Medicine and Pharmacology

Abstract: Sickle cell disease (encompassing genotypes of HbSS, HbSC, and HbSβ-thalassemia) is a debilitating hematologic disease affecting nearly 7.7 million people worldwide. Most commonly caused by a single base pair mutation in the hemoglobin beta globin (HBB) gene, red blood cells (RBCs) are distorted into a sickle shape during physiologic stress, causing microscopic vascular occlusions in every organ in the body. The hallmark of this disease is the “pain crisis” caused by these occlusions and resulting tissue infarction. For the patient, frequent pain leads to reduced functional capacity, depression/anxiety, and difficulty maintaining employment, pursuing education, or stable relationships. This negatively affects healthcare systems as well through provider burnout, negative perceptions of the patients, and increased utilization of healthcare resources. Repeated bouts of acute pain can lead to the development of chronic pain over time. The pain associated with sickle cell disease is the most common reason for hospitalization. It presents a formidable challenge to healthcare providers due to its complexity. It is multi-faceted, mediated by physical, emotional, and sociologic factors. The aim of this review is to help the clinician gain a better understanding and appreciation for the pain experienced by these patients and manage it effectively.

Abstract: Background and Aim: Exportin 1 (XPO1) is the principal nuclear export receptor for numerous tumor-suppressor proteins, regulatory factors, and selected oncogenic mRNAs and has emerged as a therapeutically relevant vulnerability in multiple myeloma (MM). Selinexor, a first-in-class oral selective inhibitor of nuclear export (SINE), targets XPO1 and has demonstrated antimyeloma activity both as a doublet and in combination with established therapeutic agents. This review summarizes the biological rationale and molecular mechanisms of XPO1 inhibition, clinical evidence supporting selinexor-based therapy, mechanisms of resistance and potential predictive biomarkers, and practical considerations regarding toxicity management. Materials and Methods: A narrative review of the published literature on XPO1 biology and selinexor in MM was performed, with emphasis on preclinical mechanistic studies, prospective clinical trials, and studies addressing resistance, biomarkers, pharmacology, and treatment-related toxicity. Particular attention was given to pivotal and clinically relevant studies evaluating selinexor-based regimens, including Selinexor Treatment of Refractory Myeloma (STORM), BOSTON, and combination cohorts from the STOMP program, together with recent translational studies expanding the molecular framework of XPO1 inhibition. Results: XPO1 inhibition exerts pleiotropic antimyeloma effects through nuclear retention and reactivation of tumor-suppressor proteins, suppression of NF-κB-dependent signaling and oncogenic mRNA translation, enhancement of glucocorticoid signaling, and disruption of cellular protein homeostasis. More recent findings implicate treatment-induced XPO1 degradation through ubiquitin-regulatory mechanisms and suppression of lipid biosynthesis through the Lipin1–SREBP axis. Clinically, selinexor demonstrated activity in heavily pretreated triple-class refractory MM and subsequently showed improved efficacy when incorporated into once-weekly combination regimens, particularly with bortezomib and dexamethasone. Additional combinations with carfilzomib, pomalidomide, lenalidomide, and daratumumab have demonstrated clinically meaningful activity in selected relapsed/refractory multiple myeloma (RRMM) populations. Candidate determinants of response and resistance include XPO1 Cys528 alterations, hnRNPU, USP7-dependent regulation of XPO1 stability, and Lipin1–SREBP signaling, although none is currently prospectively validated for patient selection. Treatment-related cytopenias, gastrointestinal toxicity, fatigue, and hyponatremia remain important but can frequently be addressed through proactive supportive care and dose optimization. Conclusion: XPO1 inhibition represents a mechanistically distinct therapeutic strategy in MM, and selinexor has established clinical activity across multiple relapsed/refractory settings. Increasing use of lower-dose, once-weekly combination strategies has improved its therapeutic feasibility, while emerging insights into XPO1 degradation, metabolic regulation, and molecular determinants of response are broadening the biological framework of this drug class. Prospective biomarker validation and optimization of treatment sequencing will be important for defining the future role of XPO1-directed therapy in the evolving MM treatment landscape.

Abstract: Fat embolism syndrome (FES) is a rare, life-threatening complication of sickle cell disease (SCD), often underrecognized due to overlap with acute chest syndrome, sepsis, and thrombotic microangiopathies. We report a 37-year-old man with sickle cell disease who presented with an acute vaso-occlusive crisis and rapidly deteriorated with respiratory failure, cardiovascular collapse, and neurological dysfunction. Common etiologies including pulmonary embolism, infection, and stroke were excluded. Laboratory evidence of hemolysis, cytopenias, elevated ferritin, and acute cor pulmonale suggested systemic FES secondary to bone marrow necrosis. The patient underwent urgent red cell exchange transfusion, followed by therapeutic plasma exchange and corticosteroids, resulting in significant clinical and hemodynamic recovery. This case highlights the importance of early recognition and aggressive multimodal therapy in SCD-FES.

Abstract: Background: Intravascular hemolysis releases cell-free hemoglobin and free heme when endogenous haptoglobin and hemopexin scavenging capacity is exceeded, converting erythrocyte injury into a systemic vascular and inflammatory process. Objective: This narrative review examines the emerging concept that heme-driven neutrophil extracellular trap (NET) formation provides a mechanistic axis linking hemolysis, sterile inflammation and immunothrombosis. Methods: Relevant experimental, translational and clinical literature was identified through targeted literature searches, with emphasis on primary mechanistic studies, disease-specific investigations and recent translational evidence. Landmark studies were retained where necessary to establish foundational mechanisms, and findings were synthesized thematically rather than quantitatively. Synthesis: Current evidence indicates that free heme can act as a damage-associated molecular pattern and promote neutrophil activation through reactive oxygen species and peptidylarginine deiminase 4-dependent pathways, while also interacting with inflammasome and PANoptosome signaling, complement, endothelial activation and platelet–neutrophil interactions. NETs provide a procoagulant scaffold that promotes platelet activation, fibrin deposition and thrombus stabilization. Evidence is strongest in sickle cell disease, whereas heme-specific evidence in sepsis and other thrombo-inflammatory disorders remains more limited or emerging. Upstream heme detoxification and downstream NET-targeted strategies have strong mechanistic rationale but remain incompletely validated clinically. Conclusion: heme-driven NETosis represents a potentially druggable convergence point within the heme–neutrophil–platelet–endothelium axis. Biomarker-guided strategies integrating heme scavenging with selective NET modulation warrant prospective clinical evaluation.

Abstract: Balancing thrombotic and bleeding risk remains the central challenge of anticoagulation, and clinically significant bleeding continues to limit even direct oral anticoagulants, especially in high-bleeding-risk patients. Factor XI (FXI) and activated FXI (FXIa) inhibitors are a mechanistically novel class that seeks to uncouple thrombosis from hemostasis; FXI amplifies clot formation through the intrinsic pathway but contributes little to physiologic hemostasis. This state-of-the-art review examines three classes of FXI/FXI inhibitors (antisense oligonucleotides, monoclonal antibodies, and small-molecule inhibitors) that are in advanced phase II and III clinical trials, and synthesizes currently available evidence across six indications, including primary thromboprophylaxis in high-bleed risk orthopedic surgery, primary thromboprophylaxis in end-stage renal disease, stroke prevention in atrial fibrillation, acute coronary syndromes, secondary stroke prevention, and treatment of cancer-associated venous thromboembolism. A pattern emerges, where FXI/FXIa inhibition offers a favorable safety profile across multiple settings and high-risk subgroups, yet clear efficacy has so far been established only in secondary prevention of noncardioembolic ischemic stroke over existing antiplatelet strategies. Although unlikely to completely replace current anticoagulants, these agents may offer important therapeutic options for selected high-risk populations. Ongoing Phase II and III trials will further define their potential advantages in areas of unmet clinical need.

Abstract: Autoimmune hemolytic anemia is a rare but potentially life-threatening disorder characterized by immune-mediated red blood cell destruction. Warm AIHA accounts for most pediatric cases and in childhood AIHA differs substantially from adult disease because of its stronger association with infections, immune dysregulation syndromes and inborn errors of immunity. The disease is clinically heterogeneous, ranging from self-limited episodes to severe chronic relapsing forms requiring prolonged immunosuppression. Diagnostic evaluation should not be limited to the direct antiglobulin test, but must include confirmation of hemolysis, exclusion of alternative causes of anemia, and a systematic search for underlying disorders. Corticosteroids (CS) remain the cornerstone of first-line therapy for warm AIHA, whereas rituximab has emerged as the preferred second-line treatment in CS-dependent or CS-refractory patients. Management of cold-antibody AIHA, paroxysmal cold hemoglobinuria, Evans syndrome, and AIHA associated with giant cell hepatitis requires specific diagnostic and therapeutic considerations. Novel targeted therapies directed against B cells, plasma cells, complement activation, Fc receptors, and intracellular signaling pathways are expanding the therapeutic landscape and may improve outcomes in refractory disease.

Abstract: ABO and Rhesus blood groups have been associated with COVID-19 susceptibility and severity in several international cohorts, but African data remain scarce his study evaluates the association between ABO/Rh blood groups and COVID-19 severity and mortality in Senegal. We conducted a retrospective study of RT-PCR-confirmed COVID-19 patients with available blood group data. Clinical severity (severe forms: Severe and Critical) and in-hospital mortality were analyzed by ABO group and Rhesus status using Fisher’s exact test with Bonferroni correction (×4 for ABO groups) and global Chi-square. Odds Ratios (OR) with 95% confidence intervals (Woolf method) were calculated. ABO distribution: O (47.8%), A (28.8%), B (16.9%), AB (6.4%); Rh+ 94.2%. Severe forms accounted for 27.1% and deaths for 10.2%. No statistically significant association was found between ABO/Rh and severe disease (Chi²=2.40; p=0.494) or mortality (Chi²=1.00; p=0.802). All ORs remained* non-significant after Bonferroni correction. A non-significant trend toward higher mortality in group B (14.0% vs 9.4%; OR=1.57; p=0.312) and zero deaths among Rh− patients (0/17) warrant cautious interpretation. ABO and Rhesus blood groups have no significant impact on COVID-19 severity or mortality in this Senegalese cohort, suggesting that the role of blood groups in COVID-19 outcomes may vary across population.

Abstract: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for hematological malignancies but is associated with severe neurological complications. Although cerebrovascular events are relatively uncommon after allo-HSCT, with reported rates of 2–8%, they are difficult to manage and may substantially increase mortality. Their epidemiology, timing, risk factors, and influence on transplantation outcomes remain insufficiently characterized. This study aimed to assess the impact of post-transplant stroke on transplantation outcomes in patients with hematological malignancies.

Abstract: Blood donation sustains an estimated 118 million annual donations worldwide, and while advances in infectious disease screening have greatly reduced recipient risk, the long-term health of repeat donors has received comparatively less attention. This cumulative narrative review synthesises current evidence on the principal acquired complications of regular blood donation across all modalities — whole blood, plasmapheresis, and plateletpheresis — addressing iron deficiency, plasma protein depletion, apheresis-related lymphopenia, clonal haematopoiesis of indeterminate potential (CHIP), and micronutrient deficiency. Iron deficiency affects 15–36% of frequent whole blood donors and is systematically underdetected by haemoglobin-based screening alone; ferritin-guided interval adjustment and oral supplementation are effective countermeasures. Regular plasmapheresis depletes immunoglobulins (IgG below normal in 5–15% of high-frequency donors), albumin, and coagulation factors, compounded by cumulative citrate-mediated hypocalcaemia. Plateletpheresis causes measurable subset-selective T-cell and NK-cell depletion, with CD4⁺ counts below clinically significant thresholds in a minority of the most frequent donors and attenuated vaccine responses documented in affected individuals. Emerging molecular data indicate that repeated haematopoietic stress selectively enriches low-risk, EPO-responsive DNMT3A clonal variants without increasing malignant risk. Regular blood donation if properly applied is a safe process. Across all domains, current eligibility criteria based on haemoglobin alone turn out to be inadequate; a shift to multiparameter, individualised and targeted donor monitoring — integrating ferritin, serum proteins, differential leucocyte counts, and micronutrient profiling — is both evidence-based and ethically imperative to sustain the long-term health of voluntary donor populations.

Abstract: Background/Objectives: Myeloproliferative neoplasms are a group of clonal myeloid malignancies that affect bone marrow and include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). PV is caused in most of patients by the JAK2-V617F mutation and is characterized at phenotypic level by overproduction and accumulation of red blood cells. PV is associated with significant morbidity, including risk of thrombotic events and of hematologic evolution (myelofibrotic or leukemic transformation) and reduced survival. In addition to JAK2-V617F mutation, PV patients display additional molecular abnormalities. The aim of this study is to review recent studies investigating molecular abnormalities observed in PV. Methods: An extensive search of the most recent literature was performed, selecting and critically analyzing the most relevant studies. Results: The studies carried out in the last years have provided an extensive molecular characterization of PV, showing its heterogeneity, characterized in many patients by the presence of additional cytogenetic and non-driver gene mutations that contribute to the disease development and evolution. Conclusions: PV is a complex disease that needs to be carefully characterized at molecular level at diagnosis, to be monitored in time to predict the risk for thrombotic complications and hematologic evolution and to receive an adequate treatment.

Abstract: Introduction and Clinical Significance: Older, frail patients with relapsed diffuse large B-cell lymphoma (DLBCL) face limited treatment options due to poor tolerance for standard cytotoxic chemotherapy. While novel chemotherapy-free regimens like polatuzumab vedotin plus rituximab (Pola-R) have emerged, optimizing their use requires careful evaluation of patient vulnerability via geriatric assessment (GA) and shared decision-making (SDM). Case presentation: We present the case of a male in his late 70s with multiply relapsed DLBCL who was classified as frail by a comprehensive geriatric assessment, complicated by cognitive impairment and functional decline. Due to his frailty and previous intolerance to cytotoxic chemotherapy, a safety-prioritized, chemotherapy-free Pola-R regimen was selected through an SDM process involving his family as surrogate decision-makers. The patient achieved a complete metabolic response without severe adverse events and has remained progression-free for 15 months. Conclusion: This case highlights the efficacy and safety of the chemotherapy-free Pola-R regimen for frail older patients with DLBCL, underscoring the critical role of integrating GA and SDM to individualize therapy and honor patient goals.

Abstract: Acute myeloid leukemia (AML) is cytogenetically and phenotypically heterogeneous, and this diversity contributes to differences in how patients respond to therapies that target apoptosis. Venetoclax, a selective BCL-2 inhibitor, has been shown to improve outcomes when used in combination with hypomethylating agents (HMAs) such as azacitidine or decitabine; however, clinical experience has shown resistance and relapse are common. This review examines the current evidence linking chromosomal abnormalities and cellular differentiation state to mitochondrial apoptotic pathways, with an emphasis on how these factors influence dependence on certain anti-apoptotic BCL-2 family proteins such as BCL-2, MCL-1, and BCL-XL. We summarize how specific cytogenetic subtypes and high-risk groups (including monosomy 7/del(7q) and complex karyotype/TP53-altered AML) frequently show stress-adaptive signaling and reliance on multiple anti-apoptotic pathways, which can limit the durability of response to BCL-2 inhibition. Lineage-associated dependencies are also examined, such as monocytic differentiation (which leads to increased MCL-1 reliance) and erythroid/megakaryocytic differentiation, which has been associated with increased BCL-XL dependence and venetoclax resistance. Resistance mechanisms can be grouped into three categories: primary resistance (low BCL-2 dependence), adaptive resistance (therapy-induced MCL-1/BCL-XL upregulation), and execution failure (impaired BAX/BAK function). Finally, we discuss the therapeutic implications of dependence mapping, including venetoclax combinations and direct MCL-1/BCL-XL targeting, and propose promising biomarker strategies that can detect dependence shifts early and guide appropriate treatment selection.

Abstract: Human herpesvirus 8 (HHV-8), also known as Kaposi sarcoma–associated herpesvirus (KSHV), is a gamma-2 herpesvirus implicated in a distinctive group of lymphoproliferative disorders (LPD) and lymphomas, in several of which the neoplastic cells are concurrently infected with Epstein–Barr virus (EBV), a gamma-1 herpesvirus. This review summarizes the spectrum of HHV-8/EBV co-positive lymphoproliferations. We first outline the biology of both viruses—their latent and lytic life cycles and the viral gene products (including LANA, vFLIP and v-cyclin for HHV-8 and EBNA-1 and LMP-1 for EBV) through which they deregulate the cell cycle, inhibit apoptosis, and evade immune recognition and may create conditions permissive for B-cell transformation. We then place the principal KSHV/HHV8-associated entities—primary effusion lymphoma and its extracavitary presentation, KSHV/HHV8-positive germinotropic lymphoproliferative disorder, KSHV/HHV8-associated multicentric Castleman disease, and KSHV/HHV8-positive diffuse large B-cell lymphoma—within the current WHO-HAEM5 and ICC frameworks. PEL is frequently EBV-positive, and GLPD is characteristically dual-positive, whereas the KSHV/HHV8-positive lesional cells of MCD and KSHV/HHV8-positive DLBCL are usually EBV-negative. For the purposes of this review, dual positivity denotes demonstration of LANA and EBER within the same morphologically defined lesional cell population and is distinguished from concurrent viral positivity in separate or insufficiently characterized cell populations. Particular attention is given to rare atypical lesions with overlapping features. These cases suggest possible biological relationships among KSHV/HHV8-associated proliferations but do not yet establish a single continuous disease spectrum or a uniform mechanism of viral cooperation.

Abstract: Hereditary hemolytic anemias (HHAs) have quite similar clinical manifestations, complicating differential diagnosis and determining treatment, such as splenectomy. For the differential diagnosis of hereditary spherocytosis (HS), pyruvate kinase deficiency (PKD), and hereditary stomatocytosis (HSt), we proposed to measure erythrocyte filterability through membrane filters with a pore diameter of 3 or 3.5 μm. Our modified method provides improved reproducibility reducing the variation in results caused by differences in the filters used. The filterability of erythrocytes significantly differs in patients with HS, HSt and PKD (medians and 1.5 IQR were: 0.045 [0; 0.51] (n=88); 0.685 [0.46; 0.79] (n=12) and 0.75 [0.55; 0.86] (n=28) rel. un., respectively). The specificity of the filterability test for HS diagnosis was 100%, comparable to the best available tests, while its sensitivity (85.2%) was somewhat lower than that of some alternative methods. Only the filterability test could identify a second subgroup in HS patients (14.8%) with higher filterability (close to normal), but their HS diagnosis was confirmed by the decreased filterability by 3-µm pore filter. This subgroup requires further detailed study. The proposed filterability measurement method is promising for diagnosing HS. It has high sensitivity and specificity and can be performed quickly without expensive equipment.

Abstract: Acute myeloid leukemia (AML) produces more molecular, imaging, and clinical data per patient than any hematologist can hold in mind at once, and each revision of the WHO, ICC, and European LeukemiaNet (ELN) frameworks adds to the load. Artificial intelligence (AI) and machine learning (ML) now reach into every stage of AML care. Deep-learning models read therapy-relevant mutations directly from bone-marrow smears; automated flow-cytometry gating reproduces expert calls in under a minute; and the first AI pathology devices for hematology have cleared regulatory review and entered clinical use. Beyond diagnosis, ML captures the age-dependent weight of individual mutations that categorical ELN scoring misses, drug-response prediction for venetoclax–azacitidine has been validated across multiple external cohorts, and large language models are being tested for tumor-board support and trial matching. The next wave, from clonal-architecture modeling and single-cell foundation models to digital twins and reinforcement learning for adaptive dosing, could move AML management from reactive toward predictive, evolution-aware care. This review departs from existing AI-in-hematology surveys in three ways: we (i) restrict scope to AML and organize the field around clinical decision points rather than technology categories, (ii) grade every tool on a five-tier clinical-readiness level (CRL-AML 1–5), which exposes hundreds of models clustered at CRL-AML 1–2 and none yet in prospective clinical evaluation, and (iii) close with a numbered three-year agenda naming the consortia, datasets, and pragmatic trials needed to carry the field from publication to practice.

Abstract:

Background: Multiple myeloma (MM) is a biologically heterogeneous plasma cell malignancy with variable responses to induction therapy that are not fully explained by current risk stratification systems. Mutations in RAS family genes are prevalent in MM, yet contemporary risk stratification systems do not include them despite their oncogenic potential. Our previous findings showed reduced tumor cell sensitivity to bortezomib-containing triplet induction regimens in the presence of RAS mutations. The aim of this study is to identify RAS pathway–related molecular targets and evaluate their relationship with clinical outcomes. Methods: Forty-four patients with newly diagnosed MM received bortezomib-based induction therapy (VCD or PAD/VCD). Bone marrow CD138+ plasma cells were isolated for transcriptome analysis. KRAS and NRAS gene mutations were identified by Sanger sequencing, and RNA sequencing was performed on the Illumina HiSeq 3000 platform. Gene expression was analyzed using Salmon and DESeq2. The clinical endpoints were depth of response, progression-free survival (PFS), and overall survival (OS). Results: Of 66 candidate RAS-pathway genes examined, five—CREM, NRL, IL-6, MMP14 and MEB2B—showed significantly higher expression in samples with KRAS and NRAS gene mutations (t-test, p < 0.05). Lower NRL gene expression was associated with achieving a deep response (CR/VGPR; p = 0.02). Elevated IL6 gene expression correlated with poorer OS (HR 3.18; p = 0.05), while increased CREM gene expression was associated with shorter PFS (HR 2.62; p = 0.01). Conclusions: Increased expression of NRL, CREM, and IL6 genes could serve as potential prognostic biomarkers in MM and may reflect the molecular mechanisms underlying the adverse effects of KRAS and NRAS gene mutations.

Abstract: Fms related receptor tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations occur in approximately 20–25% of patients with acute myeloid leukemia (AML) and are associated with increased relapse risk and inferior survival outcomes. Although measurable residual disease (MRD) has become a key prognostic tool for guiding post-remission treatment decisions, FLT3-ITD was historically considered a suboptimal MRD marker because of its subclonal nature, structural heterogeneity and dynamic behavior during disease evolution. Despite its strong diagnostic and prognostic relevance, FLT3-ITD has not yet been fully integrated into routine MRD monitoring also due to methodological limitations, and lack of standardized workflows. Recent evidence supports the use of ultra-high sensitivity (UHS) next-generation sequencing (NGS) approaches to detect FLT3-ITD MRD with improved precision, enabling reliable longitudinal tracking of patient-specific clones at very low variant allele frequencies (VAF), and potentially informing clinical decision-making. Indeed, although MRD evaluation is complicated by clonal heterogeneity and molecular instability, advances in high-sensitivity detection techniques have allowed more accurate monitoring of residual leukemic burden. The present review summarizes the biological underpinnings of FLT3-ITD mutated (FLT3-ITD^mut) AML, discusses the methodological challenges of MRD detection, and critically evaluates the evolving role of MRD in refining relapse prediction, supporting post-remission therapy tailoring, and contributing to a harmonized framework for FLT3-ITD^mut AML management.

Abstract: Background: Leg ulceration is a debilitating complication of thalassaemia syndromes, particularly among patients with non-transfusion-dependent thalassaemia (NTDT). Although chronic anaemia is considered a major contributor, clinically relevant haemoglobin (Hb) thresholds associated with ulcer development remain poorly defined. Methods: We conducted a retrospective longitudinal cohort study of patients managed at a specialised Adult and Adolescent Thalassaemia Care Centre established in 2011. Iterative generalised linear mixed-effects modelling (GLMM) with a logit link function was utilised across 84 patients to systematically identify high-risk longitudinal Hb thresholds for the entire cohort and stratified by genotype. A subsequent multi-exposure GLMM framework evaluated independent clinical risk factors, adjusted for sex and genotype. Results: Iterative threshold testing across the entire cohort identified an optimal biological and statistical cutoff at Hb < 5.0 g/dL, associated with a significant risk of ulceration (partially adjusted OR = 2.87, 95% CI: 1.15 - 7.14, P = 0.024). Genotype-stratified analysis revealed that this threshold effect was predominantly driven by the HbEβ-thalassaemia subpopulation, in which the risk escalated sharply between 4.5g/dL (OR = 33.28, P = 0.001) and 5.5g/dL (OR = 2.42, P = 0.023). In the fully adjusted multivariable model, an Hb < 5.0g/dL remained a robust, independent driver of ulceration (aOR = 2.67, 95%CI: 1.08 - 6.62, P = 0.034). Additionally, active follow-up duration (aOR = 1.17 per year, P < 0.001) and cumulative transfusion burden (aOR = 1.43 per unit, P = 0.004) were identified as independent risk factors. Gender and underlying genotype demonstrated no independent association (P > 0.05). Conclusions: A longitudinal hemoglobin level below 5.0g/dL represents a critical threshold for lower-extremity ulceration in thalassaemia, exhibiting a particularly profound risk in HbE/β-thalassaemia. Proactive clinical management targeted at sustaining Hb levels strictly above this threshold, while managing secondary complications reflected by transfusion burden, may optimise microvascular outcomes.

Abstract: Background: Relapsed/refractory multiple myeloma is marked by frequent triple-class refractoriness and poor survival, whereas bispecific antibodies targeting BCMA, GPRC5D, or FcRH5 show meaningful activity even in heavily pretreated and post-BCMA disease.This meta-analysis evaluates and compares the efficacy and safety of these agents in RRMM using direct and indirect evidence. Methods: We manually searched 7 databases and identified 44 studies for quantitative analysis. Forest plots were created using R 4.1.x software. Results: Versus SOC, odds of ORR were higher with Talquetamab, Teclistamab, Elranatamab, and Linvoseltamab (5.73, 4.86, 3.84, 2.63). PFS improved with Teclistamab (HR 0.50, 95% CI 0.36–0.55), Talquetamab (0.50, 0.36–0.55), Elranatamab (0.45, 0.36–0.55), and Linvoseltamab (0.23, 0.17–0.31). Linoseltamab and Elranatamab showed numerically longer OS relative to SOC ( HR 0.41, 0.24–0.70) and (HR 0.58, 0.43–0.78), but numerically shorter OS with Teclistamab (HR 1.82, 1.37–2.42) and Talquetamab (HR 1.75, 1.20–2.57). In pooled single‑arm data, Talquetamab had the highest ORR (72%) and CRS (68%); Teclistamab showed ORR of 61% with CRS 61% and Linvoseltamab showed ORR of 60% with CRS 51%. Cevostamab and Elranatamab had ORR 49% and 56% with CRS 61% and 52%, respectively. Conclusion: In RRMM, all bispecific antibodies showed superior ORR along with improved PFS as compared to SOC. Linoseltamab and Elranatamab showed numerically longer OS relative to SOC, whereas Talquetamab and Teclistamab showed numerically shorter OS versus SOC, within the constraints of adjusted cross-trial comparisons.

Abstract: The introduction of Bruton tyrosine kinase inhibitors (BTKis) has significantly improved prognosis in the treatment of MCL. BTK inhibitors have demonstrated strong activity in the treatment of relapsed/refractory patients with mantle cell lymphoma (MCL), and several trials indicate that they also have potential as first-line treatment. Furthermore, combining BTKis with immunochemotherapy has enabled time-limited therapy as an alternative for continuous treatment with BTK inhibitors alone. In 2013, ibrutinib became the first BTK inhibitor to be approved by the FDA for previously-treated MCL. The TRIANGLE study found ibrutinib to improve the efficacy of standard immunochemotherapy and reduce the need for autologous stem cell transplantation (ASCT) in younger patients; however, its findings do not conclusively confirm whether ASCT enhanced the activity of the ibrutinib-containing regimen in treatment-naïve patients. The next-generation covalent, irreversible BTK inhibitors acalabrutinib and zanubrutinib demonstrate greater selectivity and better pharmacological characteristics than ibrutinib. The FDA approved acalabrutinib and zanubrutinib as single drugs for the treatment of R/R patients with MCL who have received at least one prior therapy. Acalabrutinib combined with bendamustine and rituximab was also approved for TN MCL unsuitable for ASCT. Pirtobrutinib, a first-in-class noncovalent reversible BTK inhibitor, was approved for the treatment of R/R MCL patients, including those resistant to covalent BTK inhibitors. Several other covalent and non-covalent BTK inhibitors are currently under investigation in MCL. Finally, BTK degraders have entered early clinical trials in B-cell lymphoid malignancies, and some of them in MCL.