Gowda K, Gupta M, Aguilar A
… +15 more, Cruz C, Warner A, Rodriguez ER, Ahmed S, Cuglievan B, Milam J, Freyer DR, Miller KA, Aune G, Eshelman-Kent D, Albritton K, Koutroumpakis E, Roth ME, Wang J, Hildebrandt MAT
Cardiac dysfunction is a major morbidity among survivors of adolescent and young adult (AYA) lymphoma. Although high mortality after cardiovascular disease (CVD) diagnosis has been shown in other cancer survivor populati...Cardiac dysfunction is a major morbidity among survivors of adolescent and young adult (AYA) lymphoma. Although high mortality after cardiovascular disease (CVD) diagnosis has been shown in other cancer survivor populations, this has not been investigated in a diverse population of survivors of AYA lymphoma. Therefore, in this study we evaluated survival after a diagnosis of CVD and investigated differences in the CVD-survival relationship. Demographics, treatment variables, and CVD diagnoses occurring at least 3 months after their lymphoma diagnosis were collected in a diverse population of AYA lymphoma survivors (N = 825; race/ethnicity: 58.5% White, 26.9% Hispanic, 14.5% Black). Nearly 25% (23.6%; N = 195) had a CVD diagnosis during the median follow-up time of 9.8 years with the median age at CVD diagnosis being 33.0 years. In Cox models with CVD as a time-varying covariate, the development of a CVD was highly associated with inferior survival (HR: 7.11, 95% CI: [4.03-12.5]). This adverse CVD-survival relationship was consistently observed among patient subpopulations; however, the magnitudes of the adverse effect of CVD on survival were most pronounced (HR > 7) among Black and Hispanic patients, NHL survivors, and those with a healthy baseline BMI. Together these findings underscore the need for cardiovascular health surveillance among survivors of AYA lymphoma to potentially mitigate this adverse effect of CVD on survival in this at-risk population.
Post-transplant cyclophosphamide (PT-CY) remains the standard of care for graft-versus-host disease (GvHD) prophylaxis in haploidentical hematopoietic cell transplantation (HCT), yet relapse, delayed immune reconstitutio...Post-transplant cyclophosphamide (PT-CY) remains the standard of care for graft-versus-host disease (GvHD) prophylaxis in haploidentical hematopoietic cell transplantation (HCT), yet relapse, delayed immune reconstitution, infections, and organ toxicity represent persistent and clinically meaningful limitations. Post-transplant bendamustine (PT-BEN) has been investigated as a biologically distinct alternative. In stringent haploidentical murine models, PT-BEN uncoupled GvHD from graft-versus-leukemia (GvL) effects through mechanisms centered on myeloid modulation and preservation of innate immunity rather than regulatory T-cell expansion. These findings were extended in humanized xenogeneic models, where PT-BEN combined with calcineurin inhibition demonstrated superior survival compared to PT-CY. Clinical translation began with a phase I partial-substitution platform (PT-CY day +3/PT-BEN day +4), demonstrating safety, accelerated hematopoietic recovery, reduced chronic GvHD, and improved GvHD-free relapse-free survival in a small non-randomized cohort. Immune profiling revealed earlier CD4 reconstitution, restrained CD8 effector skewing, and preserved T-cell receptor diversity. Independent studies from multiple international centers have provided preliminary corroboration of these signals and clarified a dose- and platform-dependent cytokine release syndrome as the principal emerging toxicity. The accumulating preclinical consistency and early multi-institutional clinical signals now provide sufficient biological plausibility to justify formal randomized evaluation of PT-BEN against the PT-CY standard. PT-BEN appears to be a mechanistically distinct strategy with immunomodulatory properties that requires randomized validation before platform-level conclusions can be drawn. A multicenter randomized trial incorporating a reduced-dose PT-CY comparator arm will be essential to establish PT-BEN's independent contribution and define its role in improving long-term HCT outcomes.
Sisinni L, Enríquez SV, Herrera MV
… +15 more, Fornieles MP, Torija IL, Erburu AU, García LA, García AR, Del Castillo MT, Bardón-Cancho EJ, León-Triana O, Chacón CM, Soler JLF, Pérez-Martínez A, López PB, Gonzalez-Vicent M, de Heredia CD, GETH‐TC Pediatric Working Group
Third allogeneic hematopoietic stem cell transplantation (HSCT3) is rarely performed in pediatric patients and is associated with high toxicity and mortality. Data on outcomes in this setting remain scarce. We conducted...Third allogeneic hematopoietic stem cell transplantation (HSCT3) is rarely performed in pediatric patients and is associated with high toxicity and mortality. Data on outcomes in this setting remain scarce. We conducted a retrospective multicenter study within the Spanish GETH-TC Pediatric group including 29 children and adolescents who underwent HSCT3 between 2011 and 2024 for malignant (n = 21) or nonmalignant (n = 8) diseases. Patient-, disease-, and transplant-related variables were analyzed, and survival outcomes were estimated using Kaplan-Meier methods. Engraftment was achieved in 22 patients (75.8%). Grade III-IV acute GvHD occurred in 7% and chronic GvHD in 11%. Severe viral infections were frequent (48%), as were bacterial (34%) and fungal infections (21%). By day +100, TRM was 31%, and overall mortality at last follow-up was 66%, predominantly transplant-related. Estimated 12-month overall survival (OS) and event-free survival (EFS) were 39.5% and 32.7%, respectively. Outcomes differed by indication: patients with malignant diseases had limited survival, particularly when transplanted with measurable residual disease, whereas outcomes were more favorable in nonmalignant disorders, with a 12-month EFS of 50%. Survival was also associated with preserved performance status. HSCT3 in children remains a high-risk procedure. Meaningful survival is restricted to carefully selected patients and appears more achievable in nonmalignant indications.
Sainatham C, Goloubeva O, Margiotta P
… +16 more, Alharthy H, Patel I, Gaddipati G, Bukhari A, Law J, Lee ST, Kocoglu M, Yared J, Hardy N, Nelson M, Ahmed N, Mushtaq MU, McGuirk J, Rapoport AP, Dahiya S, Lutfi F
Axicabtagene ciloleucel (Axi-cel) is a chimeric antigen receptor T-cell (CAR-T) therapy approved for the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL). The registrational phase 1/2 ZUMA-1 study coho...Axicabtagene ciloleucel (Axi-cel) is a chimeric antigen receptor T-cell (CAR-T) therapy approved for the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL). The registrational phase 1/2 ZUMA-1 study cohorts 1 and 4 addressed toxicity management in terms of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) whereby tocilizumab and corticosteroids were deployed earlier in cohort 4. In this real-world, single-institution study of 119 patients receiving Axi-cel CAR-T therapy for R/R LBCL with 70 in cohort 1 and 49 in cohort 4, we demonstrate significantly less toxicity, intensive care unit (ICU) utilization, and cumulative steroid use with an early intervention strategy. Laboratory parameters and comorbidities did not significantly differ between groups except for a higher incidence of renal insufficiency in the cohort 4 group (28.6% vs. 4.3%, p < 0.01). The maximum grade CRS was significantly lower for cohort 4 versus 1 (1 vs. 2, p < 0.01). Furthermore, cumulative corticosteroid use was significantly less in the cohort 4 early intervention group (110 mg vs. 190 mg dexamethasone equivalents). These favorable findings did not have a deleterious impact on outcomes and efficacy with similar overall response rate, progression-free survival, and overall survival with both toxicity management approaches.
Jara Rubio R, Martinez-Mellado AJ, Kiwitt-Cárdenas J
… +36 more, Clavel JG, García-Perez B, Castro P, Diaz-Ricart M, Carrillo-Alcaraz A, López-Bernús A, Bernal Morell E, Roura A, Marín S, Ruiz-López FJ, Solana-Martinez E, Martinez-Baño D, Albacete Moreno CL, Andreu Soler E, Tellez Santoyo A, Fernández Méndez S, Noguera Velasco JA, Cebreiros Lopez I, Parrilla A, Espuny-Miró A, García-Bernal D, Blanquer M, Sánchez-Salinas A, Iniesta F, Hernandez Garcia C, Muro M, Minguela Puras A, Moreno-Docón A, Torres-Cantero AM, Munoz Garcia M, Serrano M, Iacobelli M, Carlo-Stella C, Wei LJ, Richardson PG, Moraleda JM
INTRODUCTION: Endothelial dysfunction is key in COVID-19 pathogenesis. This randomized, double-blind phase IIb trial investigated continuous intravenous infusion of defibrotide in patients hospitalized with SARS-CoV-2 in...INTRODUCTION: Endothelial dysfunction is key in COVID-19 pathogenesis. This randomized, double-blind phase IIb trial investigated continuous intravenous infusion of defibrotide in patients hospitalized with SARS-CoV-2 infection and respiratory failure. METHODS: One-hundred and fifty patients were randomized (2:1) to defibrotide or placebo, stratified by disease severity (WHO COVID-19 severity scale 4/5 vs. 6). The primary endpoint was clinical improvement time (days from first improvement through Day 30). RESULTS: Median clinical improvement time was not significantly different with defibrotide versus placebo (15.0 [IQR: 0-24] vs. 20.0 [IQR: 9-25] days; p = 0.10). Day-30 (23.0% vs. 22.0%) and Day-60 (26.0% vs. 22.0%) mortality, reduction in mean fraction of inspired oxygen during treatment, and median duration of hospitalization did not differ with defibrotide versus placebo. Defibrotide demonstrated favorable safety, with no differences versus placebo in serious adverse events (34.0% vs. 36.0%), hypotension (16.0% vs. 12.0%), or hemorrhage (13.0% vs. 8.0%). Exploratory pre-specified biomarker analyses showed greater early d-dimer reduction and lymphocyte recovery with defibrotide, although these results require validation. CONCLUSION: Continuous intravenous infusion of defibrotide was safe but did not improve clinical outcomes in severe COVID-19. Further analyses will explore mechanistic actions and pharmacokinetics of defibrotide and the pathophysiology of endothelial dysfunction in COVID-19. TRIAL REGISTRATION: EudraCT identifier: 2020-001409-21. CLINICALTRIALS: gov identifier: NCT04348383.
OBJECTIVES: Somatic mutations in the UBA1 gene cause VEXAS syndrome, which presents with inflammatory and hematological symptoms. Case studies show a strong overlap between VEXAS and myelodysplastic syndrome (MDS). Recog...OBJECTIVES: Somatic mutations in the UBA1 gene cause VEXAS syndrome, which presents with inflammatory and hematological symptoms. Case studies show a strong overlap between VEXAS and myelodysplastic syndrome (MDS). Recognizing VEXAS is important for differential diagnosis in patients with both inflammation and MDS, as accurate identification guides treatment. The study focuses on determining how often canonical UBA1 mutations linked to VEXAS occur in MDS patients. METHODS: Patients diagnosed with MDS were enrolled in the study, and genomic DNA was isolated from bone marrow FFPE samples. Molecular analysis was performed using a specifically designed ARMS-PCR approach. Additionally, protein-protein interaction (PPI) studies combined with bioinformatic analyses were carried out to explore potential links between UBA1 and pyroptosis. RESULTS: Among the 149 MDS patients analyzed, none exhibited high-Variant Allele Frequency (VAF) the canonical UBA1 point mutations linked to VEXAS syndrome. PPI analysis revealed a possible association between UBA1 and the NLRP3 inflammasome component. CONCLUSIONS: Expanding the sample size and using targeted NGS or ddPCR would improve mutation detection sensitivity and could reveal UBA1 canonical and non-canonical variants and more accurately estimate the frequency of VEXAS-related mutations in the MDS population.
Iron-deficiency anemia is frequently accompanied by reactive thrombocytosis, yet the mechanisms underlying this association remain incompletely understood. Beyond impaired erythropoiesis, iron availability has emerged as...Iron-deficiency anemia is frequently accompanied by reactive thrombocytosis, yet the mechanisms underlying this association remain incompletely understood. Beyond impaired erythropoiesis, iron availability has emerged as an active regulator of hematopoietic lineage decisions. This review synthesizes current evidence on how iron deficiency influences megakaryocytic-erythroid balance, with emphasis on progenitor-level regulation, iron sensing pathways and downstream megakaryocyte maturation. We discuss experimental and clinical studies supporting compensatory hematopoietic responses under iron-deficient conditions and propose an integrated framework linking systemic iron status to altered platelet and erythroid output.
McKay KG, Zhao OS, Badrieh SS
… +5 more, Bastarache L, Niu X, He J, Kannankeril PJ, Robinson JR
Eur J Haematol
· 2026 May · PMID 42093615
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BACKGROUND: Venous thromboembolism (VTE) is a major cause of morbidity in patients of all ages. Despite growing interest in polygenic risk scores (PRS) for VTE, their utility remains understudied. Our objective was to ev...BACKGROUND: Venous thromboembolism (VTE) is a major cause of morbidity in patients of all ages. Despite growing interest in polygenic risk scores (PRS) for VTE, their utility remains understudied. Our objective was to evaluate the independent impact of a PRS on VTE susceptibility in adults and children. METHODS: We completed a retrospective, case-control study of two separate cohorts with evaluation of three VTE PRS models, with the primary analysis focused on a 293 single nucleotide polymorphism (SNP) PRS. The adult cohort included 597 VTE cases and 31 998 controls, and the pediatric cohort included 109 cases and 448 controls, both obtained from a de-identified databank with linked genetic data. Separate adult and pediatric multivariable logistic regressions were performed to measure the association of risk factors with VTE. RESULTS: Higher PRS in adults was significantly associated with increased odds of VTE, with each 1-standard deviation increase in PRS conferring an adjusted odds ratio of 1.25 (OR = 1.25, 95% CI 1.15-1.36, p < 0.001). Leading risk factors for adults were cancer (OR = 2.43, 95% CI: 2.04-2.89, p < 0.001) and recent surgery (OR = 2.16, 95% CI: 1.83-2.54, p < 0.001). The standardized PRS also exhibited increased risk for VTE in children (OR = 1.38, 95% CI 1.10-1.74, p = 0.003). Central venous catheterization (OR = 5.65, 95% CI 3.40-9.50, p < 0.001) was the foremost risk factor for pediatric VTE. CONCLUSION: VTE in adults and children is multifactorial, with clinical and genome-wide risk factors contributing. PRS may serve as a valuable adjunct to clinical risk factors for VTE risk stratification.
Riller Q, Ben Salem T, Emile JF
… +13 more, Charlotte F, Idbaih A, Faucher B, De Almeida S, Martin-Blondel G, Tazi A, Donadieu J, Riviere E, Samson M, Souffir C, Amoura Z, Haroche J, Cohen-Aubart F
BACKGROUND: Erdheim-Chester Disease (ECD) and Rosai-Dorfman Disease (RDD) Are Rare Non-Langerhans Cell Histiocytoses That Share Several Clinical and Histological Features, Including the Accumulation of CD1a- Histiocytes...BACKGROUND: Erdheim-Chester Disease (ECD) and Rosai-Dorfman Disease (RDD) Are Rare Non-Langerhans Cell Histiocytoses That Share Several Clinical and Histological Features, Including the Accumulation of CD1a- Histiocytes in Organs. Cladribine, a Purine Analog, Leads to an Overall Response Rate (ORR) of 91% in Langerhans-Cell Histiocytoses. Whether the Same Results Could Be Obtained in Non-Langerhans Cell Histiocytoses Remains To Be Determined. PATIENTS AND METHODS: We retrospectively assessed the efficacy of cladribine according to clinical and radiological responses in consecutive patients with a diagnosis of ECD, RDD, or non-classified non-Langerhans cell histiocytosis. RESULTS: Twenty-One Patients Were Included in This Study (17 Males, Median Age at Cladribine Treatment 53 Years). The Clinical ORR Was 62% (44% in ECD, 70% in RDD), whereas the Radiological ORR Was 43% (44% in ECD, 30% in RDD). Four of Five Patients With Cranial Nerve Palsy Responded Clinically (80%), whereas Pseudo-Degenerative CNS Involvement Did Not Improve (n = 3). Six Patients With Multisystemic Involvement Did Not Require Additional Treatment After Achieving a Radiological Response (n = 4) or After Achieving Radiological Stable Disease (n = 2), with a Median Follow-Up of 2.3 Years (Range 0.5-9.5). After They Achieved a Radiological Response, 4/9 (44%) Patients Relapsed in a Median Time of 18 Months (Range 6-95). The Safety Profile Showed That 19/19 Patients Experienced Lymphopenia, Whereas Only 2/19 Had Clinical Infectious Events (9%). CONCLUSIONS: These Results Provide New Evidence of the Efficacy of Cladribine in Non-Langerhans Cell Histiocytosis and Brings New Data on the Safety Profile of This Drug in Histiocytoses.
BACKGROUND: Delayed diagnosis of haemoglobinopathy in adulthood is a recognised but incompletely characterised clinical problem, particularly in populations with high carrier prevalence. Adults with thalassaemia syndrome...BACKGROUND: Delayed diagnosis of haemoglobinopathy in adulthood is a recognised but incompletely characterised clinical problem, particularly in populations with high carrier prevalence. Adults with thalassaemia syndromes and haemoglobin variants are frequently misclassified as having iron deficiency or other common causes of microcytic anaemia, leading to prolonged diagnostic uncertainty, inappropriate iron supplementation and deferred access to genetic counselling and disease-specific management. The present exploratory study aimed to characterise diagnostic trajectories and candidate clinical cues associated with delayed recognition in a small single-centre cohort. METHODS: This was a retrospective, descriptive, single-centre pilot study of 19 adults who received a confirmed haemoglobinopathy diagnosis after a prolonged diagnostic delay, defined as a documented interval of ≥ 12 months between the first recorded abnormal haematological finding or symptom onset and the final confirmed diagnosis. We extracted clinical presentation, laboratory parameters, diagnostic pathway and retrospectively identified candidate clinical cues. Data are reported descriptively. As a secondary, hypothesis-generating exercise, we describe the components and cohort-level distribution of a preliminary clinical suspicion framework-the Haemoglobinopathy Suspicion Score (HSS) derived from the recurrent features observed in this dataset. No external comparator group was available; all analyses are descriptive and exploratory only. RESULTS: Median age at diagnosis was 39.0 years (IQR 31.0-53.5); five patients (26.3%) were diagnosed at age ≥ 54 years. The cohort was predominantly of Greek origin (18/19, 94.7%) with combined α/β phenotypes predominating (12/19, 63.2%). Recurring descriptive features within this small cohort included a combined microcytosis-hemolysis laboratory profile: median MCV was 63.6 fL (IQR 61.8-67.6), ferritin 201 ng/mL (IQR 89.6-283.9) and total bilirubin 1.8 mg/dL (IQR 1.1-2.3). Persistence of microcytic anaemia despite documented iron supplementation was retrospectively identified in 12/19 patients (63.2%; exact 95% CI 38.4%-83.7%). Iron deficiency anaemia was the initial misdiagnosis in 6/19 patients (31.6%). Patients consulted a median of 2.0 specialties (IQR 1.0-2.5) before a correct diagnosis was established. Applying HSS components retrospectively, a score of ≥ 3 was present in 18/19 patients (94.7%); this observation is descriptive only and cannot be interpreted as diagnostic performance in the absence of a comparator population. CONCLUSIONS: This exploratory single-Centre pilot study identifies recurring descriptive features associated with diagnostic delay in a small cohort of adults with haemoglobinopathy. The proposed HSS is a preliminary, hypothesis-generating clinical suspicion framework and has not been validated for clinical use. Larger, prospective, multicentric studies with appropriate comparator populations are required to derive and formally validate any bedside suspicion tool for this setting.
Uchida Y, Tateo S, Wakao M
… +5 more, Shinchi H, Sawayama H, Fukumoto A, Yoshimitsu M, Suda Y
Eur J Haematol
· 2026 Aug · PMID 42070769
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Adult T-cell leukemia/lymphoma (ATL) is an aggressive hematological malignancy with a poor prognosis and limited therapeutic options. ATL cells exhibit aberrant surface glycosylation patterns resulting from dysregulated...Adult T-cell leukemia/lymphoma (ATL) is an aggressive hematological malignancy with a poor prognosis and limited therapeutic options. ATL cells exhibit aberrant surface glycosylation patterns resulting from dysregulated glycosyltransferase expression, representing a potentially tumor-specific therapeutic target. We previously isolated an ATL-specific single-chain variable fragment (scFv), S1TSCFR3-1, that selectively binds to ATL cell surface glycans. In this study, we engineered natural killer (NK) cells to express a chimeric antigen receptor (CAR) incorporating S1TSCFR3-1 and evaluated their therapeutic potential against ATL. In vitro, CAR-NK cells exhibited dose-dependent cytotoxicity against ATL cell lines, mediated primarily through enhanced granzyme B production, whereas no augmentation of cytotoxic activity was observed against non-ATL cell lines. S1TSCFR3-1 binding was detected in PBMCs from 3 of 7 ATL patients, and CAR-NK cells demonstrated significant cytotoxicity against PBMCs from a binding-positive patient. In a xenograft mouse model, administration of irradiated CAR-NK cells partially suppressed tumor burden as evidenced by reduced serum hsIL-2R levels, although survival benefit did not reach statistical significance. These findings suggest that CAR-NK cell therapy targeting ATL-associated aberrant glycan epitopes represents a potentially valuable therapeutic approach warranting further investigation.
OBJECTIVES: Chimeric antigen receptor T-cell (CAR-T) therapy has become an established treatment for hematological malignancies. Lymphodepleting (LD) chemotherapy is a preparatory step that facilitates CAR-T cell expansi...OBJECTIVES: Chimeric antigen receptor T-cell (CAR-T) therapy has become an established treatment for hematological malignancies. Lymphodepleting (LD) chemotherapy is a preparatory step that facilitates CAR-T cell expansion and persistence. While fludarabine and cyclophosphamide (Flu/Cy) are a standard LD regimen, bendamustine has emerged as a potential alternative. METHODS: We performed a systematic review and meta-analysis comparing the efficacy and safety of bendamustine versus Flu/Cy as LD regimens. We systematically searched PubMed, Scopus, and the Cochrane Central Register of Controlled Trials from inception to July 2025. RESULTS: Nine retrospective studies comprising 768 patients were included. The bendamustine cohort demonstrated a lower incidence of all-grade cytokine release syndrome (CRS) compared with Flu/Cy (60.2% vs. 71.7%; p = 0.011), whereas no difference was observed in grade ≥ 3 CRS. Overall infections were less frequent with bendamustine (18.3% vs. 53.7%; p < 0.001). There were no significant differences between groups in the incidence of immune effector cell-associated neurotoxicity syndrome, overall response rate, overall survival, and progression-free survival. CONCLUSION: Bendamustine LD therapy significantly reduced the incidence of all-grade CRS and overall infections without compromising CAR-T efficacy. These findings suggest that bendamustine may serve as a viable alternative LD regimen.
BCR::ABL1 acquisition is an emerging but poorly characterized resistance mechanism in FLT3-mutated AML. Using multiomic single-cell DNA sequencing, we characterized clonal evolution in a patient with FLT3-ITD AML who acq...BCR::ABL1 acquisition is an emerging but poorly characterized resistance mechanism in FLT3-mutated AML. Using multiomic single-cell DNA sequencing, we characterized clonal evolution in a patient with FLT3-ITD AML who acquired BCR::ABL1 with FLT3 inhibitor resistance. Phylogenetic reconstruction confirmed BCR::ABL1 as a branch event co-occurring with FLT3-ITD and restricted to specific blast populations, supporting BCR::ABL1 acquisition as a resistance mechanism.
INTRODUCTION: Hereditary spherocytosis (HS) is a congenital hemolytic anemia caused by erythrocyte membrane protein defects. While the eosin-5'-maleimide (EMA) binding test by flow cytometry is the established first-line...INTRODUCTION: Hereditary spherocytosis (HS) is a congenital hemolytic anemia caused by erythrocyte membrane protein defects. While the eosin-5'-maleimide (EMA) binding test by flow cytometry is the established first-line assay, this study evaluates its optimal cut-offs and performance within a large, real-world cohort. METHODS: We retrospectively analyzed 181 consecutive samples (2017-2024) with suspected HS. EMA binding was performed by flow cytometry using conventional and standardized protocols; the latter (implemented in 2023) utilized fixed erythrocyte counts and FL1 bead calibration. Accuracy was assessed against a composite clinical-laboratory reference standard. ROC analysis determined sensitivity, specificity, likelihood ratios, and AUC. RESULTS: HS was confirmed in 50/181 cases (27.6%). EMA fluorescence reduction was significantly greater in HS (median 23.0%) than in non-HS samples (9.0%). The optimal cut-off (16.5%) yielded 96.0% sensitivity, 96.9% specificity, and AUC = 0.990 (95% CI 0.979-0.998). Both conventional and standardized protocols showed equivalent accuracy (AUC 0.988 vs. 0.992). False positives were mainly associated with severe microcytosis or autoimmune hemolytic anemia. CONCLUSIONS: In a consecutive, real-world cohort of patients with suspected hereditary spherocytosis referred to a single reference laboratory receiving samples from across the country, the EMA test demonstrated high diagnostic accuracy consistent with previous reports. Importantly, implementation of a standardized protocol resolved reproducibility issues in fluorescence intensity measurement without compromising diagnostic performance, supporting its robustness and applicability in routine clinical laboratories.
Sickle cell disease and thalassemia syndromes are increasingly recognized as chronic multisystem disorders, with cardiovascular (CV) sequelae representing a significant proportion of long-term morbidity and mortality. Su...Sickle cell disease and thalassemia syndromes are increasingly recognized as chronic multisystem disorders, with cardiovascular (CV) sequelae representing a significant proportion of long-term morbidity and mortality. Survival has improved considerably due to better transfusion practice, the administration of iron chelation, and disease-modifying treatments; a broad and expanding phenotypic spectrum of cardiac and vascular manifestations is being recognized. These include cardiomyopathy, heart failure, pulmonary hypertension, arrhythmias, microvascular ischemia, and functional valvular disease, often resulting insidiously and progressing over time. CV pathogenesis of hemoglobinopathies is complex and heterogeneous. Chronic anemia induces a long-lasting high-output circulatory state, while iron overload related to transfusion produces myocardial siderosis, oxidative damage, and electrical instability in particular in transfusion-dependent thalassemia. Moreover, hemolysis-mediated endothelial dysfunction, deficiency of nitric oxide, inflammation, and microvascular pathology play a central role in sickle cell disease, resulting in diastolic dysfunction, pulmonary vascular remodeling, and heart failure with preserved ejection fraction. These pathomechanisms create disease-specific CV phenotypes that have important diagnostic and therapeutic implications. This narrative review was performed by searching the PubMed, Cochrane Library, and Google Scholar databases for original studies, systematic reviews, and guidelines for the period of 2009-2025. This review summarizes available data on the epidemiology and pathophysiological mechanisms contributing to CV complications of hemoglobinopathies and clinical manifestations of CV compromise. The review summarizes developments in diagnosis and screening methods such as echocardiography, cardiac magnetic resonance imaging, biomarkers, and functional measures, disease-modifying drugs, and CV lovastatin by phenotype. We finally highlight major evidence gaps and research priorities needed to improve CV outcomes. This multidisciplinary approach is essential for transforming mechanistic insight into improved survival and quality of life for individuals with hemoglobinopathies through a systematic, interdisciplinary, and proactive CV strategy.
Caserta S, Martino EA, Vigna E
… +12 more, Skafi M, Bruzzese A, Amodio N, Lucia E, D'Arrigo G, Olivito V, Labanca C, Mendicino F, Alvaro ME, Tripepi G, Morabito F, Gentile M
Eur J Haematol
· 2026 Aug · PMID 42036772
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Minimal residual disease (MRD) has emerged as a central biomarker in hematologic malignancies, enabling highly sensitive detection of tumor persistence beyond conventional morphologic assessment and serving as an increas...Minimal residual disease (MRD) has emerged as a central biomarker in hematologic malignancies, enabling highly sensitive detection of tumor persistence beyond conventional morphologic assessment and serving as an increasingly important surrogate endpoint in clinical trials. Despite these advances, MRD remains predominantly conceptualized as a quantitative variable reflecting residual tumor burden below assay detection thresholds. While this paradigm has enabled standardization of response criteria and cross-trial comparisons, it does not fully explain key clinical observations, including heterogeneous outcomes among MRD-positive patients, durable remissions despite detectable disease, and discordance between molecular and imaging-based assessments. Here, we propose a conceptual framework in which MRD is redefined as a biologically determined trait-a functional phenotype of persistence-rather than a purely quantitative state. We review the mechanisms that shape this phenotype, including therapy-driven clonal selection, epigenetic and transcriptional plasticity, metabolic adaptation, immune evasion, and microenvironmental niche protection. These processes collectively define the functional fitness of residual tumor cells and their capacity to survive therapeutic pressure, remain dormant, and ultimately drive relapse. This framework provides a mechanistic explanation for clinically observed phenomena-including molecular-imaging discordance and variable relapse kinetics-arguing that these are not merely technical artifacts but reflect distinct, partially independent biological dimensions of residual disease. We further outline a multidimensional model of MRD integrating molecular, spatial, immune, metabolic, and functional dimensions. Operationally, we define MRD as a biological trait across five interacting axes: (i) clonal fitness, (ii) phenotypic plasticity, (iii) metabolic adaptability, (iv) immune evasion, and (v) microenvironmental dependence. Conceptualizing MRD as a dynamic biological trait offers a more comprehensive and testable model of disease persistence and supports the development of mechanism-based MRD-directed therapeutic strategies in hematologic malignancies.
Diaw M, Connes P, Charlot K
… +16 more, Diop S, Gallou-Guyot M, Coly MS, Carin R, Ducray M, Gadji M, Miyachi M, Yoshida T, Seck M, Gueye M, Thioune NM, Samb A, Gueye A, Nader E, Ranque B, Tripette J
BACKGROUND: Sickle cell anemia (SCA) is characterized by recurrent pain, chronic hemolysis, autonomic imbalance, and progressive vascular dysfunction. In sub-Saharan Africa, where access to disease-modifying therapies re...BACKGROUND: Sickle cell anemia (SCA) is characterized by recurrent pain, chronic hemolysis, autonomic imbalance, and progressive vascular dysfunction. In sub-Saharan Africa, where access to disease-modifying therapies remains limited, identifying modifiable behavioral determinants such as physical activity (PA) is of particular clinical relevance. This study examined the associations between objectively measured daily step count and clinical, biological, hemorheological, vascular, and autonomic parameters in adults with SCA. METHODS: Ninety-eight adults with SCA were stratified into tertiles according to accelerometer-derived daily step count. Pain burden, renal indices (albuminuria and estimated glomerular filtration rate [eGFR]), hematological and hemorheological parameters, arterial stiffness (carotid-femoral pulse wave velocity), and heart rate variability were assessed. RESULTS: Higher daily step counts were associated with less frequent intense pain, reduced blood viscosity, and a higher hematocrit-to-viscosity ratio. More active participants also exhibited lower arterial stiffness and greater parasympathetic modulation. A graded, linear pattern was observed across tertiles for most outcomes. Although eGFR was positively associated with physical activity, this relationship was largely explained by age differences between groups. DISCUSSION: Greater daily physical activity is associated with a more favorable clinical and physiological profile in adults with SCA. While causality cannot be inferred, daily PA may represent both a marker of health status and a potential target for preventive strategies in this population. TRIAL REGISTRATION: UMIN000042826.
Martino EA, Chiarenza A, Mancuso S
… +20 more, Rossi M, Stelitano C, Abbene I, Cabibbo S, Caracciolo D, Cotzia E, Figuera A, Greco A, Innao V, Levato L, Marino C, Mineo G, Nocilli L, Penna G, Porrazzo M, Tona G, Vigna E, Morabito F, D'Angela D, Gentile M
Eur J Haematol
· 2026 Aug · PMID 42026890
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The therapeutic landscape of chronic lymphocytic leukemia (CLL) has been profoundly transformed by the introduction of Bruton tyrosine kinase and BCL-2 inhibitors. Despite improved survival outcomes, treatment selection...The therapeutic landscape of chronic lymphocytic leukemia (CLL) has been profoundly transformed by the introduction of Bruton tyrosine kinase and BCL-2 inhibitors. Despite improved survival outcomes, treatment selection remains complex, particularly in older patients with comorbidities, frailty, and increased infectious vulnerability. To address areas of clinical heterogeneity and support real-world decision-making, a two-round Delphi consensus process was conducted among 15 hematologists from 15 hematology departments across two Italian regions, Calabria and Sicily. A steering committee developed 12 statements covering key clinical and organizational aspects of CLL management, including infectious risk assessment, frailty evaluation, and the role of TP53 alterations in therapeutic choice. Agreement was assessed using a four-point Likert scale, with consensus predefined as ≥ 70% agreement or disagreement. All invited clinicians participated in both rounds (100% response rate). In the first round, consensus was achieved for 8 of 12 statements (66.7%). Following reformulation of unresolved items, two additional statements reached consensus in the second round. Overall, strong agreement was observed for five statements, while moderate convergence persisted for others. Panelists emphasized that infectious risk assessment should systematically inform treatment decisions and that structured frailty tools, including ECOG Performance Status and the Clinical Frailty Scale, may improve patient stratification. Although TP53 alterations were recognized as critical biological determinants, therapeutic decisions in older patients should balance genetic risk with age, comorbidities, frailty, and socioeconomic context. This regional initiative highlights priorities for patient-centered, multidimensional CLL management and may inform the development of optimized care pathways within coordinated regional networks.