BACKGROUND: Severe sickle cell disease (SCD) leads to recurrent vaso-occlusive events (VOEs), progressive organ damage, and premature death. Autologous gene therapy has emerged as a potential curative strategy, but trial...BACKGROUND: Severe sickle cell disease (SCD) leads to recurrent vaso-occlusive events (VOEs), progressive organ damage, and premature death. Autologous gene therapy has emerged as a potential curative strategy, but trial efficacy must be interpreted together with mobilization, apheresis collection, manufacturing, conditioning, cost, fertility preservation, and long-term surveillance requirements. OBJECTIVE: To evaluate the efficacy, safety, and treatment-delivery feasibility of autologous gene therapy for SCD across lentiviral, shmiR-BCL11A, CRISPR-Cas9, CRISPR-Cas12a, and base-editing platforms. METHODS: We searched PubMed, Embase, Scopus, Cochrane CENTRAL, ClinicalTrials.gov, FDA, and EMA sources, and ASH/EHA/EBMT/ASPHO conference proceedings through June 23, 2026. Eligible studies were interventional trials or long-term follow-up studies of autologous gene therapy for SCD. Two reviewers independently screened records, extracted data, and assessed risk of bias. Because endpoint definitions were heterogeneous and fewer than three prospectively comparable cohorts were available for the main efficacy outcomes, formal pooling and forest plots were not performed; outcome proportions are presented descriptively. RESULTS: The updated synthesis included 25 reports describing nine interventional clinical programs and associated follow-up reports, with 148 infused patients across lentiviral, shmiR, CRISPR-Cas9, CRISPR-Cas12a, and base-editing platforms. Prospectively defined VF12 was 96.7% (29/30) in the exa-cel pivotal cohort, and severe VOE resolution was 100% (25/25) in the lovo-cel pivotal cohort; both products achieved transfusion independence in evaluable patients. Reni-cel and risto-cel added contemporary Cas12a and base-editing evidence, with early follow-up showing high HbF induction and few or no reported post-infusion VOEs, but follow-up was shorter, and endpoints were not pooled with pivotal VF12 cohorts. Treatment-delivery outcomes differed across programs, including 44/46 infused for exa-cel and 35/47 infused for lovo-cel. CONCLUSION: Autologous gene therapy for SCD produces substantial short- to medium-term reductions in severe VOEs and improves hemoglobin biology, but certainty remains limited by single-arm designs, small samples, evolving protocols, and incomplete long-term follow-up. Successful delivery depends on separable processes: transfusion preparation, mobilization, apheresis collection, ex vivo manufacturing/editing, product release, conditioning, and reinfusion. Long-term safety, fertility, organ outcomes, reimbursement, and global scalability remain unresolved implementation barriers.
Leukemia is a heterogeneous malignancy with poor outcomes in refractory cases, and fusion genes involving JAK2 are known oncogenic drivers. The ARHGEF2::JAK2 fusion gene combines hyperactive kinase signaling with cytoske...Leukemia is a heterogeneous malignancy with poor outcomes in refractory cases, and fusion genes involving JAK2 are known oncogenic drivers. The ARHGEF2::JAK2 fusion gene combines hyperactive kinase signaling with cytoskeletal regulation, but its functional role in leukemia remains unclear. This study aimed to characterize the oncogenic mechanisms of ARHGEF2::JAK2 and identify key downstream targets. Ba/F3 cells transduced with ARHGEF2::JAK2 and mouse xenograft models were used to assess proliferation, apoptosis, and leukemogenic potential. RNA sequencing, qPCR, and Western blotting were used to analyze downstream targets, followed by functional validation via shRNA knockdown. Results showed that ARHGEF2::JAK2 conferred cytokine-independent growth, suppressed apoptosis, and drove aggressive leukemia in mice. Ruxolitinib ameliorates ARHGEF2::JAK2-induced leukemogenesis in vivo. Transcriptomic analysis identified CCNB1 as a critical downstream effector, and its knockdown reversed the oncogenic effects of ARHGEF2::JAK2, improving survival and reducing organ infiltration. These findings demonstrate that ARHGEF2::JAK2 promotes leukemogenesis via CCNB1 upregulation, suggesting CCNB1 as a potential therapeutic target. This study provides new insights into fusion-driven leukemia pathogenesis.
Light chain monoclonal gammopathy of undetermined significance (LC-MGUS) is defined by an abnormal serum free light chain ratio and elevated involved light chain in the absence of a detectable immunoglobulin heavy chain...Light chain monoclonal gammopathy of undetermined significance (LC-MGUS) is defined by an abnormal serum free light chain ratio and elevated involved light chain in the absence of a detectable immunoglobulin heavy chain on immunofixation and of end-organ damage attributable to a plasma cell disorder. It is the least characterized of the MGUS subtypes and the one whose accurate diagnosis is most dependent on the precision of the reference intervals used to interpret free light chain measurements. Population-based screening has demonstrated that standard reference intervals substantially overdiagnose LC-MGUS through three independent mechanisms: age-related physiological free light chain elevation, impaired renal clearance in chronic kidney disease, and ancestry-related differences in individuals of African descent. Revised age-stratified and kidney function-adjusted reference intervals reduce LC-MGUS prevalence by 82%, with no observed progressions among reclassified individuals during available follow-up of 4.6 years and have been validated across multiple independent international cohorts. For individuals of African ancestry, ancestry-adjusted reference intervals provide a further essential and independent correction. True LC-MGUS progresses along two biologically distinct trajectories: clonal expansion toward light chain multiple myeloma and toxic light chain misfolding toward AL amyloidosis. These pathways differ fundamentally in biology, determinants of progression, and clinical consequences. Risk models designed to predict myeloma progression incompletely capture the risk of amyloidogenic transformation. Because amyloidogenic transformation can occur in the setting of low clonal burden and only modestly abnormal free light chain levels, clinical evaluation must independently and explicitly address both trajectories at every patient encounter.
Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematologic malignancies, producing unprecedented clinical responses in relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL...Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematologic malignancies, producing unprecedented clinical responses in relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), diffuse large B-cell lymphoma, and multiple myeloma. Despite these advances, durable remission remains limited by disease relapse, with antigen escape emerging as one of the principal mechanisms of therapeutic resistance. This review comprehensively summarizes the biologic mechanisms underlying antigen escape and highlights emerging engineering strategies designed to overcome immune evasion and improve long-term CAR T-cell efficacy. We discuss both irreversible and reversible resistance pathways, including genetic alterations, alternative splicing, lineage plasticity, trogocytosis, epigenetic repression, and tumor microenvironment-mediated antigen modulation. Particular emphasis is placed on clinically relevant examples such as CD19 loss in B-ALL and BCMA dysregulation in multiple myeloma. The review further examines next-generation approaches developed to prevent antigen-negative relapse, including dual- and multi-target CAR constructs, logic-gated systems, pharmacologic enhancement of antigen density, epitope spreading, and TCR-mimic CAR platforms targeting intracellular antigens. In addition, we evaluate the major translational and biologic challenges associated with these advanced strategies, including structural complexity, manufacturing barriers, toxicity control, tumor heterogeneity, and limited long-term clinical validation. Finally, we discuss future perspectives involving single-cell and multi-omic technologies, computational modeling, and universal modular CAR systems that may enable the development of safer, more adaptable, and precision-guided cellular immunotherapies for hematologic malignancies.
May M, Limon De la Rosa N, Duarte C
… +14 more, Boosma G, Abbott D, Sanchez KG, Pereira R, Borg J, Ransom M, Stevens B, Burchill MA, Zhang J, Pollyea DA, Haverkos B, Gillen AE, Marchetti C, Amaya ML
OBJECTIVES: Myeloproliferative neoplasms (MPNs) are associated with increased thrombosis risk, and earlier identification is essential to reduce preventable complications. We investigated whether platelet counts during p...OBJECTIVES: Myeloproliferative neoplasms (MPNs) are associated with increased thrombosis risk, and earlier identification is essential to reduce preventable complications. We investigated whether platelet counts during pregnancy were higher in women diagnosed with MPN after pregnancy than in controls. METHODS: We conducted a nested case-control study of pregnant women in two Danish regions between 2010 and 2017 using registry and laboratory data. The primary exposure was platelet counts during pregnancy, and the primary outcome was a subsequent MPN diagnosis. RESULTS: We included 49 cases with subsequent MPN, and 979 matched controls. Cases had significantly higher platelet counts (×10/L) during pregnancy (325 (IQR 199-419) vs. 219 (IQR 183-254), p = 0.002), and platelet counts > 400 occurred in 29% of cases versus 2% of controls (p < 0.001). Adjusted models showed an estimated 85 higher platelet count in cases, and platelet counts > 400 during pregnancy were associated with an 18-fold increased odds ratio (95% CI: 6-61) for later MPN. MPN status was strongly associated with higher platelet counts before, during, and after pregnancy. CONCLUSION: Elevated platelet counts during pregnancy are strongly associated with subsequent MPN, suggesting that routine prenatal platelet counts may enable early identification of women at risk of MPN.
Renal dysfunction is common in patients with hematologic diseases and frequently emerges at diagnosis or during treatment. Acute kidney injury, chronic kidney disease, and glomerular involvement may arise from disease bi...Renal dysfunction is common in patients with hematologic diseases and frequently emerges at diagnosis or during treatment. Acute kidney injury, chronic kidney disease, and glomerular involvement may arise from disease biology, antineoplastic therapy, infection, transplantation-related injury, or cumulative supportive exposures. In clinical practice, impaired kidney function rarely represents an isolated comorbidity; rather, it modifies therapeutic feasibility, dose intensity, supportive management, and long-term outcomes. Renal impairment affects delivery of conventional chemotherapy, targeted and immune-based therapies, complicates antimicrobial selection during immunosuppression, and influences eligibility and risk stratification for hematopoietic stem cell transplantation (HSCT). Beyond its immediate consequences, renal dysfunction carries prognostic significance and may reshape therapeutic goals as renal reserve evolves. Considering renal dysfunction as a modifier of hematologic management, rather than solely as a renal endpoint, clarifies its role in treatment planning across the disease continuum.
The ubiquitous human gamma-herpesvirus Epstein-Barr virus (EBV) infects over 90% of adults globally and was the first human virus identified with oncogenic potential. EBV enters a lifelong persistence in the host via a f...The ubiquitous human gamma-herpesvirus Epstein-Barr virus (EBV) infects over 90% of adults globally and was the first human virus identified with oncogenic potential. EBV enters a lifelong persistence in the host via a finely regulated life-cycle comprising primary infection, latency and lytic reactivation. Within infected B-cells and epithelial cells, EBV encodes a distinct repertoire of microRNAs (miRNAs), primarily from the BART (BamHI A rightward transcript) and BHRF1 (BamHI H rightward open reading frame) clusters, which play pivotal roles in modulating both viral and host gene expression. These viral miRNAs contribute to key oncogenic processes: by dampening apoptotic responses (e.g., via targeting PUMA, Bim, and PTEN), promoting proliferation of latently-infected B-cells, inhibiting host immune responses (e.g., via down-regulation of CXCL-11 by miR-BHRF1-3), and promoting epithelial-mesenchymal transition (EMT) and metastasis through modulation of E-cadherin and other adhesion molecules. In human lymphomas, such as Burkitt lymphoma, Hodgkin lymphoma, and EBV-positive diffuse large B-cell lymphoma, the interplay of latent viral gene expression, miRNA-mediated regulatory networks, and host microenvironmental factors underlies malignant transformation and disease progression. Emerging evidence also supports the utility of EBV-encoded miRNAs as diagnostic and prognostic biomarkers in EBV-associated cancers. Importantly, therapeutic strategies aimed at interrupting viral miRNA function, restoring host tumor-suppressor pathways, and re-sensitizing tumor cells to immune surveillance hold promise. This review synthesizes current mechanistic insights into EBV-encoded miRNAs in oncogenesis, elaborates on their roles in lymphoma pathogenesis, and evaluates the translational potential of miRNA-targeted therapies in EBV-associated malignancies.
OBJECTIVES: To determine whether the reported 0%-70% prevalence of vitamin B12 deficiency in sickle cell disease (SCD) reflects true population variation or diagnostic misclassification. METHODS: We conducted a PRISMA 20...OBJECTIVES: To determine whether the reported 0%-70% prevalence of vitamin B12 deficiency in sickle cell disease (SCD) reflects true population variation or diagnostic misclassification. METHODS: We conducted a PRISMA 2020-compliant systematic review of observational studies (January 1, 2000-May 13, 2026; PROSPERO CRD420251087800) assessing B12 status in SCD. PubMed, AJOL, and Google Scholar were searched with citation tracking and dual screening. Diagnostic validity was assessed across biomarker strategy, analytical platform, thresholds, and confounder control using a proposed context-integrated framework to classify methodological robustness and discordance. RESULTS: Fourteen studies were included (57% high-income; 43% LMIC). The evidence base was dominated by limited diagnostic approaches: 71% used immunoassays, over one-third relied on circulating B12 alone, and functional biomarkers were inconsistently applied without systematic confounder adjustment. Prevalence estimates were strongly influenced by diagnostic methods rather than underlying population biology, ranging from 0% to 70% in single-marker studies (mostly 0%-7.1%, with outliers ~50%-70%) and 6.9%-53% in multi-marker studies. Discordance was substantial and greater in LMIC settings than HIC. CONCLUSION: Current diagnostic approaches in SCD appear method-dependent, generating heterogeneous prevalence estimates with uncertain clinical validity. These findings challenge existing estimates and have implications for clinical practice, research design, and diagnostic equity. TRIAL REGISTRATION: ClinicalTrials.gov identifier: CRD420251087800.
OBJECTIVE: Chronic myeloid leukaemia in chronic phase (CML-CP) treatment recommendations have changed substantially in recent years. The ADAPT 2.0 survey aimed to provide an updated understanding of CML-CP management in...OBJECTIVE: Chronic myeloid leukaemia in chronic phase (CML-CP) treatment recommendations have changed substantially in recent years. The ADAPT 2.0 survey aimed to provide an updated understanding of CML-CP management in the UK. METHODS: This healthcare professional (HCP) survey, conducted between December 2023 and June 2024, assessed treatment goals, choice of tyrosine kinase inhibitors (TKIs), unmet needs and approaches to treatment-free remission (TFR). RESULTS: UK CML-CP practise is generally aligned with the contemporary guidelines for CML management. Key treatment goals were major molecular response (54%-77% across treatment lines) and deep molecular response (5%-46%). The main factors influencing first-line (1 L) TKI selection were treatment guidelines (97%), comorbidities (90%) and TFR as a treatment goal (82%). Therapy switch after one warning European LeukemiaNet (ELN) 2020 response was rare (10% vs. 56% in patients with > 1 warning response and 100% in failure response). BCR::ABL1 mutation analysis was less common after one warning response versus > 1 warning response (54% vs. 82%). TKI toxicity, resistance, intolerance and T315I mutation management were key unmet needs in later treatment lines; achieving and maintaining TFR were key unmet needs in 1 L. CONCLUSION: The ADAPT 2.0 survey highlights potential areas of improvement in current CML-CP management in the UK.
Skafi M, Caserta S, Martino EA
… +13 more, Vigna E, Bruzzese A, Amodio N, Fiorillo M, Lucia E, D'Arrigo G, Olivito V, Labanca C, Mendicino F, Alvaro ME, Tripepi G, Morabito F, Gentile M
Extranodal marginal zone lymphoma (EMZL) represents a unique paradigm among indolent B-cell neoplasms, in which lymphomagenesis is frequently driven by chronic antigenic stimulation within tissue-specific microenvironmen...Extranodal marginal zone lymphoma (EMZL) represents a unique paradigm among indolent B-cell neoplasms, in which lymphomagenesis is frequently driven by chronic antigenic stimulation within tissue-specific microenvironments. Persistent infectious or autoimmune triggers promote the development of ectopic lymphoid tissue and sustain B-cell activation, while recurrent genetic alterations-most prominently those that converge on NF-κB signaling-enable progressive escape from antigen dependence. This dual biological foundation explains both the indolent clinical course of most cases and the remarkable therapeutic vulnerability of early-stage, infection-driven disease. Clinically, EMZL arise across a wide range of anatomical sites, each characterized by distinct etiologic associations and patterns of progression. As a result, management strategies must be tailored to disease site, stage, and biological context, with a consistent preference for the least intensive intervention capable of achieving durable disease control. Pathogen-directed antibiotic therapy and involved-site radiotherapy can be curative in localized disease. In contrast, systemic anti-CD20-based immunochemotherapy and targeted agents are reserved for disseminated, refractory, or biologically autonomous lymphomas. Recent advances in molecular profiling, functional imaging, and response assessment are refining risk stratification and treatment selection, shifting therapeutic goals toward early depth of response and quality of life rather than maximal cytotoxic intensity. EMZL thus serves as a model for biologically informed, precision-oriented management of indolent lymphoid malignancies.
Chronic lymphocytic leukemia (CLL) in patients aged ≥ 80 years represents a growing and clinically distinct population that remains underrepresented in clinical trials. Consequently, treatment decisions are often extrapo...Chronic lymphocytic leukemia (CLL) in patients aged ≥ 80 years represents a growing and clinically distinct population that remains underrepresented in clinical trials. Consequently, treatment decisions are often extrapolated from younger or "fit" cohorts, limiting their applicability in routine practice. While targeted therapies (i.e., novel agents such as Bruton tyrosine kinase inhibitors [BTKi] and BCL2 inhibitors) have substantially improved outcomes compared with chemoimmunotherapy, their use in very elderly patients is associated with higher rates of treatment discontinuation, dose reductions, and adverse events. Conventional frailty tools, largely based on comorbidity burden and renal function, fail to capture key age-related vulnerabilities, such as functional decline, cognitive impairment, and reduced physiological reserve. Emerging data suggest that chronological age ≥ 80 years may identify a subgroup with specific clinical behavior and toxicity profiles that are insufficiently characterized by existing assessment models. In summary, elderly patients (aged ≥ 80 years) with CLL should be considered a distinct population requiring individualized, safety-oriented therapeutic approaches. Dedicated clinical trials and adapted treatment algorithms are needed to optimize outcomes in this setting.
OBJECTIVE: To evaluate the efficacy and safety of the complement C3 inhibitor pegcetacoplan in patients with paroxysmal nocturnal hemoglobinuria (PNH). METHODS: PubMed, Embase, Web of Science, and Cochrane Library were s...OBJECTIVE: To evaluate the efficacy and safety of the complement C3 inhibitor pegcetacoplan in patients with paroxysmal nocturnal hemoglobinuria (PNH). METHODS: PubMed, Embase, Web of Science, and Cochrane Library were systematically searched for studies reporting pegcetacoplan use in PNH. Outcomes included transfusion-requirement, hemoglobin normalization, mean hemoglobin levels, lactate dehydrogenase normalization, reticulocyte count normalization, and safety endpoints. Pooled proportions with 95% confidence intervals were calculated using random-effects models, and heterogeneity was assessed using the I statistic. RESULTS: Five studies comprising 271 patients were included. Transfusion avoidance was observed in 80.6% of patients, with a pooled transfusion-requirement rate of 19.4%. LDH normalization occurred in 68.5% of patients (I = 0%). Hemoglobin normalization was observed in 42.9%, while reticulocyte count normalization reached 66%. Any-grade adverse events occurred in 83.5% of patients, most commonly pyrexia, headache, and dizziness. Serious adverse events occurred in 16.6%, decreasing to 12% after sensitivity analysis. Breakthrough hemolysis was reported in 14.8%, and infections in 17%. CONCLUSION: Pegcetacoplan demonstrates consistent efficacy signals across key hematologic endpoints and an acceptable safety profile, supporting its potential role as an important therapeutic option, particularly in patients with persistent extravascular hemolysis despite C5 inhibition.
Guilcher GMT, Abraham A, Arnold SD
… +18 more, Camacho-Bydume C, Duong J, Gillespie S, Haight A, Hulbert ML, Kumar N, Liu K, Mammen C, Mineyko A, Morgan A, Ngwube A, Nickel RS, Roberts A, Schulte F, Sands S, Sharma A, Horan JT, Stenger EO
BACKGROUND: Sickle cell disease (SCD) is a chronic and life-limiting hemoglobin and systemic vascular disease. While over 1000 people have undergone hematopoietic cell transplantation (HCT) over the last 40 years, long-t...BACKGROUND: Sickle cell disease (SCD) is a chronic and life-limiting hemoglobin and systemic vascular disease. While over 1000 people have undergone hematopoietic cell transplantation (HCT) over the last 40 years, long-term disease-specific and health-related quality of life data are lacking. The American Society of Hematology 2021 Guidelines for SCD emphasized the need for more detailed registry data to inform patients and providers with decision-making and practice recommendations. PROCEDURES: In January 2021, the Sickle Cell Transplant Advocacy and Research Alliance (STAR) launched Project Sickle Cure (PSC). This multi-center, prospective study of patients who have undergone HCT for SCD includes baseline demographics and SCD-specific post-HCT outcomes, serial neurocognitive testing, health-related quality of life measures, health equity evaluations, a neuroimaging bank, detailed evaluation of neurologic status pre- and post-transplant, and chronic pain evaluation. A biorepository is in the planning stage of development. RESULTS: As of November 2025, 115 participants have enrolled at 18 STAR sites with enrollment ongoing. CONCLUSIONS: PSC is a STAR prospective study which will address a major gap in our understanding of outcomes post-HCT specific to SCD. WeDecide, a larger study comparing HCT health-related quality of life outcomes to those who receive non-transplant disease modifying therapy (NT-DMT) is in development, and PSC will provide the HCT comparator data. These data will also be highly relevant as other curative and transformative therapies, such as gene therapy, become more widely used.
BACKGROUND: Bloodstream infections remain a major cause of mortality among cancer patients. Pathogen surveillance and risk stratification tools are key to improved management. This study describes trends in causative pat...BACKGROUND: Bloodstream infections remain a major cause of mortality among cancer patients. Pathogen surveillance and risk stratification tools are key to improved management. This study describes trends in causative pathogens and explores risk factors for positive blood cultures (PBCs) and post-infection mortality in cancer patients. METHODS: We performed a cohort study of patients diagnosed with a B-cell malignancy in the North Denmark Region between 2013 and 2022, linking cancer registry data to health records. Causative pathogens were described. LASSO regression was used to select variables associated with PBCs and post-infection mortality. Odds ratios were estimated by univariate analyses. RESULTS: Among 1592 patients with B-cell malignancies, 341 patients (21.4%) had at least one PBC, yielding 484 PBCs. We observed a shift from Gram-positive to Gram-negative dominance, driven by an increased frequency of the most common pathogen Escherichia coli (24.8%). Patients with neutropenia, elevated CRP, sepsis, hypotension, or kidney failure had a higher risk of a PBC. Advanced age, kidney failure, and sepsis were all associated with 30- and 90-day post-infection mortality. CONCLUSION: Routinely available parameters obtained at time of admission were associated with blood culture positivity and mortality. Our findings support the rationale for developing predictive models to individualise infection management.
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyper-inflammatory condition that can be triggered by viral infections. However, influenza is not commonly recognized as a cause of HLH, and there is no comp...Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyper-inflammatory condition that can be triggered by viral infections. However, influenza is not commonly recognized as a cause of HLH, and there is no comprehensive synthesis of influenza-associated HLH in the literature to guide clinicians. We conducted a systematic search of Pubmed and Embase to identify case reports and case series on influenza-associated HLH, and included 29 articles involving 47 patients. Their age ranged from 2 months to 72 years. 67% were males. Influenza A accounted for 91.3% of the cases, predominantly H1N1 (90.2%). All patients had fever, 60% had anemia, 69.7% had thrombocytopenia, 46.6% had leukopenia, 61.3% had splenomegaly, 71.4% had hypertriglyceridemia, and 94.7% had elevated ferritin levels. 97.6% had hemophagocytosis on biopsy. Antiviral therapy was administered in 89.5% of patients. HLH-directed therapy included corticosteroids (77%), intravenous immunoglobulin (36%), and etoposide (23.1%). Intensive care was required in 95.2% of cases. Overall survival was 53.2%. Survival rate was 50% among patients who received either antiviral therapy alone or HLH-directed therapy alone, compared with 65.4% among those who received both. Further studies are necessary to establish standardized diagnostic and therapeutic protocols for influenza-associated HLH.