Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide. The role of macrophage receptor with collagenous structure (MARCO), a scavenger receptor class-A protein expressed on macrophage surface, in PDAC progression remains unclear. Here, we identified a subset of MARCO-expressing macrophages with strong immunosuppressive signatures that were markedly increased in PDAC patients. Analysis of MARCOhi PDAC samples displayed reduced proportion of CD8⁺ T cells and NK cells, accompanied by an increased proportion of regulatory T cells (Tregs). In vitro, co-culture with multiple PDAC cell lines potently induced MARCO expression on both human and murine macrophages, driving them to a pro-tumorigenic polarization phenotype. Cell-cell interaction analyses further indicated that vascular endothelial growth factor (VEGF) selectively targets MARCO⁺ macrophages, and VEGF stimulation significantly upregulates MARCO expression in vitro. Notably, genetic ablation of Marco markedly suppressed tumor growth in a murine PDAC model, at least partly through enhanced proportion of NK and T cells. Furthermore, MARCO⁺ macrophages were also enriched across several other cancer types, suggesting a potential pan-cancer relevance. Collectively, our findings uncover a critical role of MARCO⁺ macrophages in PDAC progression and highlight MARCO as a promising therapeutic target with potential applicability across multiple malignancies.

Eradicating leukemia stem cells (LSCs) and overcoming tyrosine kinase inhibitor (TKI) resistance is urgent for chronic myeloid leukemia (CML) treatment. We find that F-box protein 3 (FBXO3) is highly upregulated in CD34+ CML stem cells from TKI-resistant patients and identify it as an innovative CML-LSC marker via single-cell RNA sequencing (scRNA-seq). FBXO3 deficiency induces apoptosis and reduces proliferation of CML cell lines and LSCs in vitro and in vivo, with minimal effects on normal CD34+ hematopoietic stem cells (HSCs). Mechanistically, FBXO3 interacts with DUSP9 to promote its ubiquitination and activate the MAPK pathway, critical for CML cell activity. DUSP9 knockdown partially reverses FBXO3-deficiency-mediated LSC elimination. Furthermore, FBXO3 inhibitor monotherapy or combination with imatinib effectively eradicates CML-LSCs, overcomes TKI resistance, and spares normal hematopoiesis. Collectively, our findings highlight FBXO3’s role in CML progression and support combining FBXO3 inhibitors with TKIs for durable LSC elimination.

Current staging systems for natural killer/T cell lymphoma (NKTCL) inadequately reflect its predominantly extranodal presentation and lack prognostic accuracy in the asparaginase era. This retrospective multicenter study analyzes 1,872 newly diagnosed NKTCL patients treated with asparaginase-based regimens or radiotherapy alone, from 15 institutions across China. For nasal-type NKTCL, skull base invasion (SBI) is identified as an independent adverse prognostic factor. We reclassify Ann Arbor stage I patients with SBI as stage II and stage II patients with SBI as stage III. For non-nasal-type NKTCL, we retain the Chinese Southwest Oncology Group and Asia Lymphoma Study Group (CA) system due to its superior prognostic discrimination. The revised system demonstrates improved outcome prediction, hazard discrimination, hazard consistency, and sample balance across training, internal, and external validation cohorts. Time-dependent receiver operating characteristic (ROC) analysis confirms superior predictive accuracy over existing systems. This proposal provides a refined prognostic framework to guide clinical decision-making and optimize patient selection for future trials.

Leukemia is a malignant clonal disease of hematopoietic stem cells. Currently, primary treatments include chemotherapy, targeted drugs, hematopoietic stem cell transplantation, and immunotherapy. Although advances in treatment have improved survival for leukemia patients, treatment failure still occurs in some individuals for various reasons. This necessitates the discovery of new pathogenic mechanisms and the exploration of novel biological targets. Tumor Necrosis Factor Receptor-Associated Factors (TRAFs) are a family of cytoplasmic adapter proteins, typically comprising seven members. The TRAF protein family is widely involved in cell proliferation, differentiation, survival, and apoptosis, and also regulates immune and inflammatory responses. TRAFs perform dual roles in a broad range of biological activities—as adapter proteins and as E3 ubiquitin ligases—both essential for activating receptor-mediated signaling. In recent years, growing evidence has highlighted the significant role of TRAFs in leukemia, linking them to leukemic stem cell activity, drug resistance, apoptosis, and autophagy. This review introduces the functions and characteristics of TRAFs and summarizes research progress on their involvement in leukemia, underscoring their potential as novel therapeutic targets for the disease.

Glucocorticoids(GCs) are widely used to treat erythropoietin-resistant anemias, yet the precise mechanisms underlying their erythropoiesis-promoting effects remain incompletely understood. This study used single-cell RNA sequencing, ATAC-seq, ChIP-seq, RNA-seq,quantitative PCR (qPCR), enzyme-linked immunosorbent assay (ELISA) and flow cytometry in vivo models (AIHA patients, CD163-/- mice, Gypa-eGFP-cremice, Epor-tdtomato-cre mice, and Epor-eGFP-cre rats) and in vitro human erythroblastic island(EBI) formation and EBI enrichment and cytospins, Giemsa and Prussian blue staining, quantification and co-culture systems to delineate CD163+ macrophages coordinating erythroblastic island formation and iron metabolism. GC promote erythropoiesis by regulating CD163-mediated EBI formation and modulating iron metabolism within EBI macrophages, a phenomenon conserved across humans, rats, and mice. We demonstrated that CD163+macrophages-but not their CD163- counterparts-exhibit heightened iron metabolism in the bone marrow, and that GC-induced erythropoiesis is markedly attenuated in CD163-deficient mice due to disrupted EBI architecture and impaired iron handling. Importantly, GC therapy restores iron metabolism and mitigates inflammatory responses in BM CD163+macrophages, likely contributing to improved erythropoiesis in patients with autoimmune hemolytic anemia. CD163⁺macrophages support GC-induced erythropoiesis by coordinating erythroblastic island formation and iron metabolism. These findings uncover a previously unrecognized GC-CD163-EBI axis that governs erythropoiesis and highlight the potential of targeting EBI macrophage function as a novel therapeutic strategy for anemia.

Abstract Before November 2023, CD19 chimeric antigen receptor (CAR) T-cell therapies had not been approved in China for patients with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), leaving a significant unmet need. In response, inaticabtagene autoleucel (Inati-cel), a novel CD19 CAR T-cell therapy with a distinct single-chain variable fragment (HI19α), was developed and showed promising efficacy in preliminary clinical research. We conducted a phase 2, single-arm, multicenter study of Inati-cel in adult CD19+ R/R B-ALL in China. The primary end point was the overall remission rate (ORR) at the end of month 3. Forty-eight patients who underwent Inati-cel infusion were evaluated for both efficacy and safety. Among them, 34 patients achieved and maintained remission beyond 3 months, with a 3-month ORR of 70.8% (95% confidence interval [CI], 55.9-83.1). The best ORR was 85.4%, with all responders reaching minimal residual disease negativity. With a median follow-up of 23.7 months, the median duration of remission was 20.7 months (95% CI, 6.4 to not reached), and the median overall survival was not reached (95% CI, 13.0 months to not reached). Additionally, grade ≥3 cytokine release syndrome and neurologic events occurred in 12.5% and 6.2% of patients, respectively. The 2-year follow-up data suggest that Inati-cel demonstrates encouraging and durable responses with manageable safety profiles in R/R B-ALL. Based on the data from this pivotal trial, Inati-cel was approved as the first CAR T-cell therapy for adult R/R B-ALL in China and underscores its potential therapeutic benefits for this patient population. This trial was registered at www.ClinicalTrials.gov as #NCT04684147.

Abstract Background Several approaches are being explored for engineering off-the-shelf chimeric antigen receptor (CAR) T cells. In this study, we engineered chimeric Fcγ receptor (FcγR) T cells and tested their potential as a versatile platform for universal T cell therapy. Methods Chimeric FcγR (CFR) constructs were generated using three distinct forms of FcγR, namely CD16A, CD32A, and CD64. The functionality of CFR T cells was evaluated through degranulation assays, specific target lysis experiments, in vitro cytokine production analysis, and assessment of tumor xenograft destruction specificity in mouse models using different monoclonal antibodies (MoAbs). Results Three types of CFR T cells were engineered, 16s3, 32-8a, 64-8a CFR T cells. In the presence of rituximab (RTX), cytotoxicity of all three types of CFR T cells against CD20+ Raji-wt, K562-CD20+, and primary tumor cells was significantly higher than that of the mock T cells (P < 0.001). When herceptin was used, all three types of CFR T cells exhibited significant cytotoxicity against HER2+ cell lines of SK-BR-3, SK-OV-3, and HCC1954 (P < 0.001). The cytotoxicity of 64-8a CFR T cells was significantly inhibited by free human IgG at a physiological dose (P < 0.001), which was not observed in 16s3, 32-8a CFR T cells. Compared to 32-8a CFR T cells, 16s3 CFR T cells exhibited more prolonged cytotoxicity than 32-8a CFR T cells (P < 0.01). In in vivo assays using xenograft models, 16s3 CFR T cells significantly prolonged the survival of mice xenografted with Raji-wt cells in the presence of RTX (P < 0.001), and effectively reduced tumor burden in mice xenografted with SK-OV-3 cells in the presence of herceptin (P < 0.05). No significant non-specific cytotoxicity of CFR T cells was found in vivo. Conclusion The anti-tumor effects of the CFR T cells in vitro and in xenograft mouse models are mediated by specific MoAbs such as RTX and herceptin. The CFR T cells therefore have the features of universal T cells with specificity directed by MoAbs. 16s3 CFR T cells are chosen for clinical trials.

Introduction Bronchiolitis obliterans syndrome ( BOS ) is a clinical syndrome characterized by new-onset persistent airflow limitation after hematopoietic stem cell transplantation ( HSCT ), which is one of the leading causes of late deaths after HSCT, severely restricting the ability of patients to perform their daily activities and reducing their quality of life. Traditional treatments for BOS rely on glucocorticoids combined with FAM regimens ( fluticasone + azithromycin + montelukast ) and calmodulin phosphatase inhibitors ( CNIs ), but they have limited efficacy with an even lower overall remission rate ( ORR ) and poor prognosis once progression to steroid-refractory cGVHD (SR-cGVHD) is achieved. Therefore, there is an urgent need to explore new treatments and strategies. Methods A retrospective analysis of 14 patients, 11 males and 3 females, with a median age of 19 years (7-54 years), who underwent hematopoietic stem cell transplantation combined with BOS at Henan Cancer Hospital from 2018 to 2025, including 6 cases of mild BOS, 3 cases of moderate BOS, 5 cases of severe BOS, Among them, 6 cases of mild, 3 cases of moderate, and 5 cases of severe BOS were treated with low-dose rucotinib ( 5 mg qd po) combined with piroxicam (200 mg tid po), small-dose CNI (half of the effective therapeutic concentration), and FAM first-line treatment. Patients' lung function was assessed at one and three months after treatment, with first-second forced expiratory volume (FEV1) as the primary study endpoint, and secondary endpoints including best-remission rate (BOR) at three months, no recurrence rate (NRM) at 1 year, overall survival (OS) at 1 year, and treatment-related adverse events. Results After three months of treatment, no patients had worsened according to the NIH scale. 35.7% (5 patients) had stable disease, 14.5% (2 patients) achieved partial remission (PR), and 50.0% (7 patients) achieved complete remission (CR).In terms of lung function, FEV1 improved in 85% of patients, with the largest improvement being 27.5% and the smallest only 2.6%. Only two patients showed a decrease in FEV1 (both patients had severe BOS). the 3-month best-remission rate was 64.5%, the 1-year NRM rate was 7.1% ± 6.9%, and the 1-year OS was 92.9% ± 6.9%. In terms of safety, no serious pulmonary infections occurred and no hematologic adverse events were observed. Conclusions In conclusion, the first-line treatment of BOS patients with low-dose ruxolitinib in combination with pirfenidone, low-dose CNI, and FAM had better efficacy and safety, and improved the overall survival of patients.Keywords Low-dose ruxolitinib, pirfenidone, low-dose calcineurin inhibitors, bronchiolitis obliterans syndrome, allogeneic transplantation

Introduction Aplastic anemia (AA), a rare disorder characterized by bone marrow failure and pancytopenia, poses exceptionally high risks when it occurs during pregnancy. This condition endangers both the mother and fetus, significantly increasing the likelihood of maternal complications such as hemorrhage and infection, as well as adverse perinatal outcomes such as preterm birth and fetal growth restriction. Consequently, pregnancy with AA demands careful management. However, tools to predict these adverse outcomes in affected pregnant women are currently lacking. Here, we applied a machine learning approach to develop and validate a prediction model for adverse pregnancy outcomes in patients with AA, with the goal of guiding early clinical decision-making and improving their overall health outcomes. Methods This study was registered at Clinicaltrials.gov: NCT07101770. We collected data from 310 pregnant women with AA admitted between January 2000 and December 2024 to 15 tertiary hospitals in China. Adverse pregnancy outcomes included at least one of placental abruption, amniotic fluid embolism, postpartum hemorrhage, postpartum infection, maternal mortality, stillbirths, preterm birth, low birthweight, fetal growth restriction, neonatal intensive care unit admission, or neonatal mortality (BJOG, 2014). Feature selection was performed through least absolute shrinkage and selection operator (LASSO) regression. The reliability of the models was evaluated using the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, accuracy, F1 score, calibration plots, and decision curve analysis (DCA). The SHapley Additive exPlanation (SHAP) method was used to rank the feature importance and explain the final model. Results Among the 310 patients with AA (median age, 30.2 [27.6-33.9]), 201 from 7 specialized tertiary hospitals composed the derivation cohort (training set), whereas an independent cohort of 109 patients from 8 distinct academic medical centers formed the external validation set. To ensure robust model development, the training set underwent a stratified random split, yielding a model-building subset (136 patients, 67.7%) and a hold-out internal validation subset (65 patients, 32.3%), preserving the distribution of adverse outcomes, including postpartum hemorrhage, placental abruption, fetal growth restriction, and preterm delivery. In this study, anemia was present in 280 patients (90.3%). Overall, 195 patients (62.9%) experienced adverse pregnancy outcomes. Notably, among the subgroup with severe aplastic anemia (SAA, n=8), the rate of adverse pregnancy outcomes rose significantly to 75.0% (6/8). These findings underscored the high-risk nature of this cohort, particularly those with SAA, highlighting the critical need for accurate prediction tools to guide targeted antenatal interventions. The data for the variables evaluated in this study, including demographic and clinical characteristics, laboratory results, and treatment, were obtained from patient electronic medical records. Using multivariable LASSO regression, we selected the top five features for model construction: age, hemoglobin level, platelet count, neutrophil count, and the percentage of lymphocytes. Seven state-of-the-art machine learning algorithms were rigorously trained and tuned. The RF model emerged as optimal, demonstrating good discriminative ability both in internal validation (AUC: 0.765, 95% CI: 0.737–0.851) and, crucially, in external validation (AUC: 0.743, 95% CI: 0.723–0.814), confirming its generalizability across heterogeneous health care settings. Furthermore, calibration plots revealed agreement between the predicted probabilities and observed event rates, indicating reliability across risk strata. DCA indicated that the clinical implementation of the prognostic model could benefit pregnant women with AA. Conclusions To our knowledge, it's the world's largest cohort of pregnant women with AA to date. We demonstrated that the model could predict the risk of adverse pregnancy outcomes in patients with AA. The model will help clinicians identify pregnant women at high risk early and provide a basis for individualized patient treatment plans.

BACKGROUND:Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of aggressive non-Hodgkin's lymphoma with distinct clinical and molecular heterogeneity. DLBCL that arises in extranodal organs is particularly linked to poor prognosis. This study aimed to determine the clinical and molecular characteristics of extranodal involvement (ENI) in DLBCL and assess the actual survival status of the patients. METHODS:In this population-based cohort study, we investigated the clinical features of 5,023 patients newly diagnosed with DLBCL. Their clinical conditions, eligibility criteria, and sociodemographic details were recorded and analyzed. Gene panel sequencing was performed on 1,050 patients to discern molecular patterns according to ENI. RESULTS:The 2-year overall survival (OS) rate was 76.2% [95% confidence interval (CI), 74.0%-78.2%], and the 5-year OS rate was 67.9% (95% CI, 65.2%-70.4%). The primary treatment was immunochemotherapy with rituximab. Specific lymphoma involvement sites, especially the bones, bone marrow, and central nervous system, were identified as independent adverse prognostic factors. A high prevalence of non-germinal center B-cell (non-GCB) phenotype and myeloid differentiation primary response 88 (MYD88)/CD79B mutations were noted in lymphomas affecting the breasts, skin, uterus, and immune-privileged sites. Conversely, the thyroid and gastrointestinal tract showed a low occurrence of non-GCB phenotype. Remarkably, patients with multiple ENIs exhibited a high frequency of MYD88, tet methylcytosine dioxygenase 2 (TET2), CREB binding protein (CREBBP) mutations, increased MYD88L265P and CD79B mutation (MCD)-like subtypes, and poor prognosis. Genetic subtype-guided immunochemotherapy showed good efficacy in subgroup analyses after propensity score matching with 5-year OS and progression-free survival rates of 85.0% (95% CI, 80.6%-89.5%) and 72.1% (95% CI, 67.3%-76.7%). CONCLUSIONS:In the rituximab era, this large-scale retrospective analysis from Asia confirmed the poor prognosis of DLBCL with multiple ENIs and underscored the efficacy of genetic subtype-guided immunochemotherapy in treating extranodal DLBCL.

Abstract Introduction Treating acute myeloid leukemia (AML), a diverse group of hematological cancers affecting bone marrow and blood, remains difficult, with a five-year survival rate of about 30%. Although screening for genetic mutations and fusion genes has become essential in AML diagnosis and risk stratification, the clinical significance of copy number aberrations (CNAs) remains poorly understood. To this end, we conducted a multicenter prospective clinical trial (ChiCTR2300077695) to characterize the genomic landscape of CNAs using shallow whole-genome sequencing (sWGS), termed LeukoPrint, in AML. Interim results from the first 205 patients (pts) are reported here. Methods In this prospective multicenter clinical trial, we aim to enroll 600 newly diagnosed AML pts (excluding APL) across 13 participating hospitals in China. Bone marrow samples were collected and underwent CNA profiling via LeukoPrint (1× sWGS) at three stages: pretreatment, post-induction, and relapse. CNAs only those greater than 5 Mbp were analyzed. Conventional karyotyping analysis was performed in parallel for this cohort, and its diagnostic performance was compared with LeukoPrint. European Leukemia Net (ELN)-defined CNAs were used for risk stratification, consistent with standard cytogenetic analysis protocols. The trial received approval from the Ethics Committees of all participating hospitals, and all pts provided informed consent. By April 9, 2025, 205 pts were enrolled in this study, with 136 in the younger group (aged 18–59) and 69 in the older group (aged ≥60). All pts underwent CNA profiling using LeukoPrint at least twice, at pretreatment and post-induction phases. Results Using LeukoPrint, we detected 193 CNAs in 87 pts (42.4% of the cohort). No notable difference in detection rates was observed between younger and older groups (41.9% vs. 43.5%). CNAs were frequently identified in chromosomes 7, 8, 11, and Y (each with >5% prevalence), with the most common recurrent CNAs occurring at 8q24.21 (13% prevalence), the locus containing the MYC oncogene. Recurrent deletions were predominantly observed in 5q31.3 and 7q36.1, the genomic regions harboring the oncogenes ACSL6, CD74, and EZH2. LeukoPrint outperformed karyotyping in CNA detection (42.4% vs. 27.3%), enhancing results for 51 pts (24.9% of the cohort). Notably, 38 pts, initially classified with normal karyotypes or failed karyotyping, were reclassified as carrying CNAs. Applying the 2022 ELN criteria, three pts initially classified as low- or intermediate-risk based on genetic mutations, fusions, and karyotypes were reclassified as high-risk following LeukoPrint analysis in place of karyotyping. Clinical follow-up in two cases confirmed poor outcomes in one, supporting LeukoPrint’s prognostic value. LeukoPrint demonstrates strong potential for prognostic prediction by monitoring dynamic change of molecular response in 115 pts. A significantly higher proportion of pts with post-induction CNAs were identified as non-responders than those without CNAs (6 vs. 3). Similarly, the proportion of pts without detectable post-induction CNAs was 95.5% in complete remission (CR, n=22), 83.3% in CR with partial hematologic recovery (CRh, n=6), 71.4% in CR with incomplete hematologic recovery (CRi, n=7), 0% in partial remission (PR, n=3), and 0% in non-responders (NR, n=3). Copy-neutral loss of heterozygosity (CN-LOH) occurs when one allele is lost and the remaining allele is duplicated, resulting in no net change in copy number. This genomic alteration, such as TP53 CN-LOH, can have significant clinical impact but is undetectable by traditional karyotyping or fluorescence in situ hybridization (FISH). LeukoPrint identified CN-LOH in 43 (20.9%) of 205 pts in this cohort. Notably, CN-LOH was detected in 25 out of 114 pts without detectable CNAs, revealing that LeukoPrint provides additional insights into chromosomal aberrations in 12% (25/205) of pts. Combined with 24.9% from standard LeukoPrint analysis, LeukoPrint enhanced CNA detection in at least 36.9% of pts. Conclusions LeukoPrint outperforms traditional karyotyping in detecting CNAs, improving data accuracy in over one-third of pts in this cohort. It enables dynamic monitoring of treatment response and disease progression, demonstrating strong correlation with clinical outcomes. These findings suggest that LeukoPrint holds significant promise as a complementary or alternative tool for conventional cytogenetic methods in AML.

BACKGROUND:Acute leukaemia represents a crucial health challenge. However, nationwide data delineating the incidence of acute leukaemia subtypes, as well as mortality and survival outcomes, remain scarce in China. We aimed to provide a comprehensive assessment of the epidemiology of acute leukaemia subtypes across China. METHODS:We conducted a population-based cancer registry analysis and cohort study in China, by integrating data from five national databases through unique national identification numbers. The main outcomes were age-standardised rates (ASRs) for incidence and mortality and overall survival for acute leukaemia subtypes. Acute leukaemia incidence and mortality data in 2019 were extracted from National Cancer Centre (NCC) registries linked to the Hospital Quality Monitoring System (HQMS), stratified by age, sex, and region. ASRs were calculated with Segi's world standard population with 95% CIs across the general population. For the survival analysis, we established a cohort from the Chinese Childhood Leukaemia Registry (33 530 children aged 0-14 years) and National Adult Acute Leukaemia Registry of China (71 477 adults aged ≥15 years) for 2016-20, integrated with the Cause of Death Reporting System and HQMS. Patients were stratified by subtype, age, sex, region, molecular characteristics, treatment modalities, and diagnosis period (2016-18 vs 2019-20). Overall survival and cause-specific survival were assessed with the Kaplan-Meier method at multiple timepoints (1 month, and year 1 to year 5) in our cohort. Multivariate Cox regression analysis was performed to identify prognostic factors. FINDINGS:Based on NCC registries covering a population of 628·4 million, we estimated 43 275 new acute leukaemia cases and 27 049 deaths in 2019 in China, with an ASR for incidence 2·83 (95% CI 2·78-2·88) per 100 000 population and an ASR for mortality of 1·51 (1·48-1·54) per 100 000 population. The ASR for the incidence of non-acute promyelocytic leukaemia-acute myeloid leukaemia was 1·24 (95% CI 1·21-1·26) per 100 000 population, that of acute lymphoblastic leukaemia was 0·92 (0·89-0·95) per 100 000 population, and that of acute promyelocytic leukaemia was 0·22 (0·21-0·23) per 100 000 population. The incidence of acute leukaemia spiked in children aged 1-4 years (4·54 per 100 000), then declined, and then rose markedly after age 60 years, peaking at 9·33 per 100 000 in people aged 75-79 years, before declining, while overall mortality remained relatively low across younger age groups (0-44 years), then increased progressively with advancing age, from 1·23 per 100 000 in adults aged 45-49 years to 8·77 per 100 000 in those aged 80-84 years. In children, 5-year overall survival was 66·5% (95% CI 65·3-67·9) for non-acute promyelocytic leukaemia acute myeloid leukaemia, 91·1% (89·6-92·6) for acute promyelocytic leukaemia, and 85·4% (84·9-85·8) for acute lymphoblastic leukaemia; in adults, 5-year overall survival was 23·9% (23·4-24·3) for non-acute promyelocytic leukaemia acute myeloid leukaemia, 82·5% (81·7-83·4) for acute promyelocytic leukaemia, and 30·1% (29·2-30·9) for acute lymphoblastic leukaemia. Survival improved in the more recent period (2019-20 vs 2016-18: hazard ratio 0·97 [95% CI 0·95-0·99]; p=0·0014), particularly among younger adults with non-acute promyelocytic leukaemia acute myeloid leukaemia (aged <60 years) and acute lymphoblastic leukaemia (aged <40 years), with improvements primarily attributable to expanded application of allogeneic haematopoietic stem-cell transplantation. However, prognosis remained poor in patients with acute leukaemia aged 60 years and older (5-year overall survival 14·9% [95% CI 14·3-15·5] in patients aged 60-74 years, and 4·8% [4·2-5·4] in patients aged ≥75 years). INTERPRETATION:This comprehensive nationwide study of acute leukaemia incidence, mortality and survival outcomes across China establishes age-specific epidemiological benchmarks, enabling ongoing risk factor monitoring, while supporting expanded transplantation access for eligible patients and highlighting the urgent need for novel, less toxic therapies for older patients who bear a disproportionately higher disease burden. FUNDING:State Key Laboratory of Medical Genomics, Double First-Class Project, Overseas Expertise Introduction Project for Discipline Innovation, National Natural Science Foundation of China, Innovative Research Team of High-level Local Universities in Shanghai, Shanghai Guangci Translational Medical Research Development Foundation, and CAMS Innovation Fund for Medical Sciences. TRANSLATIONS:For the Chinese translation of the abstract see Supplementary Materials section.

IntroductionPure red cell aplasia (PRCA) is one of the complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Its main pathogenesis is immune dysfunction leading to erythrocytes destruction. Currently, there is no gold standard for PRCA after allo-HSCT. Umbilical cord blood (UCB) and mesenchymal stem cells (MSCs) have been widely used in hematological and immune system diseases due to their hematopoietic reconstitution and immunomodulatory functions. However, few studies about using UCB and MSCs to treat PRCA after allo-HSCT have been reported.Case presentationIn this report, different cell therapy regimens of UCB and MSCs were used in 3 acute myeloid leukemia (AML) patients diagnosed with PRCA after allo-HSCT. Results showed that all patients achieved significant progress without adverse reactions or complications. Furthermore, Case 1 treated with UCB combined with umbilical cord MSCs (UC-MSCs), and Case 2 treated with 3 doses of UCB mononuclear cells (UCB-MNC) achieved earlier RBC transfusion independence (2 months and 2 weeks after cell therapy, respectively) than Case 3 treated with one unit of UCB (3 months after cell therapy).ConclusionThis report provides cell therapy strategies using UCB/UCB-MNC and UC-MSCs to treat PRCA after allo-HSCT. Our study demonstrates the safety and efficacy of 3 doses of UCB-MNC regimen and UCB combined with UC-MSCs regimen, providing a new treatment option for patients with PRCA after allo-HSCT.

Macrophages are critical components of the innate immune system and play a pivotal role in the hematological tumor microenvironment. Their metabolic reprogramming can exert dual effects, either promoting or suppressing tumor progression. Significant advances have been made in the understanding of the functions of macrophages and their metabolic regulatory mechanisms. However, there are various uncertainties and challenges regarding the specific metabolic pathways of macrophages in different hematological malignancies and their interactions. This review summarized the recent research progress on macrophage metabolic reprogramming in hematological tumors, explored potential targeted therapeutic strategies based on macrophage metabolic reprogramming, and provided new research directions and clinical insights for the immunotherapy of hematological malignancies.

This was a multicenter, randomized, registrational phase 2 study to assess efficacy and safety of olverembatinib vs. BAT in pts with CML-CP resistant and/or intolerant to three TKIs (imatinib [I]), dasatinib [D], nilotinib [N]) in China. This report updates an oral presentation at the 2023 American Society of Hematology Annual Meeting (data cutoff date of October 17, 2023), with median (range) follow-up 21.40 (0.6-54.7) months in the olverembatinib and 2.91 (0-48.9) months in the BAT arm. Eligible CP-CML pts were adults resistant or intolerant to three TKIs and in ECOG PS 0-2 with adequate organ function. Pts were randomized 2:1 to olverembatinib (40 mg QOD) or the BAT arm: TKIs (I, D, or N), interferon, hydroxyurea, and/or homoharringtonine by investigator choice. The primary endpoint was event-free survival (EFS), including time from randomization to CML progression; all-cause mortality; relapse; treatment failure; loss of complete hematologic response; and treatment intolerance as per investigator and study sponsor. Efficacy was analyzed in the intention-to-treat (ITT) efficacy population and safety in pts receiving ≥1 dose of olverembatinib. As of January 13, 2025, a total of 144 pts (96, olverembatinib; 48, BAT) were enrolled (69.4% male), with a median (range) age of 49.0 (18-77) years. Pts without the T315I mutation included a somewhat lower proportion of males (68/105; 64.8%) and had the same median age. A total of 129/144 pts (89.6%) were previously treated with ≥ 3 TKIs (I, D, N), including all 105 (100.0%) of those without the T315I mutation. Sixty-six (45.8%) of all pts (27/105; 25.7% of those without the T315I mutation) had ≥1 BCR::ABL1 mutation and 39 (27.1%) BCR::ABL1T315I. A total of 96 (66.7%) of all pts discontinued therapies (54 [56.3%] olverembatinib, 42 [91.3%] BAT) due to disease progression/treatment failure, adverse event (AE), consent withdrawal, poor compliance, or death. Median EFS was significantly longer with olverembatinib (vs. BAT) in pts without T315I mutations: 11.96 (95% CI 8.28-22.11) vs. 3.14 (95% CI, 2.53-12.98) (P = 0.0159; HR, 0.550; 95% CI, 0.335-0.901). Median EFS was also significantly longer in the olverembatinib (vs. BAT) group in all pts: 21.22 (95% CI, 10.15-not reached [NR]) months vs. 2.86 (95% CI 2.53-4.73) months (P < .0001; HR, 0.355; 95% CI, 0.230-0.549). In pts without T315I mutations, estimated EFS at 6, 12, and 24 months was 68.5% (95% CI, 55.5%-78.4%), 49.7% (95% CI, 36.7%-61.5%), and 36.9% (95% CI, 24.7%-49.1%), respectively, in the olverembatinib arm and 41.2% (24.8%-56.9%), 35.3% (19.9%-51.0%), and 22.9% (10.5%-38.1%) in the BAT arm. In the olverembatinib arm in all pts, respective data were 73.0% (95% CI, 62.5%-81.0%), 58.7% (95% CI, 47.5%-68.2%), and 47.0% (95% CI, 35.9%-57.2%). In the BAT group, it was 32.6% (95% CI, 19.7%-46.2%), 26.1% (14.5%-39.3%), and 16.9% (7.7%-29.2%), respectively. Median OS was not reached in both treatment groups (P = 0.21 in those without the T315I mutation and P = 0.17 in all patients). In pts without T315I mutations who were treated with olverembatinib, 32 of 39 (82.1%) achieved complete hematologic response (CHR); 16 of 62 (25.8%) complete cytogenetic response (CCyR); and 10 of 62 (16.1%) major molecular response (MMR). Among those without T315I mutations treated with BAT, these data were 8/16 (50.0%) CHR; 6/29 (20.7%) CCyR; and 3/29 (10.3%) MMR. In the ITT efficacy group, 51 of 60 (85.0%) of all evaluable patients treated with olverembatinib achieved CHR; 33/88 (37.5%), CCyR; and 26/88 (29.5%) MMR. In the BAT group, these values were 8/23 (34.8%) for CHR; 7/37 (18.9%), CCyR; and 3/37 (8.1%) MMR. In the safety population, 85/96 (88.5%) of all pts receiving olverembatinib (60/69; 87.0% in the non-T315I mutation group) and 31/46 (67.4%) BAT (27/35; 77.1% non-T315I) experienced grade ≥ 3 AEs. In all pts and those without T315I mutations, frequent any-grade TEAEs in pts treated with olverembatinib included thrombocytopenia, leukopenia, neutropenia, and CPK increased. Serious AEs (SAEs) (>15%) included thrombocytopenia and leukopenia. This study represents the largest population of pts with CML-CP resistant to or intolerant of both 1G and 2G TKIs, who have now been monitored for up to 4 years. Olverembatinib was more efficacious and better tolerated than BAT in treating these pts (including those without T315I mutations). Internal study (CT.gov) numbers: HQP1351CC203 (NCT04126681).