Haematologica最新文献

We evaluated response to VEN/HMA in 46 patients with acute myeloid leukemia (AML) characterized by extramedullary disease (EMD). Median age was 65 (range, 19-81) years. Patients had a median of two EMD sites (range, 1-5) and 35 (76%) patients had concurrent bone marrow involvement. Twenty (43%) patients had highrisk genetic features according to the European Leukemia Net 2022 classification. Twenty-nine (63%) were relapsed or refractory after intensive chemotherapy (CTX) including 13 (28%) with prior allogeneic hematopoietic cell transplantation (allo-HCT). Patients received a median of 2 cycles of VEN/HMA (range, 1-31). Twenty (43%) patients achieved complete remission (CR) or CR with incomplete hematological recovery (CRi) after VEN/HMA and five (11%) achieved a partial remission (PR). Six patients were subsequently consolidated with allo-HCT (CR/CRi, n=4; PR, n=2). Median follow-up was 49.1 months (95%-CI, 26.1 months - not reached) and median overall survival (OS) 6.4 months (95%-CI, 5.1-11 months). One-year and 2-years OS rates were 29.3% (95%-CI, 18.6-46.2%) and 12.3% (95%-CI, 5.5-27.6%), respectively. Age with a cut-off of 60 years had no impact on OS (P=0.90). Relapse occurred in 12 of 20 (60%) patients who achieved CR/CRi after VEN/HMA treatment. Of those, all except one succumbed to their disease. Six (30%) patients were in CR/CRi at last follow-up and 2 (10%) died in CR. In our cohort of patients with AML with EMD with high-risk features, treatment with VEN/HMA resulted in an encouraging ORR of 54% with a CR/CRi rate of 43.5%. However, VEN/HMA alone may not be effective in maintaining disease control.

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This study aimed to demonstrate the clinical outcomes of granulocyte colony-stimulating factor (G-CSF)/antithymocyte globulin (ATG), posttransplantation cyclophosphamide (PTCy) and PTCy combined with lowdose ATG (PTCy with ATGlow)-based haploidentical transplantation protocols in patients with haematologic malignancies. The comparisons were conducted via propensity score matching (PSM) analysis to balance the basic characteristics among different groups and were based on the transplantation data reported to the Chinese Bone Marrow Transplantation Registry Group (CBMTRG) from January 2020 to December 2022. For each patient in the PTCy or PTCy with ATGlow group, patients (at a 1:2 ratio) from the GCSF/ ATG group were selected. In total, the PTCy group (n=122) was matched with G-CSF/ATG Group 1 (n=230), and the PTCy+ATGlow group (n=123) was matched with G-CSF/ATG Group 2 (n=226). Compared with those in the PTCy group, the incidences of 28-day neutrophil engraftment (P=0.005), 100- day platelet engraftment (P=0.002), median time to neutrophil engraftment (P.

Bruton tyrosine kinase inhibitors (BTKi) have transformed the treatment of B-cell malignancies, but intolerance has often led to their discontinuation. The phase 1/2 BRUIN study evaluated pirtobrutinib, a highly selective non-covalent (reversible) BTKi, in patients with R/R B-cell malignancies (NCT03740529). Pirtobrutinib was investigated in 127 patients with intolerance to at least one prior BTKi therapy in the absence of progressive disease. The most common adverse event (AE) leading to BTKi discontinuation was cardiac disorders (n=40, 31.5%), specifically atrial fibrillation (n=30, 23.6%). The median follow-up was 17.4 months and the median time on pirtobrutinib was 15.3 months. The most common reasons for pirtobrutinib discontinuation were progressive disease (26.8%), AE (10.2%), or death (5.5%). The most frequent treatment-emergent AEs were fatigue (39.4%) and neutropenia (37.0%). Among patients who discontinued a prior BTKi for a cardiac issue, 75% had no recurrence of their cardiac AE. No patient discontinued pirtobrutinib for the same AE that led to discontinuation of the prior BTKi. In 78 CLL/SLL and 21 MCL patients intolerant to prior BTKi, ORR to pirtobrutinib was 76.9% and 81.0%, respectively. Median PFS for CLL/SLL was 28.4 months and was not estimable for MCL. These results suggest that pirtobrutinib was safe, well-tolerated, and an efficacious option in patients with prior BTKi-intolerance.

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The ubiquitination or SUMOylation of hematopoietic related factors plays pivotal roles in hematopoiesis. RNF111, known as a ubiquitin ligase (Ubl), is a newly discovered SUMO-targeted ubiquitin ligase (STUbl) involved in multiple signaling pathways mediated by TGF-β family members. However, its role in hematopoiesis remains unclear. Herein, a heritable Rnf111 mutant zebrafish line was generated by CRISPR/Cas9-mediated genome editing. Impaired hematopoietic stem and progenitor cells (HSPC) of definitive hematopoiesis was found in Rnf111 deficient mutants. Ablation of Rnf111 resulted in decreased phosphorylation of Smad2/3 in HSPC. Definitive endoderm 2 inducer (IDE2), which specifically activates TGF-β signaling and downstream Smad2 phosphorylation, can restore the definitive hematopoiesis in Rnf111-deficient embryos. Further molecular mechanism studies revealed that Gcsfr/NO signaling was an important target pathway of Smad2/3 involved in Rnf111-mediated HSPC development. In conclusion, our study demonstrated that Rnf111 contributes to the development of HSPC by maintaining Smad2/3 phosphorylation and the Gcsfr/NO signaling pathway activation. Keywords: Rnf111, Ubiquitin ligase (UbL), HSPC, Smad2/3, Gcsfr/NO.