Search Results (247)

Backgroundand Objectives: Targeted therapies are increasingly used in the management of chronic lymphocytic leukemia (CLL); however, real-world data from routine clinical practice remain limited. Materials and Methods: We performed a retrospective analysis of 47 patients with CLL who received at least one targeted therapy at a tertiary university hospital. Clinical characteristics, treatment responses, and adverse events were assessed. A total of 58 treatment events were included. Results: Obinutuzumab, ibrutinib, and venetoclax were administered in 34.5%, 46.5%, and 19.0% of treatment events, respectively. Numerically higher response rates were observed in treatment events involving obinutuzumab compared with ibrutinib and venetoclax (92.9% vs. 54.5% and 55.6%, respectively); however, treatment allocation was not randomized and these findings should be interpreted descriptively. Median overall survival from initiation of the first targeted therapy was 30.9 months. Adverse events occurred in more than 80% of treatment events. Neutropenia was more frequent with obinutuzumab and venetoclax, whereas bleeding events were more common with ibrutinib. Conclusions: In this real-world cohort, targeted therapies showed response patterns and safety findings consistent with routine clinical practice. Obinutuzumab was more frequently prescribed in older and more comorbid patients, reflecting treatment patterns rather than comparative superiority. These findings should be considered descriptive and hypothesis-generating, given the retrospective and single-center design. Full article

Objectives: The co-administration of Bruton’s tyrosine kinase (BTK) inhibitors with antiretroviral drugs is challenging due to potential drug–drug interactions (DDIs). However, clinical trials specifically assessing such DDIs are lacking. We aimed to evaluate DDIs between the BTK inhibitors ibrutinib, zanubrutinib and acalabrutinib with representative antiretroviral drugs and to provide dose adjustment strategies using physiologically based pharmacokinetic (PBPK) models. Methods: PBPK models were developed in PK-Sim software. Model performance was verified by comparing simulated pharmacokinetic parameters and DDI magnitudes with probe drugs (midazolam or maraviroc) with reported clinical data. The validated models were subsequently applied to assess DDIs and explore dose adjustment strategies. Results: The developed PBPK model accurately describes the pharmacokinetics of each drug. Darunavir/ritonavir substantially increased the maximum plasma concentration (C_max) of ibrutinib, zanubrutinib, and acalabrutinib by 496%, 312%, and 160%, respectively. In contrast, efavirenz reduced C_max by 43%, 33%, and 37%, respectively, while etravirine caused smaller decreases of 5%, 0%, and 10%. Based on these predictions, recommended dose adjustment strategies include ibrutinib 105 mg once daily, zanubrutinib 40 mg twice daily, and acalabrutinib 50 mg twice daily when co-administered with darunavir/ritonavir or ibrutinib 980 mg once daily, zanubrutinib 240 mg twice daily, and acalabrutinib 150 mg twice daily when co-administered with efavirenz. No dose adjustment is required with etravirine. Conclusions: The PBPK models accurately predicted the in vivo pharmacokinetics of ibrutinib, zanubrutinib, acalabrutinib, and those of the antiretrovirals darunavir/ritonavir, efavirenz, and etravirine, and the DDIs between them. The dose adjustment strategies provided information valuable to the optimization of antineoplastic therapy in HIV-related lymphoma (HRL) patients. Full article

Background/Objectives: Ibrutinib has significantly improved outcomes in chronic lymphocytic leukemia (CLL), but evidence from real-world settings on the impact of early dose modifications and consequent relative dose intensity (RDI) maintenance on survival outcomes is limited. This study evaluated the impact of dose reductions and RDI maintenance during the first 90 days of treatment on clinical outcomes in patients with CLL receiving ibrutinib in routine clinical practice. Methods: A post hoc analysis of the prospective observational EVIdeNCE study (NCT03720561) was conducted, including 275 patients with CLL treated with ibrutinib. Baseline clinical and biological factors associated with early dose modifications and RDI maintenance over the first 90 days were analyzed. Cox proportional hazards models, adjusted for disease- and patient-related covariates, were applied to assess associations with overall survival (OS) and progression-free survival (PFS), using a landmark approach to control for immortal time bias. Results: Patients with higher comorbidity burden—indicated by higher Cumulative Illness Rating Scale scores and poorer ECOG performance status—were more likely to undergo early dose reductions. RDI declined slightly over 90 days, but most patients maintained ≥80% of their RDI. The impact of disease-risk factors appeared more clearly when assessing the relationship between 100% RDI at 90 days and PFS, with ibrutinib at 100% RDI associated with improved PFS (hazard ratio, HR 2.26, 95% confidence interval, CI: 1.23–4.15). However, after adjusting for patient characteristics (e.g., comorbidity burden and cardiovascular history), the 100% RDI rate no longer showed a statistically significant effect on PFS (HR 1.84, 95% CI: 0.93–3.63). Conclusions: Baseline comorbidities and functional status drive early dose modifications, but these adjustments and RDI variability do not independently impact survival outcomes, confirming the overall tolerability of ibrutinib in real-world CLL management. Full article

Background and Clinical Significance: Plasmablastic lymphoma (PBL) is a rare and highly aggressive B-cell neoplasm most often associated with immunodeficiency. Transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) into PBL is exceptionally uncommon, particularly in immunocompetent individuals. This paper describes a rare synchronous SLL-to-PBL transformation and summarizes current knowledge on synchronous and metachronous cases reported in the literature. Case Presentation A midle-aged immunocompetent patent presented with generalized lymphadenopathy and lumbar pain. Concurrent biopsies of an axillary lymph node and a retroperitoneal mass were obtained. Diagnostic evaluation included immunohistochemistry; fluorescent in situ hybridization (FISH); PCR-based assessment of IGH, IGK, and IGL loci; and next-generation sequencing (NGS) of IGHV to assess clonal relatedness. The patient was treated with six cycles of Dara-CHOP, followed by autologous stem cell transplantation and maintenance therapy with daratumumab and ibrutinib. The axillary node showed SLL (CD20+, CD5+, CD23+), while the retroperitoneal mass demonstrated classic features of PBL (CD138+, MUM1+, MYC+, Ki-67 ~100%, CD20−). FISH detected MYC rearrangement in the PBL component. PCR and NGS confirmed identical IGHV1-69 rearrangements, establishing clonal relatedness and Richter transformation. A review of published cases shows that both synchronous and metachronous CLL/SLL-to-PBL transformations are exceedingly rare. The patient achieved partial metabolic remission after treatment and remains in sustained metabolic response 24 months after diagnosis. Conclusions: This case highlights a rare example of synchronous CLL/SLL-to-PBL transformation in an immunocompetent patient. Integration of detailed molecular diagnostics enabled early recognition and guided a personalized treatment approach incorporating CD38-targeted therapy and BTK inhibition, resulting in an excellent long-term clinical outcome. Full article

Background: There are multiple effective treatment options for patients diagnosed with chronic lymphocytic leukemia and small lymphocytic lymphoma (hereafter, simply CLL). In 2025, two phase 3 randomized clinical trials of pirtobrutinib, a non-covalent BTK inhibitor, were reported, demonstrating improved outcomes versus comparator therapies in the treatment-naïve setting (NCT05254743 and NCT05023980). Methods: A systematic literature review was conducted to identify RCTs in the first-line setting for CLL. A Bayesian NMA was performed to compare overall response rate (ORR) and progression-free survival (PFS) of pirtobrutinib versus treatments recommended by the National Comprehensive Cancer Network in the first-line setting, with a focus on BTKi monotherapy. Results: Eight unique trials were identified for comparison versus pirtobrutinib. Eligible RCTs formed two disconnected networks (pirtobrutinib, ibrutinib and zanubrutinib were in Network 1; acalabrutinib was in Network 2). Results from Network 1 for ORR showed an odds ratio (OR) = 0.56 (95% credible interval [CrI], 0.28, 1.12) for ibrutinib versus pirtobrutinib and OR = 0.50 (95% CrI, 0.20, 1.27) for zanubrutinib versus pirtobrutinib. The PFS of ibrutinib was inferior to pirtobrutinib (hazard ratio (HR) = 1.89, 95% CrI, 1.13, 3.19); the PFS HR comparing zanubrutinib with pirtobrutinib was 1.51 (95% CrI, 0.84, 2.72). Conclusions: This NMA shows that pirtobrutinib has better PFS outcomes than ibrutinib. While PFS outcomes suggest that pirtobrutinib is comparable to second-generation covalent BTKi monotherapies, uncertainty exists in the interpretation of the treatment effect, as evidenced by wide credible intervals. These findings suggest the value of pirtobrutinib as a future treatment option for patients in the first-line setting. Full article

Background: Bruton’s tyrosine kinase inhibitors, particularly ibrutinib, have improved outcomes in patients with chronic lymphocytic leukemia but are associated with an increased risk of atrial fibrillation. The early identification of patients with increased susceptibility to atrial fibrillation remains a major challenge in cardio-oncology. Methods: This prospective pilot study included 45 patients with chronic lymphocytic leukemia treated with ibrutinib. All patients underwent comprehensive transthoracic echocardiography at baseline and after 6 months. Left atrial structure and function were assessed, with particular emphasis on speckle-tracking-derived left atrial strain parameters, including peak atrial longitudinal strain and peak atrial contraction strain. Results: At follow-up, a modest but significant increase in indexed left atrial volume was observed, while left atrial functional parameters remained stable. Patients who developed atrial fibrillation showed significantly lower baseline Peak Atrial Contraction Strain values compared with those who remained in sinus rhythm, whereas no significant differences in Peak Atrial Longitudinal Strain were detected. Conclusions: Ibrutinib-related atrial fibrillation appears to be driven primarily by pre-existing atrial vulnerability rather than early drug-induced atrial dysfunction. The baseline impairment of left atrial contractile function may represent a candidate echocardiographic marker of atrial functional vulnerability and may inform cardiovascular surveillance and monitoring strategies in patients treated with ibrutinib. Full article

Bruton’s tyrosine kinase (BTK) inhibitors have revolutionized the treatment landscape for patients with indolent lymphoid malignancies such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). The most common adverse events include cardiac arrhythmia, bleeding, infection, diarrhea, arthralgias, hypertension, and skin changes. Second-generation BTK inhibitors, e.g., acalabrutinib and zanubrutinib and the non-covalent BTK inhibitor pirtobrutinib, are less toxic than the first-generation BTK inhibitor ibrutinib. The most common toxic skin symptoms related to BTKi treatment include hemorrhage, bleeding events, bruising, skin ecchymoses, and contusion; they are particularly common in patients treated with ibrutinib. Other dermatologic symptoms include rash, cellulitis, skin infections, subcutaneous abscesses and peripheral edema. This article discusses the development of skin symptoms in patients with ibrutinib and newer BTK inhibitors, and summarizes their clinical and pathological characteristics. A literature search was performed using PubMed, Web of Science, and Google Scholar for articles published in English. Additional relevant publications were obtained by reviewing the references from the chosen articles. Full article

BTK (Bruton’s tyrosine kinase) has become a key therapeutic target across several hematologic diseases, beginning with its original use in CLL/SLL. As a central mediator of B-cell receptor signaling and microenvironment interactions, BTK supports survival, proliferation, and trafficking in multiple mature B-cell malignancies (mantle cell lymphoma, marginal zone lymphoma, Waldenström macroglobulinemia, and other indolent/aggressive lymphomas) and in selected immune-mediated conditions such as chronic graft-versus-host disease. Covalent BTK inhibitors (ibrutinib, acalabrutinib, and zanubrutinib) irreversibly bind the C481 residue and have produced high response rates and durable disease control, often replacing chemoimmunotherapy in the relapsed setting and, for some entities, even in the first line. Differences in kinase selectivity lead to different safety profiles: second-generation covalent agents generally maintain efficacy while reducing significant off-target toxicities, especially atrial fibrillation and hypertension. Resistance to covalent BTK inhibitors most commonly develops through BTK C481 substitutions and activating PLCG2 mutations, with other kinase-domain variants increasingly recognized. Non-covalent BTK inhibitors (e.g., pirtobrutinib) bind BTK independently of C481, can overcome classic C481-mediated resistance, and extend BTK pathway targeting into later lines of therapy. Overall, BTK inhibition has evolved into a versatile platform enabling long-term, often chemo-free management strategies. Full article

Systemic lupus erythematosus (SLE) is a chronic and refractory autoimmune disease characterized by multi-organ damage, for which reliably safe and effective treatment remains an unmet need. Autoantibodies, secreted by autoreactive B cells, deposition is the central pathogenesis of organ damage in SLE. Current studies reported B cell receptor and B cell activating factor (BAFF)-mediated signals regulate the activation and survival of B cells and production of autoantibodies. We showed that marginal zone B cells and CD11c⁺T-bet⁺ autoreactive B cells expressed higher levels of BAFF receptor and BTK in MRL/lpr mice. Here, a liposome-delivery system capable of targeting BAFFR^high autoreactive B cells by conjugating anti-BAFFR antibody on the surface of the PEG-liposomes and loading BTK-inhibitor ibrutinib (BTEL) was rationally designed. Notably, the BTEL nanoparticles could inhibit the survival and activation of B cells, and systemic administration of BTEL could alleviate the development of the lupus mouse model by decreasing the production of anti-dsDNA autoantibodies, along with reduced secretion of inflammatory cytokines and kidney damage, and without apparent side effects. These findings suggest the potential of BTEL in targeting autoreactive B cells, blocking signaling pathways, and improving the efficacy of BTK inhibitors, providing a promising therapeutic approach for SLE, while also reducing toxicity. Full article

Chronic lymphocytic leukemia (CLL) has systemic effects that extend beyond malignant lymphocytes, potentially altering the structure and function of circulating red blood cells (RBCs). In this study, atomic force microscopy (AFM) was combined with complementary calorimetric analysis to investigate the membrane ultrastructure, nanomechanical characteristics, and thermodynamic behavior of RBCs from untreated CLL patients and those receiving targeted therapies (Obinutuzumab/Venetoclax or Ibrutinib). RBCs from untreated patients exhibited pronounced reduction in membrane roughness, increased stiffness and adhesion forces, and altered thermal unfolding of cytoskeletal and membrane proteins, indicative of impaired structural flexibility and stability. Treatment with Obinutuzumab/Venetoclax partially restored surface topography, but stiffness and adhesion forces remained elevated, suggesting persistent cytoskeletal rigidity. The obscured spectrin and Band 2–4 thermal transitions and the elevated total enthalpy change revealed by differential scanning calorimetry indicated a modified conformation or binding state of membrane proteins. In contrast, Ibrutinib therapy produced near-normal nanomechanical and thermal characteristics, reflecting a more comprehensive restoration of RBC integrity. These findings demonstrate that CLL and its therapies distinctly influence erythrocyte morphology and mechanics, underscoring the systemic impact of the disease. The strong correspondence between AFM and calorimetric data highlights the potential of integrated biophysical approaches to detect subtle RBC alterations and to serve as complementary indicators for therapeutic monitoring. Full article

Chronic lymphocytic leukemia (CLL) is an indolent malignancy with modest proliferation in the lymph nodes and accumulation of quiescent B cells in the peripheral blood. Targeted agents, including BTK inhibitors such as ibrutinib and the BCL2 antagonist venetoclax, have transformed therapy by disrupting proliferation, survival, and lymph node retention of CLL cells, yet CLL remains incurable. Recent studies reveal that CLL cells exist along a spectrum of proliferating, activated, and quiescent states, with dynamic transitions that shape intraclonal behavior. Whilst proliferation occurs mainly in lymph nodes, most emigrant cells in the peripheral blood become quiescent, with only a minority remaining activated. Quiescent, activated, and proliferating fractions display distinct phenotypes and CXCR4 and CD5 levels can be used to distinguish these states in the CLL life cycle. While proliferating and activated cells are more susceptible to BTK inhibition, quiescent subsets show greater sensitivity to BCL2 blockade. These functional differences, together with emerging evidence that phenotypic markers may correlate with residual disease activity, point to potential translational significance. Understanding how CLL cells switch between proliferative, activated and quiescent states will be important to uncover novel vulnerabilities and inform rational treatment strategies. Full article

Background: Ibrutinib, a Bruton’s tyrosine kinase inhibitor (BTKi), has revolutionized the treatment of Chronic Lymphocytic Leukemia (CLL), yet hepatotoxicity remains a rare and poorly characterized adverse event. Case Presentation: We report the case of a 54-year-old man with progressive CLL and radiologically confirmed hepatic involvement who developed acute hepatocellular injury during ibrutinib monotherapy. Baseline liver tests showed mild abnormalities attributed to hepatic steatosis and leukemic infiltration. After approximately 10–12 weeks of ibrutinib (420 mg/day), transaminases markedly increased (ALT 660 U/L, AST 326 U/L), while bilirubin and synthetic function remained normal. Viral, autoimmune, and obstructive causes were excluded. Stepwise dose reductions to 140 mg/day provided limited benefit. The addition of prednisone (50 mg/day) led to rapid biochemical improvement. Ibrutinib was successfully re-escalated to 280 mg/day alongside venetoclax initiation, maintaining disease control without recurrence of liver injury. Discussion: The temporal relationship, exclusion of alternative causes, and corticosteroid responsiveness suggest an ibrutinib-induced liver injury, possibly exacerbated by pre-existing hepatic steatosis and leukemic infiltration. Conclusions: This case underscores the multifactorial pathogenesis of BTKi-related hepatotoxicity and highlights the potential role of corticosteroids in management. Prompt recognition, stepwise dose adjustment, and corticosteroid therapy may enable continued treatment and sustained disease control in selected patients. Full article

Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries, and B-cell receptor (BCR) pathway inhibitors such as idelalisib and ibrutinib are currently established therapies for CLL. Although effective, these drugs frequently lead to resistance, but the mechanisms are still not fully understood. Activation-induced cytidine deaminase (AID) is a B-cell enzyme essential for antibody diversification. However, it can also introduce off-target mutations, leading to genomic instability. This study investigates whether treatment with BCR pathway inhibitors increases AID activity in CLL and whether this activity contributes to the development of drug resistance. Peripheral blood samples from CLL patients were collected before and after treatment with idelalisib or ibrutinib. Targeted sequencing was used to identify mutations in known AID off-target genes. Concurrently, AID-wild type (AID-WT) and AID-knockout (AID-KO) CLL cell lines were established and subsequently exposed to escalating doses of BCR pathway inhibitors to develop drug-resistant models. In patient samples, treatment with BCR pathway inhibitors was associated with an increase in AID-dependent mutations in off-target genes, including BCL2, MYC, and IRF8. The in vitro models efficiently recapitulated the patients’ data, as only AID-WT CLL cells accumulated mutations in the same AID off-target genes after drug exposure. However, no mutations were detected in genes that could mediate drug resistance. We conclude that BCR pathway inhibitors enhance AID mutational activity in CLL, but this does not appear to be directly involved in driving drug resistance. AID-targeted loci may nonetheless serve as biomarkers for monitoring genomic instability during treatment and inform further study. Full article

Ibrutinib (IB), a Bruton’s tyrosine kinase (BTK) inhibitor, is widely used against B-cell malignancies. However, its adverse effects on stem cell-dependent processes and tissue homeostasis remain incompletely understood. Freshwater planarians possess pluripotent stem cells (neoblasts), which enable remarkable regeneration of various tissues, including the central nervous system. This makes them ideal in vivo models for studying chemical toxicity within a whole-organism context. Here, we utilized planarian Dugesia constrictiva to assess IB toxicity and elucidate its mechanisms, focusing on its impact on stem cell dynamics and regeneration. Our results demonstrated that exposure to IB at concentrations as low as 0.9 mg/L, far below clinical plasma levels, led to severe morphological and regenerative impairments, including disrupted neural regeneration. Mechanistically, IB disrupted stem cell dynamics by suppressing proliferation and differentiation and by inducing oxidative stress via ROS overproduction. Notably, IB exposure significantly downregulated BTK expression. Crucially, BTK RNAi caused the key toxic effects of IB exposure, including morphological and regenerative defects, suppression of stem cell proliferation and differentiation, and increased apoptosis. Therefore, we conclude that IB may exert its toxicity in planarians primarily through BTK inhibition. This finding provides direct functional evidence linking BTK inhibition to stem cell dysfunction and regenerative defects in a novel in vivo context, offering critical insights for refining the clinical safety profile of IB. Full article

Tyrosine kinases (TKs) and cyclin-dependent kinases (CDKs) contain reactive cysteines that can be exploited by targeted covalent inhibitors. In this exploratory computational study, we asked whether selected natural-product-like (NP-like) electrophiles bearing Michael-acceptor (MA) motifs could adopt geometries consistent with covalent approaches to these cysteines, in a manner analogous to approved covalent TKIs. Using AutoDockFR with cysteine-centered grids and explicit side-chain flexibility, we performed pocket-focused, within-receptor covalent docking for EGFR, VEGFR2/KDR, PDGFRβ (via PDGFRα surrogate), BTK, CDK7, and CDK12. Reference inhibitors (osimertinib–EGFR, ibrutinib–BTK, THZ1–CDK7, and THZ531–CDK12) reproduced the expected geometries and served as internal controls. NP-like electrophiles (parthenolide, withaferin A, celastrol, and curcumin as a low-reactivity geometry probe) displayed pocket-compatible orientations in several targets, particularly EGFR and BTK, suggesting feasible pre-reaction alignment toward the reactive cysteine. Although no quantitative affinity was inferred, the consistent geometric feasibility supports their potential as structural templates for covalent-binding natural scaffolds. These results provide a qualitative, structure-based rationale for further chemoproteomic and enzymatic validation of NP-derived or hybrid compounds as potential leads in cancer therapy, expanding covalent chemical space beyond existing synthetic scaffolds. Full article