Booster and BTKi Interruption Improve Response to SARS-CoV-2 Vaccine in Patients With CLL

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 response to vaccines. Here, we aimed to evaluate clinical and laboratory parameters associated with vaccine response and the effect of BTKi interruption around the time of booster. Methods: A single-institution cohort study of patients with CLL was conducted at the National Institutes of Health. 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 3 months of vaccination were excluded. Anti-spike antibody titers were measured after completion of the primary series (two doses of Pfizer-BioNTech/Moderna vaccines or one dose of Janssen vaccine) and the first booster. Results: There were 86 patients in total (54 BTKi, 14 VEN, and 18 TN). The median age was 68.0, and 97.7% of patients received mRNA vaccine. After the primary series, seroconversion (anti-spike >0.8 U/mL) was detected in 53% of BTKi-treated patients, 43% of patients on single-agent VEN, and 67% of TN patients. After booster, seroconversion was detected in 87% of BTKi-treated patients, 50% of patients on single-agent VEN, and 83% of TN patients. Anti-spike antibodies increased after booster in 90% of patients who responded to the primary series. No patients who received anti-CD20 mAb within 12 months of vaccination (in combination with VEN) responded to the primary series or booster. Seroconversion was associated with higher serum IgM (P=0.023 after the primary series and P=0.039 after booster). Twelve patients interrupted BTKi for a median of 19 days (range 8–23) around the time of booster. Patients who interrupted BTKi had higher anti-spike antibodies (median 7,148 U/mL) than those who continued therapy (median 1,198 U/mL, P=0.018). Of the 12 patients who interrupted BTKi, 3 experienced lymph node pain and swelling and resumed BTKi earlier than intended. Conclusions: Increasing anti-spike antibodies with subsequent vaccinations support additional boosters in this population. BTKi interruption at the time of vaccination results in a more robust antibody response.

Effect of Bruton tyrosine kinase inhibitor on efficacy of adjuvanted recombinant hepatitis B and zoster vaccines.

Vaccinations are effective in preventing infections; however, it is unknown if patients with chronic lymphocytic leukemia (CLL) who are treatment naïve (TN) or receiving Bruton tyrosine kinase inhibitors (BTKi's) respond to novel adjuvanted vaccines. Understanding the effect of BTKi's on humoral immunity is timely because BTKi's are widely used and vaccination against coronavirus disease 2019 is urgently needed. In 2 open-label, single-arm clinical trials, we measured the effect of BTKi's on de novo immune response against recombinant hepatitis B vaccine (HepB-CpG) and recall response against recombinant zoster vaccine (RZV) in CLL patients who were TN or on BTKi. The primary end point was serologic response to HepB-CpG (anti-hepatitis B surface antibodies ≥10 mIU/mL) and RZV (≥fourfold increase in anti-glycoprotein E). The response rate to HepB-CpG was lower in patients on BTKi (3.8%; 95% confidence interval [CI], 0.7-18.9) than patients who were TN (28.1%; 95% CI, 15.6-45.4; P = .017). In contrast, the response rate to RZV did not differ significantly between the BTKi (41.5%; 95% CI, 27.8-56.6) and TN cohorts (59.1%; 95% CI, 38.7-76.7; P = .2). BTKi's were associated with a decreased de novo immune response following HepB-CpG, whereas recall immune response following RZV was not significantly affected by BTKi therapy. These trials were registered at www.clinicaltrials.gov as #NCT03685708 (Hep-CpG) and #NCT03702231 (RZV).

Outcomes of COVID-19 in patients with CLL: a multicenter international experience.

Given advanced age, comorbidities, and immune dysfunction, chronic lymphocytic leukemia (CLL) patients may be at particularly high risk of infection and poor outcomes related to coronavirus disease 2019 (COVID-19). Robust analysis of outcomes for CLL patients, particularly examining effects of baseline characteristics and CLL-directed therapy, is critical to optimally manage CLL patients through this evolving pandemic. CLL patients diagnosed with symptomatic COVID-19 across 43 international centers (n = 198) were included. Hospital admission occurred in 90%. Median age at COVID-19 diagnosis was 70.5 years. Median Cumulative Illness Rating Scale score was 8 (range, 4-32). Thirty-nine percent were treatment naive ("watch and wait"), while 61% had received ≥1 CLL-directed therapy (median, 2; range, 1-8). Ninety patients (45%) were receiving active CLL therapy at COVID-19 diagnosis, most commonly Bruton tyrosine kinase inhibitors (BTKi's; n = 68/90 [76%]). At a median follow-up of 16 days, the overall case fatality rate was 33%, though 25% remain admitted. Watch-and-wait and treated cohorts had similar rates of admission (89% vs 90%), intensive care unit admission (35% vs 36%), intubation (33% vs 25%), and mortality (37% vs 32%). CLL-directed treatment with BTKi's at COVID-19 diagnosis did not impact survival (case fatality rate, 34% vs 35%), though the BTKi was held during the COVID-19 course for most patients. These data suggest that the subgroup of CLL patients admitted with COVID-19, regardless of disease phase or treatment status, are at high risk of death. Future epidemiologic studies are needed to assess severe acute respiratory syndrome coronavirus 2 infection risk, these data should be validated independently, and randomized studies of BTKi's in COVID-19 are needed to provide definitive evidence of benefit.