Chronic Lymphocytic Research Articles

A charter for improving care for people living with chronic lymphocytic leukemia: six principles for excellence.

Chronic Lymphocytic Leukemia (CLL)is the most common leukemia in adults in Western countries, and its incidence is increasing. It is a complex, chronic disease with highly variable behavior. People living with CLL deserve an accurate diagnosis and should be empowered to play an active role in their care. They should be treated holistically as a person, not simply by their diagnosis. This charter has been developed with input from patient advocacy organizations, people living with CLL, and clinical specialists. It highlights the elements of care and support that matter most to people living with CLL as they navigate life with their diagnosis. We urge governments, decision-makers, healthcare providers, patient advocacy organizations, and professional organizations worldwide to embed these principles in their work and ensure they are hardwired into healthcare systems and support services to reform and improve CLL care.

Ibrutinib increases miR-181a/b in leukemic cells from patients with chronic lymphocytic leukemia.

Ibrutinib increases miR-181a/b in leukemic cells from patients with chronic lymphocytic leukemia.

Blood biomarkers are altered in elderly hematological patients exhibiting a mosaic loss of the Y chromosome in bone marrow cells

BackgroundMosaic loss of the Y chromosome (LOY) is a frequent somatic alteration observed in aging males, linked to clonal hematopoiesis and elevated risks of hematologic malignancies. However, the direct physiological implications of LOY in elderly patients with hematologic disorders remain unclear. We investigated blood biomarker changes associated with LOY in elderly male patients with hematologic malignancies.MethodsWe retrospectively analyzed 196 elderly male patients (median age, 71 years) with LOY detected via bone marrow karyotyping (2017–2022). Participants were stratified into four groups: no disease (n = 22); acute myelogenous leukemia, myelodysplastic syndrome (including refractory anemia [RA], refractory anemia with excess blasts [RAEB], and RAEB in transformation [RAEB-T]), chronic myelomonocytic leukemia (CMML) (AML/MDS group, n = 52); multiple myeloma (MM, n = 37); and chronic lymphocytic leukemia (CLL), Hodgkin’s lymphoma (HL), and non-Hodgkin’s lymphoma (NHL) (CLL/lymphoma group, n = 85). Controls (n = 120) exhibited normal 46,XY karyotypes. Blood markers (n = 22)—including blood cell counts, cytokines, immunoglobulins, and thyroid hormones—were assessed using non-parametric tests and multivariate regression analysis.ResultsLOY was detected in 4% of patients (3% pure LOY, 1% LOY with additional abnormalities). AML/MDS patients with LOY were younger (median 68.5 vs. 75.5 years in no-disease, p = 0.004) and exhibited higher LOY burden (60% vs. 33% in CLL/lymphoma, p < 0.001). Multivariate analysis revealed age as an independent risk factor for AML/MDS (p = 0.002), while LOY burden specifically correlated with CLL/lymphoma (p = 0.012). Distinct biomarker profiles emerged: LOY-positive AML/MDS patients showed reduced hemoglobin, platelets, and cytokines (e.g., reduced interleukin-2, interferon-gamma) versus controls (p < 0.05), whereas CLL/lymphoma cases correlated with decreased immunoglobulins (IgM) and cytokines (e.g., interleukin-4, interleukin-17 A). Notably, individuals without hematologic disease exhibited stable biomarker profiles irrespective of LOY status, suggesting context-dependent effects of LOY. A high LOY burden (≥ 75%) was associated with cytopenias in AML/MDS, characterized by decreased white blood cell (WBC) count, neutrophil count (NEC), and platelet (PLT) count (p < 0.05).ConclusionLOY exhibits disease-specific associations with immune-metabolic dysregulation, particularly in AML/MDS and CLL/lymphoma. Its varying burden and biomarker profiles suggest potential utility in risk stratification, warranting further prospective validation.

Resistance to Bruton Tyrosine Kinase Inhibitors.

Resistance to Bruton Tyrosine Kinase Inhibitors.

Abstract B046: Enhancing the Diagnosis and Monitoring of Chronic Lymphocytic Leukemia with Artificial Intelligence-Driven Peripheral Blood Smear Image Analysis

Abstract Chronic lymphocytic leukemia (CLL), the most common leukemia in adults, presents with a broad morphological spectrum, particularly as the disease progresses. Peripheral blood (PB) smear review is essential for evaluating neoplastic cell morphology in CLL. Manual PB smear review, however, is labor-intensive, time-consuming, and subject to inter-observer variability. These limitations underscore the need for more objective and scalable diagnostic tools. Integrating artificial intelligence (AI) into CLL diagnostics may offer a promising solution for automating and standardizing PB smear evaluation. To develop the Convolutional Neural Network (CNN) models for CLL, we are expanding our current image database for MDA-LeukoLens system to include three more categories: (1) typical and atypical CLL cells, (2) prolymphocytes, and (3) large lymphoma cells. Given the variability in cell size across PB smears, we use the ratio of lymphocyte-to-RBC surface area, calculated as the square of the diameter ratio, for quantitative analysis. Approximately 10,000 CellaVision images per cell type are being collected for CNN model training. In addition to having one WBC, each CellaVision image also contains multiple RBCs. The image analysis model for this CLL project was used to create bounding boxes around all RBCs, and those with similar x- and y-axis diameters were selected to calculate the average RBC area per image. The area of each CNN-classified lymphocyte was then compared to the average RBC area in the same image by computing the ratio of the bounding box of the lymphocyte and the average bounding box area of the RBCs. RBCs in approximately 1,000 CellaVision images were labeled with bounding box to train the model for RBC cropping. An independent 1,001 CellaVision images containing atypical lymphoid cells from CLL patients were used to calculate the size ratio of lymphoid cells to RBCs. In the typical CLL cases (737 images), the size of atypical lymphoid cells was variable with the lymphocyte-to-RBC area ratio ranging from 0.5 to 4.49. Approximately 90% of lymphocytes were within the 1.0–2.5 range (1.0–1.49: 27.4%; 1.5–1.99: 42.9%; 2.0–2.49: 19.9%), with only 2.7% exceeding a ratio of 3.0. In the case of accelerated phase (67 images), the area ratio ranged from 2.0 to 7.99. 1.0–2.5: 6.0%; 2.5–4.0: 44.8%, 4.0–5.99: 40.3%, and 6.0–6.99: 7.5%. In the cases of Richter transformation (197 images), the area ratio ranged from 2.5 to 9.99, specifically, 1.0–2.5: 0%; 2.5–4.0: 10.2%; 4.0–5.99: 47.2%; and 6.0–9.99: 28.4%. In summary, our AI-assisted image analysis has revealed certain morphological variability among neoplastic B cells, even in classical CLL cases. A higher proportion of large lymphoid cells correlates with disease progression. This approach has demonstrated improved performance over existing automated imaging platforms and traditional reporting workflows. Overall, these findings support the utility of AI-assisted image analysis in reducing observer variability and providing a scalable framework for monitoring disease evolution and progression in CLL. Citation Format: J. Matthew. Liu, Yun Gong, Amaris Shi, Jeffrey Liu, Xiaoping Sun, Zhihong Hu. Enhancing the Diagnosis and Monitoring of Chronic Lymphocytic Leukemia with Artificial Intelligence-Driven Peripheral Blood Smear Image Analysis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Artificial Intelligence and Machine Learning; 2025 Jul 10-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(13_Suppl):Abstract nr B046.

Efficacy, Toxicity and Effect of Pretreatment Cardiologic Consultation on Outcomes of Ibrutinib Therapy for Chronic Lymphocytic Leukemia—A KroHem Study

Background/Objectives: Ibrutinib has revolutionized the treatment of chronic lymphocytic leukemia but has off-target side effects, most notably cardiac. In order to evaluate the efficacy and toxicity of ibrutinib treatment, risk factors for adverse outcomes and the influence of pretreatment cardiologic evaluation, KroHem collected data on Croatian patients with chronic lymphocytic leukemia treated with this drug. Methods: This is a retrospective survey performed in order to analyze the efficacy and toxicity of ibrutinib in a real-life setting. Patients starting therapy with ibrutinib for chronic lymphocytic leukemia between the time the drug became reimbursable in 2015 and 31 December 2021 were included, irrespective of treatment line. Results: We identified 436 patients fulfilling entry criteria; 404 (92.7%) responded to treatment. Cardiovascular side effects occurred in 25.0% of patients and hemorrhagic in 15.6%. The dose of ibrutinib was permanently reduced in 22.2% of patients. Median follow-up of the cohort was 29 months (IQR 18–41 months), estimated median overall survival 75 months (IQR 36 months–not reached), progression-free survival 54 months (IQR 24–81 months) and time on ibrutinib treatment 44 months (IQR 14–78 months). Factors significantly related to overall survival in multivariate analysis were stage, treatment line and age. Factors significantly related to progression-free survival in multivariate analysis were treatment line, age and pretreatment history or ECG finding of cardiac arrhythmia. Factors significantly related to time on ibrutinib treatment in multivariate analysis were age, pretreatment history or ECG finding of cardiac arrhythmia, and permanent dose reduction for toxicity. Sex, FISH and the presence of arterial hypertension were not independently significantly related to any of these outcomes. Pretreatment cardiologic consultation did not improve time on ibrutinib therapy, progression-free survival, overall survival, risk of stopping treatment due to cardiovascular side effects or risk of cardiovascular or sudden death, neither in the whole cohort nor in the subgroup of patients with and without pretreatment cardiac arrhythmia. Conclusions: Our analysis confirms the efficacy and tolerability of ibrutinib for the treatment of chronic lymphocytic leukemia. Patients older than 75 do significantly less well. Routine pretreatment cardiologic consultation does not improve outcomes and should not be considered part of standard pretreatment assessment without additional proof of its usefulness. Future investigations should aim at identifying predictive factors, mechanisms, and preventive strategies for reducing cardiotoxicity in chronic lymphocytic leukemia patients taking Bruton tyrosine kinase inhibitors.

A noncoding mutation in the NOTCH1 gene initiates oncogenic NOTCH signaling via wild-type NICD stabilization in CLL.

A noncoding mutation in the NOTCH1 gene initiates oncogenic NOTCH signaling via wild-type NICD stabilization in CLL.

Clinicopathologic, genetic, and prognostic characteristics of single-hit versus multi-hit TP53-mutated chronic lymphocytic leukemia in the era of novel therapies.

Clinicopathologic, genetic, and prognostic characteristics of single-hit versus multi-hit TP53-mutated chronic lymphocytic leukemia in the era of novel therapies.

Physical Activity, Symptoms, Quality of Life and Exercise Program Preferences in People With Chronic Lymphocytic Leukaemia

ABSTRACTBackgroundChronic lymphocytic leukaemia (CLL) has a heterogeneous lifelong course. While some patients never require treatment, most experience intermittent periods of active monitoring with other time points in active treatment. Most patients experience significant symptoms which negatively impact their quality of life (QoL). Although physical activity and exercise may help manage symptoms, it is unclear what disease‐related factors drive the physical inactivity observed in people with CLL.MethodsThis study explored physical activity among people with CLL and assessed differences and relationships in treatment stage, symptoms, quality of life, and preferences for physical activity using an online questionnaire.ResultsA total of 128 individuals with CLL [66 M/62F: mean age 67 ± 9.1 years (range 38–91 years)] completed the questionnaire. Those who are being/have been treated (N = 55) exhibited worse QoL (p = 0.018) and lower engagement in higher levels of physical activity (p = 0.045) when compared to their treatment naïve (N = 73) counterparts. Both groups had similar symptomology, with fatigue (∼77%) and insomnia (∼55%) being the most reported and associated with less likelihood of being physically active. Physically active participants reported better QoL (p = 0.020), physical functioning (p = 0.003) and role functioning (p = 0.020) as well as lower levels of fatigue (p = 0.036), pain (p = 0.017) and symptom burden (p = 0.026) compared to those who were insufficiently active. Although 79% of respondents wanted to engage in exercise programs for their CLL, 70% reported never receiving exercise guidance from their healthcare professionals.ConclusionThese findings highlight a significant need for targeted interventions to increase physical activity, likely improving QoL, in people with CLL. Furthermore, there is considerable interest from the CLL community in receiving exercise guidance; however, factors such as treatment status and symptomology should be considered when developing CLL‐specific exercise programs.

Disseminated Mucormycosis in an Immunocompromised Patient with Richter Transformation of Chronic Lymphocytic Leukemia: A Case Report of Concurrent Findings on [18F]-Fluorodeoxyglucose PET-CT

Abstract A case of chronic lymphocytic leukemia/small lymphocytic lymphoma with Richter transformation. After initiating R-CHOP chemotherapy, patient developed severe neutropenia and necrotizing cellulitis, necessitating an above-knee amputation. Subsequent positron emission tomography-computed tomography (PET-CT) imaging revealed new lesions suggestive of an abscess, confirmed as mucormycosis upon biopsy. This report highlights the importance of fludeoxyglucose PET-CT in detecting fungal infections in immunocompromised patients and its role in disease management.

Thrombotic Thrombocytopenic Purpura Triggered by Chronic Lymphocytic Leukemia: A Case Report

Background: Chronic lymphocytic leukemia (CLL) is an incurable lymphoproliferative disorder characterized by the accumulation of mature malignant B-cells in the blood, bone marrow, and secondary lymphoid tissues. While it has a heterogenous clinical course, individuals with CLL are at increased risk for autoimmune complications, infections, and secondary non-hematologic secondary malignancies. Peripheral autoimmune cytopenias are a well-known phenomenon in CLL. However, other autoimmune complications, including immune thrombotic thrombocytopenic purpura (TTP), are rare and less investigated. We hereby report the first case of a patient with TTP triggered by CLL. Case report: A 74-year-old male presented with fatigue, cough, left upper quadrant abdominal pain, and diffuse petechiae over the proceeding several weeks. The initial laboratory work was suggestive of anemia and thrombocytopenia with hemoglobin of 9.4 g/dl and platelets at 6 x 109/L. He was initially started on corticosteroids and intravenous immunoglobulin. Additional laboratory studies revealed a microangiopathic hemolytic with lactate dehydrogenase 1,124 U/L; total bilirubin 3.9; haptoglobin undectectable. The direct Coombs’ test was negative, and review of peripheral smear showed 5-6 schistocytes per high power field. Leukocyte count 15.6 x 109/L with absolute lymphocyte count of 4.0 K/ul. ADAMTS13 activity was &lt; 9%. A diagnosis of TTP was made, and he was initiated on directed therapy. A bone marrow biopsy was ultimately performed, given the concern of immune-mediated or disease-related cytopenias and for confirmation of CLL. Subsequent bone marrow biopsy and flow cytometry confirmed the diagnosis of CLL. Conclusion: Our case illustrates the first case of TTP precipitated by CLL. This case highlights the immune dysregulation underlying CLL and the autoimmune phenomena that may develop as a result.

&lt;b&gt;Patterns of hematological malignancies in Kordofan Oncology Center, Sudan&lt;/b&gt;

Background: Hematological Malignancies (HM) incidence is uprising in developing countries with limited resources especially in Sudan. Methodology: This descriptive retrospective study was conducted by utilizing leukemia data acquired from Kordofan Oncology Center for Chemotherapy, El-Obeid, Sudan between 2016 to 2023. The study included a total of one hundred patients. Data were retrieved from the files of patients who were admitted to Kordofan Oncology center with hematological malignancies. Results: CLL is the most prevalent HM representing 61%, followed by CML accounting for 17%, then NHL which is 11%, MM 6% and HL 3%. Approximately 58% of males and 42% of females were affected with HM. Although HM were more prevalent among older individuals, chronic lymphocytic leukemia (CLL) was more usually observed in those aged over 71 years, accounting for 23 out of 61 cases (36%). The majority of participants in this study were persons residing in urban areas. The majority of patients with HM were housewives, followed by self-employed individuals and farmers, accounting for 31 out of 88 (35%), 28 out of 88 (32%), and 13 out of 88 (15%) patients, respectively. Regarding staging 39% of patients were at stage 1, 27% patients stage II, 25% patients stage IV, and 9% patients at stage III. Hamar appears to be the most affected tribe (9%), followed by Dar Hamed, Hawazma, Jalia, Gawamaa and Nuba (2%) each. Conclusion: CLL was the dominant type of hematological malignancies observed in Kordofan Oncology Center. beside the majority of cases were observed among males, urban residents, and elder populations aged &gt;70 years. Special focus should be given to the highly affected population. Further more detailed studies are required in the Sudan.

Richter transformation: biological insights, diagnostic challenges and emerging therapies.

this review aims to underscore the significance of the growing number of advances related to Richter transformation (RT), an aggressive form of lymphoma arising in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma. The development of sequencing analytic tools and single-cell approaches has overcome the major challenge of cellular admixture in RT, enabling a deeper understanding of the genetic alterations driving transformation from CLL to RT. These techniques have also made it possible to detect RT clones long before clinical onset. In parallel, novel targeted therapies for CLL and immunotherapeutic strategies for lymphomas are offering renewed hope. Recent phase 2 studies notably support the potential role of immune checkpoint inhibitors and bispecific T-cell engagers in RT, while experience with chimeric antigen receptor T-cell therapies continues to grow, raising hopes for improved outcomes in this historically difficult-to-treat condition. recent research is focusing on better understanding the transformation process, improving the early detection of RT, and developing novel targeted and immunotherapy treatments and combinations for patients with RT.

Concurrent Metastatic Clear Cell Renal Cell Carcinoma and Chronic Lymphocytic Leukemia Within the Same Lymph Node: A Case Report and Review of Dual Malignancy Management

Concurrent Metastatic Clear Cell Renal Cell Carcinoma and Chronic Lymphocytic Leukemia Within the Same Lymph Node: A Case Report and Review of Dual Malignancy Management

Precision Medicine in Hematologic Malignancies: Evolving Concepts and Clinical Applications

Precision medicine is transforming hematologic cancer care by tailoring treatments to individual patient profiles and moving beyond the traditional “one-size-fits-all” model. This review outlines foundational technologies, disease-specific advances, and emerging directions in precision hematology. The field is enabled by molecular profiling techniques, including next-generation sequencing (NGS), whole-exome sequencing (WES), and RNA sequencing (RNA-seq), as well as epigenomic and proteomic analyses. Complementary tools such as liquid biopsy and minimal residual disease (MRD) monitoring have improved diagnosis, risk stratification, and therapeutic decision making. We discuss major molecular targets and personalized strategies across hematologic malignancies: FLT3 and IDH1/2 in acute myeloid leukemia (AML); Philadelphia chromosome–positive and Ph-like subtypes in acute lymphoblastic leukemia (ALL); BCR-ABL1 in chronic myeloid leukemia (CML); TP53 and IGHV mutations in chronic lymphocytic leukemia (CLL); molecular subtypes and immune targets in diffuse large B-cell lymphoma (DLBCL) and other lymphomas; and B-cell maturation antigen (BCMA) in multiple myeloma. Despite significant progress, challenges remain, including high costs, disparities in access, a lack of standardization, and integration barriers in clinical practice. However, advances in single-cell sequencing, spatial transcriptomics, drug repurposing, immunotherapies, pan-cancer trials, precision prevention, and AI-guided algorithms offer promising avenues to refine treatment and improve outcomes. Overcoming these barriers will be critical for ensuring the equitable and widespread implementation of precision medicine in routine hematologic oncology care.

Underlying Chronic Lymphocytic Leukemia in a Case of Vivax Malaria With Thrombocytopenia: A Case Report

Underlying Chronic Lymphocytic Leukemia in a Case of Vivax Malaria With Thrombocytopenia: A Case Report

SOX4 in chronic lymphocytic leukaemia: the forgotten transcription factor

PurposeSRY-box transcription factor 4 (SOX4) is a transcription factor involved in early B cell development and has been implicated in various malignancies; however, its role in chronic lymphocytic leukemia (CLL) remains poorly understood. This study investigated the correlation between SOX4 expression and prognostic factors in CLL to determine its relevance to disease progression and clinical outcomes.MethodsA cohort of patients with CLL with a known immunoglobulin heavy chain variable region (IGHV) mutational status was analyzed for SOX4 expression using quantitative polymerase chain reaction (qPCR). Correlations between SOX4 levels and established prognostic markers including IGHV mutational status, cytogenetic abnormalities, and clinical outcomes were evaluated. Statistical analyses were performed to assess the association between SOX4 expression and patient survival.ResultsHigher SOX4 expression was observed to be significantly associated with unmutated CLL (U-CLL) and adverse prognostic markers, including del(17)(p13). In contrast, lower SOX4 levels were observed in mutated CLL (M-CLL), and cytogenetic abnormalities were noted to be linked to favorable outcomes [del(13)(q21)]. Survival analysis indicated that elevated SOX4 expression was correlated with poor prognosis.ConclusionSOX4 expression stratifies CLL subtypes and aligns with established prognostic markers. High SOX4 levels are associated with aggressive disease phenotypes, whereas low SOX4 expression is associated with better clinical outcomes. These findings indicate that SOX4 may serve as a potential biomarker for disease classification and risk stratification. Further studies are required to elucidate the biological significance of this phenomenon.

Patterns of development of immune complications in patients with lymphoproliferative diseases receiving rituximab therapy

Rituximab is a synthetic (genetically engineered) chimeric monoclonal antibody that has occupied its niche of application not only in relation to lymphoproliferative diseases (non-Hodgkin lymphomas and chronic lymphocytic leukemia), but also in relation to a number of other diseases. However, when using this drug, a number of complications occur, including immune ones. A certain pattern of development of immune complications has been revealed depending on the stage of therapy. During rituximab therapy, cases of transient decrease in B-lymphocytes or immunoglobulin levels are often reported, which are leveled 6-12 months after the end of treatment with this drug. It also describes the development of prolonged and persistent neutropenia, which develops delayed in relation to the end of therapy. There are risk factors associated with immunological complications: male gender, Caucasian race, age over 50 years, immunocompromised conditions (immunosuppressive therapy, primary and secondary immunodeficiency). The most effective methods of prevention include: detection of severe infectious complications in the last 6 months of patient follow-up, detection of a critical decrease in the level of class G immunoglobulins (less than 4 g /l) and its correction by immunosuppression therapy; determination of the content of mature B lymphocytes in peripheral blood and preventive sanitation of foci of chronic infection.

A novel method for the diagnosis and monitoring of cardiac arrhythmias in patients with chronic lymphocytic leukemia treated with ibrutinib.

A novel method for the diagnosis and monitoring of cardiac arrhythmias in patients with chronic lymphocytic leukemia treated with ibrutinib.

CD6 expression is an independent predictor of time to first treatment in chronic lymphocytic leukemia.

CD6 is a lymphocytic receptor expressed by all T cells and a subset of B and NK cells. It physically associates with the antigen-specific clonotypic receptor of T (TCR) cells, where it modulates the activation and differentiation signals delivered along lymphocyte development and upon peripheral antigen recognition. CD6 is also expressed in some B cell malignancies (e.g., chronic lymphocytic leukemia, CLL), though its biological role and clinical performance is largely unknown. To this end, we have evaluated the potential impact of CD6 differential expression in a CLL patient cohort. 270 CLL patient histories from the CLL-ES project with available RNA-Seq data have been analysed. High CD6 expression was found to be associated with mutated IGHV status and predictive of longer time to first treatment in a uni- and multivariable model (10-year probability of receiving treatment was 33 vs. 55 % in CD6hi and CD6lo groups, respectively, P = 0.0003) along with the lymphocyte count and the CLL International Prognostic Index. Further gene set enrichment analyses (GSEA) showed association of high CD6 expression with downregulation of MYC-regulated, mitotic spindle-related and RNA splicing-associated genes, all positively related to cancer progression. Interestingly, CD38, a widely studied adverse prognostic marker in CLL, was significantly downregulated in the CD6 high group, in agreement with flow cytometry data. These results reinforce the notion that CD6 may play a pivotal role in neoplastic B cell biology and lay the ground to further explore CD6 expression in the context of CLL prognoses.