Search Results (692)

Introduction: This review specifically focuses on interventional clinical trials in leukemias and myelodysplastic syndromes (MDS), summarizing how patient-reported outcome measures (PROMs) have been implemented to evaluate treatment effects rather than to directly influence clinical outcomes. Objective: Clinical outcomes of interest typically include response rates, disease-free survival (DFS), and overall survival (OS). Patient-reported outcome measures (PROMs) are standardized questionnaires that collect information regarding health outcomes directly from the patient and are used to evaluate new treatments and healthcare quality. In addition, the use of PROMs in cancer care has been shown to improve patient-provider communication and patient satisfaction. Material and Methods: This is a qualitative, narrative synthesis and review structured around PROMs focused on six critical themes: symptoms/symptom burden, physical, emotional, social/role, and functional status, and global health status measurement. Results: PROMs that are assessed in oncologic research include the EORTC QLQ-C30, FACT-Leu, QLQ-CLL16, and EQ-5D. PROs are associated with clinical outcomes such as DFS and OS, and the FACT-Leu scales, HRQOL and physical functioning scores were independent prognosticators of OS in patients with AML. Conclusions: Through our review, notable trends were identified that further highlight the importance of greater incorporation of PRO measures in future clinical trials, particularly in the understudied realm of hematologic malignancies, in order to better delineate the link between survival and HRQOL. Full article

Background/Objectives: Tissue niches, such as those in the spleen, bone marrow, and lymph nodes, are crucial for the survival and growth of leukemic cells in chronic lymphocytic leukemia (CLL). Methods: A growing amount of research over the last 20 years has shown how important the tumor microenvironment (TME) is to the pathophysiology, development, and resistance to treatment of CLL. This protective environment, which is made up of various cell types (including stromal and immune cells), extracellular matrix components, and soluble factors, supports CLL cells and encourages their survival, growth, and drug resistance. Even in the absence of mutations, Notch2 is functionally activated in the CLL system, in addition to the well-known Notch1. This occurs because leukemic cells aberrantly express the ligand Jagged1/2, which activates the Notch2 receptor on both stromal and CLL cells themselves. Notch2 activation on stromal cells leads to the triggering of the Wnt/β-catenin program in CLL cells, whereas the activation of Notch2 in CLL cells promotes the expression of Mcl-1, which confers drug tolerance (especially in cases with trisomy 12). Results: In addition to these mechanisms, Notch2 acts as a transcription factor that directly controls the expression of key targets, such as CD23 and Hes1, that are fundamental for B cell proliferation, differentiation, and survival in CLL. Conclusions: All of these circuits represent important therapeutic targets and help explain the cells’ dependence on their niche, the formation of proliferation centers, and resistance to modern targeted agents. Full article

Transcriptomic analyses of public datasets (TCGA and GTEx) revealed that both CD74 and Cathepsin L (CTSL) are significantly overexpressed in diffuse large B-cell lymphoma (DLBCL) compared to normal tissues, and that their expression levels are highly correlated to each other (Spearman R = 0.64, p = 3 × 10⁻⁴⁶). Kaplan–Meier analysis showed that elevated expression of both genes is associated with reduced overall survival (OS), defining a high-risk CD74+/CTSL+ DLBCL subgroup. This is the first study demonstrating coordinated overexpression of CD74 and CTSL and proposing their dual targeting via antibody–drug conjugates (ADCs) to improve outcomes in relapsed or refractory DLBCL. Cysteine cathepsins, a family of proteases, are upregulated in many cancers, facilitating tumor invasion and metastasis. Cathepsins are overexpressed and play key roles in DLBCL progression. GB111-NH₂, a potent broad-spectrum cathepsin inhibitor, significantly reduced cathepsin activity in lymphoma cell lines and patient samples. GB111-NH₂ treatment increased apoptosis and caspase-3 activation in DLBCL patient cells and chronic lymphocytic leukemia (CLL) mononuclear cells. Here, we developed a modified cathepsin inhibitor, M-GB, containing a maleimide linker for site-specific antibody conjugation. While M-GB alone has poor cell permeability, when conjugated to an antibody, it forms an ADC (M-GB–ADC) that selectively induces lymphoma cell death. One M-GB–ADC demonstrated high specificity for CD74-expressing lymphoma cells while exhibiting minimal toxicity to non-target cells in vitro. Our findings highlight the potential of another M-GB–ADC as a targeted therapy for overcoming rituximab resistance and treatment failure in DLBCL. This strategy enhances therapeutic efficacy and represents a preclinical proof-of-concept treatment option by directing a cathepsin-inhibitor payload specifically to malignant B cells. Full article

SLAMF7, also known as CD319, a SLAM (signaling lymphocytic activation molecule) family receptor, is relatively weakly expressed on chronic lymphocytic leukemia (CLL) B cells. This study evaluated the ability of elotuzumab (E), an anti-SLAMF7/CD319 antibody, to induce antibody-dependent cellular cytotoxicity (ADCC) against CLL cell lines (MEC-1, MEC-2, CI, HG-3, PGA-1, WA-OSEL). ADCC was assessed by flow cytometry using E (100 μg/mL), rituximab (R, 100 μg/mL), and their combination (E + R). CLL lines served as targets (T), while peripheral blood mononuclear cells (PBMCs) or NK cells from healthy donors served as effectors (E) at an 8:1 E:T ratio for 4 h. With PBMCs, E-induced ADCC ranged from 1.3 ± 1.2% (PGA-1) to 14.6 ± 8.1% (MEC-1); R-induced ADCC ranged from 9.2 ± 4.6% (PGA-1) to 16.6 ± 9.4% (WA-OSEL). With NK cells, E-induced ADCC ranged from 1.8 ± 3.7% (PGA-1) to 27.3 ± 4.7% (MEC-1); R-induced ADCC ranged from 5.1 ± 4.3% (PGA-1) to 27.5 ± 13.6% (CI). E outperformed R in MEC-1, while R was superior elsewhere. Cell lines with higher SLAMF7/CD319 expression displayed increased sensitivity to E. Cell lines with del17p showed higher SLAMF7/CD319 expression. The combination of E + R showed no significant synergy over monotherapies. In conclusion, elotuzumab induced significant ADCC in CLL cells, warranting further therapeutic evaluation. Full article

Richter transformation (RT) represents a rare but highly lethal evolution of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), most frequently manifesting as diffuse large B-cell lymphoma (DLBCL). Despite therapeutic advances in CLL, DLBCL-RT remains characterized by rapid progression, profound treatment refractoriness, and short survival with conventional chemoimmunotherapy, underscoring the need for a refined biological and therapeutic framework. A defining feature of RT is clonal relatedness: most cases arise through linear or branched evolution of the antecedent CLL clone and carry an inferior prognosis compared with clonally unrelated cases that resemble de novo DLBCL. Recent multi-omic data further indicate that clonally related RT commonly originates from minute, transformation-primed subclones detectable years before clinical emergence, shifting RT from a late stochastic event to an early-established evolutionary trajectory. At transformation, recurrent genetic lesions of TP53, CDKN2A/B, NOTCH1, and MYC cooperate with B-cell receptor-associated programs, epigenetic reconfiguration, and metabolic rewiring toward OXPHOS- and mTOR-driven states, collectively promoting genomic instability and aggressive growth. In parallel, RT develops within a profoundly immunosuppressive microenvironment marked by PD-1-expressing malignant B cells, PD-L1-rich myeloid niches, exhausted T cells, expanded regulatory T cells, and M2-skewed macrophages interconnected by redundant checkpoint and cytokine networks. Therapeutic strategies are rapidly evolving, including pathway inhibitors, immune checkpoint blockade, T-cell-engaging bispecific antibodies, CAR-T therapies, and antibody–drug conjugates. This review integrates current insights into RT pathogenesis, immune escape, and emerging therapies, highlighting opportunities for biomarker-driven patient stratification, rational combinations, and earlier interception of transformation-prone disease. Full article

Chronic lymphocytic leukemia (CLL) is a dynamic malignancy in which intraclonal subfractions differ in activation history and responsiveness to microenvironmental signals. Here, we investigated the expression and inducibility of IL-12 family receptor subunits (IL-23R, IL-12Rβ1, IL-12Rβ2) and the related receptor complexes in recirculating CLL cells, with a focus on CXCR4/CD5-defined fractions: the proliferative fraction (PF; CXCR4^dim/CD5^bright; most recently divided, tissue-emigrated cells) and the resting fraction (RF; CXCR4^bright/CD5^dim; older, quiescent cells). At baseline, IL-12Rβ1 was enriched in the PF and was associated with a higher proportion of cells expressing IL-23R and IL-12R receptor complexes. Concomitantly, RT-qPCR disclosed higher IL-12Rβ1 mRNA levels. Following antigen-independent activation with CpG or CpG + IL-15, there was a marked increase in IL-23R and IL-12Rβ1 but not in IL-12Rβ2 surface expression, resulting in preferential upregulation of the IL-23R complex over the IL-12R complex. Fraction-specific analyses showed stronger induction of IL-23R and IL-23R complex expression in PF compared with RF. These findings identify an intraclonal bias toward IL-23 responsiveness in the CLL cells with a phenotype of recently divided, tissue-emigrated cells and suggest the IL-23/IL-23R axis as a potential therapeutic target. 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

The increased complexity of CLL management, driven by the advent of targeted therapies, makes it necessary to redefine the concept of fitness, which until a few years ago was limited to the patient’s ability to undergo chemoimmunotherapy. In the current therapeutic landscape, fitness assessment must also consider biological age, comorbidities, and frailty, which have become increasingly relevant due to evolving treatment options and a more nuanced understanding of the elderly CLL population. In this context, the general condition of the patient should be preserved with greater attention to physical activity and nutrition. This narrative review analyzed in depth all these aspects with the aim of providing insights into fitness assessments and their actualization. Full article

Background: Optical genome mapping (OGM) detects genome-wide structural variants (SVs), including balanced rearrangements and complex copy-number alterations beyond standard-of-care cytogenomic assays. In chronic lymphocytic leukemia (CLL), cytogenetic and genomic risk stratification is traditionally based on fluorescence in situ hybridization (FISH), karyotyping, targeted next-generation sequencing (NGS), and immunogenetic assessment of immunoglobulin heavy chain variable region (IGHV) somatic hypermutation status, each of which interrogates only a limited aspect of disease biology. Methods: We retrospectively evaluated fifty patients with CLL using OGM and integrated these findings with cytogenomics, targeted NGS, IGHV mutational status, and clinical time-to-first-treatment (TTFT) data. Structural variants were detected using OGM and pathogenic NGS variants were derived from a clinical heme malignancy panel. Clinical outcomes were extracted from the electronic medical record. Results: OGM identified reportable structural variants in 82% (41/50) of cases. The most frequent abnormality was del(13q), observed in 29/50 (58%) and comprising 73% (29/40) of all OGM-detected deletions with pathologic significance. Among these, 12/29 (42%) represented large RB1-spanning deletions, while 17/29 (58%) were focal deletions restricted to the miR15a/miR16-1 minimal region, mapping to the non-coding host gene DLEU2. Co-occurrence of adverse lesions, including deletion 11q/ATM, BIRC3 loss, trisomy 12, and deletion 17p/TP53, were recurrent and strongly associated with shorter TTFT. OGM also uncovered multiple cryptic rearrangements involving chromosomal loci that are not represented in the canonical CLL FISH probe panel, including IGL::CCND1, IGH::BCL2, IGH::BCL11A, IGH::BCL3, and multi-chromosomal copy-number complexity. IGHV data were available in 37/50 (74%) of patients; IGHV-unmutated status frequently co-segregated with OGM-defined high-risk profiles (del(11q), del(17p), trisomy 12 with secondary hits, and complex genomes whereas mutated IGHV predominated in OGM-negative or structurally simple del(13q) cases and aligned with indolent TTFT. Integration of OGM with NGS further improved genomic risk classification, particularly in cases with discordant or inconclusive routine testing. Conclusions: OGM provides a comprehensive, genome-wide view of structural variation in CLL, resolving deletion architecture, identifying cryptic translocations, and defining complex multi-hit genomic profiles that tracked closely with clinical behavior. Combining OGM and NGS analysis refined risk stratification beyond standard FISH panels and supports more precise, individualized management strategies in CLL. Prospective studies are warranted to evaluate the clinical utility of OGM-guided genomic profiling in contemporary treatment paradigms. Full article

Background: A strikingly unusual pattern with a possible up-field shift in Hemoglobin A1c (HbA1c) and A0 (HbA0) peaks and an unexplained hemoglobin F (HbF) peak with capillary electrophoretic shift in the HbA1c chromatograms of a leukemia patient were found while performing a HbA1c screen. Methods: A review of the patient’s history with an exhaustive search of the literature ruled out medications as interfering factors or contributing to the abnormal findings. Other than hyperleukocytosis, the patient did not have the aberrant HbF peak noted previously in the electrophoresis or contributing factors. We hypothesized that the irregular chromatographic pattern and wrong location of the HbA1c peak, hereafter referred to as the downfield shift in the electrophoretic species, was due to various glycation or fructosamine adducts and derivatives within the HbA1c and A0 protein. Results: A literature search offered little guidance. However, the instrument troubleshooting measures suggested a hemoglobin variant or exogenous transfusion as a putative source for the HbF peak, while the downfield shift in the chromatogram remained unexplained. 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

Background/Objectives: Conventional workflows, peripheral blood smears, and bone marrow assessment supplemented by LDI-PCR, molecular cytogenetics, and array-CGH, are expert-driven in the face of biological and imaging variability. Methods: We propose an AI pipeline that integrates convolutional neural networks (CNNs) and transfer learning-based models with two explainable AI (XAI) approaches, LIME and Grad-Cam, to deliver both high diagnostic accuracy and transparent rationale. Seven public sources were curated into a unified benchmark (66,550 images) covering ALL, AML, CLL, CML, and healthy controls; images were standardized, ROI-cropped, and split with stratification (80/10/10). We fine-tuned multiple backbones (DenseNet-121, MobileNetV2, VGG16, InceptionV3, ResNet50, Xception, and a custom CNN) and evaluated the accuracy and F1-score, benchmarking against the recent literature. Results: On the five-class task (ALL/AML/CLL/CML/Healthy), MobileNetV2 achieved 97.9% accuracy/F1, with DenseNet-121 reaching 97.66% F1. On ALL subtypes (Benign, Early, Pre, Pro) and across tasks, DenseNet121 and MobileNetV2 were the most reliable, achieving state-of-the-art accuracy with the strongest, nucleus-centric explanations. Conclusions: XAI analyses (LIME, Grad-CAM) consistently localized leukemic nuclei and other cell-intrinsic morphology, aligning saliency with clinical cues and model performance. Compared with baselines, our approach matched or exceeded accuracy while providing stronger, corroborated interpretability on a substantially larger and more diverse dataset. 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 a heterogenous disease, with varied clinical outcomes. Multiplex assays used to measure soluble immune checkpoints offer a less laborious method of monitoring patients with CLL, but none of these panels have been validated. The aim of the study was to assess soluble immune checkpoint profiles in patients with CLL and to correlate these with independent prognostic markers such as β2-microglobulin (B2M), Rai stage, fluorescence in situ hybridization (FISH) status, and the International Prognostic Index for Chronic Lymphocytic Leukemia (CLL-IPI). We measured plasma levels of soluble interleukin-2 receptor alpha (sCD25), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), galectin-9, programmed cell death 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) using cytometric bead array-based assays. We further measured plasma levels of B2M using an enzyme-linked immunosorbent assay (ELISA) kit. Soluble immune checkpoints were correlated with prognostic markers. The plasma levels of sCD25, TIM-3, galectin-9, PD-1, and PD-L1 were significantly increased in patients with CLL compared to the control group, p < 0.0001. Galectin-9 plasma levels were directly associated with B2M levels (β = 0.65, p = 0.012). Our findings suggest that galectin-9 may provide valuable prognostic significance for patients with CLL. 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