This multicenter, randomized, controlled study was conducted to explore the safety and efficacy of low-dose baricitinib plus danazol for ITP patients who had failed corticosteroids and at least one recommended subsequent treatment. Participants were randomly assigned to receive baricitinib plus danazol (n = 108) or danazol alone (n = 108) by a central, interactive web-based system. Patients and caregivers were not blinded to group assignment. Efficacy assessments were performed in the intention-to-treat population by investigators blinded to group assignment. The primary endpoint was 6-month durable response. Forty-nine (45.4%) patients in the combination arm and 22 (20.4%) patients in the monotherapy arm achieved 6-month durable response (P < 0.001). The safety analysis set included patients who received at least one dose of study medication (n = 108 in the combination arm and n = 105 in the monotherapy arm). Fifty-two (48.1%) patients receiving baricitinib plus danazol and 47 (44.7%) patients receiving danazol alone reported at least one adverse event. Each arm reported two patients who developed an adverse event causing study discontinuation and one patient who developed a grade 3 or more severe adverse event. Low-dose baricitinib plus danazol might be a novel option for difficult-to-treat ITP. Funding: National Key Research and Development Program of China (No. 2023YFC2507800), National Natural Science Foundation of China (No. 82230004, No. 82430006, No. 82400157), Capital Health Development and Research of Special (No. 2022-1-4082), and Beijing Natural Science Foundation (No. 7242154 and No. 7232188). ClinicalTrials.gov identifier: NCT05852847.

Background and Objectives:Patients with autoimmune diseases (ADs) are at an increased risk of developing hematological malignancies (HMs). While allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative option for HMs, the outcomes in patients with concomitant ADs and the effects of transplantation on autoimmune conditions remain poorly characterized. Methods:In this real-world study, we compared transplantation outcomes between 41 patients with HMs and preexisting ADs and 123 matched controls with HMs but without ADs. Results:A total of 65.8% of the patients with ADs had a disease duration of ≥ 3 years. All patients achieved hematological recovery. The AD group had a significantly higher incidence of chronic graft-versus-host disease (70.7% vs. 26.8%, P < 0.001). After a median follow-up of 24 (8-75) months, the 3-year overall survival (73.2% [95% CI: 60.2%-89.1%] vs. 76.3% [95% CI: 68.9%-84.4%], P = 0.76) and disease-free survival rates (68.8% [95% CI: 55.6%-85.3%] vs. 74.7% [95% CI: 67.2%-82.9%], P = 0.57) were comparable between the AD and control groups. No significant differences were observed in the 3-year cumulative incidence of relapse (7.7% [95% CI: 1.9%-18.8%] vs. 9.5% [95% CI: 5.0%-15.7%], P = 0.61) or nonrelapse mortality (23.5% [95% CI: 11.5%-38.0%] vs. 16.7% [95% CI: 10.6%-23.9%], P = 0.40). Multivariable analysis confirmed that preexisting AD was not an independent risk factor for survival, relapse, or nonrelapse mortality. Conclusions:Our results suggest that allo-HSCT in patients with HMs and ADs is associated with survival outcomes that appear comparable to those in patients without ADs but also induces complete remission of AD in most patients.

Acute myocardial infarction (MI) is a relatively rare but life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Information regarding the clinical characteristics, outcomes, and prognostication of post-transplant MI is lacking. We conducted a nationally representative cohort study at 34 centers in China. Patients with MI were retrospectively identified among those who underwent allo-HSCT. The diagnosis and classification of MI were reviewed according to established guidelines. One hundred thirteen patients were analyzed, including 23 patients with T1MI, 87 patients with T2MI, and three patients with T3MI. Patients with T2MI had a significantly higher mortality rate. Thrombotic microangiopathy (TMA) frequently coexisted with T2MI and adversely affected the overall survival. Disease relapse or progression, a platelet count <20 × 109/L, active TMA at MI onset, and Killip class 3-4 were identified as independent risk factors for 2-month mortality. We divided these patients into a low-risk group (without risk factors), an intermediate-risk group (1-2 risk factors), and a high-risk group (3-4 risk factors). Significantly different 2-month mortality rates were observed across these groups (11.1 %, 59.3 %, and 100.0 %, respectively). Available angiographic imaging data and antiplatelet therapy after MI onset may be associated with improved outcome, but the survival benefits and optimized medication use in patients with post-transplant MI require further validation. These findings may facilitate refined monitoring and management strategies of MI in the post-transplant population.

Our previous clinical studies show that all-trans retinoic acid (ATRA) induces a sustained response in patients with immune thrombocytopenia (ITP). However, its mechanisms of action remain unclear. In this study, we observed disorganized cytoskeleton and impaired proplatelet formation (PPF) in megakaryocytes from patients with ITP. Metabolite profiling revealed reduced sphingosine 1-phosphate (S1P) levels in ITP. Decreased sphingosine kinase 2 (SPHK2) expression was responsible for the low S1P levels in ITP. In addition, S1P was essential for activating S1P receptor 1 and Rac1, which regulate cytoskeletal reorganization and PPF. Furthermore, hypoxia-inducible factor-1α (HIF-1α) was shown to mediate SPHK2 and S1P production. Decreased HIF-1α expression in megakaryocytes from patients with ITP contributed to impaired PPF. We subsequently found that ATRA up-regulated HIF-1α and corrected impaired PPF in vitro and in vivo. These findings reveal that ATRA targets the HIF-1α/SPHK2/S1P pathway to improve PPF dysfunction, offering mechanistic insights into its clinical efficacy in ITP.

Introduction:The advent of highly active antiretroviral therapy (HAART) has changed infection by human immunodeficiency virus (HIV) from an acute disease to a manageable chronic condition; however, pulmonary complications continue to affect patient quality of life. The goal of this research was to examine the link between CD4+ levels, viral load, and respiratory function in patients infected with HIV. Methods:Patients were grouped as HIV-infected and non-infected (1:2 ratio). The analysis included between-group comparisons of the post-bronchodilator FEV1, FVC, FEV1/FVC ratio, forced expiratory flows at various lung volumes (FEF75, FEF50, FEF75/25), and carbon monoxide diffusion capacity (DLCO). We analyzed CD4+ counts and viral load effects on lung function using stepwise regression. For normally distributed continuous variables (presented as means ± SD), intergroup comparisons were performed using independent two-sample t-tests. Non-normal distributions (reported as medians [IQR]) were analyzed with Mann-Whitney U-tests. Categorical variables were compared using χ² or Fisher's exact tests, with statistical significance set at p < 0.05. Results:The study enrolled 150 participants infected with HIV with a mean age of 48 (39.25, 57.75) years; 87.33% were male and 46% had a history of smoking. The DLCO was significantly lower in patients with HIV (69.37 vs 82.23, p < 0.05) compared to patients without HIV. In patients with HIV, the DLCO was positively correlated with CD4+ T lymphocyte counts (r=0.5521, p < 0.0001) and negatively correlated with the HIV viral load (r=-0.3942, p < 0.0001), and both were statistically significant. Patients with CD4+ ≥ 200 cells/μL had significantly higher VC (89.52 vs 79.31), FVC (91.80 vs 83.55), FEV1 (91.60 vs 84.40), and DLCO (74.61 vs 57.96) than those with CD4+ < 200 cells/μL. Similarly, patients with undetectable viral loads had higher VC (87.99 vs 81.08), FVC (90.90 vs 83.70), and DLCO (72.59 vs 60.62) than those with detectable viremia (all p < 0.05). The CD4+ count and FVC were significant predictors of the DLCO (p < 0.05). Conclusion:HIV infection is significantly associated with impaired pulmonary diffusion function. Even after antiviral therapy when the viral load becomes undetectable (CD4+ T lymphocytes > 400), the impairment of pulmonary diffusion still persists. Therefore, we should strengthen the pulmonary function testing for AIDS patients, detect the risk of lung injury as early as possible, carry out timely interventions, and reduce the risk of chronic obstructive pulmonary disease (COPD).

Therapy-related acute myeloid leukemia (t-AML), which develops after cytotoxic therapy, has a poorer prognosis. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potential cure, its efficacy varies among patients. In this retrospective study, we analyzed 154 patients with t-AML who underwent hematopoietic stem cell transplantation (HSCT) at our institution to determine their clinical characteristics and develop a prognostic nomogram. The median ages at t-AML diagnosis prior disease diagnosis was 42 and 39 years, respectively. Multivariate analysis identified key prognostic indicators: leukocyte count at AML diagnosis >= 7 x 10<^>9/L, genetic abnormalities before HSCT, platelet engraftment >= 28 days, age at prior disease >= 45 years, and relapse of prior disease. We developed a prognostic nomogram for LGPAR by categorizing patients into low, medium, and high-risk groups. The 3-year and 5-year overall survival (OS) rates for these groups were 92.6 %, 84.4 %, 14 %, and 92.6 %, 76.6 %, and 7 %, respectively. The 3-year and 5-year relapse-free survival (RFS) rates were 80 %, 75.9 %, 10.7 % and 80 %, 72.6 %, and 10.7 % for the respective risk groups. The 3-year and 5-year non-relapse mortality (NRM) rates were 0 %, 5.6 %, 63.3 % and 0 %, 9.3 %, and 63.3 % for these groups, respectively. This novel prognostic nomogram culminates in the development of a clinical decision-support tool for patients with t-AML undergoing allo-HSCT.

Background： Early death in high-risk acute promyelocytic leukemia (APL) is closely related to the leukocytosis at the onset of the disease. During induction, cytoreductive chemotherapy is a critical early intervention. Current international and Chinese guidelines recommend all-trans-retinoic acid (ATRA) plus arsenic tri-oxide, combined with either an anthracycline or cytarabine. Realgar-Indigo naturalis formula (RIF)，an oral realgar (As4S4)-containing formula, has been incorporated into the Chinese APL guideline. However, the intravenous cytotoxic agents must be administered in specialized inpatient units. During the COVID-19 pandemic we treated two pts(pts) with newly diagnosed high-risk APL in the emergency department with an exploratory all-oral regimen consisting of etoposide (VP-16) plus ATRA and RIF. Both pts achieved complete remission and have remained disease-free for five years (Leuk Res Rep,2021). To evaluate the efficacy and safety of oral etoposide combined with ATRA and RIF in high-risk APL, we have initiated a single-arm, prospective cohort study (ChiCTR2100053926). Method: Once high-risk APL was suspected, ATRA 25mg/m2/day, hydroxyurea (Hu) and oral VP16 100-150 mg/day were given simultaneously. Hu and VP16 discontinued when white blood cells (WBC) creases to ≤10×109 /L. RIF was administered by 60mg/kg/day when PML::RARA fusion gene or t (15;17) translocation was confirmed. RIF was used no more than 45 days. Corticosteroid was added during induction to prevent differentiation syndrome. The primary end point was complete remission (CR) rate. Relapse, survival and safety were assessed. Results: From January 2022 to February 2025, 35 pts were included. Median follow-up time was 17.1 (0.2-42.7) months. The median age was 37(18-65) years with 74.3% (26/35) males. The median counts of WBC, platelet, fibrinogen level and PML::RARA transcript level were 20.0 (10.2-145.5) ×109/L, 25(5-83) ×109/L, 122 (41-267) g/L and 33.5(18.9-88.8) %. In PML::RARA sub-types, S, L, and V type were 62.3% (22/35), 34.3% (12/35), 2.9% (1/35), and 31.4% (11/35) expression CD34 by multi-parameter flow cytometry. Mutated FLT3-ITD and FLT3-TKD were found in 40.0% (14/35) and 5.7% (2/35) pts respectively, and 59.1% (13/22) pts had mutated FLT3-ITD (p=0.006) in PML::RARA (S) type. Except for t (15;17), 20.0% (7/35) pts had additional abnormal karyotype. As a result of 5.7% (2/35) pts dying of cerebral hemorrhage within 5 days, the response and survival were assessed in 33 pts. During induction, the median time of oral VP16 administration was 9 (5-13) days with a median dose of 1150 (650-1650) mg. Nine (27.3%) pts used venetoclax to combinate with VP 16 with a median dose of 100 (50-300) mg. All pts achieved CR after 45(28-63) days with a median PML::RARA transcript level of 0.0089 (0-5.6) %. 11 pts (33.3%) pts achieved complete molecular remission (CMR) after induction. After 2.4 (1.4-5.5) months, all pts achieved CMR. None of the 33 pts died during the induction. The median infusion of red blood cells, platelet and fibrinogen were 4 (0-18) U, 3.5(0-8) U, and 15 (0-61) g. Neutropenia was observed in 36.3% (12/33) pts with a duration of 5 (1-17) days. Only 1 patient occurred obvious differentiation syndrome. Ten (30.3%) pts experienced grade 1-2 hepatotoxicity and 3.0%(1/33) grade 3. In each case, 3 (9.1%) pts suffered from gastrointestinal bleeding and cerebral hemorrhage respectively，and 1 (3.0%) patient experienced diffuse alveolar hemorrhage. After 6.9 (4.0-8.3) months, 3(9.1%) pts experienced molecular relapse, and 2 (6.1%) pts suffered from haematological relapse after 20.5 and 30.8 months. In the two haematological relapse pts, one patient acquired new mutated FLT3-TKD, and the other patient's mutated FLT3-ITD at diagnosis contributed to the relapse. The 2-year relapse free survival and overall survival were 80.0% (95%CI, 59.2-100%) and 91.7% (95%CI, 76.0-100%). Univariate and multivariate analysis showed no correlation between recurrence and S or L type, mutated FLT3-ITD, dose of VP16. Conclusion: Compared with historical cases, oral VP16, instead of intravenous cytoreductive agent, in combination with ATRA and RIF as complete oral induction in high-risk APL, could control leukocytosis effectively and safely. Meanwhile high CR rate, RFS and OS could also achieve. In addition, this regimen is convenient for pts to receive fast and professional treatment as soon as possible without the limitation of space.

Background Patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) have dismal outcomes, representing an urgent unmet need. Venetoclax has exhibit encouraging anti-tumor activity in AML. The clinical efficacy of the CAG regimen (cytarabine, aclarubicin, G-CSF) in patients with R/R AML has been confirmed in previous studies. The aim of this study was to explore the safety and efficacy of the venetoclax plus CAG regimen and in patients with R/R AML. Methods A total of 51 patients with refractory/relapsed acute myeloid leukemia (AML) who received venetoclax combined with CAG treatment at Peking University People's Hospital from February 2023 to September 2024 were prospectively enrolled in this study (NCT05918198). Patients who achieve CCR typically undergo 1–2 cycles of consolidation chemotherapy prior to proceeding with hematopoietic stem cell transplantation (HSCT). To assess efficacy, we evaluated the CCR rate, minimal residual disease (MRD) elimination rate, overall response rate (ORR), disease-free survival (DFS), and overall survival (OS) following treatment with the Venetoclax plus CAG regimen. Adverse events (AEs) were assessed using the NCI CTCAE version 5.0 to evaluate both the overall incidence of AEs and the incidence of grade 3 or higher AEs, thereby providing a comprehensive safety profile for the venetoclax combined with CAG regimen in relapsed/refractory AML patients. Results Among the 51 patients who accepted data analysis, there were 19 relapse patients (37.3%) and 32 refractory patients (62.7%).The proportions of patients in the favorable, intermediate and poor groups were 24 cases (47.1%), 12 cases (23.5%) and 15 cases (24.9%), respectively.The median follow-up time was 391.5 (36 - 606) days. After one cycle of venetoclax plus CAG regimen treatment, 43 patients achieved CCR. Among the 50 patients evaluated for efficacy after treatment, the CCR rate was 86.0%. One patient (1.9%) achieved a partial response (PR) and six patients were non-responders (NR) (12%). The ORR was 88%. Among the 43 patients who achieved CCR, nine patients (17.3%) had negative MRD, and the MRD elimination rate among patients who achieved CCR was 20.9%. Of the 19 patients in the relapse group, all achieved CCR, with a CCR rate of 100%. Among them, 6 patients had MRD negativity, and the MRD clearance rate was 31.6%. In the refractory group of 32 patients, 24 patients achieved CCR, with a CCR rate of 75%. Among them, 3 patients had MRD negativity, and the MRD clearance rate was 12.5%. The CCR rate of the relapse group was significantly higher than that of the refractory group (P=0.018). Among the patients who achieved CCR, the 1-year cumulative relapse rate was 23.8%. The 1-year DFS is 68.6%. The1-year DFS of favorable, intermediate, and poor risk groups were 77.1%, 65.6%, and 54.0%, respectively. The 1-year OS is 76.2%. The1-year OS of favorable, intermediate, and poor risk groups were 85.1%, 56.3%, and 78.6%, respectively. The1-year OS of relapsed and refractory groups were 81.5%and 72.1%, respectively. Of the 43 patients who achieved CCR, 16 (37.2%) underwent HSCT after achieving remission. Of the 6 patients with NR, 2 (33.3%) patients received HSCT. Notably, all patients who underwent HSCT remained alive during the follow-up period, the median survival time after HSCT was 424 (105 - 540) days. For all enrolled patients, the overall incidence of grade 3 or higher hematological AEs was 88.2%, with 74.5% attributed to treatment-related causes. Specifically, febrile neutropenia occurred in 41.2% of patients. For grade 3-4 leukopenia, the total incidence was 86.3%, including 35.3% observed prior to treatment and 51.0% induced by treatment. The incidence of grade 3 and above non-hematological AEs was 25.5%. The most common non-hematological AE was infection (23.5%). Conclusion The venetoclax plus CAG regimen can serve as a safe and effective new option for salvage chemotherapy in patients with R/R AML. This combined regimen may help more patients to achieve the opportunity to recieve HSCT with a smaller tumor budern and improve the outcomes of patients.

BACKGROUND:Immune thrombocytopenia during pregnancy (PITP) is the most common cause of platelet reduction in early and mid-pregnancy. However, the pathogenesis of PITP is still unclear. OBJECTIVES:To determine the characteristics of bone marrow mesenchymal stem cells (BM-MSCs) in PITP patients and to explore the associations between metabolites, the gut microbiota, and BM-MSCs in PITP. METHODS:The characteristics of BM-MSCs were detected through in vitro and in vivo experiments. Nontargeted metabolomics was used to screen metabolites. The features of the gut microbiota were analyzed by 16S rDNA sequencing. PITP and fecal microbiota transplantation (FMT) mouse model were established to explore the associations between metabolites, gut microbiota, and BM-MSCs. RESULTS:BM-MSCs from PITP patients had significant senescence and apoptosis, as well as impaired immunoregulatory function. Metabolomic analysis indicated that progesterone was the most significant specific metabolite in PITP patients. In vivo studies showed that progesterone mediated MSC injury. Further analysis of the gut microbiota and FMT experiments revealed that progesterone mediated BM-MSCs injury by regulating the composition of the gut microbiota in PITP. RNA sequencing analysis of BM-MSCs from FMT mice revealed abnormal expression of genes related to cell aging and the NOD-like receptor signaling pathway. CONCLUSION:In conclusion, BM-MSCs in the PITP were significantly impaired, which was associated with increased progesterone and changes in the gut microbiota regulated by progesterone. Intervening with the gut microbiota may become a new treatment for PITP.

The clinical features and outcomes of adult acute leukemia (AL)-associated hemophagocytic lymphohistiocytosis (AL-HLH) remain insufficiently characterized. We retrospectively analyzed 45 adult patients diagnosed with AL-HLH between December 2019 and June 2023. Among 746 AL patients, 45 developed HLH, with 40 developing acute myeloid leukemia (AML), 4 developing acute lymphoblastic leukemia (ALL), and 1 developing mixed-phenotype acute leukemia (MPAL). According to the ELN 2022 criteria, 16 (35.6%) had favorable, 3 (6.7%) had interediate, and 26 (57.7%) had poor risk. At the time of HLH onset, seven (15.6%) patients were in composite complete remission (CCR), and 38 (84.4%) were in non-CCR states; 25 (55.6%) patients were newly diagnosed before induction chemotherapy. The HLH-94/04-based regimens (etoposide and dexamethasone) with or without ruxolitinib achieved an ORR (overall remission rate) of 82.2% and a CR rate of 66.7%. After anti-leukemic therapy, 60% (27/45) of patients achieved CCR for leukemia (including patients in CCR at HLH onset and those achieving CCR after treatment). Hematopoietic stem cell transplantation (HSCT) independently predicted sustained remission. The estimated overall rates at 6 and 12 months after HLH diagnosis were 73.1% and 59.2%, respectively. Multivariate Cox analysis identified failure to achieve CCR for leukemia as the only independent adverse prognostic factor. AL-HLH is an uncommon but severe complication that predominantly occurs in AML patients with poor-risk cytogenetics or active disease. Early recognition, effective HLH control, and achievement of CCR in AL are crucial for improving patient prognosis.

Immune thrombocytopenia (ITP) is characterized by impaired platelet production and increased platelet destruction. Zanubrutinib is a highly selective next-generation Bruton tyrosine kinase (BTK) inhibitor that may reduce autoantibody production and reduce macrophage Fcγ receptor-mediated platelet destruction. In this single-arm, phase II study, we aimed to assess the efficacy and safety of zanubrutinib in corticosteroid-resistant or relapsed ITP. All patients received 80 mg zanubrutinib once daily for 6 weeks followed by a 20-week safety follow-up period. The primary endpoint was overall response (OR), defined as at least two consecutive platelet counts of at least 30 × 109/L, at least a 2-fold increase in the baseline count, the absence of bleeding, and no need for rescue therapy at 4 weeks. The trial was registered with ClinicalTrials.gov, number NCT05279872. Between January 1, 2022 and October 30, 2022, 20 patients were enrolled. The median platelet count was 19 (10-25) × 109/L at the time of enrollment. Participants had received a median of 4 (3-6) different therapies for ITP. Eleven (55%, 95% CI: 31.5%-76.9%) patients achieved an OR to the intervention. Two (10%) patients achieved a complete response. At the 6-month follow-up, a sustained response was achieved in seven (35.0%, 95% CI: 15.4%-59.2%) patients. There were no grade 4 or worse adverse events or treatment-related deaths. The most common adverse events were upper respiratory tract infection (in 25% of the patients). Zanubrutinib showed an encouraging response rate and tolerability, supporting its therapeutic potential for the treatment of ITP. Trial Registration: ClinicalTrials.gov identifier: NCT05279872.

Corticosteroids (CSs) are the initial therapy for immune thrombocytopenia (ITP); however, their efficacy is not adequately predicted. As a novel biomarker, the composition of the gut microbiota is non-invasively tested and altered in patients with ITP. This study aims to develop a predictive model that leverages gut microbiome data to predict the CS response in patients with ITP within the initial four weeks of treatment. Metagenomic sequencing is performed on fecal samples from 212 patients with ITP, 152 of whom underwent CS treatment and follow-up. Predictive models are trained using six machine-learning algorithms, integrating clinical indices and gut microbiome data. The support vector machine (SVM) algorithm-based model has the highest accuracy (AUC = 0.80). This model utilized a comprehensive feature set that combined clinical data (including sex, age, duration, platelet count, and bleeding scales) with selected microbial species (including Bacteroides ovatus, Bacteroides xylanisolvens, and Parabacteroides gordonii), alpha diversities, KEGG pathways, and microbial modules. This study will provide new ideas for the prediction of clinical CS efficacy, enabling informed decision-making regarding the initiation of CS or personalized treatment in patients with ITP.

Introduction The optimal treatment for corticosteroid-resistant or relapsed immune thrombocytopenia (ITP) remains uncertain. Iguratimod is a small molecule compound that is widely used as a novel antirheumatic drug in the treatment of several autoimmune diseases. Our previous study revealed that iguratimod could regulate CD4+ T-cell homeostasis and function by restoring PINK1/parkin-mediated mitophagy in ITP patients (the 65th ASH oral presentation). Rituximab (RTX), a chimeric anti-CD20 monoclonal antibody that targets B cells, has been frequently used in treating ITP. Previous studies on low-dose rituximab (100 mg weekly for 4 weeks, LD-RTX) in ITP patients revealed an OR comparable to that of standard-dose rituximab (375 mg/m2 weekly for 4 weeks, SD-RTX). However, LD-RTX was reported to have a longer time to response and a lower sustained response rate than SD-RTX. Since iguratimod and rituximab target T cells and B cells respectively, their combination may exert synergistic effects and potentially overcome the long time to response and improve sustained response. This study aimed to compare the efficacy and safety of iguratimod plus LD-RTX with those of LD-RTX monotherapy in corticosteroid-resistant or relapsed ITP patients. Methods Adult ITP patients from 6 tertiary medical centers in China participated in this randomized, controlled, multicenter, open-label trial. Eligible corticosteroid-resistant or relapsed ITP patients with a platelet count <30×109/L or bleeding symptoms at enrollment were randomly allocated at a 1:1 ratio to receive oral iguratimod at 25 mg twice daily for 12 weeks plus low-dose rituximab or low-dose rituximab monotherapy. RTX was given at a fixed dose of 100 mg weekly for 4 weeks. The primary endpoint was the initial overall response (OR), defined as achieving a platelet count of ≥30 × 109/L, at least a doubling of the baseline platelet count without any other ITP-specific treatment, and the absence of bleeding. The second endpoint included a 6-month sustained response (SR), defined as platelet counts of ≥50 × 109/L for two-thirds or more during the 26-week follow up in the absence of rescue therapy. This trial was registered with ClinicalTrials.gov (NCT07057778). Results From September 1, 2022, to December 31, 2024, a total of 151 patients were screened for eligibility; 31 were excluded, and 120 were randomly assigned. A total of 120 patients were included in the intention-to-treat analysis: 60 in the iguratimod plus LD-RTX group and 60 in the LD-RTX group. The median age of the patients was 45 years, and 66.7% (80/120) of them were females. All patients enrolled failed to respond to first-line treatment with corticosteroids, and 70 (58.3%) of all patients had received three or more therapies. An OR was observed in more patients in the iguratimod plus LD-RTX group (75.0%) than in the LD-RTX monotherapy group (51.7%) (between-group difference, 0.23; 95% CI, 0.05–0.41). In patients who achieved an overall response, the median time to treatment response was 18 days in the iguratimod plus LD-RTX group, whereas it was 35 days in the LD-RTX monotherapy group. SR was achieved by 33 (55.0%) patients in the combination group and 23 (38.3%) patients in the monotherapy group (between-group difference, 0.17; 95% CI, 0.03–0.39). Compared with baseline, both groups showed improvements in the mean scores of all the ITP-PAQ scales at week 26. For the scales of psychological health and social activity, the changes in the scores exceeded the minimal important difference estimates in both groups. Compared with those in the LD-RTX monotherapy group, the scores for symptoms, fatigue, work, social activity, and overall quality of life of the participants in the combination therapy group significantly improved. Serious adverse events (AEs), rescue treatment, and treatment side effects were similar in the two groups, and all patients tolerated the treatment well, without any grade 4 AEs or treatment-related deaths reported. Conclusions Our findings demonstrate that iguratimod plus LD-RTX significantly increased the initial and sustained response rates, and shortened the time to response, indicating that it is a promising treatment option for corticosteroid-resistant or relapsed adult ITP.

Introduction Immune thrombocytopenia (ITP) affects approximately 1 to10 per 10,000 pregnancies. It showed that bone marrow mesenchymal stem cells (BM-MSCs) in ITP patients during pregnancy exhibit significant impairment, including increased senescence, apoptosis, and compromised immunoregulatory functions as our previous study. Progesterone has been identified as a critical metabolite influencing the composition of gut microbiota, which in turn contributes to BM-MSCs injury in ITP during pregnancy (J Thromb Haemost,2025). Nevertheless, the precise mechanism by which progesterone-mediated alterations in gut microbiota lead to MSCs injury in ITP during pregnancy remains inadequately understood. It is also needed to explore the potential of targeting gut microbiota as a therapeutic strategy for managing pregnant ITP patients. Methods Fresh fecal samples were collected from pregnant ITP patients, non-pregnant ITP patients,and healthy controls. Humanized fecal microbiota mice were development through fecal microbiota transplantation (FMT). The gut microbiota profiles of mice were analyzed using 16S rDNA sequencing technology. Subsequently, an ITP model was established. The senescence and apoptosis of BM-MSCs in mice with different fecal microbiota sources were assessed, and these MSCs were co-cultured with CD34+cells to examine their effects on megakaryocytes (MKs) maturation and platelet production. Serum levels of NOD1 ligand (NOD1L) in FMT mice were measured. C12-iE-DAP was used to treat MSCs in vitro to investigate changes in MSCs senescence, apoptosis, and the expression of RIP2, IRF3, JAK1 and STAT1 before and after C12-iE-DAP intervention. The levels of cytokines secreted by MSCs were also measured. In vivo, mice of different groups were administered probiotics or C12-iE-DAP via gavage. Platelet counts and serum NOD1L levels in the mice were subsequently determined. Results Fresh fecal samples were collected from three groups: ITP patients during pregnancy, non-pregnant ITP patients, and healthy controls. Mice were then inoculated with fecal microbiota from these resources, resulting in three experimental groups: the ITP during pregnancy-FMT, the ITP-FMT and the HC-FMT group. The gut microbiota profiles analysis indicated that the α-diversity of the gut microbiota in the ITP during pregnancy-FMT group was lower compared to both the ITP-FMT and HC-FMT groups. Furthermore, the abundance of Gram-negative bacteria was significantly reduced in the ITP during pregnancy-FMT group. The abundances of unclassified Ruminococcaceae, Intestinibacter, Barnesiella, Staphylococcus, and Bacillus were increased in this group. BM-MSCs were subsequently isolated from the recipient mice, revealing that the proportion of senescent and apoptotic cells was significantly higher in ITP during pregnancy-FMT-MSCs compared to other groups. The MSCs from different groups were co-cultured with CD34+ cells, which were induced to differentiate into MKs. In the group with ITP during pregnancy-FMT-MSCs, there was a significant reduction in the proportion of CD41+CD42b+ MKs and platelets. Concurrently, serum levels of NOD1L were significantly lower in ITP during pregnancy-FMT recipients. Subsequently, MSCs from ITP during pregnancy-FMT mice were stimulated in vitro with C12-iE-DAP. Following stimulation with C12-iE-DAP, there was a notable decrease in the proportion of senescent and apoptotic MSCs. Additionally, there was an upregulation in the expression of RIP2, IRF3, JAK1, STAT1, and an increase in the level of IFN-I in the supernatant. The proportion of CD41+CD42b+ MKs and platelets also significantly increased when co-cultured with bone marrow-derived CD34+ cells. Finally, established mouse models of ITP during pregnancy mice and ITP during pregnancy-FMT mice were randomly assigned to control and experimental groups. The experimental groups received gavage administration of probiotics and C12-iE-DAP, respectively. Elevated levels of NOD1L and platelet counts were observed in the experimental groups. Conclusions Supplementation with probiotics, elevation of NOD1L levels, and activation of the NOD1 receptor signaling pathway, which subsequently triggers the IFN-I/STAT1 signaling cascade, may ameliorate the senescence and apoptosis of MSCs in ITP during pregnancy, thereby promoting platelet production. This approach represents a potentially novel therapeutic strategy for managing ITP during pregnancy.

Introduction Despite all-trans retinoic acid (ATRA) -arsenical regimens achieve high cure rates in low-risk APL, relapse persists as a key challenge. Recent studies and our prior work suggest intravenous chemotherapy during induction may reduce relapses (Br J Haematol, 2021; Am J Hematol, 2019; Blood, 2010). Our clinical experience with oral etoposide in APL treatment indicated its efficacy, safety, and convenience as a cytoreductive agent during induction therapy (Zhu XL et al. J Cell Mol Med. 2024; Leuk Res Rep, 2021). Here we designed a randomized, phase II clinical trial (NCT05832320) comparing oral etoposide versus intravenous daunorubicin as cytoreductive therapy, both combined with ATRA and the realgar-indigo naturalis formula (RIF, an oral arsenic tetra-sulfide [As₄S₄] preparation), for induction therapy in low-risk APL patients. Methods Newly diagnosed adult patients (aged 18-75 years) with low-risk APL were enrolled. Between January 1, 2023, and December 16, 2024, eligible patients were randomized 1:1 to receive double-induction therapy with either oral etoposide or intravenous daunorubicin. ATRA plus RIF was administered following the 2018 Chinese APL management guidelines. When WBC exceeded 4.0×109/L during induction , patients were given oral etoposide (50 mg QD to 50 mg TID) with a cumulative dosage ≤1500mg. Initiation of intravenous daunorubicin (20 to 40 mg per dose) was at the same situation and adjust the dose according to the patients' condition and WBC counts. The primary outcome were CR and the incidence of PML-RARA transcript levels of ≥6.5% at the end of induction, which was proved to be associated with a subsequent risk of relapse in our study. Secondary endpoints included early death (ED), 2-year cumulative incidence of relapse (CIR), 2-year disease-free survival rate (EFS) and safety. Results Seventy-eight patients were randomized to cytoreductive therapy with intravenous daunorubicin (n = 39) or oral etoposide (n = 39). Median follow-up was 538 (range 196-880) days. During induction, mean cumulative doses were 180 (0-240) mg for daunorubicin and 1000 (250-1500) mg for etoposide. All evaluable patients achieved hematological CR without any ED events. The median time to hematological CR was 47 (30-63) days. During the follow-up period, relapse events were observed in both treatment groups with distinct patterns. In the daunorubicin group (n=6), the median time to relapse was 451 (183-691) days, comprising one hematologic relapse (occurring in a patient without daunorubicin exposure) and five molecular relapses (including two cases with ≤100 mg cumulative daunorubicin exposure). The etoposide group (n = 3) showed a median time to relapse of 330 (189-570) days, with one hematologic relapse and two molecular relapses (both occurring in patients with ≤500 mg cumulative etoposide exposure). The 2-year cumulative incidence of hematologic relapse was 3.85% in the daunorubicin group and 7.14% in the etoposide group (P = 0.638). The 2-year EFS were 57.8% and 86.8%, respectively (P = 0.238). All molecular relapse cases (n = 7) achieved complete molecular remission after reinduction therapy. One daunorubicin-treated patient developed hematological relapse with PML-RARA transcripts ≥6.5% post-induction, whereas no etoposide-treated patients achieved this transcript level at induction completion. Univariate analysis revealed statistically significant associations between relapse and both CD56 expression (P = 0.030) and FLT3-ITD positivity at diagnosis (P = 0.023). Variables with P <0.2 in univariate analysis (CD34/CD56 expression, FLT3-ITD positivity at diagnosis, and induction-phase differentiation syndrome) were included in multivariate modeling, though none achieved independent significance. Importantly, the incidence of treatment-related adverse events did not differ significantly between treatment groups. Conclusions In summary, the combination of oral etoposide and RIF-ATRA as induction therapy demonstrates comparable efficacy in preventing relapse and offers superior convenience compared to intravenous daunorubicin in low-risk APL.The data suggest a potential link between reduced cytoreductive dosing and increased relapse risk, while maintaining a manageable safety profile. Ongoing studies with extended follow-up will further define long-term outcomes.

Background With the identification of increasing molecular markers, acute myeloid leukemia (AML) patients in the adverse risk group constitute a growing proportion of the overall AML population according to the 2022 European LeukemiaNet genetic risk stratification. However, these patients who received intensive chemotherapy (IC) had lower complete remission (CR) rate and more dismal outcomes than those in favorable and intermediate risk groups. Therefore, new induction regimens are urgently needed to improve remission rates in the adverse risk group. Method This prospective, single-armed, multi-center cohort study (ChiCTR2400083301) was conducted in newly diagnosed AML adults in adverse risk group, who were eligible for intensive chemotherapy. We intenteded to enrolled 38 patients (pts) who would receive venetoclax (VEN) combined with decitabine (DEC), cytarabine (Ara-C), aclacinomycin (Acla) and granulocyte colony-stimulating factor (G-CSF) (DCAG). VEN was orally taken 100mg on day 1,200mg on day 2 and 400mg on days 3 to 12. The details of DCAG were as follows: DEC 20mg/m2 on day 1 to 5, Ara-C 10mg/m2 q12h on day 6 to 12, Acla 10mg on day 6 to 10, and G-CSF 5ug/kg on day 6 to 12, which was adjusted according to the white blood cell count. The primary endpoint was response rate. Results: Between October 2023 to April 2025, 40 patients (pts) were enrolled in this study. The median follow-up time was 6 (2.4-20.8) months. The median age was 54 (21-72) years, in which 72.5% (29/40) pts were less than 60 years, and 57.5% (23/40) pts were male. There were 12.5% (5/40) pts with preceding hematological disease, and 5% (2/40) pts with malignant tumor treatment. In total, 47.5% (19/40) pts had myelodysplasia-related (MR) gene mutation, 22.5% (9/40) pts with KMT2A-rearranged, 12.5% (5/40) pts with mutated TP53and complex karyotype (CK), 7.5% (3/40) pts with CK, 5.0% (2/40) with DEK::NUP214,1 pts with NUP98::TOP1, and 1 pts with t (3;3). After one cycle of induction, overall response was 80.0% (32/40). CR/CR with incomplete blood count recovery (CRi) rate was 70.0% (28/40). Partial remission (PR) rate was 7.5% (3/40)，and 1 pts achieved morphologic leukemia free state (MLFS). None of them died during the induction. The median time of achieving response was 1.5 (0.7-3.2) months. The response rate in MR gene mutation group was 94.7% (18/19), including 1 pts achieved PR and 1 pts MLFS. In KMT2A-rearranged group, 55.6% (5/9) pts and 22.2%(2/9) pts achieved CR/CRi and PR. Three (60%) of 5 pts with mutated TP53 and CK achieved CR. Four (57.1%) out of the left 7 pts achieved CR. Measurable residual disease (MRD) of multi-parameter flow cytometry (MFC) in 50.0% (16/32) pts achieved negativity. No response (NR) rate was 20% (8/40). After 5.1(3.2-7.0) months, 18.8% (6/32) pts relapsed. Six (15%) pts died. In total, 60.0% (24/40) pts underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). Among them, 87.5% (21/24) pts were allo-HSCT after the first response, and 3 with salvaged allo-HSCT. The median time from receiving response to allo-HSCT was 2.9 (1.9-6.3) months. Both of the median relapse free survival (RFS) and overall survival (OS) did not reach, with estimated 1-year RFS rate of 66.6% (95%CI, 45.6-87.6), and OS rate of 80.6% (95%CI, 65.7-95.5) respectively. Patients who underwent allo-HSCT had higher RFS rate (estimated 1-year, 38.6% vs. 78.0%, p=0.022) and OS (estimated 1-year, 46.8% vs. 95.7%，p=0.002). In MR gene mutation group, 63.2% (12/19) pts received allo-HSCT and estimated 1-year RFS and OS compared with chemotherapy were 55.6% vs.88.9%(p=0.090%) and 100% vs.71.4% (p=0.054) respectively. In 5 pts with mutated TP53 and CK, 2 pts underwent allo-HSCT is still alive at 13.9 and 16.1 months, 2 pts with NR were lost at 2.5 and 4.7 months, and 1 pts with CR is preparing for allo-HSCT with a OS of 4.0 months without relapse. Conclusion VEN combined with DCAG regimen was effective and well-tolerated in newly diagnosed adverse risk AML when used as induction therapy, which could provide more opportunity to adverse risk AML pts in remission with allo-HSCT to improve survival.

EVI1 is frequently overexpressed in acute myeloid leukemia (AML) and associated with poor prognosis. Although MDS patients with 3q26 rearrangements often show EVI1 overexpression and are prone to progression to AML, the clinical significance of EVI1 expression in MDS remains unclear. To evaluate the clinical and prognostic relevance of EVI1 expression in patients with MDS. We retrospectively analyzed 522 MDS patients who had not received prior therapy between January 2023 and December 2024. EVI1 expression was quantified by qPCR, with high-expression defined as EVI1/ABL ≥8.0%. Patients were stratified using IPSS-R and IPSS-M scores. Clinical features, immunophenotypes, mutational profiles (in 100 patients with NGS data), and survival outcomes (in 168 patients with follow-up data) were compared between EVI1-high and EVI1-low groups. Among 522 patients, 260 (49.8%) showed EVI1 high expression. These patients had a higher percentage of bone marrow blasts, elevated WT1 and PRAME expression, and were more often categorized as intermediate/high risk by IPSS-R. Flow cytometry showed enrichment of aberrant immature myeloid phenotypes (CD34⁺CD117⁺CD33⁺CD38⁺) in the EVI1-high group, whereas the EVI1-low group more frequently exhibited aberrant erythroid features (CD36⁺CD105⁺). EVI1 expression was significantly higher in patients with 3q26 rearrangements compared to those without (105.0% vs. 17.1%, p<0.0001). SETBP1 mutation was more frequent in the EVI1-high group (8.0% vs. 0.0%, p=0.002). EVI1 overexpression was associated with inferior overall survival (OS) and event-free survival (EFS) (p=0.003 and p=0.025, respectively). Multivariate Cox analysis identified EVI1 expression and age as independent predictors of OS. In IPSS-R low-risk patients, EVI1 overexpression predicted worse EFS (p=0.037), but had no impact in intermediate/high-risk patients. Using IPSS-M, no patients fell into the very low-risk category, and 88% were classified as moderate-high to very high risk. Within each IPSS-M subgroup, EVI1 expression was not significantly associated with survival outcomes. EVI1 overexpression defines a biologically and clinically distinct high-risk MDS subgroup, associated with adverse outcomes, especially in IPSS-R low-risk patients. EVI1 may serve as an independent prognostic biomarker. In patients with NGS data, IPSS-M provided robust risk stratification, and EVI1 expression had no additional prognostic impact within IPSS-M subgroups.

Pyroptosis, a novel form of inflammation-related programmed cell death that often occurs in myeloid cells, plays an important role in multiple inflammatory diseases. Our previous study revealed macrophage dysfunction in acute graft-versus-host disease (aGVHD). However, whether macrophages undergo pyroptosis in aGVHD remains unknown. In our study, macrophage pyroptosis was observed in aGVHD mice. Additionally, serum IL-1β and IL-18 levels were increased in aGVHD patients. Almost all peritoneal macrophages in the aGVHD mice were derived from the donors. Less pathological damage and a longer survival time were observed in the mice that received purified T cells and bone marrow (BM) from AAV9-F4/80-GSDMD mice, indicating that macrophage pyroptosis in donor mice promoted the development of aGVHD. In addition, decreased proportions of CD69+CD4+ T cells, Th1 cells and Th17 cells and an increased proportion of Tregs were observed in the recipients when GSDMD was suppressed in the donor macrophages. Administration of a pyroptosis inhibitor significantly alleviated the severity of aGVHD without impairing graft-versus-lymphoma (GVL) effects. Our results suggested that donor-derived macrophages undergo pyroptosis in aGVHD, and these cells might participate in the development of aGVHD by affecting the activation and differentiation of CD4+ cells. The pyroptosis inhibitor disulfiram is a potentially promising agent for aGVHD treatment.

Introduction Neutrophils are innate immune phagocytes that have a central role in immune defense. Neutrophils have been shown to play critical roles in the initiation and perpetuation of autoimmune disorders. Recent studies revealed direct cellular interactions between neutrophils and megakaryocytes (MKs) in the bone marrow (BM). Neutrophils are recruited to the proplatelet budding site of MKs and control thrombopoiesis by plucking on forming proplatelets, in turn accelerating their growth and release into the circulation (Immunity 2022, Blood 2025). The pathogenic mechanisms of immune thrombocytopenia (ITP) are not fully understood. Our previous data indicated that impaired proplatelet formation (PPF) contributed to the development of thrombocytopenia in ITP. To further explore the underlying mechanism of impaired PPF in ITP, we found that activation of the type I interferon (IFN) pathway caused dysfunction of neutrophil chemotaxis via CXCL12/CXCR4. The oral selective Janus kinase 1 (JAK1) inhibitor upadacitinib, which has been approved for the treatment of multiple autoimmune diseases, including ulcerative colitis and rheumatoid arthritis, could restore neutrophil chemotaxis and promote PPF. Methods Thirty ITP patients and healthy controls from March 2023 to December 2023 were included in the study. Single-cell RNA sequencing, 4D label-free proteomics and Olink proteomics were used for the first time to characterize the changes in bone marrow neutrophil development and heterogeneity. Bone marrow neutrophils were isolated from ITP patients and controls. The chemotactic motility of neutrophils was observed through TAXIScan cell migration visualization and transwell migration assays. A coculture system of neutrophils and MKs was established. Pf4-cre(+)/confetti/Lyz2-eGFP dual reporter mice and multi-photon microscopy were used to visualize the interaction between MKs and neutrophils. An ITP mouse model was established to observe the therapeutic effects of upadacitinib on PPF. Results ITP neutrophils displayed impaired neutrophil chemotaxis, with reduced directional motility and velocity. Based on single cell sequencing data, we identified 6 neutrophil subsets including Neu_cycling, MPO_Neu, CAMP_Neu, MMP9_Neu, CXCR2_Neu, and ISG15_Neu. In patients with ITP, the number of neutrophils significantly changed during differentiation and maturation, the number of ISG15_Neu significantly increased. And pathway enrichment analysis of differential expression genes revealed that type I interferon pathway was the most enriched. After IFN-α stimulation in vitro, the chemotactic function and orientation of neutrophils were decreased. Together, the activation of type I interferon pathway may contribute to the impaired neutrophil chemotaxis in ITP. Neutrophils promote PPF through the direct cellular interactions with MKs. The neutrophil and MKs co-localization are reduced in the ITP BM microenvironment. The expression of neutrophil chemokine CXCL12 in BM demonstrated no significant differences between ITP and controls. The neutrophil chemokine receptor CXCR4 in the BM of ITP patients was significantly decrease. Taken together, the activation of type I interferon pathway accounted for impaired neutrophil chemotaxis through CXCL12/CXCR4 signaling axis, which resulted in the defective PPF in ITP. After binding to receptors, type I interferon activate the JAK/STAT pathway and exert their effects on different cytokine receptors. Upadacitinib is an oral JAK1 inhibitor that has high selectivity for JAK1 inhibition. We then investigated the effect of upadacitinib on PPF in ITP patients. Our data showed that in vitro treatment with upadacitinib inhibited the activation of the type I interferon pathway, upregulated the expression of CXCR4, and restored neutrophil chemotaxis. In vivo studies showed that upadacitinib could rescue the impaired PPF in both patients and mice model with ITP. Conclusions The BM of ITP patients displayed impaired neutrophil chemotaxis regulated by type I interferon pathway. Upadacitinib restores neutrophil chemotaxis and corrected impaired PPF by inhibiting type I interferon pathway and upregulating CXCR4. It sheds light on a novel mechanism of ITP pathogenesis and provides a basis for the therapeutic potential of upadacitinib in ITP patients.

Venetoclax combined with azacitidine (VA) is a new standard of care for newly diagnosed patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy. We retrospectively analyzed patients who were diagnosed with favorable-risk unfit AML and received VA-based induction regimen between October 2020 and December 2023 in our center. Among 70 patients, 14 had RUNX1::RUNX1T1, 11 had CBFb::MYH11, 14 had CEBPA bzip mutations and 31 had NPM1 mutations. The median age was 60 years (IQR 49–67) and the median follow-up was 18.0 months (IQR 10.9–26.1). The cumulative CR/CRi rate of VA-based induction regimen for all patients was 84.3% (59/70). The median induction course was 1 (range 1–2). The CR/CRi rate for RUNX1::RUNX1T1, CBFb::MYH11, CEBPA bzip and NPM1 mutations was 35.7% (5/14), 90.9% (10/11), 100% (14/14) and 96.8% (30/31), respectively. Twenty patients received long-term VA-based therapy, and 30 received chemotherapy after remission. The MRD negativity rate after two cycle of consolidation therapy was 85.0% (17/20) for VA group and 73.3% (23/30) for chemotherapy group (p = 0.33). There was no significant difference in 2-year OS (p = 0.90) and 2-year EFS (p = 0.58) between VA group (OS: 88.2%; EFS: 41.2%) and chemotherapy group (OS: 83.3%; EFS: 42.8%). The 2-year OS (p = 0.01) and 2-year EFS (p < 0.01) of patients with negative MRD (OS: 89.8%; EFS: 51.4%) were significantly better than those with positive MRD (OS: 65.6%; EFS: 0%). VA-based regimens was an superior option for induction in favorable-risk unfit AML patients who were non-RUNX1::RUNX1T1 positive. Further studies are needed to conform its long-term efficacy.