COVID-19 Vaccination Response and Its Practical Application in Patients With Chronic Lymphocytic Leukemia.

Patients with chronic lymphocyticleukemia (CLL) typically have innate/adaptive immune system dysregulation, thus the protective effect of coronavirus disease 2019 (COVID-19) vaccination remains uncertain. This prospective review evaluates vaccination response in these patients, including seropositivity rates by CLL treatment status, type of treatment received, and timing of vaccination. Antibody persistence, predictors of poor vaccine response, and severity of COVID-19 infection in vaccinated patients were also analyzed. Practical advice on the clinical management of patients with CLL is provided. Articles reporting COVID-19 vaccination in patients with CLL, published January 1, 2021-May 1, 2022, were included. Patients with CLL displayed the lowest vaccination responses among hematologic malignancies; however, seropositivity increased with each vaccination. One of the most commonly reported independent risk factors for poor vaccine response was active CLL treatment; others included hypogammaglobulinemia and age >65-70 years. Patients who were treatment-naive, off therapy, in remission, or who had a prior COVID-19 infection displayed the greatest responses. Further data are needed on breakthrough infection rates and a heterologous booster approach in patients with hematologic malignancies. Although vaccine response was poor for patients on active therapy regardless of treatment type, CLL management in the context of COVID-19 should aim to avoid delays in antileukemic treatment, especially with the advent of numerous strategies to mitigate risk of severe COVID-19 such as pre-exposure prophylaxis, and highly effective antivirals and monoclonal antibody therapy upon confirmed infection. Patients with CLL should remain vigilant in retaining standard prevention measures such as masks, social distancing, and hand hygiene.

Humoral Response to COVID-19 Vaccine: A Challenge in CLL

Chronic lymphocytic leukaemia (CLL) is associated with some degree of immune dysfunction as a result of the disease itself and/or treatment. COVID-19 has a major impact on patients with CLL who are at increased risk for severe disease and death. In this study, we aimed to understand the efficacy of anti-SARS-CoV-2 vaccines in patients with CLL. From January 2021, we collected data on 166 vaccinated patients with CLL followed at our site. Median age was 68 years (range 41-92);43 (26%) were treatment-naïve (TN), 25 (15%) were previously treated, 95 (57%) were on active therapy, and 3 (2%) were experiencing relapse. Most patients received BNT162b2 (87%), followed by mRNA-1273 (4%) and ChAdOx1-S (3%);data is missing in 6%. Serology testing was performed with the SARS-CoV-2 S1/S2 IgG assay (Elecsys® Anti-SARS-CoV-2) 2 to 3 weeks after second and third vaccine doses and considered negative for antibody titers below 0.4 U/ml. Vaccine response was evaluated post-dose 2 in 119 patients and post-dose 3 in 74 patients. Post second dose, a higher seroconversion rate was observed in TN patients and those with sustained clinical response after therapy discontinuation (42% and 46% respectively) compared with actively treated patients (20.5%;[p=0.024;p=0.048]). Antibody response rate in patients receiving BTKi was considerably lower 19.7% (12/61). Three (42.9%) out of 7 patients who received venetoclax monotherapy seroconverted. None of the patients exposed to anti-CD20 antibodies (3/8 with targeted therapy, 2/8 with chemotherapy, 3/8 as single agent) <12 months before vaccination responded. Among patients actively treated who failed to achieve a humoral response after two-dose, 25.6% responded to the third dose of vaccine, although with a weak antibody level (median 8.64 U/ml, range 0.55-175). Overall, post third dose a higher median (IQR) antibody titer (127.9 U/mL;0.55-2500) was observed compared to one post second dose (19.2 U/ml;0.86-2500) in patients on therapy. Notably, all patients in clinical remission after treatment present titers above the upper limit of quantification (>2500 U/mL) post third dose. Conclusions: Humoral immune response to the COVID-19 vaccine is impaired in most patients with CLL and correlates with treatment status.

Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial.

BACKGROUND: Zanubrutinib is a next-generation, selective Bruton tyrosine kinase inhibitor with efficacy in relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). We compared zanubrutinib with bendamustine-rituximab to determine its effectiveness as frontline therapy in patients with CLL or SLL. METHODS: We conducted an open-label, multicentre, phase 3 study at 153 academic or community hospitals in 14 countries and regions. Eligible patients had untreated CLL or SLL requiring treatment as per International Workshop on CLL criteria; were aged 65 years or older, or 18 years or older and had comorbidities; and had an Eastern Cooperative Oncology Group performance status score of 0-2. A central interactive web response system randomly assigned patients without del(17)(p13·1) to zanubrutinib (group A) or bendamustine-rituximab (group B) by sequential block method (permutated blocks with a random block size of four). Patients with del(17)(p13·1) were enrolled in group C and received zanubrutinib. Zanubrutinib was administered orally at 160 mg twice per day (28-day cycles); bendamustine at 90 mg/m2 of body surface area on days 1 and 2 for six cycles plus rituximab at 375 mg/m2 of body surface area the day before or on day 1 of cycle 1, and 500 mg/m2 of body surface area on day 1 of cycles 2-6, were administered intravenously. The primary endpoint was progression-free survival per independent review committee in the intention-to-treat population in groups A and B, with minimum two-sided α of 0·05 for superiority. Safety was analysed in all patients who received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, NCT03336333, and is closed to recruitment. FINDINGS: Between Oct 31, 2017, and July 22, 2019, 590 patients were enrolled; patients without del(17)(p13·1) were randomly assigned to zanubrutinib (group A; n=241) or bendamustine-rituximab (group B; n=238). At median follow-up of 26·2 months (IQR 23·7-29·6), median progression-free survival per independent review committee was not reached in either group (group A 95% CI not estimable [NE] to NE; group B 28·1 months to NE). Progression-free survival was significantly improved in group A versus group B (HR 0·42 [95% CI 0·28 to 0·63]; two-sided p<0·0001). The most common grade 3 or worse adverse event was neutropenia (27 [11%] of 240 patients in group A, 116 [51%] of 227 in group B, and 17 [15%] of 111 patients in group C). Serious adverse events occurred in 88 (37%) of 240 patients in group A, 113 (50%) of 227 patients in group B, and 45 (41%) of 111 patients in group C. Adverse events leading to death occurred in 11 (5%) of 240 patients in group A, 12 (5%) of 227 patients in group B, and three (3%) of 111 patients in group C, most commonly due to COVID-19 (four [2%] of 240 patients in group A), diarrhoea, and aspiration pneumonia (two each [1%] of 227 patients in group B). INTERPRETATION: Zanubrutinib significantly improved progression-free survival versus bendamustine-rituximab, with an acceptable safety profile consistent with previous studies. These data support zanubrutinib as a potential new treatment option for untreated CLL and SLL. FUNDING: BeiGene.

Longitudinal analysis of T cell receptor repertoires reveals shared patterns of antigen-specific response to SARS-CoV-2 infection.

T cells play a prominent role in orchestrating the immune response to viral diseases, but their role in the clinical presentation and subsequent immunity to SARS-CoV-2 infection remains poorly understood. As part of a population-based survey of the municipality of Vo', Italy, conducted after the initial SARS-CoV-2 outbreak, we sampled the T cell receptor (TCR) repertoires of the population 2 months after the initial PCR survey and followed up positive cases 9 and 15 months later. At 2 months, we found that 97.0% (98 of 101) of cases had elevated levels of TCRs associated with SARS-CoV-2. T cell frequency (depth) was increased in individuals with more severe disease. Both depth and diversity (breadth) of the TCR repertoire were positively associated with neutralizing antibody titers, driven mostly by CD4+ T cells directed against spike protein. At the later time points, detection of these TCRs remained high, with 90.7% (78 of 96) and 86.2% (25 of 29) of individuals having detectable signal at 9 and 15 months, respectively. Forty-three individuals were vaccinated by month 15 and showed a significant increase in TCRs directed against spike protein. Taken together, these results demonstrate the central role of T cells in mounting an immune defense against SARS-CoV-2 that persists out to 15 months.

MyPal ADULT study protocol: a randomised clinical trial of the MyPal ePRO-based early palliative care system in adult patients with haematological malignancies.

INTRODUCTION: The systematic collection of electronic patient-reported outcome (ePRO) in the routine care of patients with chronic haematological malignancies such as chronic lymphocytic leukaemia (CLL) and myelodysplasia syndromes (MDS) can constitute a very ambitious but worthwhile challenge. MyPal is a Horizon 2020 Research & Innovation Action aiming to meet this challenge and foster palliative care for patients with CLL or MDS by leveraging ePRO systems to adapt to the personal needs of patients and caregiver(s). METHODS AND ANALYSIS: In this interventional randomised trial, 300 patients with CLL or MDS will be recruited across Europe. Patients will be randomly allocated to early palliative care using the MyPal system (n=150) versus standard care including general palliative care if needed (n=150). Patients in the experimental arm will be given access to the MyPal digital health platform which consists of purposely designed software available on smartphones and/or tablets. The platform entails different functionalities including physical and psychoemotional symptom reporting via regular questionnaire completion, spontaneous self-reporting, motivational messages, medication management and a personalised search engine for health information. Data on patients' activity (daily steps and sleep quality) will be automatically collected via wearable devices. ETHICS AND DISSEMINATION: The integration of ePROs via mobile applications has raised ethical concerns regarding inclusion criteria, information provided to participants, free and voluntary consent, and respect for their autonomy. These have been carefully addressed by a multidisciplinary team. Data processing, dissemination and exploitation of the study findings will take place in full compliance with European Union data protection law. A participatory design was adopted in the development of the digital platform involving focus groups and discussions with patients to identify needs and preferences. The protocol was approved by the ethics committees of San Raffaele (8/2020), Thessaloniki 'George Papanikolaou' Hospital (849), Karolinska Institutet (20.10.2020), University General Hospital of Heraklion (07/15.4.2020) and University of Brno (01-120220/EK). TRIAL REGISTRATION NUMBER: NCT04370457.

COVID-19 and Chronic Lymphocytic Leukemia: Where We Stand Now.

ABSTRACT: Coronavirus disease 2019 (COVID-19) has markedly impacted on the management of patients with chronic lymphocytic leukemia (CLL) and their outcome in the last year. The cumulative incidence of COVID-19 in patients with CLL in 1 year was approximately 3% in the recent Italian CAMPUS CLL survey; large retrospective studies have documented a higher mortality in patients with CLL hospitalized for severe COVID-19 compared with the general population. Controversial results for CLL-directed treatment have been reported, with some studies suggesting a potential benefit for BTK inhibitors. Reducing the number of hospital visits, delaying treatment whenever possible, and using oral therapy have become the mainstay of management in these patients. Available results with severe acute respiratory syndrome coronavirus 2 vaccines indicate an immune serological response in 40% of patients only, with a detrimental effect of recent therapy with or without anti-CD20 therapy, older age, and hypogammaglobulinemia. Further studies are needed to determine the best strategies in patients with CLL regarding (i) management of concomitant COVID-19, (ii) identification of patients in whom CLL therapy can be safely postponed, (iii) CLL treatment algorithms, and (iv) optimal severe acute respiratory syndrome coronavirus 2 vaccination strategies.

Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia.

Patients with chronic lymphocytic leukemia (CLL) have an increased risk for severe COVID-19 disease and mortality. The goal of this study was to determine the efficacy of COVID-19 vaccine in patients with CLL. We evaluated humoral immune responses to the BNT162b2 messenger RNA (mRNA) COVID-19 vaccine in patients with CLL and compared responses with those obtained in age-matched healthy control subjects. Patients received 2 vaccine doses, 21 days apart, and antibody titers were measured by using the Elecsys Anti-SARS-CoV-2 S assay after administration of the second dose. In a total of 167 patients with CLL, the antibody response rate was 39.5%. A comparison between 52 patients with CLL and 52 sex- and aged-matched healthy control subjects revealed a significantly reduced response rate among patients (52% vs 100%, respectively; adjusted odds ratio, 0.010; 95% confidence interval, 0.001-0.162; P < .001). The response rate was highest in patients who obtained clinical remission after treatment (79.2%), followed by 55.2% in treatment-naive patients and 16.0% in patients under treatment at the time of vaccination. In patients treated with either Bruton's tyrosine kinase inhibitors or venetoclax ± anti-CD20 antibody, response rates were considerably low (16.0% and 13.6%). None of the patients exposed to anti-CD20 antibodies <12 months before vaccination responded. In a multivariate analysis, the independent predictors of response were younger age, female sex, lack of currently active treatment, immunoglobulin G levels ≥550 mg/dL, and immunoglobulin M levels ≥40 mg/dL. In conclusion, antibody-mediated response to the BNT162b2 mRNA COVID-19 vaccine in patients with CLL is markedly impaired and affected by disease activity and treatment. This trial was registered at www.clinicaltrials.gov as #NCT04746092.

How We Manage Patients With Chronic Lymphocytic Leukemia During the SARS-CoV-2 Pandemic.

Infections are a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL). These can be exacerbated by anti-leukemic treatments. In addition, the typical patients with CLL already have fragilities and background risk factors that apply to the general population for severe COVID-19. On these bases, patients with CLL may experience COVID-19 morbidity and mortality. Recurrent seasonal epidemics of SARS-CoV-2 are expected, and doctors taking care of patients with CLL must be prepared for the possibility of substantial resurgences of infection and adapt their approach to CLL management accordingly. In this Guideline Article, we aim at providing clinicians with a literature-informed expert opinion on the management of patients with CLL during SARS-CoV-2 epidemic.