Blood advances最新文献

Radiotherapy (RT) is central in the management of limited-stage extranodal NK/T-cell lymphoma (ENKTL), nasal type. Although international guidelines recommend 50-56 Gy, emerging data suggest that reduced-dose RT with a radiosensitizer may provide comparable control with less toxicity. We evaluated the long-term outcomes of 40 Gy concurrent chemoradiotherapy (CCRT) followed by systemic chemotherapy. We retrospectively analyzed 155 patients newly diagnosed with limited-stage ENKTL treated at Samsung Medical Center between 2000 and 2023. All patients received 40 Gy in RT in 20 fractions with weekly cisplatin (30mg/m2), followed by systemic chemotherapy. Clinical characteristics, treatment response, survival outcomes, and relapse patterns were assessed. The median age was 50 years, and 64.5% were male. Most patients (73.5%) had nasal-type disease, while 20.0% had combined nasal and non-nasal upper aerodigestive tract involvement. At a median follow-up of 73 months, the 5-year PFS and OS rates were 68.0% and 82.2%. Pre-treatment EBV DNA positivity correlated with inferior PFS (p=0.043). Patients receiving CCRT plus chemotherapy had better PFS compared with those receiving CCRT alone (p = 0.004). Relapses occurred in 54 (34.8%) patients, predominantly at extranodal distant sites (21.3%), while the local control rate remained high (86.5%). Secondary malignancies developed in three patients. Median SNOT-22 score was 8, indicating minimal sinonasal symptom burden. A 40 Gy CCRT regimen followed by systemic chemotherapy achieved durable local control and favorable long-term survival in limited-stage ENKTL. The predominance of distant, rather than regional, relapse supports the feasibility of this reduced-dose CCRT strategy combined with systemic therapy.

Deleterious germline RUNX1 variants cause Familial Platelet Disorder with Associated Myeloid Malignancy (FPDMM), characterized by thrombocytopenia, platelet dysfunction, and predisposition to hematologic malignancies (HM). We examined clinical and laboratory findings of pediatric (<19 years old) RUNX1-FPDMM patients enrolled in the NIH RUNX1 Natural History Study. Pediatric patients have thrombocytopenia (131,000±49,000/µL vs 314,000±55,000/µL) and mild eosinophilia (372±244/µL vs 165±100/µL) similar to adult patients. Abnormal bleeding is less frequent in children than adults (32% vs. 42%). Of 213 RUNX1-FPDMM patients, 31 developed HM (13 pediatric, 19 adult; 1 had second malignancy). Lifetime HM risk is 42% (26-55%). Median age of HM diagnosis is 36 (1-74) years. Pediatric patients have a 7.3% (3.5-11%) cumulative incidence by 18 years, 57.7-fold (27.7-86.6) higher than the general population and are 3.4-fold more likely to develop HM by 5 years than patients with Fanconi anemia. Unlike adult patients whose HM were all myeloid, pediatric patients develop a spectrum of HM subtypes, but with a myeloid excess compared with the general pediatric population (62% vs. 24%). Pediatric RUNX1-FPDMM HM is less likely than adult to have multiple somatic mutations (22% vs. 67%) but more likely to have chromosome changes (67% vs. 47%). We recommend prompt, universal cascade RUNX1 testing following a new diagnosis, regardless of age. Upon diagnosis, management of pediatric RUNX1-FPDMM should include a baseline bone marrow biopsy - once clinically acceptable - and peripheral blood evaluations. We recommend routine monitoring with quarterly complete blood counts and annual bone marrow biopsies to monitor for changes and transformation to HM. (NCT03854318).

Hemoglobinopathies are the most common monogenic genetic disorders, primarily managed through blood transfusions or bone marrow transplantation. Clinical severity other than mutational effect not well investigated and still unknown. This study aims to identify dysregulated molecular pathways in red blood cells contributing to thalassemia severity. From a cohort of 285 hemoglobinopathy patients, 10 age-matched individuals with identical compound heterozygous mutations (IVS 1-5 G>C and CD 26 G>A) were screened. Five had severe thalassemia requiring regular transfusions, while five had a non-severe form requiring fewer transfusions. RNA sequencing and proteome analysis were conducted on isolated RBCs, through Novaseq and Orbitrap MS platform respectively. Bioconductor-R and different bioinformatics tools were utilized subsequently. Integrated transcriptome-proteome analysis revealed a global loss of mRNA-protein concordance. CDK11A and MCTS1 lost positive correlation, whereas RLP38 and H3C1 showed compensatory overtranslation, linked to transcription factors regulating erythropoiesis. In TDT, WNK3, HNRNPUL1, COPS7A, and HTATSF1 displayed discordant expression, indicating post-transcriptional aberrations. PTR analysis showed reduced cytoskeletal (ankyrin, spectrin) expression, elevated chaperone activity, ferroptosis markers (FTH1, FTL, HMOX1), and suppressed autophagy. Collectively, these multilayered alterations-splicing dysfunction, post-transcriptional deregulation, ferroptosis, autophagy suppression, oxidative stress, and cytoskeletal fragility-underlie the greater disease severity observed in TDT compared with NTDT.

TP53 mutations are found in 10-15% of myeloid neoplasms and are associated with a dismal prognosis. Although hypomethylating agents, such as decitabine, are active in TP53-mutated myeloid neoplasms (TP53-MN), mutation clearance is rarely complete and nearly all patients relapse. Molecular determinants of response to hypomethylating agents in TP53-MN are poorly understood. Here, we show that decitabine induces replicative stress with decreased replication fork progression, induction of single-strand DNA breaks, and activation of the ATR pathway. Resolution of decitabine-induced replication stress is impaired in TP53-mutated acute myeloid leukemia (AML) cells, representing a potential therapeutic vulnerability. Indeed, the combination of decitabine and ATR inhibition (ATRi) induces synthetic lethality that is selective for TP53-AML and due, in part, to induction of mitotic catastrophe. Interestingly, this synergistic lethality was not observed with azacitidine or treatment with GSK3685032, a potent DNMT1 inhibitor, both of which produce a comparable level of global hypomethylation to decitabine. Treatment with decitabine and ATR inhibitor reduces leukemia burden and prolongs survival in in vivo mouse models of TP53-mutated AML. Collectively, these show that TP53 loss generates a selective vulnerability to decitabine-induced replication stress, with the combination of ATR inhibition and decitabine showing promise as a new therapeutic approach for TP53-MN.

Ravulizumab, a humanized, long-acting monoclonal antibody against complement factor C5, is a widely utilized treatment for paroxysmal nocturnal hemoglobinuria (PNH). As pregnant women with PNH are at increased risk for complications and the safety and efficacy of ravulizumab in pregnancy is not known, we performed an international multicenter retrospective analysis of 16 PNH patients with 19 pregnancies managed with ravulizumab and compared outcomes to 8 earlier pregnancies in the same patients treated with eculizumab. Of the eight eculizumab pregnancies, three resulted in miscarriages and one in early preterm delivery for threatened fetal demise and massive fetal growth retardation. All 19 pregnancies on ravulizumab resulted in birth of live infants with a median gestational age of 267 days (interquartile range (IQR) 259-275) and median birth weight of 3115grams (IQR 2458-3349 grams). Cord blood testing in two pregnancies receiving intensified ravulizumab dosing revealed detectable ravulizumab levels consistent with transplacental transfer. After a median follow-up of 16.2 months (IQR 4.4-40.1), no developmental abnormalities or severe infectious complications were observed in the children. This retrospective analysis provides evidence for the safety and effectiveness of ravulizumab in managing PNH during pregnancy and breastfeeding with favorable maternal and fetal outcomes.

The best frontline treatment for acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYAs) is unclear. To support a clinical practice guideline, we systematically reviewed and meta-analyzed evidence on (1) asparaginase-based ("pediatric") versus non-asparaginase-based ("adult") regimens, and (2) allogeneic hematopoietic stem cell transplantation (HSCT) versus no HSCT for AYAs (15-39 years old) with ALL in first complete remission (CR). Data Sources: PubMed, CINAHL, and PsycINFO from inception through November 29, 2023. Eligible studies compared regimens or use of HSCT and reported survival, remission, toxicity, or quality of life in AYAs. We included 19 studies (14 comparative, 5 single-group; N=3,607) comparing regimens and 7 studies (N=7,492) comparing HSCT and no HSCT. Studies were mostly of poor quality, with sparse randomized controlled trials [RCTs]), yielding low certainty findings. Pediatric regimens were associated with higher 5-year overall survival (OS) (relative risk [RR] 1.40, 1.18-1.65), event-free survival (RR 1.80, 1.13-2.85), disease-free survival (DFS) (RR 1.55, 1.32-1.82), and lower treatment-related mortality (TRM) (RR 0.29, 0.09-0.90).. HSCT was associated with lower 5-year OS (RR 0.72, 0.61-0.84) and DFS (RR 0.78, 0.68-0.90), and higher non-relapse mortality (RR 2.70, 1.18 - 6.18) and TRM (HR 6.88, 3.02-15.70). Relapse risk varied by time point. In AYA with Ph-negative ALL, pediatric regimens may improve survival; toxicity-related evidence remains limited. HSCT may lead to inferior overall survival and DFS. With a dearth of RCTs, low-certainty evidence highlights the need for high quality studies and sub-analyses of AYAs.

Our knowledge of which bone marrow cells affect red cell production is still incomplete. To explore the role of osteocytes in the process we performed bulk RNAseq of osteocytes isolated from control and phlebotomized mice. The second top-upregulated gene following phlebotomy was Erfe - erythroferrone. Erfe expression in osteocytes was also upregulated after erythropoietin (EPO) treatment and hypoxia in vitro. To explore if osteocytes contribute to systemic ERFE levels, we generated two mouse models. We first transplanted wild-type bone marrow (BM) in Erfe-/- mice creating a model where ERFE is produced in the BM but not by osteocytes. After phlebotomy, liver hepcidin suppression was significantly lower in mice where the osteocytes could not produce ERFE. To confirm that osteocytes are responsible for this difference, we generated mice lacking EPO receptors in osteocytes by crossing Eporflox/flox and Dmp1-Cre mice. After phlebotomy, these mice showed reduced hepcidin suppression in the liver and higher circulating serum hepcidin levels compared with controls. Our work identified a novel function of osteocytes in suppressing systemic hepcidin levels during stress erythropoiesis.

Hemoglobinopathies comprise the commonest monogenic diseases worldwide. In Europe, formerly low-prevalence regions have seen increasing numbers of carriers and patients, with important public health implications. Implementation of policies and laboratory methodologies varies across countries, affecting equitable care. This study aimed to provide a snapshot of current screening and diagnostic practices and to identify gaps and priorities. A cross-sectional online survey was conducted from May to October 2024 across the COST Action HELIOS network participants. The survey, including 21 questions, covered hematological methods, molecular diagnostics, and laboratory practices and policies. Responses were provided directly by centers and summarized descriptively in tables and maps. Responses were received from 38 centers in 20 countries. Hematology remains the diagnostic backbone for hemoglobinopathies, DNA-based testing is widely adopted though advanced genomics are limited, NBS is implemented widely for SCD and thalassemia, carrier reporting practices vary, and genetic modifier testing is emerging. The findings highlight opportunities for cross-country collaboration and targeted capacity-building, identifying centers that could benefit from shared expertise and resources. They can guide strategies to harmonize protocols, strengthen diagnostic capabilities, and support broader implementation of best practices across Europe.

Von Willebrand factor (VWF) is a key coagulation protein, tethering platelets to sites of injury through binding sites for platelet GPIbα and for exposed subendothelial collagen. VWF synthesis occurs in endothelial cells and megakaryocytes, a complex process involving the VWF propeptide, dimerization and multimerization, and glycosylation. Von Willebrand disease (VWD) results from defects or dysfunction in VWF and includes both quantitative and qualitative issues with the VWF protein. VWF is cleaved by ADAMTS13 and ultimately cleared from circulation. While it is clear that VWF plays an important role in clot formation, it may also be important in a number of other areas including angiogenesis. Our knowledge of VWF has come a long way in the 100 years since the first publication by Erik von Willebrand in 1926 thanks to a large number of researchers in the VWF biology field.