State of the art biology, progression, and clinical management of monoclonal B-cell lymphocytosis (MBL): consensus report from the Intercepting Blood Cancers Workshop Committee.

In March 2023 and 2024, a panel of international experts convened at the first and second Intercepting Blood Cancers (IBC) Workshops, with the aim of better appreciating the diagnostic challenges, pathophysiology, and potential therapeutic interventions for precursor malignant hematology conditions. Here, we report a summary of the proceedings from the sessions focused on monoclonal B-cell lymphocytosis (MBL)/chronic lymphocytic leukemia (CLL). We highlight four main content areas: biology of MBL, clinical implications of MBL, progression of MBL and transformation from indolent CLL to aggressive disease, and opportunities for therapeutic intervention in early CLL.

The role of imaging studies in predicting time to first treatment and overall survival in high-count monoclonal B-cell lymphocytosis.

In individuals with high-count monoclonal B-cell lymphocytosis (MBL), we investigated if lymphadenopathy or splenomegaly found by imaging was associated with shorter time to first chronic lymphocytic leukaemia (CLL) therapy (TTFT) and overall survival (OS). Individuals with MBL seen at Mayo Clinic (2002-2019) were retrospectively divided into three cohorts based on imaging studies within 1 year of diagnosis: no imaging studies (Cohort A); imaging with no evidence of lymphadenopathy/splenomegaly (Cohort B); imaging with evidence of lymphadenopathy/splenomegaly (Cohort C). We compared baseline characteristics, TTFT and OS across the MBL cohorts to a cohort of individuals with small lymphocytic lymphoma (SLL).

Disease-specific U1 spliceosomal RNA mutations in mature B-cell neoplasms.

Recurrent mutations in the third base of U1 spliceosomal RNA responsible for marked splicing and expression abnormalities have been described in chronic lymphocytic leukemia (CLL) and some solid tumors. However, the clinical significance of these mutations in large and independent CLL cohorts as well as their presence in other B-cell neoplasms is unknown. Here we characterized U1 mutations in 1670 CLL and 363 mature B-cell lymphomas.

Profound phenotypic deficiencies in mature blood and bone marrow progenitor dendritic cells in chronic lymphocytic leukemia patients.

Chronic lymphocytic leukemia (CLL) patients are immunocompromised and highly vulnerable to serious recurrent infections. Conventional dendritic cells (cDCs) and plasmacytoid DCs (pDCs) are principal sensors of pathogen challenge and are essential in orchestrating innate and adaptive immune responses to resolve infection. This study identified significant deficiencies in six functionally distinct DC subsets in blood of untreated CLL (UT-CLL) patients and selective normalization of pDCs in response to acalabrutinib (a Bruton tyrosine kinase inhibitor) therapy.

Aberrant heterochromatin silences immune response genes in chronic lymphocytic leukemia.

Epigenetic alterations have been found in chronic lymphocytic leukemia (CLL), but the functional importance of these changes remains underexplored. Here, we characterized the genome-wide histone modification landscapes of CLL using patient-derived samples across the disease course. Compared with normal B cells, we found that the enhancers specifically lost in CLL B cells are associated with the downregulation of genes involved in immune response.

A pilot study to determine the feasibility and safety of pharmacist and nurse driven management of venetoclax ramp-up in patients with chronic lymphocytic leukemia.

PurposeVenetoclax-based treatment for chronic lymphocytic leukemia (CLL) can be a logistically burdensome regimen due to extensive required monitoring of tumor lysis syndrome (TLS). The purpose of this study was to evaluate the feasibility and safety of pharmacist and registered nurse (RN) driven management of venetoclax ramp-up in CLL.MethodsThis was a prospective, pilot program for patients receiving venetoclax-based therapy for CLL.

Genomic characterization of chronic lymphocytic leukemia in patients of African ancestry.

Despite the considerable effort to characterize the genomic landscape of chronic lymphocytic leukemia (CLL), published data have been almost exclusively derived from patients of European Ancestry (EA), with significant underrepresentation of minorities, including patients of African Ancestry (AA). To begin to address this gap, we evaluated whether differences exist in the genetic and transcriptomic features of 157 AA and 440 EA individuals diagnosed with CLL. We sequenced 59 putative driver genes and found an increased frequency of high-impact mutations in AA CLL, including genes of the DNA damage repair (DDR) pathway.

Profound deficiencies in mature blood and bone marrow progenitor dendritic cells in Chronic Lymphocyticcytic Leukemia patients.

Chronic lymphocytic leukemia (CLL) patients are immunocompromised and highly vulnerable to serious recurrent infections. Conventional dendritic cells (cDCs) and plasmacytoid DCs (pDCs) are principal sensors of infection and are essential in orchestrating innate and adaptive immune responses to resolve infection. This study identified significant deficiencies in six functionally distinct DC subsets in blood of untreated CLL (UT-CLL) patients and selective normalization of pDCs in response to acalabrutinib (a Bruton tyrosine kinase inhibitor) therapy.

Incidence, risk factors, and outcomes of patients with monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia who develop venous thromboembolism.

Background: The incidence, risk factors, and outcomes of venous thromboembolism (VTE) in patients with chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL) are not well described.

Objectives: We aimed to determine the clinical characteristics, risk factors, and outcomes of incident VTE in patients with newly diagnosed MBL/CLL and compare the incidence to the age- and sex-matched general population.

Methods: Using the Mayo Clinic CLL Database, we identified 946 patients with newly diagnosed MBL/CLL between 1998 and 2021.

Risk of Incident Melanoma Among Individuals With Low-Count Monoclonal B-Cell Lymphocytosis.

Purpose: Chronic lymphocytic leukemia (CLL)-phenotype monoclonal B-cell lymphocytosis (MBL) is a premalignant condition that is roughly 500-fold more common than CLL. It is unknown whether the two-fold increased risk of developing melanoma associated with CLL extends to individuals with MBL.

Methods: Using the Mayo Clinic Biobank, we identified participants who were 40 years or older with no previous hematological malignancies, who resided in the 27 counties around Mayo Clinic, and who had available biospecimens for screening.

Pericardial events associated with ibrutinib-based therapies for chronic lymphocytic leukaemia in two landmark trials.

In the past decade, ibrutinib has transformed the treatment landscape for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Two pivotal US Intergroups trials (E1912 and A041202) have established ibrutinib as the frontline treatment option for patients with treatment-naïve CLL in both young and fit, and old and frail populations. The cardiovascular side effect profile such as cardiac dysrhythmias, ischemic events and hypertension continues to be meticulously reported in all trials investigating ibrutinib and all other Bruton tyrosine kinase inhibitors for CLL/SLL.

Utility of Targeted Sequencing Compared to FISH for Detection of Chronic Lymphocytic Leukemia Copy Number Alterations.

Chronic lymphocytic leukemia (CLL) is characterized by multiple copy number alterations (CNAs) and somatic mutations that are central to disease prognosis, risk stratification, and mechanisms of therapy resistance. Fluorescence in situ hybridization (FISH) panels are widely used in clinical applications as the gold standard for screening prognostic chromosomal abnormalities in CLL. DNA sequencing is an alternative approach to identifying CNAs but is not an established method for clinical CNA screening.

Artificial Intelligence Electrocardiography to Predict Atrial Fibrillation in Patients With Chronic Lymphocytic Leukemia.

Background: The use of an artificial intelligence electrocardiography (AI-ECG) algorithm has demonstrated its reliability in predicting the risk of atrial fibrillation (AF) within the general population.

Objectives: This study aimed to determine the effectiveness of the AI-ECG score in identifying patients with chronic lymphocytic leukemia (CLL) who are at high risk of developing AF.

Methods: We estimated the probability of AF based on AI-ECG among patients with CLL extracted from the Mayo Clinic CLL database.

Monocyte response to SARS-CoV-2 protein ORF8 is associated with severe COVID-19 infection in patients with chronic lymphocytic leukemia.

The open reading frame 8 (ORF8) protein, encoded by the SARS-CoV-2 virus after infection, stimulates monocytes/macrophages to produce pro-inflammatory cytokines. We hypothesized that a positive ex vivo monocyte response to ORF8 protein pre-COVID-19 would be associated with subsequent severe Coronavirus disease 2019 (COVID-19). We tested ORF8 ex vivo on peripheral blood mononuclear cells from 26 anonymous healthy blood donors and measured intracellular cytokine/ chemokine levels in monocytes by flow cytometry.

Outpatient treatment with concomitant vaccine-boosted convalescent plasma for patients with immunosuppression and COVID-19.

Although severe coronavirus disease 2019 (COVID-19) and hospitalization associated with COVID-19 are generally preventable among healthy vaccine recipients, patients with immunosuppression have poor immunogenic responses to COVID-19 vaccines and remain at high risk of infection with SARS-CoV-2 and hospitalization. In addition, monoclonal antibody therapy is limited by the emergence of novel SARS-CoV-2 variants that have serially escaped neutralization. In this context, there is interest in understanding the clinical benefit associated with COVID-19 convalescent plasma collected from persons who have been both naturally infected with SARS-CoV-2 and vaccinated against SARS-CoV-2 ("vax-plasma").