Chronic Lymphocytic Leukemia in the SARS-CoV-2 Pandemic.

PURPOSE OF REVIEW: Chronic lymphocytic leukemia (CLL) is the most frequent lymphoproliferative disease in the elderly of the western world. Immune defective responses and treatment can worsen the immune system's competence of CLL patients. Consequently, they may present a higher incidence of recurrent severe infections, second malignancies, and reduced efficacy of vaccines. The outbreak of COVID-19 is an ongoing pandemic, and patients with comorbidities experience more severe forms of the disease. Hematological malignancies are associated with higher case fatality rates (CFRs) than other cancers. Knowledge about COVID-19 incidence, clinical course, and immune response to the infection and vaccination in CLL may contribute to design strategies that improve the outcomes of patients in the future. RECENT FINDINGS: The prevalence of SARS-CoV-2 positivity in CLL is not significantly higher than seen in the general population. CFRs for CLL patients are 16.5-fold more elevated than the median reported worldwide and even higher in older patients, those who require hospitalization have significant comorbidities or need oxygen therapy. CLL status decreases the anti-SARS-CoV-2 positivity after infection or vaccination by around 40%, and the spike-specific antibody titers are 74-fold lower than healthy age-matched controls. The response rate to COVID-19 vaccines is even worse in patients with active CLL-directed therapies like BTKi, BCL-2 antagonists, or anti-CD20 monoclonal antibodies. CLL patients are at a greater risk of death from COVID-19. Inherent immunosuppression of CLL and immune deficiencies caused by treatment significantly decrease the ability to produce natural or vaccine-induced anti-SARS-CoV-2 immune responses.

Efficacy of a third BNT162b2 mRNA COVID-19 vaccine dose in patients with CLL who failed standard 2-dose vaccination.

Patients with chronic lymphocytic leukemia (CLL) have an impaired antibody response to coronavirus disease 2019 (COVID-19) vaccination. Here, we evaluated the antibody response to a third BNT162b2 mRNA vaccine in patients with CLL/small lymphocytic lymphoma (SLL) who failed to achieve a humoral response after standard 2-dose vaccination regimen. Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies were measured 3 weeks after administration of the third dose. In 172 patients with CLL, the antibody response rate was 23.8%. Response rate among actively treated patients (12.0%; n = 12/100) was lower compared with treatment-naïve patients (40.0%; n = 16/40; OR = 4.9, 95% CI 1.9-12.9; P < .001) and patients off-therapy (40.6%; n = 13/32; OR = 5.0, 95% CI 1.8-14.1; P < .001), (P < .001). In patients actively treated with Bruton's tyrosine kinase (BTK) inhibitors or venetoclax ± anti-CD20 antibody, response rates were extremely low (15.3%, n = 9/59, and 7.7%, n = 3/39, respectively). Only 1 of the 28 patients (3.6%) treated with anti-CD20 antibodies <12 months prior to vaccination responded. In a multivariate analysis, the independent variables that were associated with response included lack of active therapy (OR = 5.6, 95% CI 2.3-13.8; P < .001) and serum immunoglobulin A levels ≥80 mg/dL (OR = 5.8, 95% CI 2.1-15.9; P < .001). In patients with CLL/SLL who failed to achieve a humoral response after standard 2-dose BNT162b2 mRNA vaccination regimen, close to a quarter responded to the third dose of vaccine. The antibody response rates were lower during active treatment and in patients with a recent exposure (<12 months prior to vaccination) to anti-CD20 therapy. This trial was registered at www.clinicaltrials.gov as #NCT04862806.

Reasons and consequences of COVID-19 vaccine failure in patients with chronic lymphocytic leukemia.

People with hematologic malignancies are at a high risk of morbidity and mortality from COVID-19. The response to vaccination is highly limited in patients with chronic lymphocytic leukemia. Less than half of the patients develop antibody response, suggesting that they remain at risk of SARS-CoV-2 infection even after the vaccination. Reasons for inadequate response to COVID-19 vaccination in chronic lymphocytic leukemia are multifactorial and attributed to disease-related immune dysregulation and patient- and therapy-related factors. The negative predictors of response to vaccination include hypogammaglobulinemia, advanced age, current active treatment, and past treatment anti-CD20 monoclonal antibodies. Despite using booster doses and heterologous immunization to improve humoral and cellular immunity, some patients with chronic lymphocytic leukemia will fail to respond. Active treatment at the time of vaccination and a recent history of anti-CD20 monoclonal antibodies use are the strongest predictors of the non-response. Current data support informing patients with chronic lymphocytic leukemia and other hematologic malignancies about the risk of infection regardless of vaccination. These individuals and members of their households should continue extreme preventive actions despite relaxed local regulations. Other emerging non-vaccine preventive strategies include passive and post-exposure prevention with monoclonal antibodies.

Covid-19 in patients with chronic lymphocytic leukemia: clinical outcome and B- and T-cell immunity during 13 months in consecutive patients.

We studied clinical and immunological outcome of Covid-19 in consecutive CLL patients from a well-defined area during month 1-13 of the pandemic. Sixty patients (median age 71 y, range 43-97) were identified. Median CIRS was eight (4-20). Patients had indolent CLL (n = 38), had completed (n = 12) or ongoing therapy (n = 10). Forty-six patients (77%) were hospitalized due to severe Covid-19 and 11 were admitted to ICU. Severe Covid-19 was equally distributed across subgroups irrespective of age, gender, BMI, CLL status except CIRS (p < 0.05). Fourteen patients (23%) died; age ≥75 y was the only significant risk factor (p < 0.05, multivariate analysis with limited power). Comparing month 1-6 vs 7-13 of the pandemic, deaths were numerically reduced from 32% to 18%, ICU admission from 37% to 15% whereas hospitalizations remained frequent (86% vs 71%). Seroconversion occurred in 33/40 patients (82%) and anti-SARS-CoV-2 antibodies were detectable at six and 12 months in 17/22 and 8/11 patients, respectively. Most (13/17) had neutralizing antibodies and 19/28 had antibodies in saliva. SARS-CoV-2-specific T-cells (ELISpot) were detected in 14/17 patients. Covid-19 continued to result in high admission even among consecutive and young early- stage CLL patients. A robust and durable B and/or T cell immunity was observed in most convalescents.

Serological SARS-CoV-2 antibody response, potential predictive markers and safety of BNT162b2 mRNA COVID-19 vaccine in haematological and oncological patients.

Haemato-oncological patients are at risk in case of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Currently, vaccination is the best-evaluated preventive strategy. In the present study, we aimed to assess serological response, predictive markers, and safety of BNT162b2 in haemato-oncological patients. A total of 259 haemato-oncological patients were vaccinated with two 30 µg doses of BNT162b2 administered 21 days apart. Serological response was assessed by ELECSYS® Anti-SARS-CoV-2-S immunoassay before vaccination, and at 3 and 7 weeks after the first dose (T1, T2). Safety assessment was performed. At T2 spike protein receptor binding domain (S/RBD) antibodies were detected in 71·4% of haematological and in 94·5% of oncological patients (P < 0·001). Haematological patients receiving systemic treatment had a 14·2-fold increased risk of non-responding (95% confidence interval 3·2-63·3, P = 0·001). Subgroups of patients with lymphoma or chronic lymphocytic leukaemia were at highest risk of serological non-response. Low immunoglobulin G (IgG) level, lymphocyte- and natural killer (NK)-cell counts were significantly associated with poor serological response (P < 0·05). Vaccination was well tolerated with only 2·7% of patients reporting severe side-effects. Patients with side-effects developed a higher S/RBD-antibody titre compared to patients without side-effects (P = 0·038). Haematological patients under treatment were at highest risk of serological non-response. Low lymphocytes, NK cells and IgG levels were found to be associated with serological non-response. Serological response in oncological patients was encouraging. The use of BNT162b2 is safe in haemato-oncological patients.

Antibody responses after first and second Covid-19 vaccination in patients with chronic lymphocytic leukaemia.

B-cell chronic lymphocytic leukaemia (CLL) is associated with immunosuppression and patients are at increased clinical risk following SARS-CoV-2 infection. Covid-19 vaccines offer the potential for protection against severe infection but relatively little is known regarding the profile of the antibody response following first or second vaccination. We studied spike-specific antibody responses following first and/or second Covid-19 vaccination in 299 patients with CLL compared with healthy donors. 286 patients underwent extended interval (10-12 week) vaccination. 154 patients received the BNT162b2 mRNA vaccine and 145 patients received ChAdOx1. Blood samples were taken either by venepuncture or as dried blood spots on filter paper. Spike-specific antibody responses were detectable in 34% of patients with CLL after one vaccine (n = 267) compared to 94% in healthy donors with antibody titres 104-fold lower in the patient group. Antibody responses increased to 75% after second vaccine (n = 55), compared to 100% in healthy donors, although titres remained lower. Multivariate analysis showed that current treatment with BTK inhibitors or IgA deficiency were independently associated with failure to generate an antibody response after the second vaccine. This work supports the need for optimisation of vaccination strategy in patients with CLL including the potential utility of booster vaccines.

BNT162b2 COVID-19 vaccine is significantly less effective in patients with hematologic malignancies.

Patients with hematologic malignancies have an increased risk of severe COVID-19 infection. Vaccination against COVID-19 is especially important in these patients, but whether they develop an immune response following vaccination is unknown. We studied serologic responses to the BNT162b2 vaccine in this population. A lower proportion of patients were seropositive following vaccination (75%) than in a comparison group (99%; p < 0.001), and median (interquartile range [IQR]) antibody titers in patients were lower (90 [12.4-185.5] and 173 [133-232] AU/ml, respectively; p < 0.001). Older age, higher lactate dehydrogenase, and number of treatment lines correlated with lower seropositivity likelihood and antibody titers, while absolute lymphocyte count, globulin level, and time from last treatment to vaccination correlated with higher seropositivity likelihood and antibody titers. Chronic lymphocytic leukemia patients had the lowest seropositivity rate followed by indolent lymphoma. Patients recently treated with chemo-immunotherapy, anti-CD20 antibodies, BCL2, BTK or JAK2 inhibitors had significantly less seropositive responses and lower median (IQR) antibody titers (29%, 1.9 [1.9-12] AU/ml; 0%, 1.9 [1.9-1.9] AU/ml; 25%, 1.9 [1.9-25] AU/ml; 40%, 1.9 [1.9-92.8] AU/ml; and 42%, 10.9 [5.7-66.4] AU/ml, respectively; p < 0.001). Serological response to BNT162b2 vaccine in patients with hematologic malignancies is considerably impaired, and they could remain at risk for severe COVID-19 infection and death.

Chronic Lymphocytic Leukemia-Induced Humoral Immunosuppression: A Systematic Review.

Secondary immunodeficiency is observed in all patients with chronic lymphocytic leukemia (CLL) in varying degrees. The aim of the study was to review the available literature data on patients with CLL, with particular regard to the pathogenesis of the disease and the impact of humoral immunity deficiency on the clinical and therapeutic approach. A systematic literature review was carried out by two independent authors who searched PubMed databases for studies published up to January 2020. Additionally, Google Scholar was used to evaluate search results and support manual research. The search resulted in 240 articles eligible for analysis. After all criteria and filters were applied, 22 studies were finally applied to the analysis. The data analysis showed that the clinical heterogeneity of CLL patients correlates with the diversity of molecular abnormalities determining the clinical picture of the disease, the analysis of which enables setting therapeutic targets. Additionally, in improving the therapeutic method, it is worth introducing supportive therapies with the use of vaccines, antibiotics and/or immunoglobins. Moreover, humoral immunodeficiency in CLL has a strong influence on the risk of infection in patients for whom infections are a major cause of morbidity and mortality.

Immune Dysfunction in Patients with Chronic Lymphocytic Leukemia and Challenges during COVID-19 Pandemic.

The novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) has been first described in December 2019 in Wuhan, China, and has led to a worldwide pandemic ever since. Initial clinical data imply that cancer patients are particularly at risk for a severe course of SARS-CoV-2. In patients with chronic lymphocytic leukemia (CLL), infections are a main contributor to morbidity and mortality driven by an impaired immune system. Treatment initiation is likely to induce immune modulation that further increases the risk for severe infections. This article aims to give an overview on pathogenesis and risk of infectious complications in patients with CLL. In this context, we discuss current data of SARS-CoV-2 infections in patients with CLL and how the pandemic impacts their management.

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).

Case Study: Prolonged Infectious SARS-CoV-2 Shedding from an Asymptomatic Immunocompromised Individual with Cancer.

Long-term severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shedding was observed from the upper respiratory tract of a female immunocompromised individual with chronic lymphocytic leukemia and acquired hypogammaglobulinemia. Shedding of infectious SARS-CoV-2 was observed up to 70 days, and of genomic and subgenomic RNA up to 105 days, after initial diagnosis. The infection was not cleared after the first treatment with convalescent plasma, suggesting a limited effect on SARS-CoV-2 in the upper respiratory tract of this individual. Several weeks after a second convalescent plasma transfusion, SARS-CoV-2 RNA was no longer detected. We observed marked within-host genomic evolution of SARS-CoV-2 with continuous turnover of dominant viral variants. However, replication kinetics in Vero E6 cells and primary human alveolar epithelial tissues were not affected. Our data indicate that certain immunocompromised individuals may shed infectious virus longer than previously recognized. Detection of subgenomic RNA is recommended in persistently SARS-CoV-2-positive individuals as a proxy for shedding of infectious virus.