independent predictors of positive serological responses. Strong neutralization and T-cell responses had high concordance with high anti-spike levels. Multiple sequential COVID-19 vaccination significantly increased seroconversion and anti-spike antibody levels in CLL and MBL.

COVID‐19 vaccination: Evaluation of humoral and cellular immunity after the booster dose in chronic lymphocytic leukemia patients

“…[3][4][5]7,8 Notably, this skewed distribution turned out less evident after the 3rd booster dose, yielding p values of 0.016 and 0.051, respectively (Figure 1B), suggesting a progressive capability of repeated boosters to overcome at least in part the negative impact of unfavorable CLL features. 8,10 Finally, 9/40 patients of the present cohort developed moderate COVID-19 within 6 months from the 3rd booster dose (Figure 1A); all cases but one had developed an insufficient humoral and cellular response to vaccination, and 8/9 were on therapy with ibrutinib as R/R cases (7/9) or in 1st line (1/9). 1,2 This updating of our previous report 7 confirmed the impairment of efficient humoral and/or cellular responses to SARS-CoV-2 S protein vaccination in patients affected by CLL, especially if under treatment and/or in an advanced/more aggressive stage.…”

Prospective comprehensive profiling of immune responses to COVID‐19 vaccination in patients on zanubrutinib therapy

“…While on zanubrutinib, the proportion of patients who developed CD4 + and CD8 + T‐cell responses was 7%–18% higher than the proportion of patients who developed RBD antibody responses. Response rates of 70% achieved with two doses and 80%–90% with three doses were comparable to rates in CLL patients not on active therapy and higher than patients with prior lines of therapy or on ibrutinib [2, 12, 13]. Higher BTK selectivity and lower off‐target activity of zanubrutinib on other kinases, such as interleukin‐2‐inducible T‐cell kinase compared to ibrutinib may contribute to improved T‐cell responses [14].…”

An updated perspective on immunoglobulin replacement in chronic lymphocytic leukaemia in the era of targeted therapies

“…Generally, the primary immune response to a novel antigen is suppressed in persons with CLL compared to the brisk anamnestic immune response in healthy persons ( 30 ). A recent prospective non-interventional trial suggests that multiple doses of a COVID19 vaccine can result in high rates of seroconversion in CLL (94.2%) and MBL (100%) ( 31 ). Whether the repeated immune stimulus or a post-treatment recovering immune status is driving the response (or if this is sustained) is unclear and needs further investigation.…”