Aging and comprehensive molecular profiling in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aging-related and heterogeneous hematopoietic malignancy. In this study, a total of 1,474 newly diagnosed AML patients with RNA sequencing data were enrolled, and targeted or whole exome sequencing data were obtained in 94% cases. The correlation of aging-related factors including age and clonal hematopoiesis (CH), gender, and genomic/transcriptomic profiles (gene fusions, genetic mutations, and gene expression networks or pathways) was systematically analyzed. Overall, AML patients aged 60 y and older showed an apparently dismal prognosis. Alongside age, the frequency of gene fusions defined in the World Health Organization classification decreased, while the positive rate of gene mutations, especially CH-related ones, increased. Additionally, the number of genetic mutations was higher in gene fusion-negative (GF-) patients than those with GF. Based on the status of CH- and myelodysplastic syndromes (MDS)-related mutations, three mutant subgroups were identified among the GF- AML cohort, namely, CH-AML, CH-MDS-AML, and other GF- AML. Notably, CH-MDS-AML demonstrated a predominance of elderly and male cases, cytopenia, and significantly adverse clinical outcomes. Besides, gene expression networks including HOXA/B, platelet factors, and inflammatory responses were most striking features associated with aging and poor prognosis in AML. Our work has thus unraveled the intricate regulatory circuitry of interactions among different age, gender, and molecular groups of AML.

The OTUD1-Notch2-ICD axis orchestrates allogeneic T cell-mediated graft-versus-host disease.

Disorders of the ubiquitin-proteasome system (UPS) are known to influence the incidence and mortality of various diseases. It remains largely unknown whether and how the UPS affects the onset and progression of acute graft-verus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study demonstrated that the deubiquitinase OTUD1 is an essential regulator of aGVHD. Activation of CD4+ T cells after allo-HSCT, elevated the protein levels of OTUD1, which in turn interacted with the Notch2-ICD (NICD) to cleave the ubiquitin of NICD at the K1770 site, thereby inducing NICD protein accumulations in T cells. OTUD1-driven NICD signaling promoted the differentiation and functions of Th1 and Th17 cells and amplified the cascade of aGVHD. Moreover, by screening a FDA-approved drugs library the study identified dapagliflozin as an inhibitor targeting the OTUD1/NICD axis. Dapagliflozin administration significantly prolonged the survival of aGVHD mice. This study characterized a previously unknown role of OTUD1 in T cell-mediated allogeneic responses and provided a promising therapeutic strategy to target OTUD1 for the alleviation of aGVHD.

Safety and efficacy of an anti-human APC antibody for prophylaxis of congenital factor deficiencies in preclinical models.

Rebalance of coagulation and anticoagulation to achieve a hemostatic effect has recently gained attention as an alternative therapeutic strategy for hemophilia. We engineered a humanized chimeric antibody, SR604, based on a previously published murine antibody, HAPC1573, which selectively blocks the anticoagulant activity of human activated protein C (APC). SR604 effectively blocked the anticoagulation activities of APC in human plasma deficient in various coagulation factors in vitro with affinities ∼60 times greater than that of HAPC1573. SR604 exhibited prophylactic and therapeutic efficacy in the tail-bleeding and knee-injury models of hemophilia A and B mice expressing human APC (humanized hemophilic mice). SR604 did not interfere with the cytoprotection and endothelial barrier function of APC, nor were there obvious toxicity effects in humanized hemophilic mice. Pharmacokinetic study showed a high bioavailability (106%) of subcutaneously injected SR604 in cynomolgus monkeys. These results demonstrate that SR604 is expected to be a safe and effective therapeutic and/or prophylactic agent with a prolonged half-life for patients with congenital factor deficiencies including hemophilia A and B.

Transcriptome-based molecular subtypes and differentiation hierarchies improve the classification framework of acute myeloid leukemia.

The current classification of acute myeloid leukemia (AML) relies largely on genomic alterations. Robust identification of clinically and biologically relevant molecular subtypes from nongenomic high-throughput sequencing data remains challenging. We established the largest multicenter AML cohort (n = 655) in China, with all patients subjected to RNA sequencing (RNA-Seq) and 619 (94.5%) to targeted or whole-exome sequencing (TES/WES). Based on an enhanced consensus clustering, eight stable gene expression subgroups (G1-G8) with unique clinical and biological significance were identified, including two unreported (G5 and G8) and three redefined ones (G4, G6, and G7). Apart from four well-known low-risk subgroups including PML::RARA (G1), CBFB::MYH11 (G2), RUNX1::RUNX1T1 (G3), biallelic CEBPA mutations or -like (G4), four meta-subgroups with poor outcomes were recognized. The G5 (myelodysplasia-related/-like) subgroup enriched clinical, cytogenetic and genetic features mimicking secondary AML, and hotspot mutations of IKZF1 (p.N159S) (n = 7). In contrast, most NPM1 mutations and KMT2A and NUP98 fusions clustered into G6-G8, showing high expression of HOXA/B genes and diverse differentiation stages, from hematopoietic stem/progenitor cell down to monocyte, namely HOX-primitive (G7), HOX-mixed (G8), and HOX-committed (G6). Through constructing prediction models, the eight gene expression subgroups could be reproduced in the Cancer Genome Atlas (TCGA) and Beat AML cohorts. Each subgroup was associated with distinct prognosis and drug sensitivities, supporting the clinical applicability of this transcriptome-based classification of AML. These molecular subgroups illuminate the complex molecular network of AML, which may promote systematic studies of disease pathogenesis and foster the screening of targeted agents based on omics.

Transcriptome-wide subtyping of pediatric and adult T cell acute lymphoblastic leukemia in an international study of 707 cases.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy of T cell progenitors, known to be a heterogeneous disease in pediatric and adult patients. Here we attempted to better understand the disease at the molecular level based on the transcriptomic landscape of 707 T-ALL patients (510 pediatric, 190 adult patients, and 7 with unknown age; 599 from published cohorts and 108 newly investigated). Leveraging the information of gene expression enabled us to identify 10 subtypes (G1­G10), including the previously undescribed one characterized by GATA3 mutations, with GATA3R276Q capable of affecting lymphocyte development in zebrafish. Through associating with T cell differentiation stages, we found that high expression of LYL1/LMO2/SPI1/HOXA (G1­G6) might represent the early T cell progenitor, pro/precortical/cortical stage with a relatively high age of disease onset, and lymphoblasts with TLX3/TLX1 high expression (G7­G8) could be blocked at the cortical/postcortical stage, while those with high expression of NKX2-1/TAL1/LMO1 (G9­G10) might correspond to cortical/postcortical/mature stages of T cell development. Notably, adult patients harbored more cooperative mutations among epigenetic regulators, and genes involved in JAK-STAT and RAS signaling pathways, with 44% of patients aged 40 y or above in G1 bearing DNMT3A/IDH2 mutations usually seen in acute myeloid leukemia, suggesting the nature of mixed phenotype acute leukemia.

Cardiac effects of deferasirox in transfusion-dependent patients with myelodysplastic syndromes: TELESTO study.

Iron overload from repeated transfusions has a negative impact on cardiac function, and iron chelation therapy may help prevent cardiac dysfunction in transfusion-dependent patients with myelodysplastic syndromes (MDS). TELESTO (NCT00940602) was a prospective, placebo-controlled, randomised study to evaluate the iron chelator deferasirox in patients with low- or intermediate-1-risk MDS and iron overload. Echocardiographic parameters were collected at screening and during treatment. Patients receiving deferasirox experienced a significant decrease in the composite risk of hospitalisation for congestive heart failure (CHF) or worsening of cardiac function (HR = 0.23; 95% CI: 0.05, 0.99; nominal p = 0.0322) versus placebo. No significant differences between the arms were found in left ventricular ejection fraction, ventricular diameter and mass or pulmonary artery pressure. The absolute number of events was low, but the enrolled patients were younger than average for patients with MDS, with no serious cardiac comorbidities and a modest cardiovascular risk profile. These results support the effectiveness of deferasirox in preventing cardiac damage caused by iron overload in this patient population. Identification of patients developing CHF is challenging due to the lack of distinctive echocardiographic features. The treatment of iron overload may be important to prevent cardiac dysfunction in these patients, even those with moderate CHF risk.

Shared genetic architecture between autoimmune disorders and B-cell acute lymphoblastic leukemia: insights from large-scale genome-wide cross-trait analysis.

BACKGROUND: To study the shared genetic structure between autoimmune diseases and B-cell acute lymphoblastic leukemia (B-ALL) and identify the shared risk loci and genes and genetic mechanisms involved. METHODS: Based on large-scale genome-wide association study (GWAS) summary-level data sets, we observed genetic overlaps between autoimmune diseases and B-ALL, and cross-trait pleiotropic analysis was performed to detect shared pleiotropic loci and genes. A series of functional annotation and tissue-specific analysis were performed to determine the influence of pleiotropic genes. The heritability enrichment analysis was used to detect crucial immune cells and tissues. Finally, bidirectional Mendelian randomization (MR) methods were utilized to investigate the casual associations. RESULTS: Our research highlighted shared genetic mechanisms between seven autoimmune disorders and B-ALL. A total of 73 pleiotropic loci were identified at the genome-wide significance level (P < 5 × 10-8), 16 of which had strong evidence of colocalization. We demonstrated that several loci have been previously reported (e.g., 17q21) and discovered some novel loci (e.g., 10p12, 5p13). Further gene-level identified 194 unique pleiotropic genes, for example IKZF1, GATA3, IKZF3, GSDMB, and ORMDL3. Pathway analysis determined the key role of cellular response to cytokine stimulus, B cell activation, and JAK-STAT signaling pathways. SNP-level and gene-level tissue enrichment suggested that crucial role pleiotropic mechanisms involved in the spleen, whole blood, and EBV-transformed lymphocytes. Also, hyprcoloc and stratified LD score regression analyses revealed that B cells at different developmental stages may be involved in mechanisms shared between two different diseases. Finally, two-sample MR analysis determined causal effects of asthma and rheumatoid arthritis on B-ALL. CONCLUSIONS: Our research proved shared genetic architecture between autoimmune disorders and B-ALL and shed light on the potential mechanism that might involve in.

A phase II study of belumosudil for chronic graft-versus-host disease in patients who failed at least one line of systemic therapy in China.

BACKGROUND: Chronic graft-versus-host disease (cGVHD) is an immune-related disorder that is the most common complication post-allogenic hematopoietic stem cell transplant. Corticosteroids with or without calcineurin inhibitors (CNIs) remain the mainstay of cGVHD treatment for first-line therapy. However, for many patients, cGVHD symptoms cannot be effectively managed and thus require second-line therapy. Currently, there is no approved treatment for second-line cGVHD treatment in China. In this study, belumosudil, a highly selective and potent rho-associated coiled-coil-containing protein kinase-2 inhibitor demonstrated to be effective for cGVHD in the United States and other Western countries, is investigated in patients with cGVHD in China for its overall benefit-risk balance. METHODS: This multicenter, open-label phase II study evaluated the safety, efficacy, and pharmacokinetics of oral belumosudil 200 mg once daily in cGVHD patients who had been treated with at least one line of systemic therapy in China. The primary endpoint was overall response rate (ORR); each individual patient's response was assessed by the investigator using the 2014 National Institutes of Health consensus criteria. Secondary endpoints were duration of response (DOR), time to response (TTR), changes in Lee Symptom Scale (LSS) score, organ response rate, corticosteroid dose change, CNI dose change, failure-free survival, time-to-next-treatment, overall survival, and safety. RESULTS: Thirty patients were enrolled in the study with a median follow-up time of 12.9 months. ORR was 73.3% (95% confidence interval: 54.1-87.7%) and all responders achieved partial response. Median DOR among responders was not reached and median TTR was 4.3 weeks (range: 3.9-48.1). Fifteen patients (50.0%) achieved clinically meaningful response in terms of reduction in LSS score by ≥ 7 points from baseline. Corticosteroid and CNI dose reductions were reported in 56.7% (17/30) and 35.0% (7/20) of patients, respectively. Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity, with 11 patients (36.7%) experiencing grade ≥ 3 TEAEs. The most common grade ≥ 3 TEAE was pneumonia (n = 5, 16.7%). CONCLUSIONS: Belumosudil treatment demonstrated a favorable benefit-risk balance in treating cGVHD patients who previously have had standard corticosteroid therapy in China where approved second-line setting is absent. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04930562.

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).

Real-world evidence on treatment pattern, effectiveness, and safety of blinatumomab in Chinese patients with B-cell acute lymphoblastic leukemia.

Blinatumomab is efficacious in patients with B-cell acute lymphoblastic leukemia (B-ALL), yet limited real-world data exists in this context. This retrospective study provided real-world data on the treatment pattern, effectiveness, and safety of blinatumomab in Chinese patients with newly diagnosed (ND) and relapsed/refractory (R/R) B-ALL. Patients with B-ALL who received at least one dose of blinatumomab in frontline or R/R settings between August 2021 and June 2023 were included. The primary outcome was the treatment pattern of blinatumomab. Key secondary outcomes included complete remission (CR)/CR with incomplete blood cell recovery (CRi) rate, minimal residual disease (MRD) negativity, median event-free survival (EFS), and safety. The study included 96 patients with B-ALL; 53 (55.2%) patients were in the ND group and 43 (44.8%) patients were in the R/R group. The median treatment duration was one cycle (range: 1-5). Most patients underwent chemotherapies, allo-HSCT, or experimental CAR-T following blinatumomab. The ND patients using blinatumomab induction therapy achieved 100% CR/CRi rate; 87.2% achieved MRD negativity within two cycles of blinatumomab. In R/R re-induction patients, the CR/CRi rate was 50%; MRD negativity rate was 64.2%. In R/R patients using blinatumomab for consolidation, MRD negativity rate was 90.9%. The median EFS was not reached in both ND and R/R patients; 1-year EFS rate was 90.8% (95% CI: 67%, 97%) and 55.1% (95% CI: 30%, 74%), respectively. Grade ≥ 3 adverse events were observed in 12.5% patients. Blinatumomab was found to be effective with a tolerable safety profile in real world setting.

Current use of androgens in bone marrow failure disorders: a report from the Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation.

Androgens represent the historical therapeutic backbone of bone marrow failure (BMF) syndromes. However, their role has rarely been analyzed in a prospective setting, and systematic and long-term data regarding their usage, effectiveness and toxicity in both acquired and inherited BMF are currently unavailable. Here, taking advantage of a unique disease-specific international dataset, we retrospectively analyzed the largest cohort so far of BMF patients who received androgens before or in the absence of an allogeneic hematopoietic cell transplantation (HCT), re-evaluating their current use in these disorders. We identified 274 patients across 82 European Society for Blood and Marrow Transplantation (EBMT) affiliated centers: 193 with acquired (median age 32 years) and 81 with inherited (median age 8 years) BMF. With a median duration of androgen treatment of 5.6 and 20 months, respectively, complete and partial remission rates at 3 months were 6% and 29% in acquired and 8% and 29% in inherited disorders. Five-year overall survival and failure-free survival (FFS) were respectively 63% and 23% in acquired and 78% and 14% in inherited BMF. Androgen initiation after second-line treatments for acquired BMF, and after >12 months post diagnosis for inherited BMF were identified as factors associated with improved FFS in multivariable analysis. Androgen use was associated with a manageable incidence of organ-specific toxicity, and low rates of solid and hematologic malignancies. Sub-analysis of transplant-related outcomes after exposure to these compounds showed probabilities of survival and complications similar to other transplanted BMF cohorts. This study delivers a unique opportunity to track androgen use in BMF syndromes and represents the basis for general recommendations on this category of therapeutics on behalf of the Severe Aplastic Anemia Working Party of the EBMT.

Tislelizumab augment the efficacy of CD19/22 dual-targeted chimeric antigen receptor T cell in advanced stage relapsed or refractory B-cell non-Hodgkin lymphoma.

Dual-targeted chimeric antigen receptor T (CAR-T) cell is an important strategy to improve the efficacy of CD19 CAR-T cell against refractory or relapsed B cell non-Hodgkin lymphoma (R/R B-NHL). However, durable responses are not achieved in most patients, in part owing CAR-T cell exhaustion caused by PD-1/PD-L1 pathway. We conducted a prospective, single-arm study of dual-targeted CD19/22 CAR-T cell combined with anti-PD-1 antibody, tislelizumab, in R/R B-NHL (NCT04539444). Tislelizumab was administrated on +1 day after patients received infusion of CD19/22 CAR-T cell. Responses, survival and safety were evaluated. From 1 August 2020 to 30 March 2023, 16 patients were enrolled. The median follow-up time is 16.0 (range: 5.0-32.0 months) months. Overall response was achieved in 14 of 16 (87.5%) patients, and the complete response (CR) was achieved in 11 of 16 (68.8%) patients. The 1-year progression-free survival and overall survival rates were 68.8% and 81.3%, respectively. Of the 14 patients responded, 9 patients maintained their response until the end of follow-up. Among the 15 out of 16 (93.8%) patients who had extranodal involvement, 14 (93.3%) patients achieved overall response rate with 11 (73.3%) patients achieving CR. Eight (50%) patients experienced cytokine release syndrome. No neurologic adverse events were reported. Gene Ontology-Biological Process enrichment analysis showed that immune response-related signaling pathways were enriched in CR patients. Our results suggest that CD19/22 CAR-T cell combined with tislelizumab elicit a safe and durable response in R/R B-NHL and may improve the prognosis of those patients.

The indirect effects of CMV reactivation on patients following allogeneic hematopoietic stem cell transplantation: an evidence mapping.

Cytomegalovirus (CMV) reactivation following allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a challenging problem, and the impact on the risk of overall mortality (OM) and non-relapse mortality (NRM) in patients following allo-HSCT is still controversial. Utilizing the evidence mapping method, we aimed to assess the effect of CMV infection on outcomes of patients post-transplantation and identify research gaps through systematic reviews (SRs) and clinical studies. PubMed, EMBASE, Web of Science, and Cochrane library databases were searched from inception until 5 July 2022 to identify relevant literature. After systematic literature screening and data extraction, evidence mapping of the effects of CMV reactivation on patients post-allo-HSCT was conducted. Three SRs and 22 clinical studies were included. In one SR, CMV reactivation was associated with an increased risk of mortality (HR 1.46; 95% CI, 1.24-1.72; P ≤ 0.001). In two SRs, CMV reactivation was associated with NRM. One SR reported CMV reactivation was potentially associated with significant protection against relapse in patients with acute myelocytic leukemia (AML), but no significant correlation with graft-versus-host disease (GVHD) was found. Lastly, in one SR CMV reactivation significantly increased the risk of invasive fungal disease (IFD). Most clinical articles reported that CMV reactivation increased the risk of renal dysfunction, poor graft function, re-hospitalization, and bacterial infections. CMV reactivation following allo-HSCT is associated with an increased risk of OM, NRM, IFD, and renal dysfunction, as well as a reduced risk of relapse in patients with AML.

Successful treatment of a B/T MPAL patient by chemo-free treatment with venetoclax, azacitidine, and blinatumomab.

B/T mixed phenotype acute leukemia (MPAL), which represents only 2-3% of all MPAL cases, is classified as a high-risk leukemia subtype. Adults diagnosed with B/T MPAL have a notably low 3-year survival rate, estimated at 20-40%. The rarity and undercharacterization of B/T MPAL present substantial challenges in identifying an optimal treatment protocol. This report aims to shed light on this issue by presenting a case in which a patient with a complex karyotype was treated using a combination of venetoclax, azacitidine, and blinatumomab. This novel, chemo-free regimen resulted in the patient achieving both hematologic and molecular complete remission, with no severe organ or hematological toxicity observed. Notably, the patient continued to maintain molecular remission for 1 year following the transplantation. Based on these findings, the combination of venetoclax, azacitidine, and blinatumomab could be considered a potential therapeutic approach for B/T MPAL patients, meriting further investigation.

Impact of cladribine, cytarabine, and G-CSF (CLAG) as a bridging therapy prior to allogeneic hematopoietic stem cell transplantation in relapsed or refractory acute myeloid leukemia.

The combination of cladribine, cytarabine, and G-CSF (CLAG) has exhibited robust synergistic anti-leukemia activity as an induction therapy (IT) in acute myeloid leukemia (AML). However, the impact of CLAG as a bridging therapy (BT) administered between IT and allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with relapsed or refractory (R/R) AML remains uncertain. In this retrospective study, we examined the efficacy of CLAG as a transitional strategy prior to allo-HSCT in R/R AML. We included 234 patients with R/R AML who received the modified busulfan plus cyclophosphamide conditioning regimen for allo-HSCT in our center during the past 6 years, performed a propensity-score matching analysis, partitioned them into four distinct cohorts, and further integrated them into the CLAG group and non-CLAG group based on response to IT and utilization of CLAG. Our cohorts encompassed 12 patients in Cohort A (modified composite complete remission (mCRc) after IT, CLAG), 31 in Cohort B (mCRc after IT, non-CLAG), 35 in Cohort C (non-complete remission (non-CR) after IT, CLAG), and 80 in Cohort D (non-CR after IT, non-CLAG). Intriguingly, among patients with non-CR status, the administration of CLAG correlated with a notably statistically diminished risk of relapse and improved survival at 2-year follow-up (Cohort C vs. Cohort D). Employing CLAG as a BT prior to allo-HSCT demonstrates substantial effectiveness, a relative degree of safety, and manageable toxicity in selected R/R AML cases.

Chidamide combined with a modified Bu-Cy conditioning regimen improves survival in patients with T-cell acute lymphoblastic leukemia/lymphoma undergoing allogeneic hematopoietic stem cell transplantation.

This study aimed to evaluate the efficacy and safety of chidamide (Chi) combined with a modified Busulfan-Cyclophosphamide (mBuCy) conditioning regimen for T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Twenty-two patients received chidamide combined with mBuCy conditioning regimen (Chi group). A matched-pair control (CON) group of 44 patients (matched 1:2) received mBuCy only in the same period. The leukemia-free survival (LFS), overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse-related mortality (NRM) were evaluated. Patients in the Chi group were associated with lower 2-year CIR (19.0 vs. 41.4%, P = 0.030), better 2-year LFS (76.1 vs. 48.1%, P = 0.014), and had no significant difference in 2-year OS (80.5 vs. 66.4%, P = 0.088). Patients with minimal residual disease (MRD) positive before HSCT in the Chi group exhibited an advantage in 2-year LFS and a trend towards better 2-year OS (75.0 vs. 10.2%, P = 0.048; 75.0 vs. 11.4%, P = 0.060, respectively). Multivariable analysis showed that the chidamide intensified regimen was independently associated with better LFS (HR 0.23; 95%CI, 0.08-0.63; P = 0.004), and showed no significant impact with OS for all patients (HR 0.34, 95%CI, 0.11-1.07; P = 0.064). The cumulative incidence rates of grade II-IV aGVHD were similar (36.4 vs. 38.6%, P = 0.858). 20 patients in Chi group evinced an elevation in γ-glutamyltransferase, as compared to the mBuCy group (90.9 vs. 65.9%, P = 0.029). No transplantation-related mortality was documented within the first 100 days after transplantation. The results demonstrate that the chidamide intensified regimen may be an effective and acceptable safety option for T-ALL/LBL undergoing allo-HSCT, and further validation is needed.

Switching from eltrombopag to hetrombopag in patients with primary immune thrombocytopenia: a post-hoc analysis of a multicenter, randomized phase III trial.

While studies have explored the feasibility of switching between various thrombopoietin receptor agonists in treating immune thrombocytopenia (ITP), data on the switching from eltrombopag to hetrombopag remains scarce. This post-hoc analysis of a phase III hetrombopag trial aimed to assess the outcomes of ITP patients who switched from eltrombopag to hetrombopag. In the original phase III trial, patients initially randomized to the placebo group were switched to eltrombopag. Those who completed this 14-week eltrombopag were eligible to switch to a 24-week hetrombopag. Treatment response, defined as a platelet count of ≥ 50 × 109/L, and safety were evaluated before and after the switch. Sixty-three patients who completed the 14-week eltrombopag and switched to hetrombopag were included in this post-hoc analysis. Response rates before and after the switch were 66.7% and 88.9%, respectively. Among those with pre-switching platelet counts below 30 × 109/L, eight out of 12 patients (66.7%) responded, while eight out of nine patients (88.9%) with pre-switching platelet counts between 30 × 109/L and 50 × 109/L responded post-switching. Treatment-related adverse events were observed in 50.8% of patients during eltrombopag treatment and 38.1% during hetrombopag treatment. No severe adverse events were noted during hetrombopag treatment. Switching from eltrombopag to hetrombopag in ITP management appears to be effective and well-tolerated. Notably, hetrombopag yielded high response rates, even among patients who had previously shown limited response to eltrombopag. However, these observations need to be confirmed in future trials.

Tandem bispecific CD123/CLL-1 CAR-T cells exhibit specific cytolytic effector functions against human acute myeloid leukaemia.

OBJECTIVES: The treatment of refractory and recurrent acute myeloid leukaemia (AML) is still a challenge with poor response rates and short survival times. In an attempt to solve this problem, we constructed a tandem bispecific chimeric antigen receptor (CAR) targeting CD123 and C-type lectin-like molecule 1 (CLL-1), two different AML antigens, and verified its cytotoxic effects in vitro. METHODS: We established and cultured K562 cell lines expressing both CD123 and CLL1 antigens. Single-target CAR-T cells specific to CD123 and CLL1 were engineered, alongside tandem CD123/CLL1 bispecific CAR-T cells. Flow cytometry was used to determine cell phenotypes, transfection efficiencies, cytokine release, and CAR-T-cell proliferation, and an lactate dehydrogenase assay was used to detect the cytotoxicity of CD123/CLL-1 bispecific tandem CAR-T cells in vitro. RESULTS: Two types of tandem CAR-T cells exhibited significant killing effects on CLL-1 + CD123+ leukaemia cell lines and primary AML tumour cells. The killing efficiency of tandem CAR-T cells in the case of single antigen expression is comparable to that of single target CAR-T cells. When faced with dual target tumour cells, dual target CAR-T cells significantly surpass single target CAR-T cells. CD123/CLL-1 CAR-T cells in tandem targeted and killed CD123- and CLL-1-positive leukaemia cell lines and released a large number of cytokines. CONCLUSIONS: CD123/CLL-1 CAR-T cells in tandem can simultaneously target CD123 and CLL-1 on AML cells, demonstrating a significant ability to kill single antigens and multi-target tumour cells. This suggests that CD123/CLL-1 CAR-T cells exhibit significant advantages in the expression of multiple antigens in a wide range of target cells, which may help overcome the challenges posed by tumour heterogeneity and evasion mechanisms.

High salt activates p97 to reduce host antiviral immunity by restricting Viperin induction.

High-salt diets have recently been implicated in hypertension, cardiovascular disease, and autoimmune disease. However, whether and how dietary salt affects host antiviral response remain elusive. Here, we report that high salt induces an instant reduction in host antiviral immunity, although this effect is compromised during a long-term high-salt diet. Further studies reveal that high salt stimulates the acetylation at Lys663 of p97, which promotes the recruitment of ubiquitinated proteins for proteasome-dependent degradation. p97-mediated degradation of the deubiquitinase USP33 results in a deficiency of Viperin protein expression during viral infection, which substantially attenuates host antiviral ability. Importantly, switching to a low-salt diet during viral infection significantly enhances Viperin expression and improves host antiviral ability. These findings uncover dietary salt-induced regulation of ubiquitinated cellular proteins and host antiviral immunity, and could offer insight into the daily consumption of salt-containing diets during virus epidemics.

Hematologic health services and practical characteristics: report of a nationwide survey among Chinese hematologists.

BACKGROUND: In the past 40 years, China has experienced tremendous economic development, but the current situation of hematologists has rarely been reported. A landscape survey of human resources is essential for healthcare development and policy formulation in the future. METHODS: The Chinese Society of Hematology initiated a survey of Chinese hematologists in mainland China for evaluating demographic and practice characteristics. Respondents were anonymous, and there were no limitations regarding their age, sex, etc. RESULTS: Totally 2032 hematologists responded, with a median age bracket of 36-45 years. Respondents were well engaged into subspecialties, and 28.1% acquired doctorates of philosophy. Hematopoietic cell transplantation (HCT) centers have been established all over China. Higher-GDP regions reported more advantages, including bigger scale of transplant centers (P < 0.001), younger age structure (P = 0.039), better education qualifications (P = 0.001) and less turnover intentions (P = 0.004), despite of increased risk of medical disputes (P = 0.028). Although females accounted for 65.5% of hematologists, males were older (P < 0.001), and had more senior professional titles (P < 0.001), academic positions (P < 0.001), opportunities for continuing education (P < 0.001), and paper publishing in the recent two years (P = 0.001). For turnover intention, the higher GDP regions led to an independently reduced risk (HR = 0.673, 95%CI [0.482-0.940], P = 0.020), whereas medical disputes resulted in an increased the risk (HR = 2.037, 95%CI [1.513-2.743], P < 0.001). Considering the impact of the COVID-19 pandemic, majority of respondents believed that the decline in patient visits and delay in treatment was within 30%. 67.9% of respondents reported a decrease of the use of bone marrow as grafts but 18.8% reported an increase of cord blood units. 35.0% of the respondents switched their daily work to support the anti-epidemic medical activities. CONCLUSIONS: We concluded the discipline of hematology in China has flourished in recent years with a young workforce, while regional economic and gender disparities warrant further continuous optimization. Joint efforts against the impact of COVID-19 are needed in the post-pandemic era.