Chronic Lymphocytic Research Articles

Evaluation of the Impact of Monitoring for Tumor Lysis During Venetoclax Ramp-Up in Chronic Lymphocytic Leukemia in Routine Clinical Practice

PURPOSE Venetoclax has made a significant impact in the treatment of chronic lymphocytic leukemia (CLL) due to its ability to induce deep and durable remissions with a finite duration of oral therapy. However, it can lead to tumor lysis syndrome (TLS) which is mitigated with dose escalation strategies. Patients who initiate venetoclax need to follow rigorous, and potentially burdensome, TLS monitoring during dose ramp-up. The frequency with which this rigorous monitoring leads to therapeutic interventions in clinical practice has not been well described. We conducted a study to assess the incidence of TLS and interventions needed after initiation of venetoclax in patients with CLL. METHODS Adult patients with CLL who started treatment with venetoclax between July 2017 and March 2021 at Levine Cancer Institute were included in this study. Adherence to the venetoclax package insert (PI) for tumor lysis monitoring, incidence of laboratory as well as clinical TLS, and interventions resulting from the monitoring of TLS were collected. RESULTS We report outcomes on 73 consecutive patients with CLL who initiated venetoclax. The majority of patients had low (49%) or medium (44%) tumor burden. During venetoclax ramp-up, 66% of patients adhered strictly to TLS monitoring as per the venetoclax PI. One patient developed laboratory TLS, and no patients developed clinical TLS. Six patients received unplanned interventions to treat TLS; all had medium or high tumor burden. There were no unplanned interventions in patients with low tumor burden. CONCLUSION In patients with low and medium tumor burden CLL who start venetoclax, the incidence of TLS is very low, and interventions are uncommonly needed.

Clinical Relevance of Intensive Laboratory Monitoring With Standard Venetoclax Ramp-Up for Chronic Lymphocytic Leukemia: A Real-World Experience

PURPOSE Venetoclax is the standard of care for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) but requires intensive monitoring for optimal safety. Clinical relevance of intensive monitoring in practice is unknown, especially for patients with low or intermediate risk for tumor lysis syndrome (TLS). PATIENTS AND METHODS A retrospective review was conducted to determine clinical significance of monitoring for TLS during standard ramp-up for patients with CLL/SLL. Patients receiving abbreviated ramp-up, clinical trials, or concurrent Bruton tyrosine kinase inhibitors were excluded. The primary end point was TLS incidence, with secondary end points describing associated clinical interventions. RESULTS Fifty-five patients met study criteria. The majority of patients received venetoclax as first-line therapy (58%), with anti-CD20 antibody therapy (82%), and were at low risk of TLS (75%). No clinical TLS events occurred, whereas laboratory TLS occurred in only 1.8% of patients. No patients required antihyperuricemic therapy, and few interventions for hyperphosphatemia or hypocalcemia (3.6% of patients) were required. Additional intravenous fluids were uncommonly required (1.8% of patients), and no unplanned hospitalizations were required. CONCLUSION These findings support efforts to reduce intensive monitoring requirements during venetoclax ramp-up for patients with CLL, potentially increasing accessibility of venetoclax.

A Small Molecule Antagonist of CX3CR1 (KAND567) Inhibited the Tumor Growth-Promoting Effect of Monocytes in Chronic Lymphocytic Leukemia (CLL)

Background/Objectives: Nurse-like cells (NLCs) derived from monocytes in the tumor microenvironment support the growth of chronic lymphocytic leukemia (CLL) cells. Here, we investigated the effects of a CX3CR1 (fractalkine receptor) antagonist (KAND567) on autologous monocytes and their pro-survival effects on CLL cells in vitro. Methods: Plasma concentration of CX3CL1 was determined by ELISA and CX3CR1 expression by flow cytometry. CD19+ cells and autologous monocytes from patients with CLL and healthy donors were treated with KAND567 either in co-culture or alone. The apoptosis of CD19+ cells and monocytes was determined by Annexin V/PI staining and live-cell imaging. Results: Plasma concentration of CX3CL1 (fractalkine) was significantly higher in patients with CLL (n = 88) than in healthy donors (n = 32) (p < 0.0001), with higher levels in patients with active compared to non-active disease (p < 0.01). CX3CR1 was found on monocytes but not B cells in patients and controls. Levels of intermediate and non-classical CX3CR1+ monocytes were higher in patients with CLL than in controls (p < 0.001), particularly in those with active disease (p < 0.0001). Co-culture experiments revealed that autologous monocytes promoted the survival of both malignant and normal B cells and that KAND567 selectively inhibited the growth of CLL cells in a dose-dependent manner but only in the presence of autologous monocytes (p < 0.05). Additionally, KAND567 inhibited the transition of monocytes to NLCs in CLL (p < 0.05). Conclusions: Our data suggest that the CX3CR1/CX3CL1 axis is activated in CLL and may contribute to the NLC-driven growth-promoting effects of CLL cells. KAND567, which is in clinical trials in other disorders, should also be explored in CLL.

Measurable residual disease-driven treatment in first-line chronic lymphocytic leukaemia.

The therapeutic paradigm for patients suffering from chronic lymphocytic leukaemia continues to rapidly evolve. Fixed duration therapies continue to develop using novel-novel non-chemotherapeutic combinations. B-cell lymphoma 2 (BCL2) inhibitors in combination with either anti-CD20 antibody or Bruton tyrosine kinase inhibitors are able to achieve deep responses. Levels of attained 'negative' measurable residual disease (MRD, also known as minimal residual disease) have been shown to predict survival outcomes in a number of settings, including following immunochemotherapy and BCL2-combinations. This review will outline the current data supporting fixed duration treatment approaches, the use of MRD in clinical practice, alongside the challenges and possibilities for MRD utility in the future.

Abstract 4118380: In-Hospital Outcome of Acute Heart Failure in Patients with Active Chronic Lymphocytic Leukemia

Introduction: Chronic lymphocytic leukemia (CLL) is prevalent among adults in Western countries, posing a significant health challenge due to its incurable nature and associated complications. Among these, cardiovascular disease, particularly heart failure (HF), has emerged as a major concern. Despite growing recognition, understanding of acute HF's epidemiology, outcomes, and risk factors in CLL patients remains limited. To address these gaps, we conducted a large-scale study using the National Inpatient Sample (NIS) database, aiming to examine acute HF prevalence, trends, outcomes, and predictors among CLL hospitalizations. Methods: We employed a retrospective cohort design utilizing NIS data from 2016 to 2021. CLL hospitalizations with and without acute HF were identified using ICD-10 codes. Our analysis included demographic characteristics, in-hospital outcomes, and multivariable logistic regression to identify predictors of outcomes. Propensity score matching was performed to mitigate confounding factors. Results: Among 423,829 CLL hospitalizations, 27.8% presented with acute HF. Patients with acute HF were older and had higher rates of comorbidities. While acute HF prevalence remained stable, in-hospital mortality increased over time, contrasting with stable rates among patients without acute HF. Acute HF was associated with higher mortality, cardiogenic shock, cardiac arrest, and major adverse cardiovascular events. Propensity score-matched analysis confirmed these associations. Discussion: Our study highlights acute HF as a common complication in CLL hospitalizations, linked with worse outcomes. The multifactorial nature of HF in CLL involves disease-related factors, treatment toxicities, and traditional cardiovascular risk factors. Prompt recognition and multidisciplinary management are essential for improving outcomes. Future research should focus on developing risk stratification tools and interventions targeting acute HF in CLL patients. Conclusion: Acute HF poses a significant burden on CLL hospitalizations, emphasizing the need for heightened awareness and tailored management strategies. Our findings underscore the importance of early recognition and intervention to improve outcomes in this vulnerable population.

FoxO1 signaling in B cell malignancies and its therapeutic targeting.

FoxO transcription factors (FoxO1, FoxO3a, FoxO4, FoxO6) are a highly evolutionary conserved subfamily of the 'forkhead' box proteins. They have traditionally been considered tumor suppressors, but FoxO1 also exhibits oncogenic properties. The complex nature of FoxO1 is illustrated by its various roles in B cell development and differentiation, immunoglobulin gene rearrangement and cell-surface B cell receptor (BCR) structure, DNA damage control, cell cycle regulation, and germinal center reaction. FoxO1 is tightly regulated at a transcriptional (STAT3, HEB, EBF, FoxOs) and post-transcriptional level (Akt, AMPK, CDK2, GSK3, IKKs, JNK, MAPK/Erk, SGK1, miRNA). In B cell malignancies, recurrent FoxO1 activating mutations (S22/T24) and aberrant nuclear export and activity have been described, underscoring the potential of its therapeutic inhibition. Here, we review FoxO1's roles across B cell and myeloid malignancies, namely acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt lymphoma (BL), Hodgkin lymphoma (HL), and multiple myeloma (MM). We also discuss preclinical evidence for FoxO1 targeting by currently available inhibitors (AS1708727, AS1842856, cpd10).

NCMP-15. MULTIPLE HEMORRHAGIC CNS LESIONS IN A PATIENT WITH RELAPSED SYSTEMIC CHRONIC LYMPHOCYTIC LEUKEMIA

Abstract Although chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries, extramedullary CLL, characterized by the accumulation of clonal B cells outside of blood, bone marrow, and peripheral lymph nodes, remains rare. The central nervous system (CNS) is the most common site of extramedullary CLL involvement. However, clinically significant CLL in the CNS has been reported in fewer than 100 cases in the literature, and its true prevalence remains unknown with variable estimates. CLL in the CNS most often affects the meninges and usually spares the parenchyma unless there is a higher-grade/Richter transformation; in either case, it is typically not hemorrhagic. Furthermore, in the rare cases reported of hemorrhagic intraparenchymal CLL, patients present with isolated bleeding rather than multifocal hemorrhages. We present the case of a 63-year-old patient with multiply recurrent systemic CLL without Richter transformation who developed bilateral infratentorial and supratentorial micro and macrohemorrhages. Histopathology of a lesion showed focal subacute hemorrhage associated with reactive brain parenchyma containing CLL cells, though it was unclear whether the CLL predated the hemorrhage or if the hemorrhage introduced the CLL. Given the patient’s clinical stability, the lesions were ultimately attributed to coagulopathy in the context of CLL with subsequent secondary colonization of the hemorrhage by CLL cells. These lesions completely resolved after the patient underwent CLL-directed therapy three months after symptom onset. This case underscores the importance of considering bleeding risks associated with CLL and demonstrates that addressing the underlying CLL can lead to the improvement in bleeding sequelae.

Cumulative review of hypertension in patients with chronic lymphocytic leukemia treated with acalabrutinib.

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Increased c-MYC Expression Associated with Active IGH Locus Rearrangement: An Emerging Role for c-MYC in Chronic Lymphocytic Leukemia

This review examines the pivotal role of c-MYC in Chronic Lymphocytic Leukemia (CLL), focusing on how its overexpression leads to increased genetic instability, thereby accelerating disease progression. MYC, a major oncogene, encodes a transcription factor that regulates essential cellular processes, including cell cycle control, proliferation, and apoptosis. In CLL cases enriched with unmutated immunoglobulin heavy chain variable (IGHV) genes, MYC is significantly overexpressed and associated with active rearrangements in the IGH immunoglobulin heavy chain locus. This overexpression results in substantial DNA damage, including double-strand breaks, chromosomal translocations, and an increase in abnormal repair events. Consequently, c-MYC plays a dual role in CLL: it promotes aggressive cell proliferation while concurrently driving genomic instability through its involvement in genetic recombination. This dynamic contributes not only to CLL progression but also to the overall aggressiveness of the disease. Additionally, the review suggests that c-MYC’s influence on genetic rearrangements makes it an attractive target for therapeutic strategies aimed at mitigating CLL malignancy. These findings underscore c-MYC’s critical importance in advancing CLL progression, highlighting the need for further research to explore its potential as a target in future treatment approaches.

Mosaic chromosomal alterations (mCAs) in individuals with monoclonal B-cell lymphocytosis (MBL)

MBL is a precursor condition to chronic lymphocytic leukemia (CLL), characterized by monoclonal B-cells in blood. Mosaic chromosomal alterations (mCAs) are a form of clonal hematopoiesis that include gains, losses, and copy-neutral loss-of-heterozygosity of large DNA segments. Both MBL and mCAs have been found to increase the risk of CLL and lymphoid malignancies, and the aim of our study was to investigate how mCAs relate to MBL, which is currently unknown. We analyzed genetic, flow cytometric, and hematologic data from 4632 individuals from the Mayo Clinic Biobank and CLL Database. MBL was detected using flow cytometry and classified as high-count (HC) or low-count (LC) MBL based on clone size. mCAs were detected primarily from whole blood DNA using sensitive SNP-array-based analyses. mCAs commonly altered in CLL (deletion of 6q, 11q, 13q, 17p, and trisomy 12) were specific (>99%) to individuals with MBL and CLL. HC-MBL and LC-MBL individuals were 881-fold and 8-fold, respectively, more likely to harbor CLL-associated mCAs than those without MBL. The cell fraction bearing these mCAs typically exceeded the B-cell fraction, suggesting their origin prior to the B-cell lineage. Integrating genetic and blood count data enabled detecting HC-MBL with high specificity in a biobank sample. These results quantify the contribution of mCAs to MBL and could enable large studies of HC-MBL without the need for flow cytometric screening.

Beta-2-Microglobulin Maintains Overall Survival Prediction in Binet A Stage Chronic Lymphocytic Leukemia Patients with Compromised Kidney Function in Both Treatment Eras of Chemoimmunotherapy and Targeted Agents

Background: Elevated beta-2-microglobulin (B2M) plasma levels commonly imply a higher CLL-IPI risk category for short overall survival (OS), but the risk model was not adjusted for compromised kidney function and not validated in Binet A stage CLL patients. Methods: CLL patients were identified from 2000 to 2022 at Innsbruck University Hospital, Austria. B2M levels, CLL-IPI risk stratification, and kidney function were assessed. Treatment modalities in case of disease progression and OS data during follow-up were evaluated. Results: A total of 259 Binet A stage CLL patients were identified; 16.9% (n = 44/259) presented with concurrent chronic kidney disease (CKD, GFR < 60 mL/min). Median OS was 170 months and was similar in CKD and non-CKD patients (p = 0.25). The CLL-IPI facilitated prognostic segregation in both CKD (p = 0.02) and non-CKD patients (p = 0.008). Although more frequently elevated in CKD patients (44.1% versus 10.6%, p < 0.001), B2M > 3.5 mg/L remained associated with inferior OS in this subgroup (p = 0.03). Contrary to the CLL-IPI, the prognostic value of B2M alone was also maintained in CLL patients diagnosed and potentially treated frontline in the era of targeted agents (2014–2022, p = 0.03). Conclusions: B2M retains its prognostic value for OS in early-stage CLL patients with concurrent CKD and still represents a promising covariate for up-coming prognostic models to identify patients at high risk for inferior OS in the era of targeted agents.

Laboratory analysis of 124 chronic lymphocytic leukemia cases: Single center study

Abstract BACKGROUND: Chronic lymphocytic leukemia (CLL) is a disease characterized by an uncontrolled proliferation of malfunctioning mature B-lymphocytes. It represents a variable range of clinical presentation and prognoses. Understanding the demographic and cellular characteristics of CLL patients can aid in better disease management and treatment outcomes. OBJECTIVES: To identifying hematological parameters and patterns and potential markers that could assist in better diagnosis and of CLL in the local population. PATIENTS, MATERIALS AND METHODS: A retrospective analysis of 124 cases of newly diagnosed CLL was conducted. Data were collected from reports over 2 years (April 2022-April2024), including demographics, Hb levels, WBC counts, platelet counts and expression of CD markers (5, 19, 20, 23, 200, FMC7, LAIR1 and others) using flow cytometry on peripheral blood specimens. Based on FC findings, patients were categorized into two groups for better assessment; definite diagnosis CLL and possible diagnosis CLL; then further subdivided into poor prognosis CLL and good prognosis CLL. RESULTS: Male patients represented 59.5% of cases and females were 40.5% with a median age of 61 years at diagnosis. The mean Hb level was 109 ± 2 g/L, the mean WBC count was 58.0 ± 25.0 × 109/L, and the mean platelet count was 190 ± 40 × 109/L. CD5 was positive in 97.6% of cases, with CD23 in 96%. CONCLUSION: This study provides an overview of the demographic and cellular marker characteristics of CLL patients in FC unit. The findings underscore the heterogeneity of CLL immunophenotype and the importance of detailed characterization in improving patient management protocols; however, further research is warranted to correlate these findings with other parameters of disease burden and prognosis to optimize the therapeutic approaches for CLL patients.

Fatal borealpox in an immunosuppressed patient treated with antivirals and vaccinia immunoglobulin - Alaska, 2023.

Borealpox virus (BRPV, formerly known as Alaskapox virus) is a zoonotic member of the Orthopoxvirus genus first identified in a person in 2015. In the six patients with infection previously observed BRPV involved mild, self-limiting illness. We report the first fatal BRPV infection in an immunosuppressed patient. A man aged 69 years from Alaska's Kenai Peninsula was receiving anti-CD20 therapy for chronic lymphocytic leukemia. He presented to care for a tender, red papule in his right axilla with increasing induration and pain. The patient failed to respond to multiple prescribed antibiotic regimens and was hospitalized 65 days postsymptom onset for progression of presumed infectious cellulitis. BRPV was eventually detected through orthopoxvirus real-time polymerase chain reaction testing of mucosal swabs. He received combination antiviral therapy, including 21 days of intravenous tecovirimat, intravenous vaccinia immunoglobulin, and oral brincidofovir. Serial serology was conducted on specimens obtained posttreatment initiation. The patient's condition initially improved with plaque recession, reduced erythema, and epithelization around the axillary lesion beginning one-week post-therapy. He later exhibited delayed wound healing, malnutrition, acute renal failure, and respiratory failure. He died 138 days postsymptom onset. Serologic testing revealed no evidence the patient generated a humoral immune response. No secondary cases were detected. This report demonstrates that BRPV can cause overwhelming disseminated infection in certain immunocompromised patients. Based on the patient's initial response, early BRPV identification and antiviral therapies might have been beneficial. These therapies, in combination with optimized immune function, should be considered for patients at risk for manifestations of BRPV.

Pneumonia in patients with chronic lymphocytic leukemia treated with venetoclax‐based regimens: A real‐world analysis of Polish Adult Leukemia Group (PALG)

AbstractBackgroundPatients with chronic lymphocytic leukemia (CLL) are susceptible to infections that can affect their clinical outcomes.AimsTo assess: (1) the incidence of pneumonia in CLL patients treated with venetoclax‐based regimens in a real‐world setting, (2) the risk factors for event‐free survival (EFS), and (3) overall survival (OS).MethodsThis multicenter study included 322 patients from eight centers. Univariable and multivariable analyses (MVA) were performed, having the development of pneumonia during venetoclax‐based treatment and OS as outcomes.ResultsThe most common complication was neutropenia (59%). During treatment with venetoclax‐based regimens, 66 (20%) of patients developed pneumonia: 50 (23%) patients in the rituximab plus venetoclax (R‐VEN) group, 13 (16%) patients in the obinutuzumab plus venetoclax (O‐VEN) group (p = 0.15). Chronic obstructive pulmonary disease (COPD)/asthma, splenomegaly, elevated creatinine, and anemia <8 g/dL were the risk factors for EFS in MVA (hazard ratio [HR] = 2.08, 95% confidence interval [CI], 1.16–3.74, p = 0.014; HR 1.73, 95% CI, 1.08–2.78, p = 0.02; HR 2.13, 95% CI, 1.10–4.11, p = 0.03, HR 3.58, 95% CI, 2.18–5.89, p < 0.001, respectively). Relapsed/refractory (R/R) CLL patients treated with R‐VEN with pneumonia had worse OS than those without (p < 0.001). In patients treated with O‐VEN, median OS did not differ between patients with and without pneumonia (p = 0.45).ConclusionsOur real‐world study showed that pneumonia during venetoclax treatment occurs more frequently than reported in registration trials and has a negative impact on OS, especially in patients with R/R CLL treated with R‐VEN. Neutropenia is not a risk factor for pneumonia.

Tumour assessment of ROR1 levels in various adult leukaemia and lymphoma types.

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a tumour target currently used for the development of novel therapeutic modalities, such as antibody-drug conjugates, chimeric antigen receptor T-cell therapies, and others. Success of these new drugs depends on the selection of relevant indications based on ROR1 tumour prevalence, staining heterogeneity, and subcellular localization, among other parameters. We investigated ROR1 immunophenotype using validated antibody clones for immunohistochemistry (IHC) and flow cytometry (FC), analyzing 292 tumour specimens from 7 haematological malignancies and triple negative breast cancer (TNBC) as a reference solid tumour indication. ROR1 prevalence varied significantly across distinct tumour types, showing 100% of ROR1 positivity in all chronic lymphocytic leukaemia (n = 48) and hairy cell leukaemia (n = 14) specimens analyzed via FC with ranges between 1.1-99.8% and 0.8-62.1%, respectively. Samples analysed via IHC showed ROR1 membrane/cytoplasmic positivity in 44% of mantle cell lymphoma tumour samples (n = 27; H-score range: 10-285 in positive cases); 30% in TNBC (n = 46; H-score range: 1-200); 15% in diffuse large B-cell lymphoma (n = 45; H-score: 40-250); and 11% in follicular lymphoma (n = 34; H-score: 2-300). Finally, all acute myeloid leukaemia (n = 52) and most T-cell non-Hodgkin lymphoma (n = 31/32) tested samples were negative for ROR1 via IHC. In conclusion, ROR1 shows a heterogeneous tumour cell expression profile across multiple leukaemias and lymphomas, making it a tumour target that would require different patient selection strategies to develop novel therapeutic modalities.

Review of BCL2 inhibitors for the treatment of Waldenström’s macroglobulinaemia and non-IgM lymphoplasmacytic lymphoma

Lymphoplasmacytic lymphoma (LPL) is a relatively rare form of indolent B-cell non-Hodgkin’s lymphoma, termed Waldenström’s macroglobulinaemia (WM) in the presence of an IgM paraprotein. Although traditionally treated with combination chemoimmunotherapy, the management is evolving in the era of targeted molecular therapies including Bruton’s tyrosine kinase inhibitors (BTKi). However, intolerance and refractoriness to BTKi mean newer agents are required, and the prognosis of so-called quadruple-refractory patients is poor. BCL2 is an anti-apoptotic, pro-survival protein that promotes lymphoma cell survival. Inhibition of BCL2 using first-in-class agent venetoclax has already altered the treatment paradigm in other conditions, including chronic lymphocytic leukaemia (CLL). In-vivo inhibition of BCL2 has been shown to lead to apoptosis of LPL/WM cells. Five studies have published results on the use of BCL2 inhibitors in WM to date, including oblimersen sodium, venetoclax, and sonrotoclax. Fixed-duration venetoclax resulted in high response rates, but many patients relapsed following the completion of therapy. The combination of venetoclax with ibrutinib resulted in higher and relatively deep response rates, but unexpected deaths due to ventricular events mean this combination cannot be explored. Two pivotal trials are currently evaluating the use of fixed-duration venetoclax, either in combination with rituximab or pirtobrutinib, whereas another multi-arm study is studying the use of continuous sonrotoclax monotherapy for R/R WM or in fixed-duration combination with Zanubrutinib for treatment-naïve patients. The potential role of BCL2 inhibitors in WM/LPL remains under study, with many hopeful that they may provide an additional chemotherapy-free oral alternative for patients requiring treatment. In an indolent condition with existing effective treatment regimens, including CIT and cBTKi, cost-effectiveness and toxicity profile will be key, although an additional treatment modality for quadruple-refractory patients with limited treatment options is urgently required.

Causes of death among patients diagnosed with chronic lymphocytic leukemia: A population-based study in the Netherlands, 1996-2020.

Chronic lymphocytic leukemia (CLL) manifests heterogeneously with varying outcomes. This population-based study examined causes of death (CODs), as registered by the physician who established the death, among 20,588 CLL patients diagnosed in the Netherlands between 1996 and 2020. Utilizing cause-specific flexible parametric survival models, we estimated cause-specific hazard ratios (HRs) and cumulative incidences of death due to CLL, solid malignancies, other hematological malignancies, infections, and other causes. Our findings reveal CLL as the predominant COD, contributing to around 40% of relative mortality, with a declining 5-year death probability from 16.8% in 1996-2002 to 7.6% in 2010-2020. Also, deaths attributed to solid malignancies, other hematological malignancies, and other COD diminished over time, as evidenced by respective HRs (95% confidence interval) of 0.68 (0.60%-0.77%), 0.45 (0.38%-0.53%), and 0.77 (0.66%-0.90%). In summary, our comprehensive, population-based analysis underscores a noticeable reduction in CLL-attributed deaths and other competing causes over the studied period. Nonetheless, CLL is registered as the most prevalent cause of mortality among contemporary diagnosed patients with CLL, emphasizing the continued relevance of CLL-centric clinical strategies and research.

Venetoclax dose escalation rapidly activates a BAFF/BCL-2 survival axis in chronic lymphocytic leukemia

AbstractVenetoclax, a first-in-class BH3 mimetic drug that targets BCL-2, has improved the outcomes of patients with chronic lymphocytic leukemia (CLL). Early measurements of the depth of the venetoclax treatment response, assessed by minimal residual disease, are strong predictors of long-term clinical outcomes. However, there are limited data on the early changes induced by venetoclax treatment that might inform strategies to improve responses. To address this gap, we conducted longitudinal mass cytometric profiling of blood cells from patients with CLL during the first 5 weeks of venetoclax monotherapy. At baseline, we resolved CLL heterogeneity at the single-cell level to define multiple subpopulations in all patients based on proliferative, metabolic, and cell survival proteins. Venetoclax induced a significant reduction in all CLL subpopulations and caused rapid upregulation of the prosurvival BCL-2, BCL-XL, and mantle cell lymphoma-1 proteins in surviving cells, which had reduced sensitivity to the drug. In mouse models, the venetoclax-induced elevation of survival proteins in B cells and CLL-like cells that persisted was recapitulated, and genetic models demonstrated that extensive apoptosis and access to the B cell cytokine, B cell activating factor (BAFF), were essential. Accordingly, in patients with CLL who were treated with venetoclax or the anti-CD20 antibody obinutuzumab there was marked elevation in BAFF and an increase in prosurvival proteins in leukemic cells that persisted. Overall, these data highlight the rapid adaptation of CLL cells to targeted therapies through homeostatic factors and support cotargeting of cytokine signals to achieve deeper and more durable long-term responses.

CAT rs1001179 Single Nucleotide Polymorphism Identifies an Aggressive Clinical Behavior in Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is characterized by an extremely variable clinical course. Although several parameters have been shown to be associated with clinical outcomes in patients with CLL, there remains substantial intragroup clinical heterogeneity in otherwise molecularly and staging homogeneous CLL subgroups. We have recently shown that high catalase (CAT) expression identifies patients with an aggressive clinical course and that higher CAT expression is associated with the presence of the rs1001179 single nucleotide polymorphism (SNP) T allele in the CAT promoter. Herein, we genotyped CLL patients for CAT rs1001179 SNP in an exploratory study (n=235) and in a sequential independent validation study (n=531). Time-to-event modeling analyses for time-to-first-treatment (TTFT) from the two patients' cohorts showed that TT genotype was associated with a shorter TTFT, independently of other currently used prognostic parameters in CLL. Moreover, the TT genotype identifies CLL patients with a faster clinical progression even within subgroups of patients with low-risk biological and clinical hallmarks. In conclusion, our data show that the TT genotype identifies CLL patients with a shorter TTFT, pointing to this SNP as a possible prognostic factor, which can improve patients' risk stratification leading to better patient management and personalized therapeutic choices.

Epigenetic features support the diagnosis of B-cell prolymphocytic leukemia and identify 2 clinicobiological subtypes

AbstractThe recognition of B-cell prolymphocytic leukemia (B-PLL) as a separate entity is controversial based on the current classification systems. Here, we analyzed the DNA methylome of a cohort of 20 B-PLL cases diagnosed according to the International Consensus Classification/World Health Organization HAEM4R guidelines, and compared them with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), splenic marginal zone lymphoma (SMZL), and normal B-cell subpopulations. Unsupervised principal component analyses suggest that B-PLL is epigenetically distinct from CLL, MCL, and SMZL, which is further supported by robust differential methylation signatures in B-PLL. We also observe that B-PLL can be segregated into 2 epitypes with differential clinicobiological characteristics. B-PLL epitype 1 carries lower immunoglobulin heavy variable somatic hypermutation and a less profound germinal center–related DNA methylation imprint than epitype 2. Furthermore, epitype 1 is significantly enriched in mutations affecting MYC and SF3B1, and displays DNA hypomethylation and gene upregulation signatures enriched in MYC targets. Despite the low sample size, patients from epitype 1 have an inferior overall survival than those of epitype 2. This study provides relevant insights into the biology and differential diagnosis of B-PLL, and potentially identifies 2 subgroups with distinct biological and clinical features.