Dynamic hydrazone crosslinked salecan/chondroitin sulfate hydrogel platform as a promising wound healing Strategy: A comparative study on antibiotic and probiotic delivery.

Natural polysaccharide-based active-ingredient carriers have been a source of great concern for a long time. In order to explore potential antibiotics and probiotics carriers, a novel injectable chondroitin sulfate/salecan (CS) hydrogel was constructed by forming dynamic hydrazone bonds. Scanning electron microscope (SEM), proton nuclear magnetic resonance (1H NMR), Fourier transform infrared spectroscopy (FTIR), bacteriostatic test, and rheological experiments were used to investigate the chemical structure, inherent morphology, and enzymatic corruption of the hydrogel in vitro. The resulting hydrogels exhibited ideal probiotics loading capacity, drug release behavior, excellent antimicrobial activity and variable properties. Crucially, owing to its exceptional biocompatibility and reversible crosslinking network, this hydrogel can function as a three-dimensional extracellular matrix for cells, enabling cells to maintain high vitality and proliferation, and promote wound healing. The aforementioned findings indicated that this novel hydrogel can be a promising candidate as an active-ingredient carrier and scaffold material for tissue engineering.

Metagenomic Next-Generation Sequencing in the Diagnosis of Pulmonary Infections after Allogeneic Hematopoietic Stem Cell Transplantation.

Early and accurate identification of pathogens in pulmonary infections after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is critically important. The clinical usefulness of metagenomic next-generation sequencing (mNGS) in the diagnosis of pulmonary infections after allo-HSCT remains under discussion. This multicenter retrospective study was conducted to compare mNGS and conventional microbiological tests (CMTs) in identifying the pathogens of pulmonary infections in allo-HSCT recipients. One hundred forty allo-HSCT recipients with suspected pulmonary infections who underwent bronchoscopy were included. mNGS and CMTs performed on bronchoalveolar lavage fluid specimens showed 71.4% positivity on mNGS compared to 55.0% positivity on CMTs. mNGS identified 182 pathogens, including bacteria (n = 88), fungi (n = 35) and viruses (n = 59), compared to 106 pathogens detected by CMTs (bacteria, n = 31; fungi, n = 24; viruses, n = 51). Pulmonary infection was finally diagnosed in 98 patients, including 22 bacterial, 7 fungal, 18 viral, and 48 mixed infections and 3 infections with an unknown pathogen. Mixed infections were identified in 50.5% of the patients with pulmonary infection. The sensitivity of mNGS and CMTs for diagnosing pulmonary infections was 88.8% and 69.4%, respectively (P = .001), and the specificity were 81.0% and 85.7%, respectively (P = .688). Our findings suggest that mNGS may be a promising technology for diagnosing pulmonary infections in allo-HSCT recipients.

Anterior Segment Optical Coherence Tomography Imaging of the Lacrimal Gland in Patients With Chronic Ocular Graft-Vs-Host Disease.

PURPOSE: The purpose of this study was to explore the image characteristics of the palpebral lobe of the lacrimal gland in patients with chronic ocular graft-vs-host disease (coGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) using anterior segment optical coherence tomography (AS-OCT). METHODS: This comparative cross-sectional study included 32 patients with coGVHD, 21 patients with severe aqueous tear deficiency dry eye, and 20 healthy control subjects. All subjects underwent an AS-OCT examination on the palpebral lobe of the lacrimal gland. The main outcomes are the number of visible gland lobules, ducts, and blood vessels and the proportions of mille crêpe-like structures in the AS-OCT images. RESULTS: Compared with the other 2 groups, patients with coGVHD had significantly more blood vessels and slightly less visible lobules and ducts (all P <0.05) in the palpebral lacrimal gland. Mille crêpe-like structures were observed only in the coGVHD group. Number of blood vessels was positively correlated with time after allo-HSCT (ß: 0.14, 95% confidence interval [CI], 0.01-0.26). Mille crêpe-like structure was positively correlated with coGVHD severity (odds ratio: 9.07, 95% CI, 1.75-16.38) and time after allo-HSCT (odds ratio: 0.13, 95% CI, 0.03-0.23). CONCLUSIONS: We reported the AS-OCT characteristics of the palpebral lacrimal gland in coGVHD and found an increased number of blood vessels and mille crêpe-like structures. AS-OCT has the potential in the disease monitoring of coGVHD.

Advancing robot-guided techniques in lumbar spine surgery: a systematic review and meta-analysis.

BACKGROUND: Lumbar spine surgery is a crucial intervention for addressing spinal injuries or conditions affecting the spine, often involving lumbar fusion through pedicle screw (PS) insertion. The precision of PS placement is pivotal in orthopedic surgery. This systematic review compares the accuracy of robot-guided (RG) surgery with free-hand fluoroscopy-guided (FFG), free-hand without fluoroscopy-guided (FHG), and computed tomography image-guided (CTG) techniques for PS insertion. METHODS: A systematic search of various databases from 1 January 2013 to 30 December 2023 was conducted following PRISMA guidelines. Primary outcomes, including PS insertion accuracy and breach rate, were analyzed using a random-effects model. Risk of bias was assessed using the Newcastle-Ottawa Scale. RESULTS: The overall accuracy of PS insertion using RG, based on 37 studies involving 3,837 patients and 22,117 PS, is 97.9%, with a breach rate of 0.021. RG demonstrated superior accuracy compared to FHG and CTG, with breach rates of 3.4 and 0.015 respectively for RG versus FHG, and 3.8 and 0.026 for RG versus CTG. Additionally, RG was associated with reduced mean estimated blood loss compared to CTG, indicating improved safety. CONCLUSIONS: The RG is associated with enhanced accuracy of PS insertion and reduced breach rates over other methods. However, additional randomized controlled trials comparing these modalities are needed for further validation. PROSPERO REGISTRATION: CRD42023483997.

Vedolizumab plus basiliximab as second-line therapy for steroid-refractory lower gastrointestinal acute graft-versus-host disease.

Background: Steroid-resistant (SR) lower gastrointestinal (LGI) tract graft-versus-host disease (GVHD) is the predominant cause of morbidity and mortality from GVHD after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The role of vedolizumab in the treatment of SR-LGI acute GVHD (aGVHD) remains uncertain. We aimed to assess the efficacy and safety of vedolizumab combined with basiliximab as second-line therapy for SR-LGI-aGVHD. Methods: This study aimed to explore the efficacy of vedolizumab combined with basiliximab for SR-LGI-aGVHD. The primary endpoint was the overall response (OR) on day 28. Secondary and safety endpoints included durable OR at day 56, overall survival (OS), chronic GVHD (cGVHD), non-relapse mortality (NRM), failure-free survival (FFS), and adverse events. Results: Twenty-eight patients with SR-LGI-aGVHD were included. The median time to start of combination therapy after SR-LGI-aGVHD diagnosis was 7 (range, 4-16) days. The overall response rate (ORR) at 28 days was 75.0% (95% CI: 54.8%-88.6%), and 18 achieved a complete response (CR) (64.3%, 95% CI: 44.1%-80.7%). The durable OR at day 56 was 64.3% (95% CI: 44.1%-80.7%). The 100-day, 6-month, and 12-month OS rates for the entire cohort of patients were 60.7% (95% CI: 45.1%-81.8%), 60.7% (95% CI: 45.1%-81.8%), and 47.6% (95% CI: 31.4%-72.1%), respectively. The median failure-free survival was 276 days; (95% CI: 50-not evaluable) 12-month NRM was 42.9% (95% CI: 24.1%-60.3%). The 1-year cumulative incidence of cGVHD was 35.7%. Within 180 days after study treatments, the most common grade 3 and 4 adverse events were infections. Nine (32.1%) patients developed cytomegalovirus (CMV) reactivation complicated with bacterial infections (25.0%, CMV infection; 7.1%, CMV viremia). Epstein-Barr virus (EBV) reactivation occurred in five patients (17.9%, 95% CI: 6.8%-37.6%). Only three patients (10.7%, 95% CI: 2.8%-29.4%) in our study developed pseudomembranous colitis. Conclusions: Vedolizumab plus basiliximab demonstrated efficacy in severe SR-LGI-aGVHD and was well-tolerated. Vedolizumab plus basiliximab may be considered a potential treatment option for patients with LGI-aGVHD.

A two-tier feature selection method for predicting mortality risk in ICU patients with acute kidney injury.

Acute kidney injury (AKI) is one of the most important lethal factors for patients admitted to intensive care units (ICUs), and timely high-risk prognostic assessment and intervention are essential to improving patient prognosis. In this study, a stacking model using the MIMIC-III dataset with a two-tier feature selection approach was developed to predict the risk of in-hospital mortality in ICU patients admitted for AKI. External validation was performed using separate MIMIC-IV and eICU-CRD. The area under the curve (AUC) was calculated using the stacking model, and features were selected using the Boruta and XGBoost feature selection methods. This study compares the performance of a stacking model using two-tier feature selection with a model using single-tier feature selection (XGBoost: 85; Boruta: 83; two-tier: 0.91). The predictive effectiveness of the stacking model was further validated by using different datasets (Validation 1: 0.83; Validation 2: 0.85) and comparing it with a simpler model and traditional clinical scores (SOFA: 0.65; APACH IV: 0.61). In addition, this study combined interpretable techniques and causal inference to analyze the causal relationship between features and predicted outcomes.

The impact of the donors' COVID-19 status on the outcomes of allogeneic hematopoietic stem cell transplantation: a multi-center retrospective study.

Introduction: To explore the impact of donors' COVID-19 status on allogeneic stem cell transplantation (allo-HSCT), we compared the transplant outcomes of 74 participants. Methods: This multi-center retrospective study included nine participants receiving grafts from COVID-19 positive donors (CPD), 45 from COVID-19 experienced donors (CED), and 20 from COVID-19 naive donors (CND). We evaluated engraftment, complications, and survival rates among the three groups. Results: All apheresis procedures were successful with no significant differences in CD34+ cells or lymphocytes in grafts among the three groups. All patients achieved engraftment by day 30 post-HSCT. The incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 55.6%, 20%, and 10% in the CPD, CED, and CND groups, respectively (p = 0.024). Multivariate analysis indicated that COVID-19 positivity in donors at the time of apheresis was an independent risk factor for II-IV aGVHD (p = 0.020, OR = 12.159, 95% CI 1.783 -135.760). No differences were observed among the groups in terms of chronic GVHD, viral infection, or sinusoidal obstruction syndrome. The 6-month overall survival and disease-free survival rates were also similar among the three groups. Discussion: Our results suggest that the COVID-19-positive status of donors might not impact graft collection, engraftment, or short-term survival of allo-HSCT recipients but might increase the risk of aGVHD. Further research is needed to explore the influence of donors' COVID-19 status on long-term complications and survival in allo-HSCT recipients.

Unveiling the rheological and thermal behavior of a novel Salecan and whey protein isolate composite gel.

The burgeoning interest in the versatile hydrogel matrix, with its multifarious applications, has spurred extensive research in recent years. However, the implementation of chemically crosslinked gels on a large-scale has been hindered by their poor biosafety and excessive energy consumption. To address these challenges, this study focuses on harnessing physical methods to engineer novel composite hydrogels utilizing natural polysaccharides Salecan and whey protein isolate, obviating the need for structural modification or chemical crosslinking. The aim was to explore the rheological properties to understand their multiple behaviors. Various models, including Power-Law, Herschel-Bulkley, and Arrhenius, were also employed to compare and analyze rheological parameters. This study holds significance as it is the pioneering report on the hydrogels fabricated from Salecan/Whey protein isolate. These gels possess favorable attributes encompassing optimized elasticity, thermal-stability, enhanced injectability, and self-recovery, rendering them suitable for a multitude of applications in the realms of food and biomedicine.

Sb3+/Sm3+ Codoped Cs2NaScCl6 All-Inorganic Double Perovskite: Blue Emission of Self-Trapped Excitons and Red-Emission via Energy Transfer.

The lead-free halide perovskites possess nontoxicity and excellent chemical stability, whereas relatively weak luminescence intensity limits their potential in practical applications. Therefore, strengthening the luminescence intensity and expanding application fields are urgent tasks for the development of lead-free halide perovskites. In this paper, antimony-doped Cs2NaScCl6 crystals synthesized by a solvothermal method emit bright, deep blue photoluminescence at 447 nm. The photoluminescence (PL), photoluminescence excitation (PLE), and absorption spectra demonstrate that Sb3+ doping effectively activate the intrinsic "dark self-trapped exciton (STE)," leading to an impressive photoluminescence quantum yield (PLQY) value of 78.31% for 1% Sb3+ doping. Furthermore, the luminescence intensity remains above 92% compared with the fresh sample without secondary phases detected even after 90 days under environmental conditions. To expand the emission spectra, rare-earth Sm3+ is further incorporated into Cs2NaScCl6:1% Sb3+ crystals. The results show that Sb ions not only enhance intrinsic STE luminescence but also serve as sensitizers to boost the red-light emission of Sm3+, leading to a significant 500-fold increase in red emission intensity. Finally, the PLQY reaches a stunning 86.78%. These findings provide valuable insights in the design of Sb ion-doped lead-free double perovskites, broadening the application fields in various optoelectronic devices.

Ball-milled biochar-modified zero-valent aluminum activates peroxodisulfate for phenol degradation: Enhancement of catalysis by membrane-breaking effect.

Zero-valent aluminum (ZVAl) is a potential activator for peroxodisulfate (PDS), yet the dense oxide film on its surface hampers electron transfer for the O-O bond cleavage of PDS. We synthesized zero-valent aluminum-biochar (BM-ZVAl@BC) composites through ball milling, which effectively disrupted the native oxide layer on BM-ZVAl@BC. Within the BM-ZVAl@BC/PDS system, biochar (BC) not only suppressed the rapid oxidation of BM-ZVAl@BC but also enhanced the dispersion and electron transfer rate of ZVAl, thereby improving the overall catalytic efficiency. Consequently, the phenol removal efficacy in the BM-ZVAl@BC/PDS system was notably improved. Optimal catalytic performance of the prepared BM-ZVAl@BC was achieved at a charcoal-to­aluminum mass ratio of 2:1, resulting in 95.7 % phenol removal after 180 min. Quenching experiments and electron paramagnetic resonance (EPR) analysis revealed that both free radicals (SO4•-, •OH, and O2•-) and non-radical species (1O2) contributed to phenol degradation, with SO4•- and •OH playing predominant roles. In summary, the BM-ZVAl@BC/PDS system represented an effective and promising technology for the remediation of phenolic water pollutants.

Mini-dose methotrexate combined with methylprednisolone for the initial treatment of acute GVHD: a multicentre, randomized trial.

BACKGROUND: There is an urgent unmet need for effective initial treatment for acute graft-versus-host disease (aGVHD) adding to the standard first-line therapy with corticosteroids after allogeneic haematopoietic stem cell transplantation (allo-HSCT). METHODS: We performed a multicentre, open-label, randomized, phase 3 study. Eligible patients (aged 15 years or older, had received allo-HSCT for a haematological malignancy, developed aGVHD, and received no previous therapies for aGVHD) were randomly assigned (1:1) to receive either 5 mg/m2 MTX on Days 1, 3, or 8 and then combined with corticosteroids or corticosteroids alone weekly. RESULTS: The primary endpoint was the overall response rate (ORR) on Day 10. A total of 157 patients were randomly assigned to receive either MTX plus corticosteroids (n = 78; MTX group) or corticosteroids alone (n = 79; control group). The Day 10 ORR was 97% for the MTX group and 81% for the control group (p = .005). Among patients with mild aGVHD, the Day 10 ORR was 100% for the MTX group and 86% for the control group (p = .001). The 1-year estimated failure-free survival was 69% for the MTX group and 41% for the control group (p = .002). There were no differences in treatment-related adverse events between the two groups. CONCLUSIONS: In conclusion, mini-dose MTX combined with corticosteroids can significantly improve the ORR in patients with aGVHD and is well tolerated, although it did not achieve the prespecified 20% improvement with the addition of MTX. TRIAL REGISTRATION: The trial was registered with clinicaltrials.gov (NCT04960644).

In Situ-Grown 2D Perovskite Based on π-Conjugated Aggregation-Induced Emission Organic Spacer Boosting the Efficiency and Stability of 2D-3D Heterostructured Perovskite Solar Cells.

The two-dimensional-three-dimensional (2D-3D) heterostructured perovskite solar cells (PSCs) have drawn widespread interest, wherein the organic spacer plays a significant role in the photovoltaic performance. Herein, a novel π-conjugated organic spacer with the aggregation-induced emission (AIE) property, (Z)-2-([1,1'-biphenyl]-4-yl)-3-(5-(4-(3-aminopropoxy)phenyl)thiophen-2-yl)acrylonitrile (BPCSA-S), is designed and synthesized, which is successfully applied for the in situ construction of 2D-3D heterostructured PSCs via the two-step solution method. By virtue of the functional groups (i.e., cyano, thiophene, and amino) in BPCSA-S, the BPCSA-S organic spacer can trigger the in situ growth of 2D perovskites, which will serve as the template for the heteroepitaxial growth of 3D perovskites, thus obtaining a 2D-3D heterostructured film with high-quality and few defects. More pleasingly, benefiting from the AIE property and delocalized π-electrons in the π-conjugated BPCSA-S organic spacer, excellent photosensitization process and carrier transport can be achieved. Consequently, the resultant 2D-3D heterostructured PSCs yield a pleasing PCE of 22.07%, accompanied by mitigatory hysteresis, as well as enhanced stability. Our research shows a hopeful multifunctional organic spacer approach using the novel π-conjugated AIE organic spacer for high-performance PSCs.

Adoptive therapy with cytomegalovirus-specific cytotoxic T lymphocytes for refractory cytomegalovirus DNAemia and disease after allogeneic haematopoietic stem cell transplantation.

Cytomegalovirus (CMV) DNAemia and disease are common complications in patients undergoing allogeneic haematopoietic stem cell transplantation (allo-HSCT). Few studies have compared the efficacy and safety of the HSCT donor and third-party CMV-specific cytotoxic T lymphocytes (CMV-CTLs) in the treatment of CMV DNAemia and disease. In this study, we retrospectively compared the efficacy and safety of HSCT donor and third-party CMV-CTLs in patients with refractory CMV DNAemia or disease after allo-HSCT at our centre from January 2017 to September 2021. Fifty-three patients who received CMV-CTL therapy were enrolled, including 40 in the donor group and 13 in the third-party group, and they were adults aged 18 years or older. Within 6 weeks of treatment, 26 (65.0%) and 9 (69.2%) patients achieved complete response in the donor and third-party groups (p = 1.000). The 2-year overall survival was 59.6% (95% CI 46.1%-77.1%) and 53.8% (32.6%-89.1%) in the donor and third-party groups (p = 0.860). Four (10.0%) patients in the donor group and two (15.4%) patients in the third-party group developed acute graft-versus-host disease within 3 months after CMV-CTL infusions. In conclusion, our data suggest that donor and third-party CMV-CTLs have comparable efficacy and safety for refractory CMV DNAemia and disease.

Sorafenib plus triplet therapy with venetoclax, azacitidine and homoharringtonine for refractory/relapsed acute myeloid leukemia with FLT3-ITD: A multicenter phase 2 study.

BACKGROUND: Patients with relapsed or refractory acute myeloid leukemia (R/R AML) and FLT3-internal tandem duplication (FLT3-ITD) respond infrequently to salvage chemotherapy. OBJECTIVE: To investigate the efficacy of sorafenib plus triplet therapy with venetoclax, azacitidine, and homoharringtonine (VAH) as a salvage therapy in this population. METHODS: This multicenter, single-arm, phase 2 study was conducted at 12 hospitals across China. Eligible patients had R/R AML with FLT3-ITD (aged 18-65 years) who were treated with VAH. The primary endpoint was composite complete remission (CRc) after two cycles. Secondary outcomes included the overall response rate (ORR), safety, and survival. RESULTS: Between July 9, 2020, and March 19, 2022, 58 patients were assessed for eligibility, 51 of whom were enrolled. The median patient age was 47 years (interquartile range [IQR] 31-57). CRc was 76.5% with ORR of 82.4%. At a median follow-up of 17.7 months (IQR, 8.7-24.7), the median duration of CRc was not reached (NR), overall survival was 18.1 months (95% confidence interval [CI], 11.8-NR) and event-free survival was 11.4 months (95% CI, 5.6-NR). Grade 3 or 4 adverse events occurring in ≥10% of patients included neutropenia in 47 (92.2%), thrombocytopenia in 41 (80.4%), anemia in 35 (68.6%), febrile neutropenia in 29 (56.9%), pneumonia in 13 (25.5%), and sepsis in 6 (11.8%) patients. Treatment-related death occurred in two (3.9%) patients. CONCLUSIONS: The sorafenib plus VAH regimen was well tolerated and highly active against R/R AML with FLT3-ITD. This regimen may be a suitable therapeutic option for this population, but larger population trials are needed to be explored. TRIAL REGISTRATION: Clinical Trials Registry: NCT04424147.

PASS-ALL study of paediatric-inspired versus adult chemotherapy regimens on survival of high-risk Philadelphia-negative B-cell acute lymphoblastic leukaemia with allogeneic haematopoietic stem cell transplantation.

This PASS-ALL study was designed to explore the effect of paediatric-inspired versus adult chemotherapy regimens on survival of adolescents and young adults (AYA) with high-risk Philadelphia chromosome-negative B-cell acute lymphoblastic leukaemia (HR PH-ve B-cell ALL) eligible for allogeneic haematopoietic stem cell transplantation (allo-HSCT). The PASS-ALL study is a multicentre, observational cohort study, and 143 patients with HR B-cell PH-ve ALL were enrolled from five centres-77 patients allocated in the paediatric-inspired cohort and 66 in the adult cohort with comparable baseline characteristics. Of the 143 patients, 128 cases underwent allo-HSCT. Three-year leukaemia-free survival (LFS) in the paediatric-inspired cohort was 72.2% (95% CI 60.8%-83.6%) compared with 44.6% (95% CI 31.9%-57.3%; p = 0.001). Furthermore, time-to-positive minimal residual disease (TTP-MRD) post-HSCT was marked different, 3-year cumulative incidence of relapse was 25.9% (95% CI 15.8%-37.2%) in paediatric cohort and 45.4% (95% CI 40.0%-57.9%) in adult cohort (p = 0.026). Finally, the 3-year OS rate was 75.3% (95% CI 64.9%-85.7%) for the paediatric-inspired cohort and 64.1% (95% CI 51.8%-76.4%) for the adult cohort (p = 0.074). On a multivariate analysis, paediatric-inspired regimen is a predictive factor for LFS (HR = 2.540, 95% CI 1.327-4.862, p = 0.005). Collectively, our data suggest that paediatric-inspired chemotherapy pre-HSCT results in deeper and durable MRD response reduces relapse post-HSCT and improves survival in HR B-cell PH-ve ALL patients with allo-HSCT.

Changing epidemiology, microbiology and mortality of bloodstream infections in patients with haematological malignancies before and during SARS-CoV-2 pandemic: a retrospective cohort study.

OBJECTIVE: This study was to explore the changes in bacterial bloodstream infection (BSI) in patients with haematological malignancies (HMs) before and during SARS-CoV-2 pandemic. DESIGN: Retrospective cohort study between 2018 and 2021. SETTING: The largest haematological centre in southern China. RESULTS: A total of 599 episodes of BSI occurring in 22 717 inpatients from January 2018 to December 2021 were analysed. The frequencies of the total, Gram-negative and Gram-positive BSI before and during the pandemic were 2.90% versus 2.35% (p=0.011), 2.49% versus 1.77% (p<0.001) and 0.27% versus 0.44% (p=0.027), respectively. The main isolates from Gram-negative or Gram-positive BSI and susceptibility profiles also changed. The 30-day mortality caused by BSI was lower during the pandemic (21.1% vs 14.3%, p=0.043). Multivariate analysis revealed that disease status, pulmonary infection and shock were independent predictors of 30-day mortality. CONCLUSION: Our data showed that the incidence of total and Gram-negative organisms BSI decreased, but Gram-positive BSI incidence increased in patients with HMs during the pandemic along with the changes of main isolates and susceptibility profiles. Although the 30-day mortality due to BSI was lower during the pandemic, the new infection prevention strategy should be considered for any future pandemics.

Impact of genetic patterns on sorafenib efficacy in patients with FLT3-ITD acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation: a multi-center, cohort study.

Sorafenib therapy improves overall survival (OS) in patients with FLT3 internal tandem duplication (ITD) acute myeloid leukemia (AML) undergoing allogeneic hematopoietic stem cell transplantation. We explored the efficacy of sorafenib therapy in this population with different concomitant genetic patterns. In this multi-center, cohort study, we enrolled patients with FLT3-ITD AML undergoing allogenic hematopoietic cell transplantation. Patients with sorafenib maintenance post-transplantation for at least four weeks were allocated to the sorafenib group, and otherwise to the control group. Endpoints were OS, disease-free survival, and relapse for the whole cohort and OS for genetic pattern subgroups. Among 613 patients enrolled, 275 were in the sorafenib and 338 the control group. Median follow-up was 36.5 (interquartile range (IQR), 25.2-44.7) months post-transplantation. The 3-year OS post-transplantation was 79.6% (95% confidential interval (CI) 74.8%-84.6%) and 65.2% (95% CI 60.3%-70.6%) (Hazard ratio (HR) 0.50, 95% CI 0.37-0.69; P < 0.0001) in both groups. Sorafenib maintenance post-transplantation improved OS in the favorable (HR 0.33, 95% CI 0.14-0.77; P = 0.011) and adverse (HR 0.56, 95% CI 0.33-0.93; P = 0.026) ELN 2017 risk subgroups. Patients with mutated NPM1, DNMT3A, co-occurring NPM1/DNMT3A, "activated signaling" and "DNA methylation" genes benefited in OS from sorafenib maintenance, while those carrying CEBPA, "tumor suppressors" and "myeloid transcription factors" genes did not. Patients with FLT3-ITDhigh and FLT3-ITDlow AML both benefited in OS from sorafenib maintenance. Our results identify the response of genetic patterns to sorafenib maintenance, providing new viewpoints for the optimal use of sorafenib in FLT3-ITD AML in the transplantation setting.

Ruxolitinib versus basiliximab for steroid-refractory acute graft-versus-host disease: a retrospective study.

Acute graft-versus-host disease (aGVHD) remains a major limitation of allogeneic hematopoietic stem cell transplantation; not all patients respond to standard glucocorticoids treatment. This study retrospectively evaluated the effects of ruxolitinib compared with basiliximab for steroid-refractory aGVHD (SR-aGVHD). One hundred and twenty-nine patients were enrolled, 81 in ruxolitinib and 48 in basiliximab group. The overall response (OR) at day 28 was higher in ruxolitinib group (72.8% vs. 54.2%, P = 0.031), as with complete response (CR) (58.0% vs. 35.4%, P = 0.013). Ruxolitinib led to significantly lower 1-year cumulative incidence of chronic GVHD (cGVHD) (29.6% vs. 43.8%, P = 0.021). Besides, ruxolitinib showed higher 1-year overall survival (OS) and 1-year cumulative incidence of failure-free survival (FFS) (OS: 72.8% vs. 50.0%, P = 0.008; FFS: 58.9% vs. 39.6%, P = 0.014). The 1-year cumulative incidence of non-relapse mortality (NRM) was lower in ruxolitinib group (16.1% vs. 37.5%, P = 0.005), and the 1-year relapse was not different. The 1-year cumulative incidence of cytomegalovirus (CMV) viremia, CMV-associated diseases and Epstein-Barr virus (EBV)-associated diseases was similar between the two groups, but EBV viremia was significantly lower in ruxolitinib group (6.2% vs. 29.2%, P < 0.001). Subgroup analyses revealed that OR and survival were similar in ruxolitinib 5 mg twice daily (bid) and 10 mg bid groups. However, ruxolitinib 10 mg bid treatment markedly reduced 1-year cumulative incidence of cGVHD compared with 5 mg bid (21.1% vs. 50.0%, P = 0.016). Our study demonstrated that ruxolitinib was superior to basiliximab in SR-aGVHD treatment and cGVHD prophylaxis, therefore should be recommended.

Sorafenib maintenance after allogeneic haemopoietic stem-cell transplantation in patients with FLT3-ITD acute myeloid leukaemia: long-term follow-up of an open-label, multicentre, randomised, phase 3 trial.

BACKGROUND: Our open-label, multicentre, randomised, phase 3 trial showed that sorafenib maintenance after haematopoietic stem-cell transplantation (HSCT) improved overall survival and reduced relapse for patients with FLT3 internal tandem duplication (FLT3-ITD) acute myeloid leukaemia undergoing allogeneic HSCT. Here, we present a post-hoc analysis on the 5-year follow-up data of this trial. METHODS: This phase 3 trial, done in seven hospitals in China, included patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic HSCT, who were aged 18-60 years, had an Eastern Cooperative Oncology Group performance status of 0-2, had composite complete remission before and after transplantation, and had haematopoietic recovery within 60 days after transplantation. Patients were randomly assigned (1:1) to receive sorafenib maintenance (400 mg orally twice daily) or non-maintenance (control) at 30-60 days after transplantation. Randomisation was done with permuted blocks (block size four) via an interactive web-based system. Investigators and participants were not masked to group assignment. The primary endpoint was the 1-year cumulative incidence of relapse, which was reported previously. For this updated analysis, the 5-year endpoints were overall survival; cumulative incidence of relapse; non-relapse mortality; leukaemia-free survival; graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS); cumulative incidence of chronic GVHD; and late effects in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT02474290, and is complete. FINDINGS: Between June 20, 2015, and July 21, 2018, 202 patients were randomly assigned to sorafenib maintenance (n=100) or non-maintenance (n=102). Median follow-up was 60·4 months (IQR 16·7-73·3). Extended follow-up showed improved overall survival (72·0% [95% CI 62·1-79·7] vs 55·9% [45·7-64·9]; hazard ratio [HR] 0·55, 95% CI 0·34-0·88; p=0·011), leukaemia-free survival (70·0% [60·0-78·0] vs 49·0% [39·0-58·3]; 0·47, 0·30-0·73; p=0·0007), and GRFS (58·0% [47·7-67·0] vs 39·2% [29·8-48·5]; 0·56, 0·38-0·83; p=0·0030), lower cumulative incidence of relapse (15·0% [8·8-22·7] vs 36·3% [27·0-45·6]; 0·33, 0·18-0·60; p=0·0003), and no increase in non-relapse mortality (15·0% [8·8-22·7] vs 14·7% [8·6-22·3]; 0·79, 0·39-1·62; p=0·98) for patients in the sorafenib group compared with those in the control group. The 5-year cumulative incidence of chronic GVHD (54·0% [43·7-63·2] vs 51·0% [40·8-60·3]; 0·82, 0·56-1·19; p=0·73) did not differ significantly between the two groups and we did not find substantial differences in late effects between the two groups. There were no treatment-related deaths. INTERPRETATION: With extended follow-up, sorafenib maintenance after transplantation is associated with improved long-term survival and reduced relapse rates compared with non-maintenance, further supporting this strategy as a standard of care for patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic HSCT. FUNDING: None. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Busulfan Plus Fludarabine Compared With Busulfan Plus Cyclophosphamide for AML Undergoing HLA-Haploidentical Hematopoietic Cell Transplantation: A Multicenter Randomized Phase III Trial.

PURPOSE: The busulfan plus fludarabine (BuFlu) conditioning regimen has lower transplant-related mortality (TRM) than busulfan plus cyclophosphamide (BuCy) in HLA-matched transplantation. We aimed to compare outcomes of the BuFlu regimen with those of the BuCy regimen in HLA-haploidentical hematopoietic cell transplantation (haplo-HCT). METHODS: We performed an open-label, randomized phase III trial at 12 hospitals in China. Eligible patients with AML (18-65 years) were randomly assigned 1:1 to receive BuFlu (busulfan 0.8 mg/kg four times per day on days -6 to -3; fludarabine 30 mg/m2 once daily on days -7 to -3) or BuCy (same dose of busulfan; cyclophosphamide 60 mg/kg once daily on days -3 and -2). The primary end point was 1-year TRM in the intention-to-treat population and safety in the per-protocol population. This trial is registered with ClinicalTrials.gov (identifier: NCT02487069) and is complete. RESULTS: From November 20, 2015, to September 30, 2019, 386 patients were randomly assigned to receive the BuFlu (n = 194) or BuCy (n = 192) regimen. The median follow-up was 55.0 (IQR, 46.5-69.0) months after random assignment. The 1-year TRM was 7.2% (95% CI, 4.1 to 11.4) and 14.1% (95% CI, 9.6 to 19.4; hazard ratio [HR], 0.51; 95% CI, 0.27 to 0.97; P = .041), the 5-year relapse was 17.9% (95% CI, 9.6 to 28.3) and 14.2% (95% CI, 9.1 to 20.5; HR, 1.12; 95% CI, 0.65 to 1.95; P = .670), and the 5-year overall survival was 72.5% (95% CI, 62.2 to 80.4) and 68.2% (95% CI, 58.9 to 75.9; HR, 0.84; 95% CI, 0.56 to 1.26; P = .465) in two groups, respectively. Grade 3 regimen-related toxicity (RRT) was reported for 0 of 191 patients following the BuFlu regimen and 9 (4.7%) of 190 patients following the BuCy regimen (P = .002). At least one type of grade 3-5 adverse event was reported for 130 (68.1%) of the 191 patients and 147 (77.4%) of the 190 patients in two groups, respectively (P = .041). CONCLUSION: The BuFlu regimen has a lower TRM and RRT and similar relapse for patients with AML undergoing haplo-HCT compared with the BuCy regimen.