Journals
2026 EN
Klagge Jonas · Mazhuga Maria · Molloy John J.
ABSTRACT The strategic generation of α‐fluoro radicals underpins powerful routes to fluorine‐rich architectures of high value in molecular design. Here, we disclose an operationally simple, catalyst‐free method for the photochemical activation of α‐halo fluorinated precursors using visible light and two inexpensive additives, sodium iodide and 2,6‐lutidine. This mild protocol enables in‐situ halide exchange and subsequent homolytic C–I bond scission to generate α‐fluoro radicals under ambient conditions. The generality of the platform is demonstrated across esters, sulphones, and nitriles, facilitating intermolecular coupling with alkenes, heteroarenes, and propellanes to access diverse fluorinated scaffolds. Mechanistic studies support the formation of a weak electron donor–acceptor complex that mediates bond activation, while the benign conditions permit merger with energy transfer catalysis for stereodivergent product formation.
Journals
2026 EN
Donzelli Livia · Zullino Veronica · Torelli Giovanni Fernando
+5 more
ABSTRACT Chimeric antigen receptor T (CAR‐T) cell therapies have revolutionized the treatment of hematological malignancies, achieving high response rates in patients with relapsed or refractory disease. Despite these benefits, CAR‐T cell therapies are associated with unique toxicities, including cytokine release syndrome (CRS), immune effector cell‐associated neurotoxicity syndrome (ICANS), immune cell‐associated hematotoxicity (ICAHT), and immune effector cell‐associated hemophagocytic lymphohistiocytosis‐like syndrome (IEC‐HS), which is characterized by a rare and life‐threatening hyperinflammatory response. This paper presents a case of a 56‐year‐old woman with relapsed mantle cell lymphoma (MCL) treated with the CAR‐T cell therapy, brexucabtagene autoleucel, who had subsequently developed CRS and later IEC‐HS. Initial management included tocilizumab, corticosteroids, and anakinra, followed by the compassionate use of emapalumab, an interferon‐γ blocker. To provide broader context, we conducted a literature review of CAR‐T cell‐related toxicities, focusing on IEC‐HS and its management with emapalumab. Clinical and laboratory manifestations, such as elevated ferritin levels, cytopenias, and organ dysfunction, underpin the diagnostic criteria for IEC‐HS. Vigilant monitoring and tailored therapeutic approaches are required to effectively manage toxicities associated with CAR‐T cell therapy, to maximize its benefits and minimize adverse effects. In more severe IEC‐HS cases, emapalumab may be used as an effective targeted therapy.
Journals
2026 EN
Vigna Ernesto · Martino Enrica Antonia · Pitino Annalisa
+82 more
ABSTRACT The management of chronic lymphocytic leukemia (CLL) in older patients requires careful balancing of therapeutic efficacy with the risks of treatment intolerance. Frailty assessment is increasingly recognized as a critical determinant of clinical outcomes, but its specific role in guiding therapy with second‐generation Bruton tyrosine kinase inhibitors remains poorly defined. We conducted a prospective, multicenter investigation of 326 consecutive CLL patients aged 65 years or older who received zanubrutinib across 52 Italian centers, aiming to evaluate whether the Clinical Frailty Scale (CFS) could predict treatment discontinuation in real‐world practice. The cohort was characterized by advanced age (median 78.1 years, range 65.1–94.5), with over half of the patients presenting with Binet stage C disease. Two‐thirds were treated in the frontline setting, while the remainder received zanubrutinib as salvage therapy. After a median follow‐up of 8 months, 48 patients (14.7%) discontinued treatment, most commonly due to toxicity or disease progression. Receiver operating characteristic curve analysis identified a CFS of 3 as the optimal threshold for predicting discontinuation, with an area under the curve of 0.65 (95% CI 0.56–0.73, p < 0.001). At 12 months, the discontinuation rate was significantly higher among patients with a CFS > 3 (29.2%) compared with those with a CFS ≤ 3 (8.8%) ( p < 0.001); among conventional prognostic variables, only relapsed/refractory disease demonstrated an independent association with TTD. These findings highlight the CFS as a simple yet powerful clinical tool that provides incremental prognostic information beyond standard disease‐related factors. Incorporating frailty assessment into treatment planning may enhance patient selection and optimize therapeutic strategies for elderly CLL patients in daily practice.
Journals
2026 EN
Vetro Calogero · Azzali Irene · Petracci Elisabetta
+20 more
ABSTRACT In the AVALON cohort of relapsed/refractory AML treated with venetoclax plus hypomethylating agents, NPM1 and IDH1/2 mutations showed no significant impact on response or survival. These findings indicate that prognostic models for relapsed AML should consider treatment context rather than baseline mutation status.
Journals
2026 EN
Gramegna Doriana · Mondelli Paolo · Pappagallo Susanna Anita
+10 more
ABSTRACT Multiple myeloma (MM) is recognized as a malignancy shaped by its complex tumor microenvironment (TME), which fuels disease progression and therapeutic resistance. Recent advances in single‐cell omics, spatial transcriptomics, mass cytometry, and advanced imaging have enabled high‐resolution mapping of tumor and immune cell interactions within their native context, also revealing spatial heterogeneity that influences clinical outcomes. These tools, complemented by scalable computational frameworks and artificial intelligence, provide cost‐effective alternatives to dissect immune landscapes and derive prognostic biomarkers from both bulk and single‐cell data. However, technical complexity, resource demands, and the need for robust standardization limit their immediate clinical application. On the other hand, machine learning techniques enhance integration and predictive power of existing datasets, supporting the development of personalized, immune‐informed therapeutic strategies. This review highlights recent advances, discusses the strengths and limitations of emerging technologies with a particular focus on their integration to decipher TME biology and pave the way toward precision medicine in MM.
Journals
2026 EN
Guglielmelli Paola · Breccia Massimo · Mendicino Francesco
+53 more
ABSTRACT Ruxolitinib (RUX), a JAK1/2 inhibitor, demonstrated treatment benefits for myelofibrosis (MF) in intermediate‐1 (Int‐1)–risk patients with a significant disease burden; however, the evidence is scarce. This interim analysis investigated the efficacy and safety of ruxolitinib in patients with Int‐1‐risk MF. ROMEI, a multicenter, observational, prospective study, enrolled 508 adult patients with MF receiving ruxolitinib according to approved indications. The present interim analysis was focused on 107 eligible patients in the Int‐1‐risk group. Primary endpoints included changes in symptoms response and health‐related quality of life scores. Secondary endpoints included spleen response evaluation, overall survival, and safety including dosing pattern and dose interruptions. Among the 107 Int‐1‐risk patients with a median age of 63 years, 65.5% were highly symptomatic (total symptoms score: ≥ 20), while the spleen was palpable at ≥ 5 cm and ≥ 10 cm in 74% and 27% of patients, respectively, with baseline EuroQol visual analogue scale (EQ‐VAS) score of 65.1 ± 19.4. After RUX treatment, 42.1% and 43.9% of patients demonstrated a symptom response at 24 and 48 weeks, while 38.9% and 46.8% showed a spleen response at 24 and 48 weeks, respectively. EQ‐VAS increased to 71.8 ± 16.3 at 24 weeks and 69.3 ± 19.2 at 48 weeks. Furthermore, 11.2% and 25.2% of patients reported temporary and permanent discontinuation, respectively with no new adverse events reported. The interim analysis showed that ruxolitinib provided clinical benefits, a manageable safety profile, and improved quality of life for Int‐1‐risk subgroup patients with frequent and sustained responses with acceptable toxicity.
Journals
2026 EN
Passamonti Francesco · Foran James M. · Tandra Anand
+14 more
ABSTRACT Myelofibrosis is characterized by perturbation of the JAK/STAT pathway and upregulation of anti‐apoptotic factors leading to myeloproliferation, bone marrow fibrosis (BMF), extramedullary hematopoiesis, splenomegaly, and cytopenias. Navitoclax, a potent oral B‐cell lymphoma (BCL)‐X L /BCL‐2 inhibitor, promotes apoptosis of malignant myelofibrosis cells. Herein, we present results of Cohort 3 of the Phase 2 REFINE study (NCT03222609), which evaluated efficacy and safety of navitoclax plus ruxolitinib in JAKi‐naïve patients with myelofibrosis. JAKi‐naïve patients with primary or secondary myelofibrosis (≥ 18 years with splenomegaly, DIPSS intermediate‐2 and high‐risk myelofibrosis, and ECOG 0–2) and platelet count > 100 × 10 9 /L were enrolled and treated with navitoclax 100 mg once daily (QD) or 200 mg QD according to platelet count (≤ 150 × 10 9 /L or > 150 × 10 9 /L, respectively). Ruxolitinib was given twice daily (dose per label). Primary endpoint: spleen volume reduction of ≥ 35% (SVR 35 ) at week 24. Secondary endpoints: ≥ 50% reduction in total symptom score (TSS 50 ) at week 24, change in grade of BMF, anemia response, and safety. Thirty‐two patients received ≥ 1 dose of navitoclax plus ruxolitinib. Median (range) duration of follow‐up was 44 months (5–58). 63% (20/32) of patients achieved SVR 35 at week 24; median (range) time to first SVR 35 was 12 weeks (11─48). Of 24 evaluable patients, 21% achieved ≥ 50% reduction in driver gene variant allele frequency (VAF). Of 27 evaluable patients, 11 (41%) achieved TSS 50 at week 24; median (range) time to first TSS 50 of 3 weeks (0─16). BMF improved from baseline by ≥ 1 grade in 13/27 patients (48%) at any time on study. Anemia response rates were 38% (5/13) for transfusion‐independent and 100% (2/2) for transfusion‐dependent patients. No bleeding events or deaths were attributed to navitoclax. These findings suggest navitoclax plus ruxolitinib has a tolerable safety profile and provides clinically meaningful improvements for JAKi‐naïve patients with myelofibrosis. Trial Registration NCT03222609.
Journals
2026 EN
Gong Inna Y. · Jeeva Meenakshi · Hueniken Katrina
+18 more
ABSTRACT Bridging therapy (BT) is frequently used in patients with relapsed/refractory (R/R) large B‐cell lymphoma (LBCL) undergoing chimeric antigen receptor T cell (CAR T) therapy, but the optimal BT approach remains uncertain. We evaluated BT strategies and their associations with response and survival outcomes. Accordingly, we included patients with R/R LBCL evaluated for third‐line or later CD19‐directed CAR T at Princess Margaret Cancer Center from 2017 to 2024 (follow‐up to 01/2025). BT modalities included chemotherapy, polatuzumab‐based chemotherapy, radiotherapy, corticosteroids, and none. We assessed the associations of BT modality with overall response rate (ORR), progression‐free survival (PFS), and overall survival (OS) using logistic regression and Cox models. Among 219 patients, 188 underwent apheresis and 157 (84%) received CAR T. Of those apheresed, 79% received BT (radiotherapy 41%, polatuzumab‐based 26%, third‐line chemotherapy 16%, corticosteroids 17%, while 21% received no BT). ORR was highest with polatuzumab (50%) and radiotherapy (40%) versus chemotherapy (16%) ( p = 0.009). Median ΔSUVmax in 84 patients was higher in polatuzumab and radiotherapy treated patients, compared to chemotherapy ( p < 0.001). Radiotherapy encompassing all active disease had higher ORR (51%) versus non‐comprehensive (12%) ( p = 0.04). Two‐year PFS was highest with radiotherapy (47%) and polatuzumab (37%) BT versus chemotherapy (21%). Adjusted analyses showed improved PFS with radiotherapy (adjusted hazard ratio [aHR] 0.29) and polatuzumab (aHR 0.41). OS was also improved with radiotherapy (HR 0.40). Chemotherapy BT was associated with the highest 2‐year lymphoma‐related mortality (74%). In conclusion, polatuzumab‐based and radiotherapy BT as well as no BT were associated with improved responses and outcomes compared to chemotherapy. Although these results may have been influenced by patient selection, prospective studies integrating these approaches are needed to define optimal, individualized BT strategies.
Journals
2026 EN
Caracciolo Daniele · Gentile Carlo · Squillacioti Sara
+17 more
ABSTRACT T‐cell lymphomas (TCLs) account for a relatively small fraction of lymphoid malignancies and are characterized by highly aggressive course often refractory to current available therapies. We previously reported potent in vitro and in vivo antitumor activity of a Bispecific T‐Cell Engager (UMG1/CD3ε‐BTCE) directed against UMG1, a unique CD43 epitope that is abundantly expressed on T‐cell acute lymphoblastic leukemia (T‐ALL) and diffuse large B‐cell lymphoma (DLBCL) cells, while absent in most normal tissues, except thymocytes and a small fraction of peripheral blood T lymphocytes (< 5%). Here, we investigated the in vitro efficacy of UMG1/CD3ε‐BTCE against TCLs. IHC analysis of Tissue Micro Arrays (TMAs) revealed high UMG1 expression in 62.3% of TCL samples, including peripheral T‐cell lymphoma‐not otherwise specified (PTCL‐NOS) and ALK‐negative anaplastic large cell lymphoma (ALCL). Notably, all T‐PLL primary specimens (27/27) were positive, and 3 of 4 TCL cell lines also expressed UMG1 by flow cytometry. The asymmetric UMG1/CD3ε‐BTCE induced robust redirected cytotoxicity against UMG1‐expressing TCL cells. Moreover, this activity was strengthened by cell exposure to the HDAC inhibitor SAHA. We observed a dose‐dependent engaged T‐cell‐mediated cytotoxicity and inflammatory cytokine release, resulting in lysis of UMG1‐expressing cells, with no significant effect on UMG1‐not expressing cells. Our findings suggest that the UMG1/CD3ε‐BTCE selectively exerts potent anti‐tumor activity against a relevant subset of TCLs. These findings support the development of a precision immunotherapy approach for patients with UMG1‐expressing aggressive hematologic malignancies.
Journals
2026 EN
Velasco Yanez Romel Jonathan · Almeida De Lima Ana Luiza · Oliveira Lopes Marcos
+3 more
ABSTRACT Aim This study aims to analyse and evaluate the theory of peaceful end of life to determine its relevance and applicability in nursing research, education and practice, particularly in the areas of palliative care and end‐of‐life care. Methods We conducted a theoretical‐reflexive study using specific criteria for analysing and evaluating middle‐range theories as proposed by Ann Whall (2005). Results The theory clearly outlines the dying and death process, connecting key concepts and essential statements that support a peaceful end of life. It also implicitly incorporates elements of the nursing metaparadigm. Additionally, the theory demonstrates adequate internal consistency and empirical adequacy. Conclusions While the theory offers valuable guidance for nursing research, education and practice in palliative and end‐of‐life care, several information gaps were identified that require refinement for its optimal application. Further studies incorporating all the theory's concepts and statements are needed to confirm its testability, empirical validity and potential need for modifications. Implications for the profession The theory of peaceful end of life has been widely applied in nursing, especially in the context of palliative care, in recent years. However, no previous critiques of the theory have employed a specific evaluation framework for middle‐range theories. This study presents the first formal critique using an appropriate evaluation framework. The findings could help nurses apply this theory more effectively in the care of patients at the end of life. Patient or Public Contribution No patient or public contribution was involved in this study.