Giannella A, Vianello F, Zoletto S
… +19 more, Magrini A, Gianesello I, Binotto G, Danesin N, Ceccato J, Gualtiero G, Piazza M, Carraro S, Carabotta V, Cinetto F, Cellini A, Carraro M, Gurrieri C, Pavan L, Piazza F, Visentin A, Ageno W, Trentin L, Ceolotto G
Targeted next-generation sequencing combined with a structured interpretative framework integrating gene-disease validity, population data, computational predictions, ACMG criteria and structural modelling enabled priori...Targeted next-generation sequencing combined with a structured interpretative framework integrating gene-disease validity, population data, computational predictions, ACMG criteria and structural modelling enabled prioritisation of rare variants in idiopathic erythrocytosis, highlighting the genetic heterogeneity and biological complexity underlying this condition.
Targeted therapies have transformed modern management of chronic lymphocytic leukaemia (CLL). Still, CLL remains an incurable disease, and key unresolved challenges include development of treatment resistance and intoler...Targeted therapies have transformed modern management of chronic lymphocytic leukaemia (CLL). Still, CLL remains an incurable disease, and key unresolved challenges include development of treatment resistance and intolerance. To address these challenges, it is necessary to define clinically actionable biomarkers that can predict individual treatment responses. Here, we aimed to map the treatment sensitivity and resistance landscapes of CLL cells from treatment-naïve and treatment-exposed patients to understand the evolution of treatment vulnerabilities. We performed ex vivo drug screens with 94 single agents and 87 drug combinations on CLL cells from treatment-naïve, ibrutinib-exposed or idelalisib-exposed patients. We found that overall drug sensitivity was reduced in cells from patients who had received treatment. Specifically, sensitivity to B-cell lymphoma 2 (Bcl-2) inhibitors was significantly reduced in both ibrutinib-exposed and idelalisib-exposed patient cells. Furthermore, combined Bruton's tyrosine kinase inhibitor (BTK)/Bcl-2 inhibition became less relevant in advanced disease, while dual mitogen-activated protein kinase kinase (MEK)/Bcl-2 inhibition was identified as an effective new treatment modality. Our findings provide valuable insights that may assist clinical decisions regarding treatment sequencing and treatment options for relapsed/refractory disease.
Aladjidi N, Leblanc T, Fernandes H
… +19 more, Picard C, Bustamante J, Rieux-Laucat F, Fusaro M, Tusseau M, Durand-Teyssier C, Cohendy E, Granel J, Ducassou S, Escudier A, Moshous D, Michel M, Godeau B, Héritier S, Fahd M, Bader-Meunier B, Fischer A, Leverger G, All collaborators from the French Paediatric Haemato‐Immunologic CEREVANCE Network
Infante JB, Aguiar E, Sá I
… +16 more, Marques I, Neto M, Almeida C, Nascimento T, Pereira M, Cortesão E, Sapinho G, Esteves G, Monteiro-Brás T, Regadas L, Vieira I, Saraiva F, Alikhanov G, Santos J, Ribeiro P, Trigo F
A 24/7 phone-based referral system allows for the fast transfer of acute promyelocytic leukaemia (APL) patients to select sites specialized in APL in Portugal. A reduction in the early death (ED) rate from 11.4% in non-h...A 24/7 phone-based referral system allows for the fast transfer of acute promyelocytic leukaemia (APL) patients to select sites specialized in APL in Portugal. A reduction in the early death (ED) rate from 11.4% in non-high-risk patients to 3.7% in this cohort and universal complete response (CR) plus measurable residual disease (MRD) negativity were achieved with frontline arsenic trioxide (ATO) in APL.
Frailty is a recognized prognostic factor in acute myeloid leukaemia (AML), yet its independent impact on healthcare resource utilization remains understudied. This study evaluated frailty's association with healthcare r...Frailty is a recognized prognostic factor in acute myeloid leukaemia (AML), yet its independent impact on healthcare resource utilization remains understudied. This study evaluated frailty's association with healthcare resource utilization (HRU) burden during the first year of AML treatment. We conducted a population-based retrospective cohort study using linked administrative databases in Ontario, Canada, involving 5450 AML adults (2006-2023) initiating chemotherapy. Frailty was assessed via a validated deficit-accumulation index. HRU outcomes-total-length of stay (LOS), intensive care unit (ICU)-LOS and hospital/emergency department (ED) visits-were measured as rates per person-year and their association with frailty measured as rate ratio (RR) using multivariable negative binomial regression, adjusting for age, sex and chemotherapy intensity. Frailty was independently associated with significantly higher HRU intensity. Compared to fit patients, frail patients demonstrated increased rates of total-LOS (RR 1.18), hospital/ED visits (RR 1.12) and, notably, ICU-LOS (RR 1.81). Conversely, advanced chronological age (≥65 years) correlated with lower ICU utilization (RR 0.60), suggesting critical care decisions may be more age-driven than based on physiological reserve. Frailty is a driver of HRU in AML, superiorly predicting high-acuity resource needs compared to chronological age. Routine frailty assessments are essential to inform resource allocation, guide treatment intensity, mitigate triage bias and improve value-based care.
Vallecillo-Viejo IC, Claiborne MD, Anderson CF
… +10 more, Shafer S, Saven A, Seifert BA, Similuk M, Walkiewicz M, Maric I, Crespo PR, Broderick L, White AA, Klion AD
Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma and is characterized by substantial heterogeneity. This study aimed to develop a liquid-liquid phase separation (LLPS)-related prog...Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma and is characterized by substantial heterogeneity. This study aimed to develop a liquid-liquid phase separation (LLPS)-related prognostic model to improve risk stratification. Transcriptomic and clinical data from four cohorts (n = 768) were analysed. Multiple machine learning algorithms were applied to identify prognostic LLPS-related genes (LRGs) and construct a 6-LRG model. Model performance was assessed using survival analysis, time-dependent receiver operating characteristic curves and multivariable modelling. Additional analyses were conducted to explore potential biological and microenvironmental differences between risk groups. The 6-LRG model stratified patients into groups with significantly different overall survival across datasets, with 1-year area under curve (AUCs) ranging from 0.661 to 0.820, 3-year AUCs from 0.683 to 0.779 and 5-year AUCs from 0.711 to 0.807. The 6-LRG model remained independent of established clinical variables and improved risk prediction when integrated into a nomogram. Distinct biological and immune characteristics were observed between groups. The 6-LRG model may provide additional prognostic information in DLBCL and generates hypotheses regarding underlying biological mechanisms. However, prospective validation in larger populations is essential before any implementation.
Karsa M, Karsa A, Spurling D
… +17 more, Xiao L, Ronca E, Bongers A, Gao W, Gifford AJ, El-Ayoubi A, Cheung LC, Kotecha RS, Lock RB, Teh CE, Lessene G, Norris MD, Wei A, Haber M, Henderson MJ, Moujalled DM, Somers K
Acute myeloid leukaemia (AML) with MDS1 and EVI1 complex locus (MECOM) rearrangement is recognized by the World Health Organization as a distinct entity characterized by poor prognosis and aggressive disease progression....Acute myeloid leukaemia (AML) with MDS1 and EVI1 complex locus (MECOM) rearrangement is recognized by the World Health Organization as a distinct entity characterized by poor prognosis and aggressive disease progression. This rearrangement evokes aberrant ecotropic viral integration site 1 (EVI1) overexpression, which enhances leukaemic stem cell self-renewal and drives chemoresistance. However, the mechanisms by which EVI1 contributes to venetoclax resistance remain unclear. In this study, patients with AML were stratified into the EVI1-high and EVI1-low groups based on transcript levels. The EVI1-high subgroup exhibited significantly inferior clinical outcomes and reduced complete remission rates following chemotherapy or venetoclax-based regimens. Meanwhile, we demonstrated that elevated EVI1 expression confers resistance to venetoclax by stabilizing myeloid cell leukaemia 1 (MCL-1) through activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signalling pathway in vitro. Mechanistically, elevated EVI1 levels were associated with increased phosphorylation of MCL-1 at threonine 163 (T163pMCL-1), thereby stabilizing MCL-1 by attenuating its ubiquitin-proteasome-mediated degradation. Importantly, cotreatment with venetoclax and the clinically available AKT inhibitor capivasertib effectively restored sensitivity in both cell lines and patient-derived primary AML samples with high EVI1 expression. Overall, our findings reveal a novel molecular mechanism underlying EVI1-mediated venetoclax resistance through PI3K/AKT-driven MCL-1 stabilization and suggest a combination strategy involving AKT inhibition as a promising approach for overcoming therapeutic resistance in this high-risk AML subset.
Paediatric acute myeloid leukaemia (AML) remains a deadly disease, with survival rates reaching a plateau despite treatment with high-intensity chemotherapy. Recent advancements in therapeutic strategies, such as targete...Paediatric acute myeloid leukaemia (AML) remains a deadly disease, with survival rates reaching a plateau despite treatment with high-intensity chemotherapy. Recent advancements in therapeutic strategies, such as targeted therapies to inhibit AML dependencies, have aimed to improve outcomes. The evasion of apoptosis, regulated by the B-cell lymphoma 2 (BCL2) family of proteins, is a key feature of cancer progression and treatment resistance. Bcl-2 homology domain 3 (BH3) mimetics, such as venetoclax (ABT-199), which targets BCL2, have shown promising activity in AML. This study investigates for the first time the therapeutic potential of MIK665, a BH3 mimetic targeting myeloid cell leukaemia-1 (MCL1), in paediatric AML. We evaluated the efficacy of MIK665 against a diverse panel of AML cell lines and demonstrated its effectiveness as a single-agent treatment. Additionally, MIK665 showed significant activity against a subset of paediatric AML patient-derived xenografts (PDXs) in both ex vivo and in vivo experiments, with minimal impact on cardiac tissue pathophysiology. These findings strongly support the clinical advancement of MIK665 for paediatric AML treatment in a precision medicine approach.
Jimenez-Mira C, Tovar N, Martínez-Cibrián N
… +23 more, González-Calle V, Albiol N, López-Muñoz N, Oliver-Caldés A, González A, Mateos JM, Español-Rego M, Rosiñol L, Juan M, Charry P, Sanchez-Pina JM, Navarro S, Munárriz D, López-Corral L, Ortiz-Maldonado V, Varea S, Olesti E, Delgado J, Urbano-Ispizua Á, Martínez-López J, Mateos MV, Rodríguez-Lobato LG, Fernández de Larrea C
Ultra-high-risk multiple myeloma (uHRMM), defined by extra-medullary disease (EMD, including central nervous system [CNS] or plasma cell leukaemia [PCL]), remains as a predictor of early relapse after chimeric antigen re...Ultra-high-risk multiple myeloma (uHRMM), defined by extra-medullary disease (EMD, including central nervous system [CNS] or plasma cell leukaemia [PCL]), remains as a predictor of early relapse after chimeric antigen receptor T cell (CAR-T) therapy. We analysed the characteristics, toxicities, response and survival of patients with PCL/CNS-multiple myeloma (MM) treated with cesnicabtagene autoleucel (ARI0002h) at three Spanish centres (2020-2025). PCL was defined as per International Myeloma Working Group (IMWG) 2021 criteria; CNS-MM by leptomeningeal and/or intraparenchymal involvement. Nineteen patients (68% female; median age 61) were included: 12 patients had PCL, 5 had CNS-MM, and 2 had dual involvement. Fifty per cent had primary PCL. In CNS-MM, all had leptomeningeal disease and one had also intraparenchymal lesions. Fifty-seven per cent received CNS-directed therapy. Seventy four per cent harboured high-risk cytogenetics. Median prior lines: 3; 74% had haematopoietic stem cell transplantation (HSCT); two had prior B-cell maturation antigen (BCMA) exposure. One patient died pre-apheresis and one during manufacturing; 17 (89%) received ARI0002h. Cytokine release syndrome (CRS) occurred in 76% (none ≥G3), G3 immune effector cell (IEC)-associated neurotoxicity syndrome (ICANS) occurred in one case (not CNS-MM) and IEC-associated haemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) occurred in 18% (one fatal). Overall response rate (ORR) was 88% at day +100, of which 87% achieved ≥ very good partial response (VGPR) and 80% complete CNS response. Median progression-free survival (PFS) and overall survival (OS) were 10.5 and 15.9 months respectively. ARI0002h induces deep responses in relapsed uHRMM, supporting inclusion of PCL and CNS-MM in clinical trials.