TP53 mutations define a clinically distinct subset of acute myeloid leukaemia (AML) associated with complex cytogenetics and therapy resistance. We performed a retrospective single-centre analysis of 61 consecutive TP53-altered AML patients undergoing first allogeneic haematopoietic cell transplantation (allo-HCT) at the Medical Center Freiburg (2007-2025), compared with 636 TP53-wild-type controls. TP53-altered patients had markedly inferior overall survival (median 379 vs. 1694 days; 5-year OS 18% vs. 50%; p < 0.001). Excess relapse was the primary driver (5-year cumulative incidence 55% vs. 33%; p < 0.001), whereas non-relapse mortality did not differ (28.5% vs. 23%; p = 0.426). On multivariable Cox analysis, TP53 alteration was the strongest independent predictor of inferior OS (HR 2.54, 95% CI 1.77-3.64; p < 0.001), and this association persisted after adjustment for cytogenetic risk and for the refined Disease Risk Index. In an exploratory hierarchical clustering analysis extended by seven patients from a second centre, two subgroups emerged: a del(17p)-enriched cluster (n = 12; median OS 5.7 months) and a TP53 point mutation-enriched cluster (n = 56; median OS 15.1 months). TP53-altered AML is confirmed as the strongest independent adverse prognostic factor after allo-HCT, and molecular heterogeneity within this subtype may inform trial stratification and targeted post-transplant interventions.
Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a potentially curative treatment for high-risk acute myeloid leukemia (AML), and outcomes are strongly influenced by disease status at transplantation. In transplants using conventional graft-versus-host disease (GVHD) prophylaxis, outcomes also depend on the number of induction courses required to achieve first complete remission (CR1); however, this has not been evaluated in patients receiving post-transplant cyclophosphamide (PTCy). We retrospectively analyzed 677 adult AML patients transplanted in CR1 between 2012 and 2022 using PTCy-based GVHD prophylaxis. Outcomes were compared between patients achieving CR1 after one induction course (n = 518) and those requiring two courses (n = 159). Baseline characteristics, donor type, conditioning intensity, graft source, engraftment, and rates of acute and chronic GVHD were comparable between groups. Patients requiring two inductions had a higher 2-year cumulative incidence of relapse (27% vs. 19.3%; HR 1.75, p = 0.003). However, no significant differences were observed in 2-year overall survival (62.8% vs. 69%), leukemia-free survival (61.1% vs. 65%), GVHD-free/relapse-free survival (46.3% vs. 50.4%), or non-relapse mortality (11.9% vs. 15.7%). In AML patients receiving alloHSCT with PTCy, outcomes were largely similar regardless of whether CR1 was achieved after one or two-induction courses, with relapse incidence being higher in patients requiring 2 inductions.
Myeloablative conditioning before hematopoietic stem cell transplantation (HSCT) during childhood or adolescence reduces adult uterine volume, but its impact on future pregnancies remains uncertain. This multicenter study, nested within the LEA cohort, compared 86 pregnancies after HSCT (55 following total-body irradiation [TBI], 31 after high-dose alkylating agents) with 180 pregnancies after conventional chemotherapy in matched leukemia survivors (total: 266 pregnancies, 117 women). Twenty-nine percent of post-HSCT pregnancies required oocyte donation; 70% occurred spontaneously. Notably, 8% (n = 7) of HSCT pregnancies were unintended and ended in induced abortion. TBI markedly worsens obstetric outcomes. Live-birth rate was 35% after TBI vs. 61% after alkylating conditioning (p = 0.02). Compared with alkylating agents, TBI conferred higher risks of late pregnancy loss (24% vs. 3%), preterm birth (50% vs. 5%), low birth weight infants (33% vs. 0%), and postpartum hemorrhage (37% vs. 5%). By contrast, pregnancies after alkylating conditioning resembled those after conventional chemotherapy (live-birth 70% vs. 82%, p = 0.2) with no excess maternal or perinatal morbidity. Thus, TBI-based myeloablation during childhood or adolescence substantially compromises subsequent pregnancy outcomes, whereas high-dose alkylating conditioning appears obstetrically safe. These data may inform reproductive counseling and obstetric surveillance in female leukemia survivors treated with HSCT during childhood and adolescence.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease frequently associated with accelerated bone loss and osteoporosis. Emerging evidence implicates the NLRP3 inflammasome as a pivotal mediator of inflammation-driven bone remodeling dysregulation in SLE. This study investigates the therapeutic potential of targeting NLRP3 inhibition for SLE treatment using both a synthetic NLRP3 inhibitor (MCC950) and a natural NLRP3 inhibitor-oridonin, for its potential clinical translation. Using a combination of in vitro and in vivo approaches, we demonstrate that NLRP3 activation by lipopolysaccharide (LPS) promotes osteoclast differentiation and inhibits osteogenic differentiation through distinct molecular mechanisms. In RAW264.7 macrophages, LPS-induced NLRP3 activation upregulates autophagy-related genes (LC3B, p62) and osteoclastogenesis- related genes (TRAF6, c-Jun, NFATc1), which are effectively suppressed by MCC950 intervention. In mesenchymal stem cells, LPS exposure impairs osteogenic differentiation by reducing Runx2 and OCN gene expression while increasing pyroptosis-related genes (GSDMD, Caspase-11), these effects that are significantly ameliorated by oridonin intervention. In an SLE murine model (MRL/lpr mice), 12 weeks of NLRP3 inhibition with either MCC950 or oridonin both restore bone microstructure, enhance trabecular bone density, improve biomechanical properties, and normalize serum biomarkers of bone turnover. This study provides compelling evidence that targeting NLRP3 signaling represents a promising therapeutic strategy for SLE-associated osteoporosis. The osteogenic effect of oridonin, a naturally occurring compound with established clinical safety, highlights its potential as a promising agent for treating bone loss in SLE patients. These findings underscore the importance of inflammasome targeting in managing SLE-induced bone remodeling disorders.
Mechanical forces are integral to musculoskeletal homeostasis and pathology. Piezo1 is a mechanosensitive ion channel widely expressed in bone, cartilage, muscle, and tendon. It converts mechanical stimuli (tension, compression, shear) into Ca2+ influx and downstream signals, regulating proliferation, differentiation, metabolism, inflammation, and apoptosis. This review summarizes Piezo1's structure, gating mechanisms, tissue expression, and functions in the musculoskeletal system, focusing on cartilage degeneration, subchondral bone remodeling, skeletal remodeling, muscle maintenance, and tendon adaptation. Under physiological conditions, Piezo1 contributes to tissue homeostasis; however, under abnormal or sustained loads, excessive Piezo1 activation can disrupt Ca2+ balance, amplify inflammation, promote apoptosis, and contribute to pathological remodeling in osteoarthritis, osteoporosis, muscle injury, and tendon degeneration. Preclinical strategies, including chemical agonists/inhibitors, traditional Chinese medicine components, gene-based approaches, and stem-cell-related interventions, have been explored in cell and animal models. Piezo1 is an important mechanosensitive regulator linking mechanical cues to musculoskeletal biology, although its tissue-specific roles, interactions with other mechanosensitive channels, and clinical translational value require further study.
In a randomized pilot trial we compared ATG (standard Arm A, 4.5 mg/kg) with ATG plus PTCy (experimental Arm BE, ATG 4.5 mg/kg, PTCy 100 mg/kg). The primary safety endpoint was overall survival at 100 days. We analyzed 79 patients with AML (n = 55) or MDS (n = 24). Median age (range) was 59 (19 to 74), 47 (59.5%) were male. Conditioning was either myeloablative (n = 49) or reduced intensity (n = 30). Donors were 8/8 HLA-matched. Overall survival at 100 days was 95.0% (37 of 39 patients) vs 94.9% (38 of 40 patients) in arm A vs arm BE (p > 0.9). In arms A versus BE, serious adverse events (SAEs) occurred in 26 (65.0%) and 25 (64.1%) patients, graft failure occurred in 3 and 1 patients (p > 0.9), median (range) days to neutrophil engraftment were 19 (10-45) versus 22 (15-56) days p = 0.007), cytomegalovirus and Epstein-Barr virus reactivations occurred in 11 and 7 patients (p = 0.45) and in 6 and 5 patients (p = 0.29). Overall survival at 12 months was 72.5% versus 75.8% (p = 0.79), cumulative incidence at 6 months of relapse was 15.0% versus 15.7% (p = 0.88) and of non-relapse mortality (NRM) 7.5% versus 8.0 (p = 0.45). The combination of ATG and PTCy can safely be used in phase III trials.Registration: clinicaltrials.gov (NCT04202835), November 29, 2019.
Response kinetics after CAR T-cell therapy remain poorly characterized. In this nationwide real-world evidence study using the French DESCAR-T registry (NCT04328298), we analyzed outcomes in 1542 adults with large B-cell lymphoma treated with CAR T cells after ≥2 prior therapies. At one month (M1), 49.1% achieved complete remission (CR), 28.9% partial response (PR), 6.1% stable disease (SD), and 15.9% progressive disease. Median event-free survival (EFS) at M1 was 22.3 months for CR, 3.5 for PR, and 2.3 for SD (p < 0.001). Among 484 patients with incomplete response (PR/SD) at M1, 35.5% subsequently converted to CR, mostly within 6 months. These conversions were associated with response duration and overall survival (OS) comparable to sustained early CR. Multivariate analyses identified age >65 years, lack of response to bridging therapy, and tisagenlecleucel use as independent predictors of lower CR conversion, shorter EFS, and reduced OS. A prognostic score combining these factors stratified PR/SD patients into four risk groups with distinct outcomes. In conclusion, an incomplete response at M1 should not automatically prompt watch-and-wait. Although over one-third convert to CR with favorable outcomes, most progress or die and may require early intervention. These findings support risk-adapted post-infusion management and inform future prospective trials. CLINICAL TRIAL REGISTRATION: The DESCAR-T registry is registered under ClinicalTrials.gov identifier NCT04328298.
Hematopoietic cell transplantation, cellular and gene therapies, and (CAR)-T cells have revolutionized outcomes in hematologic disorders. However, major disparities persist in their availability, accessibility, and affordability, particularly in low- and middle-income countries (LMICs). The EBMT Global Committee aims to address these inequalities. A structured survey was distributed to EBMT members to identify regional and thematic priorities, assess current infrastructure, and assess willingness to contribute to global initiatives. Responses were analyzed descriptively and served as the basis for the current statement paper. A total of 145 responses from 43 countries were collected. Most respondents (67.1%) reported working in JACIE- or FACT-accredited centers. The highest priority regions for EBMT outreach were Eastern Europe (non-EU) (43.9%), Latin America (38.2%), and Africa (33.5%), followed by the Middle East (29.5%). The leading thematic priorities were education and training (74.3%), scientific collaboration (56.0%), and registry development (43.4%). Most respondents expressed willingness to actively contribute, particularly in educational activities (59.7%). Qualitative responses emphasized the need for practical guidelines, mentorship programs, telemedicine, virtual discussion/clinical rounds on difficult cases, and support for LMIC capacity building. The EBMT community strongly supports an expanded global role focused on education, capacity building, and collaboration in underserved regions.
