European Journal of Haematology最新文献

Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is a dNTPase that regulates intracellular nucleotide pools, preserves genomic stability, and mediates intrinsic antiviral immunity. While its role in adult hematologic malignancies is established, its implications for pediatric leukemia-particularly acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL)-remain underexplored. This review integrates transcriptomic, protein interaction, and immune correlation analyses to examine the dual role of SAMHD1 in pediatric hematological malignancies: as an antiviral restriction factor that impairs lentiviral gene therapy and as a therapeutic barrier that limits the efficacy of nucleoside analog-based chemotherapy. We compare emerging transduction-enhancing strategies, including Vpx delivery, SAMHD1 inhibition, and lipid nanoparticles, and evaluate their pediatric applicability. A conceptual schematic highlights the translational challenges unique to the developing immune and hematopoietic systems. Limitations of commonly used cellular models, such as THP-1 cells, are discussed alongside the need for pediatric-specific preclinical tools. We conclude by outlining a clinical translation roadmap and emphasizing the urgency of validating SAMHD1-targeted strategies in pediatric trials to ensure their safety, efficacy, and integration into future treatment paradigms.

Momelotinib, a novel JAK1/2 inhibitor with inhibitory activities on activin A receptor type I, has shown breakthrough clinical efficacy in patients with myelofibrosis (MF) and anemia, a disease-related manifestation of challenging management. In this retrospective real-life multicenter Italian study, we investigated the safety and efficacy of momelotinib in a cohort of 39 consecutive MF patients, regardless of prior therapy. The median duration of treatment was 7 months, and the overall response rate was 56% in transfusion-dependent patients and 46% in the transfusion-independent group. At 24 weeks of treatment, a hemoglobin increase > 1.5 g/dL was observed in 26% of patients, and constitutional symptom improvement was reported in 51% of cases, with a spleen volume reduction > 35% in 28%. Therapy discontinuation occurred in 18% of patients, with only one leukemia progression and three deaths during follow-up. The safety profile was similar to that reported in clinical trials, with most toxicities of grade I-II. In conclusion, our real-life results support the use of momelotinib as an effective and safe therapeutic option for heavily pre-treated, cytopenic MF patients in real-world clinical practice.

Mantle Cell Lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma characterized by the hallmark t(11;14)(q13;q32) translocation, resulting in cyclin D1 overexpression. Predominantly affecting elderly males, MCL exhibits marked clinical and biological heterogeneity, ranging from indolent SOX11-negative variants to highly proliferative blastoid variants. Despite initial responsiveness to chemoimmunotherapy, relapse is frequent, and median overall survival remains limited. Aberrant B-cell receptor (BCR) signaling—mediated by kinases including Bruton's tyrosine kinase (BTK)—plays a central role in MCL pathogenesis. BTK inhibitors (BTKis) such as ibrutinib (as monotherapy or combined with R-CHOP/R-DHAP), acalabrutinib (with rituximab and bendamustine), and pirtobrutinib have significantly improved outcomes of relapsed/refractory disease. However, their efficacy is challenged by resistance mutations (e.g., BTK C481S) and off-target toxicities. Next-generation reversible BTKis represent an important advance, offering activity in the setting of resistance and improved tolerability. Resistance is further sustained by the tumor microenvironment through stromal support and immunosuppressive cellular interactions. Consequently, combination strategies incorporating BTKis with BCL-2 inhibitors, monoclonal antibodies, and cellular therapies are being investigated to enhance response depth and durability. In parallel, biomarker-driven approaches and precision-medicine strategies are emerging to personalize disease monitoring and treatment selection. Collectively, these developments underscore the evolving role of BTK inhibition within broader immune-based and targeted treatment paradigms in MCL.

B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapies have revolutionized the approach and management of relapsed/refractory multiple myeloma (RRMM), and as of 2025, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) are the only BCMA-targeted CAR T-cell therapies approved by the FDA. Exceptional responses were demonstrated for heavily pretreated patients in the KarMMa-1 trial, reporting a 73% overall response rate (ORR) and 98% in the CARTITUDE-1 trial. Furthermore, both therapies show a significant improvement in progression-free survival (PFS) compared to standard regimens when administered in earlier lines. Current real-world evidence confirms their effectiveness and manageable safety in a more diverse patient population, including those who would have been ineligible for clinical trials. Key toxicities include cytokine release syndrome (CRS) and neurotoxicity, with emerging concerns regarding delayed neurotoxicities, second primary malignancies, and IEC-enterocolitis. This review provides a detailed analysis of recent clinical trial data, the reported outcomes of real-world published evidence, and the changing role of these therapies within the myeloma treatment paradigm, including challenges, gaps in knowledge, potential barriers to accessibility, and future directions aimed at optimizing the efficacy and safety of CAR T-cell therapy for MM patients.