Search Results (408)

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. It is characterized by the clonal proliferation of mature B cells. The tumor microenvironment (TME) seems to play a crucial role in the survival and proliferation of tumor cells. Multiple new classes of drugs had been approved for the management of patients with CLL, reshaping the treatment paradigm. The most important classes are Bruton’s tyrosine kinase (BTK) inhibitors and BCL-2 inhibitors. Both of them are approved as a first-line treatment in patients with CLL requiring treatment. The role of BTK and BCL-2 in the signaling pathways of the TME is very important. The aim of this review is to summarize the major components of the TME and the available data regarding targeted therapies in CLL. Full article

CLL is the most prevalent adult leukemia in Western countries, characterized by the accumulation of monoclonal B lymphocytes. Over the past decade, the therapeutic landscape for CLL has undergone significant transformations, primarily due to the introduction of targeted small molecular therapies like BTK inhibitors and BCL-2 inhibitors, that have improved patient outcomes drastically. Despite significant advances, long-term disease management remains challenging for patients with double-refractory CLL, where responses with subsequent therapies are short-lived. Resistance to these therapies can arise through several mechanisms like kinase-altering BTK mutations, alterations in the BCL-2 pathway, and adaptations within the tumor microenvironment, necessitating the exploration of new therapeutic options. This review provides an in-depth overview of the promising novel treatment approaches under investigation in CLL, focusing on advanced cellular therapies (CAR T-cell therapy), T-cell engagers, new monoclonal antibodies, and various next-generation small molecule inhibitors including BTK degraders, PI3K inhibitors, MALT1 inhibitors, c-MYC inhibitors, CDK9 inhibitors, and agents targeting angiogenesis and DNA damage repair. In this review, we will discuss the novel therapeutic targets and agents as well as ongoing trials, emphasizing the potential of these treatments to overcome resistance and meet the unmet needs of patients, particularly those with double-refractory CLL. Full article

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. Full article

Background/Objectives: Ibrutinib is a selective Bruton’s tyrosine kinase inhibitor approved for the treatment of chronic lymphocytic leukemia (CLL). This drug exhibits significant variability in response and toxicity profile, possibly due to genetic polymorphisms in drug-metabolizing enzymes and transporters. The aim of this observational study is to address interindividual variability in the efficacy and safety of ibrutinib treatment in 49 CLL patients. Methods: Genotyping of nine polymorphisms was performed by quantitative polymerase chain reaction (qPCR) using a ViiA7^® PCR Instrument and TaqMan assays, and ibrutinib plasma concentrations were determined using high-performance liquid chromatography coupled to a tandem mass spectrometry detector (HPLC-MS/MS). Results: Our study confirmed a high response rate, with 62% of patients achieving complete remission (CR), 9% CR with incomplete hematologic recovery (CRi), and 24% partial remission (PR). The impact of genetic polymorphisms on the CR rate was evaluated, revealing no statistically significant associations for CYP3A4, CYP3A5, ABCB1, ABCG2, and SLCO1B1 variants. However, a tendency was observed for patients carrying ABCB1 rs1128503, rs1045642 T/T, or rs2032582 A/A genotypes to achieve a higher CR rate. Adverse drug reactions (ADRs) were frequent, with vascular disorders (39%) and infections (27%) being the most common. Genetic polymorphisms influenced ibrutinib toxicity, with CYP3A4 *1/*22 appearing to be protective against overall ADRs. Conclusions: The unexpected association between CYP3A4 *1/*22 genotype and lower ADR incidence, as well as the trend toward improved treatment response in patients carrying ABCB1 genotypes, suggests compensatory metabolic mechanisms. However, given the small sample size, larger studies are needed to confirm these findings and their clinical implications, while also aiming to uncover other non-genetic factors that may contribute to a better understanding of the variability in treatment response and toxicity. Full article

In B-cell chronic lymphocytic leukemia (B-CLL), hypodiploidy is a rare but aggressive subtype of the disease with a very bad prognosis. Hypodiploidy, in contrast to normal B-CLL chromosomal aberrations, is marked by widespread genomic instability, which promotes treatment resistance and quick illness development. Its persistence after treatment implies that chromosomal loss gives cancerous clones a selection edge, which is made worse by telomere malfunction and epigenetic changes. Since thorough genetic profiling has a major impact on patient outcomes, advanced diagnostic methods are crucial for early detection. Treatment approaches must advance beyond accepted practices because of its resistance to traditional medicines. Hematopoietic stem cell transplantation (HSCT) and chimeric antigen receptor (CAR) T-cell therapy are two potential new therapeutic modalities. Relapse and treatment-related morbidity continue to be limiting concerns, despite the noteworthy improvements in outcomes in high-risk CLL patients receiving HSCT. Although more research is required, CAR T-cell treatment is effective in treating recurrent B-ALL and may also be used to treat B-CLL with hypodiploidy. Novel approaches are essential for enhancing patient outcomes and redefining therapeutic success when hypodiploidy challenges established treatment paradigms. Hypodiploidy is an uncommon yet aggressive form of B-CLL that has a very bad prognosis. Hypodiploidy represents significant chromosomal loss and structural imbalance, which contributes to a disordered genomic environment, in contrast to more prevalent cytogenetic changes. This instability promotes resistance to certain new drugs as well as chemoimmunotherapy and speeds up clonal evolution. Its persistence after treatment implies that hypodiploid clones have benefits in survival, which are probably strengthened by chromosomal segregation issues and damaged DNA repair pathways. Malignant progression and treatment failure are further exacerbated by telomere erosion and epigenetic dysregulation. The need for more sensitive molecular diagnostics is highlighted by the fact that standard karyotyping frequently overlooks hypodiploid clones, particularly those concealed by endoreduplication, despite the fact that these complications make early and correct diagnosis crucial. Hypodiploidy requires a move toward individualized treatment because of their link to high-risk genetic traits and resistance to conventional regimens. Although treatments like hematopoietic stem cell transplantation and CAR T-cells show promise, long-term management is still elusive. To improve long-term results and avoid early relapse, addressing this cytogenetic population necessitates combining high-resolution genomic technologies with changing therapy approaches. Full article

Background: Chronic lymphocytic leukemia (CLL) is a prevalent hematologic malignancy that predominantly affects elderly individuals, posing significant clinical challenges due to patient comorbidities and inherent resistance to conventional chemotherapy. The emergence of targeted therapies combining venetoclax, a selective inhibitor of the anti-apoptotic protein BCL-2, with anti-CD20 monoclonal antibodies has dramatically transformed the treatment landscape. Methods: This retrospective observational study analyzed the differential impacts of first-line venetoclax-obinutuzumab (VenO) and second-line venetoclax-rituximab (VenR) on immunoglobulin G (IgG) levels and absolute neutrophil count (ANC) in CLL patients. Results: Our findings indicate that during first-line VenO therapy, a significant improvement in ANC levels from baseline was observed, whereas patients undergoing second-line VenR therapy demonstrated limited impact on ANC and the decreasing tendency in IgG levels. Patients treated with VenR had a longer disease history and previous exposure to other treatment regimens, primarily chemoimmunotherapy, which could negatively influence immune recovery, making direct comparisons between these two treatment lines challenging. Although this observational study did not directly compare infection rates, the observed enhancement of ANC levels in patients receiving VenO suggests a potential for lower infection risk compared to pretreated VenR patients. Conclusions: These results underscore the clinical significance of considering both the treatment line and the patient’s prior therapeutic history when selecting venetoclax-based regimens for CLL. The potential association of first-line VenO with improved immunological parameters and the complex impact of prior therapies on immunological recovery with second-line VenR warrant further prospective investigation into the correlation between treatment regimen, patient history, immune function, and infectious complications. Full article

Red blood cell (RBC) aggregation and disaggregation are key factors in microcirculatory flow, and their disturbance can lead to alterations in the rheological properties of blood in disorders such as chronic lymphocytic leukemia (CLL). This study aimed to determine the critical shear rate required to fully disaggregate RBC aggregates using samples from healthy individuals, providing a reference point for evaluating pathological changes. Using a microfluidic system and software-image-based flow analysis, RBC disaggregation was assessed by the Aggregation-Area Indicator at a high shear rate (AAI_H) changes and the number of undestroyed aggregates. The defined critical shear rate at 446 s⁻¹ was applied to assess RBC disaggregation in CLL patients, both untreated and treated with Obinutuzumab/Venetoclax or Ibrutinib. CLL samples exhibited significantly elevated AAI_H values compared to controls, indicating a greater resistance to shear-induced dispersion. Although both treatments reduced the number of stable aggregates, neither therapy fully normalized RBC disaggregation to the levels observed in healthy controls. Moreover, there was a notable heterogeneity among Ibrutinib-treated patients, revealing different therapeutic effects on RBC rheology. These findings suggest alterations in the RBC rheology in CLL despite therapy and support the use of a shear-dependent disaggregation analysis as a complementary tool for understanding and monitoring CLL-related hematologic abnormalities. Full article

Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in the Western world, predominantly affecting older individuals. Advances in targeted therapies have extended survival, shifting the clinical focus toward the management of chronic health challenges. Patients with CLL often experience immune dysfunction due to both the disease and its treatments, resulting in an increased susceptibility to infections and second primary malignancies. This review outlines evidence-based strategies for preventive care in CLL, including age-appropriate cancer screenings, routine immunizations, and lifestyle modifications. By emphasizing proactive health maintenance, this article aims to support clinicians in delivering comprehensive, long-term care for patients with CLL. Full article

Chronic Lymphocytic Leukemia (CLL) is a highly heterogeneous tumor. Although targeted therapies such as Bruton’s Tyrosine Kinase (BTK) inhibitors and B-cell lymphoma-2 (Bcl-2) inhibitors have significantly improved patient outcomes in CLL, the disease remains incurable. A critical aspect of CLL progression is its transformation from an indolent tumor to a high-grade malignancy, a process known as Richter’s Transformation (RT) or Richter Syndrome. Treatment options for RT are very limited, and patient prognosis is often poor. The molecular mechanisms driving RT are not yet fully elucidated. This review aims to summarize recent advances in research aimed at uncovering the mechanisms underlying RT in CLL. By integrating findings from genetics, signaling pathways, epigenetics, and the tumor microenvironment, this review seeks to provide insights that could guide further basic research into RT and inform the development of novel therapeutic strategies to improve patient outcomes. Full article

Background/Objective: Bullous Pemphigoid (BP) is a well-recognized autoimmune subepidermal blistering disease. However, its occurrence following allogeneic hematopoietic stem cell transplantation (HSCT) is extremely rare. The objective of this study is to systematically review the available data on BP following an allogeneic HSCT with focus on treatment options. Methods: A systematic review of studies evaluating BP following allogeneic HSCT, incorporating a highly treatment-resistant case from our graft-versus-host disease (GvHD) dermatology clinic, of a 47-year-old patient, notable as the only reported instance of BP following HSCT in a patient with chronic lymphocytic leukemia (CLL) that transformed into diffuse large B-cell lymphoma (DLBCL) and GvHD due to HSCT. The review yielded 15 publications that met the eligibility criteria. Including our case, a total of 16 cases were analyzed. Results: Nearly all patients (14/16) in this review had chronic GvHD due to their HSCT. Twelve patients were males, and six were of Japanese origin. The mean age for BP diagnosis was 38 years (a range of 5–67). On average, BP developed one year post-HSCT. The most common treatment for BP in these patients was prednisolone, with the majority experiencing complete resolution of symptoms. Conclusions: BP following HSCT is an exceptionally rare condition with an unclear underlying mechanism. Full article

Background: Patients with refractory and relapsed acute myeloid leukemia (R/R AML) face a dismal prognosis. CAR-T therapy has emerged as a potential treatment option. This study assesses the available clinical evidence on CAR-T in R/R AML, focusing on safety and efficacy outcomes. Methods: We included studies on CAR-T therapy for R/R AML published from June 2014 to January 2025. Data on patient and disease characteristics, CAR-T constructs, response rates, post-CAR-T allogeneic HSCT (allo-HSCT), and safety outcomes were analyzed. Results: Twenty-five CAR-T clinical trials involving 296 patients were identified. The most frequently targeted antigens were CD33, CD123, and CLL-1, while CD7, CD19, NKG2D, and CD38 were also explored. Responses were heterogeneous and often short-lived when not consolidated with allo-HSCT. Cytokine release syndrome and neurotoxicity were generally low grade and manageable. Prolonged and severe myelosuppression was a frequent limiting toxicity, often requiring allo-HSCT to restore hematopoiesis. Disease progression was the leading cause of death, followed by infections. Conclusions: CAR-T cell therapy may represent a feasible therapeutic strategy, particularly as bridging to allo-HSCT to mitigate myelotoxicity and improve long-term outcomes. Nevertheless, it remains in the early stages of development and faces significant efficacy and safety challenges that must be addressed in future trials to enable the expansion of this promising therapeutic approach for a population with high unmet medical needs. Full article

Background: Long-term clinical trials and real-world data have established a comprehensive risk–benefit profile for ibrutinib, informing adverse event (AE) management strategies to optimize safety and efficacy. Methods: We retrospectively assessed the incidence of AEs of special interest and management strategies in all patients treated with ibrutinib for chronic lymphocytic leukemia (CLL) in Saskatchewan, Canada, since 2014. Results: Among 187 patients (median age 75.7 years, 63% male), the median time from ibrutinib treatment initiation to data cutoff was 3.1 years. Approximately two-thirds of patients received ibrutinib for relapsed CLL (33.7% second-line and 32.6% third-line and beyond), with 33.7% receiving it first-line. All patients initiated ibrutinib as monotherapy at 420 mg. AEs of interest were observed in 81.3% of patients, with 42.8% experiencing ≥2 AEs. No grade 5 AEs were reported. Among the 284 first-onset AEs observed in 152 patients, 90.8% were successfully managed, allowing treatment continuation. The median time to successful management ranged from 27.0 days (range: 12.5–73.0) for infections to 84.0 days (range: 55.0–141.0) for hypertension. Both AE and discontinuation rates were comparable or favourable to previous reports. Conclusion: This real-world analysis suggests that ibrutinib may be safely used in the majority of CLL patients encountered in routine practice. Full article

Background: The role of PET/CT imaging in chronic lymphoproliferative syndromes (CLL) is debated. This study examines the potential of PET/CT radiomics in predicting outcomes and genetic profiles in CLL patients. Methods: A retrospective analysis was conducted on 50 CLL patients treated at Policlinico Tor Vergata, Rome, and screened, at diagnosis, with [¹⁸F]-FDG PET/CT. Potentially pathological lymph nodes were semi-automatically segmented. Genetic mutations in TP53, NOTCH1, and IGVH were assessed. Eight hundred and sixty-five radiomic features were extracted, with the cohort split into training (70%) and validation (30%) sets. Four machine learning models, each with Random Forest, Stochastic Gradient Descent, and Support Vector Machine learners, were trained. Results: Progression occurred in 10 patients. The selected radiomic features from CT and PET datasets were correlated with four models of progression and mutations (TP53, NOTCH1, IGVH). The Random Forest models outperformed others in predicting progression (AUC = 0.94/0.88, CA = 0.87/0.75, TP = 80.00%/87.50%, TN = 72.70%/87.50%) and the occurrence of TP53 (AUC = 0.94/0.96, CA = 0.87/0.80, TP = 87.50%/90.21%, TN = 85.70%/90.90%), and NOTCH1 (AUC = 0.94/0.85, CA = 0.87/0.67, TP = 80.00%/88.90%, TN = 80.00%/83.30%)mutations. The IGVH models showed poorer performance. Conclusions: ML models based on PET/CT radiomic features effectively predict outcomes and genetic profiles in CLL patients. Full article

Introduction: In mouse models of chronic lymphocytic leukemia (CLL), an effective anti-leukemia immune response was obtained by depleting a specific regulatory T-cell (Treg) subset. While STAT5 signaling could alter the homeostasis of naïve (nTreg) and activated (aTreg) subsets, which are capable of suppressing also CLL patients’ responses to microbial antigens, perturbed STAT3 signaling could drive CXCR5 expression in circulating T-follicular regulatory cells (Tfr) and their entry into the lymph node/tumor microenvironment. Materials and Methods: By using phospho-specific flow cytometry, we monitored STAT signaling/phosphorylation (pSTAT), in vitro responses to Sars-Cov2-antigen-specific stimulation, and circulating Treg subsets in relation to Binet stage and total tumor mass/tumor distribution (TTM/TD) scoring in 62 patients with CLL. Results: The percentage of CXCR5⁺ Treg significantly increased in patients with Binet stage B disease, and Tfr-like subsets were associated with higher TTM and lower TD. The pSTAT3 levels in CD4⁺ T-cells were only significantly increased in patients undergoing therapy. Lower nTreg percentages correlated with increased disease duration, and an increased aTreg/nTreg ratio correlated with SARS-CoV-2-antigen-induced STAT5 signaling responses. Conclusions: The results show increased amounts of circulating CXCR5⁺ Tfr-like subsets in patients with extensive lymph node involvement and augmented STAT3 signaling in patients on therapy. While STAT5 responses may drive nTreg differentiation into aTreg, nTreg decline is associated with increased disease duration. Full article

Myelodysplastic neoplasms (MDS) represent a heterogeneous group of neoplastic bone marrow disorders. A crucial component in regulating bone marrow cell apoptosis is the B-cell CLL/lymphoma 2 (BCL-2) protein. This retrospective study aimed to assess BCL-2 expression by immunohistochemistry in trephine biopsy specimens from 76 patients diagnosed with MDS. The obtained retrospective results were correlated with clinical parameters, including age, sex, MDS subtype, IPSS, IPSS-R, bone marrow blast percentage, Ogata score, response to treatment, blood morphology parameters, and overall survival (OS). The median follow-up duration was 16 months. During the observation period, 58 patients died (median OS of this group: 14.6 months), and 25 patients experienced progression to acute myeloid leukemia. The median BCL-2 expression assessed using the Histoscore (H-score) was 10. Patients with BCL-2 expression below 10 had better survival outcomes than those with expression ≥ 10. Furthermore, patients without detectable BCL-2 expression had significantly better survival compared to those with detectable BCL-2 expression (p = 0.0084). Higher BCL-2 expression was significantly associated with high and very high cytogenetic risk, as defined by IPSS-R. BCL-2 immunohistochemistry should be viewed as a complementary biomarker that, when integrated with IPSS-R and mutational data, could refine therapeutic algorithms. Full article