Treatment Of Chronic Lymphocytic Leukemia Research Articles

Distinct NF-kB Regulation Favors a Synergic Action of Pevonedistat and Laduviglusib in B-Chronic Lymphocytic Leukemia Cells Ex Vivo

Background/Objectives: Chronic lymphocytic leukemia (CLL) remains an incurable B-cell malignancy. B-CLL cells exhibit an extended lifespan in part due to the activation of survival pathways such as NF-kB. A crosstalk between NF-kB and GSK-3β pathways has been reported. NF-kB has also been identified as a primary target of the NEDD8-activating enzyme inhibitor MLN4924. Our objective was to investigate potential synergies of MLN4924 with other NF-kB-targeting agents for the treatment of CLL and elucidate the mechanisms of action underlying this pathway regulation. Methods: To assess the cytotoxic efficacy of the combined ex vivo treatment with CHIR-99021 and MLN4924, we employed 7-AAD staining and XTT viability assays on primary samples from CLL patients. Subsequently, we conducted various analyses to identify the molecular mechanisms underlying the cytotoxic effects of this combination. Results: We discovered a discrepancy between the mRNA and protein levels of IkBɑ and provided evidence of translational control over its expression. This observation may explain why, unlike other cell types, B-CLL cells did not activate NF-kB signaling following inhibition of GSK-3ß. Furthermore, we describe a synergistic effect between a specific GSK-3ß inhibitor, CHIR-99021/Laduviglusib, and the NEDD8-activating enzyme inhibitor MLN4924/Pevonedistat, at doses that only slightly affect healthy B cell viability ex vivo. We investigated the molecular basis of this co-induction of cell death by analyzing the alterations in apoptosis-related gene expression. We found that the combinational treatment enhances a reduction in BCL2 mRNA expression levels, providing an alternative approach for BCL-2 inhibition in CLL that could have therapeutic implications for the treatment of refractory CLL cases. Conclusions: our findings revealed a unique interaction between GSK-3ß and NF-kB pathways in CLL and their regulation of BCL2 expression.

Comparative Safety of Ibrutinib Versus Zanubrutinib in Patients With Chronic Lymphocytic Leukemia: A Prospective Cohort Study.

This study compares the safety profiles of two Bruton's tyrosine kinase (BTK) inhibitors, Ibrutinib and Zanubrutinib, in patients with chronic lymphocytic leukemia (CLL). While Ibrutinib has transformed CLL treatment, it is associated with significant adverse events (AEs). Zanubrutinib, a second-generation BTK inhibitor, offers potential for improved safety. In this prospective study, 200 CLL patients were enrolled, with 100 receiving Ibrutinib and 100 receiving Zanubrutinib. Baseline characteristics such as age, sex, body mass index (BMI), Eastern Cooperative Oncology Group (ECOG) performance status, and genetic factors were evaluated. AEs and serious AEs (SAEs) were tracked and graded using the Common Terminology Criteria for Adverse Events (CTCAE). Multivariate logistic regression models were conducted to determine predictors of SAE and AEs grade ≥ 3. Adjusted odds ratio (aOR) and 95% confidence interval (CI) were reported. The mean ages of the Ibrutinib and Zanubrutinib groups were 49.65 and 49.16years, respectively (p=0.285). The Zanubrutinib group had a higher percentage of patients with worse ECOG status (71% vs. 57%, p=0.039). Fewer Zanubrutinib patients experienced severe AEs (4% vs. 9%, p=0.152) or SAEs (8% vs. 17%, p=0.054). Neutropenia occurred only in the Ibrutinib group (3%). Subgroup analysis showed a higher complication rate with Zanubrutinib in non-refractory patients (11.40% vs. 5.26%, p=0.065). Stage III CLL was a protective factor of grade ≥ 3 AEs (aOR=0.007; 95% CI: 0.0003-0.1829) and SAE (aOR=0.015; 95% CI: 0.001-0.177). While ECOS status (2 vs. 3) resulted in reduced risk of SAE, chromosome 17p deletion emerged as the main risk factor of SAE (aOR=6.40; 95% CI: 1.33-30.79). Zanubrutinib demonstrated a more favorable safety profile than Ibrutinib, with fewer severe adverse events. It may be a safer alternative for CLL patients, particularly those at higher risk for complications from BTK inhibitors. However, these differences stemmed from variability in baseline clinical characteristics rather than the interventions themselves.

Improving Treatment Options for Patients with Double Refractory CLL

The proliferation and survival of chronic lymphocytic leukemia (CLL) cells are heavily dependent on B-cell receptor (BCR) signaling and resistance to apoptosis. Approvals of multiple covalent Bruton’s tyrosine kinas inhibitors (cBTKis) as well as the B-cell lymphoma-2 inhibitor (BCL2i) venetoclax targeting these pathways have revolutionized the treatment of CLL and small lymphocytic lymphoma (SLL). The superiority of these treatments over chemoimmunotherapy has been proven in phase III studies in both treatment-naïve and relapsed refractory settings, leading to the majority of patients with CLL being treated sequentially with cBTKis and the BCL2i venetoclax as their first- and second-line therapies. While most patients with CLL respond for many years to these sequenced treatments, they are unfortunately not curative. There remains an unmet need for effective treatment options for patients who progressed after treatment with both cBTKis and BCL2i, also referred to as double refractory patients. Treatment options for double refractory CLL has improved recently with the approval of the non-covalent BTK inhibitor (ncBTKi) pirtobrutinib as well as the CD19 targeted chimeric antigen receptor T-cell (CAR T-cell) therapy lisocabtagene maraleucel (liso-cel). These recently approved treatment options for patients with CLL with at least two prior lines of therapy have fortunately demonstrated efficacy for double refractory CLL. Additionally, there are several novel treatment options in clinical development, including bi-specific antibodies, second-generation BCL2is, new ncBTKis, and BTK degraders. Understanding resistance mechanisms to existing cBTKis and venetoclax can potentially inform us of the best utilization of available treatment options for double refractory CLL and provide a personalized approach for these patients. In this review, a challenging example of a double refractory patient with CLL will serve as the basis for a review of available literature on the treatment of double refractory CLL/SLL.

The Impact of Targeted Therapies on Red Blood Cell Aggregation in Patients with Chronic Lymphocytic Leukemia Evaluated Using Software Image Flow Analysis.

Chronic lymphocytic leukemia (CLL), the most common type of leukemia, remains incurable with conventional therapy. Despite advances in therapies targeting Bruton's tyrosine kinase and anti-apoptotic protein BCL-2, little is known about their effect on red blood cell (RBC) aggregation in blood flow. In this study, we applied a microfluidic device and a newly developed Software Image Flow Analysis to assess the extent of RBC aggregation in CLL patients and to elucidate the hemorheological effects of the commonly applied therapeutics Obinutuzumab/Venetoclax and Ibrutinib. The results revealed that, in RBC samples from untreated CLL patients, complex 3D clusters of large RBC aggregates are formed, and their number is significantly increased compared to healthy control samples. The application of the Obinutuzumab/Venetoclax combination did not affect this aspect of RBCs' rheological behavior. In contrast, targeted therapy with Ibrutinib preserves the aggregation state of CLL RBCs to levels seen in healthy controls, demonstrating that Ibrutinib mitigates the alterations in the rheological properties of RBCs associated with CLL. Our findings highlight the alterations in RBC aggregation in CLL and the impact of different targeted therapies on RBCs' rheological properties, which is critical for predicting the potential complications and side effects of CLL treatments, particularly concerning blood flow dynamics.

Chimeric Antigen Receptor-T Cells in the Modern Era of Chronic Lymphocytic Leukemia Treatment.

Pathway inhibitors targeting Bruton tyrosine kinase (BTK) and B-cell lymphoma-2 (BCL-2) have dramatically changed the treatment landscape for both treatment-naïve and relapsed/refractory chronic lymphocytic leukemia (CLL). However, with increased utilization, a growing number of patients will experience progressive disease on both agents. This subgroup of "double refractory" patients has limited treatment options and poor prognosis. Chimeric antigen receptor (CAR)-T cells have transformed the treatment of relapsed/refractory B-cell malignancies. Although the earliest success of CAR-T cell therapy was in CLL, the clinical application of this modality has lagged until the recent approval of the first CAR-T cell product for CLL. In this review, we describe the current treatment options for upfront and subsequent therapies and the unmet need for novel agents highlighted by the burgeoning role and challenges of CAR-T cell therapy.

Incidence and impact of other malignancies after immunochemotherapy by fludarabine, cyclophosphamide, and rituximab as frontline treatment for chronic lymphocytic leukemia: A single-center retrospective study.

Individuals with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have a high risk of developing other malignancies (OMs). The development of OMs may be associated with the advanced age of CLL/SLL patients, presence of a tumor-promoting microenvironment, immune alterations inherent to CLL/SLL, or chemotherapy. Importantly, the occurrence of OMs following frontline fludarabine, cyclophosphamide and rituximab (FCR) treatment is associated with a reduction in the overall survival (OS). This retrospective study included 108 CLL/SLL patients treated with FCR immunochemotherapy, as a first line treatment. With a median follow-up of 94.9 (6-222) months, 31% developed an OM or more, within a median of 61.8 months post-FCR initiation. The most common OMs were non-melanoma skin cancers (7%), Richter’s syndrome (RS) (7%), myelodysplastic syndromes (6%), prostate cancer (4%), and acute myeloid leukemia (3%). Patients with OMs had shorter survival compared to those without (104.0 versus 149.0 months, P=0.02), with RS having the worst OS at 4.8 months (P<0.0001), followed by therapy-related myeloid neoplasia (t-MN) at 14.5 months. Although the onset of OMs in patients with CLL/SLL was observed after considerable delays, its impact on survival is significant in the immunochemotherapy era, necessitating a better understanding of these patterns to improve CLL/SLL management and guide future treatment strategies.

Managing novel therapies and concomitant medications in chronic lymphocytic leukemia: key challenges.

The treatment of chronic lymphocytic leukemia (CLL) consists of the continuous use of Bruton tyrosine kinase inhibitors (BTKis) such as ibrutinib, acalabrutinib, zanubrutinib and pirtobrutinib, or Bcl-2 inhibitors, such as venetoclax. Overall survival (OS) and progression-free survival (PFS) of CLL patients are significantly improved with the use of these therapies. Adverse effects (AEs) that can occur during treatment and the presence of pre-existing comorbidities in patients can influence subsequent treatment outcomes and, consequently, OS and PFS. Managing these AEs, including cardiologic toxicity and infections (including fungal infections), as well as treating cardiovascular and other comorbidities, can be challenging due to potential drug interactions with the medications used for the management of AEs and comorbidities. Therefore, this review examined the key challenges associated with the concomitant use of novel CLL therapies and medications for managing comorbidities and AEs. This review aims to enhance and facilitate the management of patients with CLL.

BTKi-induced cardiovascular toxicity in CLL: Risk mitigation and management strategies.

Targeted therapies, consisting of Bruton tyrosine kinase inhibitors (BTKis) or BCL-2 inhibitors, are the mainstay of contemporary treatments for chronic lymphocytic leukemia (CLL). The most common adverse effects (AEs) of BTKis are fatigue, bruising, infection, hematological and cardiovascular AEs. While AEs during treatment are usually mild (grades 1 and 2), grade 3 and 4 AEs have been detected in some patients, necessitating additional medical care and temporary or permanent drug discontinuation. In this review, we analyzed the cardiovascular effects associated with BTKi therapy for CLL and the essential practical aspects of multidisciplinary management of patients who develop cardiovascular toxicity during treatment. We particularly focus on the data and strategies for controlling cardiovascular risks associated with ibrutinib and newer BTKis (acalabrutinib, zanubrutinib and pirtobrutinib), including the development of atrial fibrillation, hypertension, ventricular arrhythmias, sudden death, heart failure, bleeding, and ischemic complications (stroke and myocardial infarction). This review highlights hematological insights underlying cardiotoxicity, an area that has received limited attention in comparison to the predominantly cardiological perspective. This review synthesizes emerging evidence on hematological biomarkers, cardiotoxic mechanisms, and therapeutic interventions, linking hematology and cardiology to enhance understanding and guide comprehensive prevention and management strategies.

Differentiation of the chronic lymphocytic leukemia response to ibrutinib and acalabrutinib treatment by single-cell MALDI-TOF MS imaging.

Ibrutinib and acalabrutinib, Bruton's tyrosine kinase inhibitors (BTKi) used for chronic lymphocytic leukemia (CLL) treatment, aim the same target but their off-target effects are different. The aim of this study was to use single-cell MALDI TOF mass spectrometry imaging to compare the CD19+lymphocytes' mass spectra in untreated and ibrutinib- or acalabrutinib-treated subjects in order to better understand the therapeutic effect of BTKi. 180 cells from 9 male subjects divided in 3 groups (untreated, ibrutinib-treated and acalabrutinib-treated) were analyzed using MALDI-TOF mass spectrometry analyzer. Mass spectra were acquired in the 300-600 Da mass range. Partial least squares discriminant analysis (PLS-DA) was used for evaluation of mass spectra, while Volcano plots and Venn diagram were used for a review of significantly altered m/z values. Cross-validated PLS-DA classification accuracy of cells was 85 %. Ibrutinib-treated cells overlap with the untreated cell population, while acalabrutinib-treated cells form a separate class. 13 m/z signals were specific for each BTKi group. In conclusion, single-cell MALDI-TOF mass spectrometry imaging detects differences in the mass spectra of CD19+ lymphocytes treated with two different BTKi. Drug-specific m/z signal clusters can be identified as a chemical fingerprint of the BTKi effect and represent candidates for the therapeutic response biomarkers.

ENPP2 promotes progression and lipid accumulation via AMPK/SREBP1/FAS pathway in chronic lymphocytic leukemia

BackgroundDisorders of lipid metabolism are critical factors in the progression of chronic lymphocytic leukemia (CLL). However, the characteristics of lipid metabolism and related regulatory mechanisms of CLL remain unclear.MethodsHence, we identified altered metabolites and aberrant lipid metabolism pathways in patients with CLL by ultra-high-performance liquid chromatography-mass spectrometry-based non-targeted lipidomics. A combination of transcriptomics and lipidomics was used to mine relevant target molecule and downstream signaling pathway. In vitro cellular assays, quantitative real-time polymerase chain reaction (qRT-PCR), western blot, fluorescent staining, RNA sequencing, and coimmunoprecipitation were used to monitor the molecular levels as well as to explore the underlying mechanisms.ResultsSignificant differences in the content of 52 lipid species were identified in CLL samples and healthy controls. Functional analysis revealed that alterations in glycerolipid metabolism, glycerophospholipid metabolism, sphingolipid metabolism, and metabolic pathways had the greatest impact on CLL. On the basis of the area under the curve value, a combination of three metabolites (phosphatidylcholine O-24:2_18:2, phosphatidylcholine O-35:3, and lysophosphatidylcholine 34:3) potentially served as a biomarker for the diagnosis of CLL. Furthermore, utilizing integrated lipidomic, transcriptomic, and molecular studies, we reveal that ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) plays a crucial role in regulating oncogenic lipogenesis. ENPP2 expression was significantly elevated in patients with CLL compared with normal cells and was validated in an independent cohort. Moreover, ENPP2 knockdown and targeted inhibitor PF-8380 treatment exerted an antitumor effect by regulating cell viability, proliferation, apoptosis, cell cycle, and enhanced the drug sensitivity to ibrutinib. Mechanistically, ENPP2 inhibited AMP-activated protein kinase (AMPK) phosphorylation and promoted lipogenesis through the sterol regulatory element-binding transcription factor 1 (SREBP-1)/fatty acid synthase (FAS) signaling pathway to promote lipogenesis.ConclusionsTaken together, our findings unravel the lipid metabolism characteristics of CLL. Moreover, we demonstrate a previously unidentified role and mechanism of ENPP2 in regulation of lipid metabolism, providing a novel therapeutic target for CLL treatment.

Obinutuzumab in Combination with Alternative Chlorambucil Schedules in Front-Line Treatment of Chronic Lymphocytic Leukemia: A Study by KroHem, the Croatian Cooperative Group for Hematologic Diseases.

Background/Objectives: Obinutuzumab was approved for front-line treatment of chronic lymphocytic leukemia in combination with chlorambucil pulses administered every 2 wks. Alternative schedules of chlorambucil enable the administration of higher total chlorambucil doses, and have better antileukemia activity. So far, evidence on the feasibility of combining obinutuzumab with alternative chlorambucil schedules is lacking. We performed this retrospective analysis to analyze real life outcomes in chronic lymphocytic leukemia patients receiving a combination of obinutuzumab with different chlorambucil schedules. Methods: This was a retrospective survey performed in order to analyze the feasibility and efficacy of different obinutuzumab and chlorambucil combinations in a real-life setting. Patients receiving this combination as a front-line therapy for chronic lymphocytic leukemia in participating centers, outside of clinical trials, in 2017 and 2018 were included. Results: Seventy-three patients fulfilling entry criteria were identified. Their median age was 76 years, and ranged from 58 to 90 years. The median follow up time was 59 months. The response rate was 89%, with a median progression-free survival time of 27 months, and an overall survival time of 49 months. Chlorambucil was administered as planned in 15 of the 22 (79%) patients treated with chlorambucil pulses every 2 weeks; in 15 of the 42 (34%) patients treated with 7-day courses of chlorambucil administered every 4 weeks; and in 0 of the 10 patients treated with a continuous high dose of chlorambucil (p = 0.002). Changes in treatment schedules were made due to side effects. The progression-free and overall survival rates were similar between the three groups. Conclusions: The combinations of obinutuzumab with more intensive chlorambucil schedules are less feasible, preventing the administration of the intended higher total dose of chlorambucil, and do not improve outcomes in comparison to chlorambucil pulses administered every 2 weeks.

Real-World Treatment Patterns After Discontinuation of Venetoclax or BTKis in the Frontline Setting Among Older Adults With Chronic Lymphocytic Leukemia.

Venetoclax and Bruton's tyrosine kinase inhibitors (BTKis) are key treatment options for patients with chronic lymphocytic leukemia (CLL) in the frontline setting. This study characterized postdiscontinuation treatment patterns and hospitalization of frontline venetoclax and BTKis in a national sample of older adults with CLL. We identified 1,770 Medicare beneficiaries 66 years and older with CLL initiating venetoclax with obinutuzumab (VEN-O, n = 193) or BTKi treatment (n = 1,577) in the frontline setting between June 01, 2019, and June 30, 2020. Discontinuation was defined as a consecutive 90-day gap in treatment at any point over an 18-month follow-up. BTKi patients were expected to receive treatment continuously; VEN-O patients were expected to complete 11 months of treatment (12 cycles × 28 days = 336 days). The rates of subsequent CLL treatment and all-cause/CLL-related hospitalization were assessed. Over an 18-month follow-up, 102 (52.8%) VEN-O patients discontinued after completing the fixed-duration period; 597 (37.9%) BTKi and 57 (29.5%) VEN-O patients discontinued treatment prematurely. The median time to discontinuation was 11.9 months (VEN-O) and 4.0 months (BTKi patients), respectively. Few patients (n < 11) who discontinued VEN-O initiated another CLL treatment over a median postdiscontinuation follow-up period of 6.1 months. By contrast, 39.0% of discontinuers in the BTKi group had evidence of subsequent CLL treatment over a median 13.8-month postdiscontinuation follow-up period. Post-BTKi regimens included BCL-2 (35.6%), subsequent BTKi (31.8%), chemotherapy (14.6%), anti-CD20 monotherapy (9.9%), and other (8.2%). The rate of postdiscontinuation all-cause and CLL-related hospitalization per 100 patient-months was 2.0 and 1.5 for the VEN-O group and 3.3 and 2.9 for the BTKi group, respectively. In this real-world study, early discontinuation was more common in patients initiating a BTKi in contrast to VEN-O. Patients who initiated a BTKi also had high rates of subsequent treatment and hospitalization.

CAR-T CELL THERAPY FOR CHRONIC LYMPHOCYTIC LEUKEMIA: A PROMISING IMMUNOTHERAPY APPROACH

Chronic Lymphocytic Leukemia (CLL) is a prevalent hematological malignancy with limited curative options, necessitating innovative and effective therapeutic approaches. Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a transformative treatment modality, leveraging genetically modified T cells for targeted antitumor activity. This study explores the advancements in CAR T cell therapy for CLL, emphasizing its clinical potential, key manufacturing processes, structural design, therapeutic mechanisms, safety considerations, and strategies for optimizing efficacy. A comprehensive analysis of current literature and clinical data was conducted to examine CAR T cell manufacturing processes, including T cell source selection, activation, genetic modification, and expansion. Detailed evaluation of CAR T cell structural components and generational developments provided insights into their design and functionality. Additionally, therapeutic mechanisms, antigen selection strategies, and toxicity management approaches were critically reviewed. Key findings highlight the iterative advancements across four generations of CAR T cells, enhancing their antitumor efficacy, targeting specificity, and safety profile. Optimal target antigen selection and refinement of structural components, such as the ectodomain, transmembrane domain, and endodomain, significantly contributed to improved functionality. While CAR T cell therapy demonstrated robust antitumor activity in CLL, associated toxicities remain a challenge. Ongoing efforts focus on mitigating adverse events and optimizing clinical outcomes. CAR T cell therapy represents a promising paradigm shift in CLL treatment, combining precision targeting with potent antitumor effects. Continued advancements in design, manufacturing, and safety strategies underscore its transformative potential to improve patient outcomes and revolutionize CLL therapeutics. Further clinical trials and research are warranted to fully realize its therapeutic promise.

Liposomal Encapsulation of Chlorambucil with a Terpyridine-Based, Glutathione-Targeted Optical Probe Facilitates Cell Entry and Cancer Cell Death.

The nitrogen mustard alkylating agent chlorambucil (CBL) is a critical component of chemotherapeutic regimens used in the treatment of chronic lymphocytic leukemia. The cancer cell-killing actions of CBL are limited by glutathione (GSH) conjugation, a process catalyzed by the GSH transferase hGSTA1-1 that triggers CBL efflux from cells. In the cancer cell microenvironment, intracellular GSH levels are elevated to counterbalance oxidative stress generated due to the high glycolytic demand. As many chemotherapeutic drugs trigger cell death through mechanisms that depend on reactive oxygen species (ROS), antioxidant capacity in cancer cells also represents a barrier to anticancer therapies. Here, we demonstrate that a heightened GSH content in cancer cells can also be exploited for cell-selective drug delivery. We successfully synthesized a malononitrile conjugate terpyridine-based derivative L1, which specifically reacts with GSH in the presence of other biologically relevant amino acids including cysteine (Cys) and homocysteine (Hcy). The significant change in the electronic spectra of L1 in the presence of GSH confirmed GSH detection, which was further corroborated by density functional theory calculations. We next encapsulated CBL into L1-containing, anthracene-functionalized, and 10,12-pentacosadiynoic acid (PCDA)- and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)-based liposomes (Lip-CBL-L1). We established successful CBL encapsulation and release from L1-containing liposomes in GSH-enriched cancer cells in vitro. Both Lip-CBL-L1 and the L1-lacking Lip-CBL control displayed cell-killing activity. However, human triple-negative breast cancer cells MDAMB231, human lung cancer cells A549, and murine leukemic WEHI cells were more sensitive to the cytotoxic effects of Lip-CBL-L1 compared to the nonmalignant cells (AC16 and HEK293). Indeed, in these cancer cell lines, Lip-CBL-L1 induced greater ROS generation compared to that of Lip-CBL. Together, our results provide initial evidence of the feasibility of exploiting the unique oxidant environment of cancer cells for optimized drug delivery.

Differential Cardiotoxicity of Ibrutinib Versus Chemoimmunotherapy in Chronic Lymphocytic Leukemia: A Population-Based Study.

Background: Chronic lymphocytic leukaemia (CLL) is the most common form of leukaemia among adults, particularly in Western nations. The introduction of Bruton's tyrosine kinase (BTK) inhibitors as a treatment of CLL, namely, ibrutinib, which is a first-generation BTK inhibitor, has significantly improved the treatment landscape for CLL. However, ibrutinib has been associated with an increased risk of atrial fibrillation (AF) and hypertension. Real-world studies that compare the cardiovascular safety of ibrutinib with bendamustine plus anti-CD20 monoclonal antibody are not widely available. Methods: A retrospective cohort analysis using the TriNetX platform identified two patient groups: one treated with ibrutinib and the other with bendamustine and an anti-CD20 antibody. Propensity score matching balanced their demographic and clinical characteristics. The outcomes evaluated included the all-cause mortality and new-onset AF/flutter, hypertension, heart failure, ventricular arrhythmias, and bleeding. Results: No significant difference was observed in the all-cause mortality between the two cohorts. However, ibrutinib was associated with a higher risk of AF/flutter (HR 1.89, 95% CI 1.36-2.62; p < 0.05) and hypertension (HR 1.22, 95% CI 1.01-1.47; p = 0.04). Other outcomes, such as heart failure, ventricular arrhythmias, and bleeding, were not different between the cohorts. Conclusions: Ibrutinib remains a valuable option for the treatment of CLL, but is associated with significant cardiovascular risks, leading to it being superseded by the newer generation of BTKis, which offer less cardiovascular toxicities. These results highlight the TriNetX platform's reliability as a real-world data source for validating clinical trial findings and highlight the importance of incorporating cardio-oncology into treatment plans for CLL patients with significant comorbidities.

Risk-stratification in frontline CLL therapy: standard of care.

The treatment of chronic lymphocytic leukemia (CLL) has been transformed over the past decade based on a better understanding of disease biology, especially regarding molecular genetic drivers and relevant signaling pathways. Agents focusing on B-cell receptor (in particular Bruton tyrosine kinase [BTK]) and apoptosis (BCL2) targets have replaced chemoimmunotherapy (CIT) as the treatment standard. BTK and BCL2 inhibitor-based therapy has consistently shown prolonged progression-free survival and in some instances even increased overall survival against CIT in frontline phase 3 trials. This improvement is particularly pronounced in high-risk CLL subgroups defined by unmutated IGHV, deletion 17p (17p-), and/or the mutation of TP53, making CIT in these subgroups essentially obsolete. Despite remarkable advances, these markers also retain a differential prognostic and predictive impact in the context of targeted therapies, mandating risk-stratification in frontline management. Furthermore, BTK- and BCL2-targeting agents differ in their adverse event profiles, requiring adjustment of treatment choice based on patient characteristics such as coexisting conditions, comedications, and delivery-of-care aspects.

Relapsed/refractory CLL: the role of allo-SCT, CAR-T, and T-cell engagers.

Chronic lymphocytic leukemia (CLL) patients who are refractory to both Bruton's tyrosine kinase and B-cell/CLL lymphoma 2 (BCL2) inhibitors face a significant treatment challenge, with limited and short-lasting disease control options. This underscores the urgent need for novel therapeutic strategies. Immunotherapy has emerged as a promising approach to address this unmet need, offering the potential for durable remissions and improved patient outcomes. Historically, allogeneic stem cell transplantation has been used for high-risk CLL patients, demonstrating promising survival rates. However, its applicability is limited by high treatment-related mortality and chronic graft-versus-host disease, especially in older and frail patients. Chimeric antigen receptor (CAR) T-cell therapy is gaining attention for its potential in relapsed/refractory CLL. Early clinical trials have shown that CAR T cells can induce durable remissions, with encouraging overall response rates in heavily pretreated patients. Additionally, bispecific antibodies are being explored as immunotherapeutic strategies, showing promising preclinical and early clinical results in targeting CLL cells effectively. One of the major challenges in CLL treatment with T-cell-based therapies is the acquired T-cell dysfunction observed in patients. To overcome these limitations, strategies such as combining targeted agents with cellular immunotherapies, modifying CAR designs, and incorporating immunomodulatory compounds into the manufacturing process are being investigated. These innovative approaches aim to enhance T-cell engagement and improve outcomes for CLL patients, offering hope for more effective and sustainable treatments in the future.

EE647 Budget Impact Analysis of Fixed-Duration Ibrutinib+Venetoclax As Frontline Treatment of Chronic Lymphocytic Leukemia in the Brazilian Private Healthcare System

EE647 Budget Impact Analysis of Fixed-Duration Ibrutinib+Venetoclax As Frontline Treatment of Chronic Lymphocytic Leukemia in the Brazilian Private Healthcare System

Interindividual variability in CYP3A-mediated venetoclax metabolism invitro and invivo in patients with chronic lymphocytic leukemia.

Venetoclax is a first-in-class orally administered B-cell lymphoma-2 inhibitor used to treat chronic lymphocytic leukemia (CLL). Venetoclax is primarily metabolized in the liver by cytochrome P450 (CYP) 3A4 to its major metabolite M27, via M5, and M2, M3, and M4 via oxidation. Although venetoclax is a breakthrough in CLL treatment, managing drug safety and toxicity remains a clinical challenge. The objectives of this study were to investigate how individual CYP3A activity and protein expression affect hepatic venetoclax metabolism invitro and examine whether plasma 4β-hydroxycholesterol (4β-HC)/cholesterol ratio can predict venetoclax metabolism invitro and invivo. In human liver microsomes (n = 20) and primary human hepatocytes (n = 15), venetoclax metabolite formation varied widely between donors and significantly correlated with CYP3A activity (midazolam 1'-hydroxylation) and CYP3A4 protein expression. Venetoclax metabolite formation positively correlated with 4β-HC/cholesterol ratio in plasma samples from the matched non-infant donors (n = 14, ages 3-63 years). In an observational pilot study of real-world patients with CLL (n = 12, ages 56-84 years) treated with venetoclax, the plasma M3/venetoclax metabolic ratio negatively correlated with plasma 4β-HC/cholesterol ratio and positively correlated with patient age. Plasma 4β-HC/cholesterol ratio negatively correlated with patient age. Differences between the invitro data, which showed a positive association between venetoclax metabolism, hepatic CYP3A markers, and plasma 4β-HC/cholesterol ratio, and the invivo findings in patients with CLL could be due to age or other factors regulating plasma 4β-HC/cholesterol and/or venetoclax disposition. Future studies with larger sample sizes are needed to investigate age-related changes in venetoclax metabolism and plasma 4β-HC/cholesterol ratio.

Ibrutinib in Early-Stage Chronic Lymphocytic Leukemia: The Randomized, Placebo-Controlled, Double-Blind, Phase III CLL12 Trial.

The CLL12 trial reassesses the watch-and-wait consensus for early-stage chronic lymphocytic leukemia (CLL) in the context of targeted therapies. The German CLL Study Group conducted a randomized, double-blind, placebo-controlled phase III trial with 363 patients with asymptomatic, treatment-naïve Binet stage A CLL at increased risk of progression to receive ibrutinib (n = 182) at a daily dose of 420 mg or placebo (n = 181). Additionally, 152 low-risk patients were allocated to the watch-and-wait group. The final analysis included event-free survival, progression-free survival, time to next treatment, overall survival, and safety assessments. Ibrutinib significantly delayed progression to symptomatic disease (P < .001; hazard ratio, 0.276 [95% CI, 0.188 to 0.407]), but no survival benefit was observed with 26 death cases (P = .562) at a median observation time of 69.3 months. Five-year survival rates were excellent: 93.3% (95% CI, 89.3 to 97.3) in the ibrutinib group, 93.6% (95% CI, 89.5 to 97.7) in the placebo group, and 97.9% (95% CI, 95.6 to 100) in the watch-and-wait cohort. Estimated 10-year survival rates from diagnosis were 86.5% (95% CI, 78.7 to 94.3, placebo), 89.8% (95% CI, 83.3 to 96.3, ibrutinib), and 95.3% (95% CI, 91.1 to 99.4, watch and wait). In the ibrutinib group, one of 12 deaths was CLL-associated, compared with four of 14 fatal cases of CLL progression or Richter transformation in the placebo group. Adverse and serious adverse events occurred in 99.4% and 60% of both treatment groups, respectively. The safety profile indicated increased cardiovascular toxicity in the ibrutinib group. Ibrutinib treatment in early-stage CLL delayed disease progression compared with placebo. However, with the given observation time and few deaths, no survival benefit was demonstrated. In the era of targeted therapies, watch and wait remains the standard of care irrespective of risk factors.