In the era of chimeric antigen receptor T-cell (CAR-T) therapy, the prognostic impact of bulky disease in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) remains unclear, prompting this study that enrolled 27 patients with bulky disease and 27 with non-bulky disease to compare clinical outcomes. Over the follow‑up period, patients with non‑bulky disease achieved a higher overall response rate (77.8% vs. 70.4%) and better one‑year progression‑free survival (PFS) and overall survival (OS), with bulky disease significantly associated with worse OS (P = 0.040) and a median OS of 12 months versus 24 months in non‑bulky patients. Multivariable Cox regression identified autologous hematopoietic stem cell transplantation combined with CAR‑T (ASCT + CAR‑T) as an independent variable, and this combination was correlated with superior PFS (HR = 7.363; 95% CI: 2.653–20.437; P < 0.001) and OS (HR = 0.208; 95% CI: 0.070–0.615; P < 0.05) compared to CAR‑T alone, irrespective of bulky disease status. Collectively, these findings indicate that R/R DLBCL patients with bulky disease have worse outcomes after CAR‑T therapy than those without, and that ASCT + CAR‑T represents a promising alternative for such patients regardless of bulky disease presence.

Rh(D)-negative individuals are relatively rare in the Chinese population, and clinical experience with Rh(D)-incompatible allogeneic haematopoietic stem cell transplantation (allo-HSCT) remains limited. Compared with ABO incompatibility, the immunohaematological consequences of Rh(D) mismatch in allo-HSCT are less well defined. Herein, we report a single-centre retrospective case series of four patients receiving Rh(D)-incompatible allo-HSCT at our institution, including two Rh(D)-negative recipients with Rh(D)-positive donors and two Rh(D)-positive recipients with Rh(D)-negative donors. We systematically evaluated post-transplant transfusion strategies, haematological recovery, anti-D alloantibody seroconversion, haemolysis or graft-versus-host disease (GVHD), and long-term survival outcomes. During a median follow-up of 36 months (range, 24-48 months), none of the patients developed detectable anti-D alloantibodies. Only one patient exhibited laboratory evidence of subclinical haemolysis responsive to low-dose prednisone, and another patient developed grade II acute gastrointestinal GVHD controlled by immunosuppressive agents. Nevertheless, all patients achieved sustained haematological engraftment without transplant-related mortalities. Combined with data from a narrative literature review, our single-centre observations are consistent with prior studies showing low risks of clinically significant haemolysis and anti-D alloimmunisation after Rh(D)-incompatible allo-HSCT. Rh(D) mismatch does not appear to be associated with severe transplant complications in our limited cohort, but these findings cannot be generalised broadly given the extremely small sample size. Rigorous peri-transplant transfusion management and regular post-transplant serological monitoring are still mandatory for Rh(D)-mismatched recipients.

Abstract The optimal graft-versus-host disease (GVHD) prophylaxis strategy in haploidentical peripheral blood stem cell transplantation remains controversial. In this open-label, phase 3 study, patients aged 14 to 70 years with acute myeloid leukemia or myelodysplastic syndromes with excess blasts Ⅰ or Ⅱ were randomized (2:1:1) to receive low-dose antithymocyte globulin (ATG; 5 mg/kg) plus posttransplant cyclophosphamide (PTCy; 50 mg/kg; referred to as ATG/PTCy), standard-dose ATG (total dose, 10 mg/kg), or a PTCy-based (total dose, 100 mg/kg) regimen for GVHD prophylaxis. The coprimary end points were the cumulative incidence (CI) of grade 2 to 4 acute GVHD (aGVHD) by day 100 and GVHD-free, relapse-free survival at 1 year after transplant. A total of 407 patients were randomized to receive an ATG/PTCy (185 patients), ATG (113 patients), or PTCy (109 patients) regimen for GVHD prophylaxis. By day +100, the CI of grade 2 to 4 aGVHD did not differ significantly among the 3 groups (P = .210). Although the overall incidence of chronic GVHD (cGVHD) was comparable across all groups (P = .110), the 2-year CI of moderate-to-severe cGVHD was numerically lower in the ATG/PTCy (17.4%) and ATG (17.3%) groups than the PTCy group (28.3%), without reaching statistical significance (P = .095). No significant differences were observed in survival outcomes among the 3 groups. Notably, the CI of neutrophil and platelet recovery was significantly higher in the ATG/PTCy group than in the other groups (P< .001). This trial suggested that the 3 GVHD prophylaxis strategies presented similar efficacy in preventing grade 2 to 4 aGVHD and yielded comparable survival. This trial was registered at www.clinicaltrials.gov as NCT03608059.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the cornerstone of curative therapy for acute myeloid leukemia (AML), yet precise molecular prognostic tools are currently insufficient. This study developed a prognostic model, AML-PRSS, integrating genomic and clinical factors from 389 adult AML patients undergoing their first allo-HSCT between 2013 and 2021. Seven genetic mutations significantly associated with leukemia-free survival (LFS) were categorized as favorable (DNMT3A, CEBPA bZIP domain, NPM1 without FLT3-ITD or with FLT3-ITD plus tyrosine kinase inhibitors), unfavorable (NRAS and GATA2), and high-risk (TP53 and U2AF1). Multivariate analysis identified molecular risk, cytogenetic risk, pre-transplant disease status, age, and hematopoietic cell transplant-comorbidity index (HCT-CI) score as independent predictors of LFS. AML-PRSS stratified patients into four risk groups with stepwise increasing hazard of LFS failure. Validation in an independent multi-center cohort of 266 patients confirmed robust predictive accuracy, highlighting AML-PRSS as an effective tool for personalized prognostication and clinical decision-making.

Background Polatuzumab vedotin, an antibody-drug conjugate targeting CD79b, has become the standard of care (SOC) for both treatment-naive (TN) and relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) patients, administered via the Pola-R-CHP (rituximab, cyclophosphamide, doxorubicin, prednisone) and Pola-BR (bendamustine plus rituximab) regimens. Unlike the strict inclusion criteria of clinical trials, real-world patients often present with poorer baseline conditions and higher disease burdens, with treatment modalities individualized based on their disease characteristics. Thus, evaluating the efficacy and safety of Pola-based regimens in real-world settings is of critical importance. Based on this, we retrospectively analyzed consecutive patients treated with Pola-based regimens at our center to investigate their disease characteristics, treatment patterns, and clinical outcomes. Methods This retrospective study enrolled consecutive patients from Changhai Hospital Affiliated to Naval Military Medical University who received Pola-based regimens. Efficacy was evaluated via whole-body 18F-FDG PET/CT or contrast-enhanced CT scans during and after treatment. Some patients were considered for autologous stem cell transplantation (ASCT) as consolidation therapy. Treatment responses were assessed using the 2014 Lugano criteria, and adverse events (AEs) were graded according to the NCI-CTCAE v5.0. Efficacy endpoints included complete response (CR) rate, objective response rate (ORR), safety profile, progression-free survival (PFS), and overall survival (OS). Results A total of 30 patients were enrolled between October 2024 and August 2025. The overall baseline characteristics indicated a high-risk profile: median age was 68.5 years (range, 46–81 years); 4 patients (13.3%) had transformed follicular lymphoma (tFL), and 2 (6.7%) had T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL). Twenty-four patients (80.0%) were staged Ann-Arbor III–IV, and 16 (53.3%) were classified as high-risk by the International Prognostic Index (IPI). Additional high-risk factors included extranodal involvement (25 patients, 83.3%), double-expressor lymphoma (DEL, 17 patients, 56.7%), double-hit/triple-hit lymphoma (DH/TH, 5 patients, 16.7%), and high P53 expression (11 patients, 36.7%). Regarding treatment history: 14 patients (46.7%) were previously untreated, and 16 (53.3%) had received at least one prior line of therapy. Among the latter, 5 had early relapse after their last treatment, 6 were refractory, and 1 had prior exposure to ASCT and chimeric antigen receptor T-cell therapy (CAR-T). To date, the median number of Pola-based regimen cycles administered was 2 (range, 1–6). Ten patients were evaluable for efficacy, with 5 achieving CR and 3 achieving partial response (PR); 3 patients (10%) proceeded to ASCT afterward. In this high-risk population, Pola-based regimens showed manageable toxicity, with 37.5% of patients experiencing grade 3–4 AEs. The most common AEs were anemia (100.0%), decreased white blood cell count (41.7%), and decreased neutrophil count (41.7%), most of which were grade 1–2. The most frequent grade 3–4 AE was anemia (25.0%). With a median follow-up of 3.8 months (95% CI: 5.7–8.9), only 2 patients progressed: one was CD5-positive, and the other had high P53 expression. Conclusion Our results characterize the real-world disease features, treatment patterns, and outcomes of DLBCL patients with high-risk prognostic factors, treated with Pola-based regimens. Even in this high-risk population, Pola-based therapy demonstrated promising efficacy and manageable toxicity. However, detailed data on response rates and survival outcomes require further reporting following extended follow-up.

Dear Editor, DNA methyltransferase 3A (DNMT3A) is wildly recognized as a tumor suppressor gene. Its deficiency leads to expanded hematopoietic stem cells (HSCs) pool, blocked HSCs differentiation, genomic instability, and a risk of malignant transformation in clonal hematopoiesis [1]. DNMT3A mutation (DNMT3AMut) is prevalent in adults, particularly in monocytic, and cytogenetically normal cases, affecting 25% of acute myeloid leukemia (AML) patients [1]. Although the distribution pattern of DNMT3AMuts has been well characterized in AML, its prognostic significance remains controversial. To better understand the reasons behind DNMT3AMut prognostic heterogeneity, we conducted a retrospective study, as detailed in two previous studies [2, 3]. Our findings show that DNMT3AMuts with stable expressed mutants are associated with poor prognosis in AML patients without receiving hematopoietic stem cell transplantation (HSCT). In this study, we enrolled 485 adult de novo AML patients, of whom 98 (20.2%) were found to have DNMT3AMuts. Our results indicate the distribution pattern of DNMT3AMuts and clinical characteristics of AML patients with these mutations were similar to previous reports. In our cohort, patients with DNMT3AMuts showed a relatively shorter overall survival (OS), relapse-free survival (RFS) and disease-free survival (DFS) (Figure 1A). We analyzed how different therapeutic strategies, with or without HSCT, affected the prognosis of various subgroups of DNMT3AMut patients. In the HSCT group, DNMT3AMut patients exhibited comparable OS, RFS, and DFS with DNMT3A wild-type (DNMT3AWT) patients (Figure 1A). Conversely, DNMT3AMut patients showed poorer OS, RFS, and DFS in the non-HSCT group, and the disparity between DNMT3AMut and DNMT3AWT patients was more pronounced in the non-HSCT group compared to the overall cohort (Figure 1A). Therefore, HSCT overcame the poor prognosis of DNMT3AMut, indicating DNMT3AMut patients without receiving HSCT were primarily responsible for the unfavorable outcomes. To further explore key factors contributing to poor prognosis of DNMT3AMut patients, we focused on DNMT3AMut types in the non-HSCT group. Near 50% of DNMT3AMut variants in AML are heterozygous DNMT3AR882, the hotspot mutation [1]. As reported, DNMT3AR882 played a dominant-negative role against DNMT3AWT via formatting dimers, leading to genome-wide hypomethylation [1]. However, DNMT3Anon-R882 has been infrequently studied. Recently, Yung-Hsin Huang et al. systematically studied protein stability of 253 disease-associated DNMT3AMut variants and their methyltransferase activity, and provided a comprehensive view on the implications of various DNMT3AMut variants [4]. In our cohort, we identified 112 DNMT3AMut variants. We first categorized DNMT3AMut patients into two groups: DNMT3AR882 and DNMT3Anon-R882. Except for OS, both of DNMT3AR882 and DNMT3Anon-R882 patients a had worse RFS and DFS compared to DNMT3AWT patients, indicating that DNMT3AR882 and DNMT3Anon-R882 did not effectively distinguish between prognostic outcomes (Figure 1A). Accurately, nearly half of DNMT3Anon-R882 variants were missense mutations, displaying similar mutant stability and diminished methyltransferase activity with DNMT3AR882, so we further divided DNMT3AMut patients into stable and instable DNMT3AMut groups (Supplementary Materials and Methods). Notably, stable but not instable DNMT3AMut patients exhibited worse OS, RFS and DFS compared to DNMT3AWT patients (Figure 1A). Additionally, we observed similar results when comparing stable DNMT3AMut to nonstable DNMT3AMut patients (nonstable DNMT3AMut included both instable DNMT3AMut and DNMT3AWT) (Figure 1A). Thus, stable DNMT3AMut was responsible for poor prognosis of DNMT3AMut patients in the non-HSCT group. As stable DNMT3AMut serves as a strong prognostic factor for AML patients, we were interested in exploring whether differences existed in distribution patterns and clinical characteristics between stable and instable DNMT3AMut. In our cohort, we identified stable DNMT3AMut in 51 patients and instable DNMT3AMut in 25 patients, while 22 DNMT3AMut cases were undefined. Apart from a relatively higher frequency of NPM1 mutation in stable DNMT3AMut patients, the distribution pattern of stable DNMT3AMut was similar to that of instable DNMT3AMut. Furthermore, compared to 412 nonstable DNMT3AMut patients, 51 stable DNMT3AMut patients presented a distribution pattern similar with DNMT3AMut compared to DNMT3AWT patients. Definitely, stable DNMT3AMut did not exhibit a specific distribution pattern. We also compared the baseline clinical characteristics of stable DNMT3AMut with those of instable DNMT3AMut or nonstable DNMT3AMut patients. However, stable DNMT3AMut patients did not obviously exhibit distinct clinical features. Although there were no significant statistical differences, the stable DNMT3AMut group showed a relatively lower complete remission rate and a higher relapse rate compared to both instable DNMT3AMut and nonstable DNMT3AMut groups, regardless of whether all patients or non-HSCT patients were considered, which possibly contributed to poor prognosis of stable DNMT3AMut patients. To determine whether stable DNMT3AMut was an independent risk factor for poor prognosis in non-HSCT patients, we divided patients into stable DNMT3AMut group and nonstable DNMT3AMut group, and displayed univariate analysis for OS, RFS, or DFS, respectively. Notably, stable DNMT3AMut exhibited an adverse effect on OS, RFS and DFS. Following this, we conducted multivariate analyses, confirming that stable DNMT3AMut was an independent adverse risk factor for OS, RFS or DFS in the non-HSCT AML patients (Table S1). Given its strong prognostic role, we sought to validate the clinical significances of stable DNMT3AMut in external cohorts. Herein, we analyzed data from The Cancer Genome Atlas TCGA (TCGA) database, and found that stable DNMT3AMut consistently indicates poor prognosis in the non-HSCT patients (Figure 1B). Although most evidences supported that DNMT3AMut was a biomarker for poor prognosis in AML, the role of DNMT3AMut in AML has not been widely accepted. In our cohort, DNMT3AMut patients exhibited a shorter OS, RFS, and DFS in the entire cohort, consistent with results from most other reported cohorts. Most stable DNMT3AMut variants are distributed across the methyltransferase domain, which is known to act as a dominant negative, resulting in decreased DNA methylation activity and a poor prognosis. HSCT eliminates leukemia cells, improves the hematopoietic function of the bone marrow, and enhances patient prognosis. A study has shown that HSCT improves outcomes of DNMT3AMut AML patients [5], and our findings also indicate that HSCT reduces the prognostic gap between DNMT3AMut and DNMT3AWT patients. In contrast, the prognostic disparity existed between DNMT3AMut and DNMT3AWT patients in the non-HSCT group. DNMT3AR882, the hotpot mutation in DNMT3AMut variants, was recognized as the primary factor contributing to the poor prognosis associated with DNMT3AMut [1]. Nearly 50% of DNMT3AMut variants are attributed to DNMT3AR882, but significant heterogeneity also exits in DNMT3Anon-R882 [1]. A recent study indicated that certain missense DNMT3Anon-R882 variants also shared similar protein stability and methyltransferase activity features with DNMT3AR882, thus, classifying DNMT3AMut into DNMT3AR882 and DNMT3Anon-R882 was not accurate [4]. Herein, we classified DNMT3AMut as stable or instable DNMT3AMut according to mutant stability, and found that stable DNMT3AMut, rather than instable DNMT3AMut, was an independent predictor for relatively shorter OS, RFS and DFS. Furthermore, stable DNMT3AMut primarily worsened the prognosis for AML genetic subtypes, indicating stable DNMT3AMut was a dominant contributor for poor prognosis in the non-HSCT patients. In the future, we aim to demonstrate the prognostic value of stable DNMT3AMut through prospective multicenter clinical studies. Collectively, stable DNMT3AMut, but not instable DNMT3AMut, should be regarded as a strong predictor of poor prognosis in AML patients without receiving HSCT, thereby providing insights into the mechanism underlying AML pathogenesis. Xiang Zhang designed this study. Xiang Zhang and Xiong Ni collected clinical data and updated follow-up. Xiong Ni and Jin Jie guided clinical managements for patients. Xiang Zhang, Lixia Liu, and Jiayue Qin displayed data analysis. Xiang Zhang and Jiayue Qin wrote the manuscript. Jie Jin provided critical comments on this study. Xiong Ni and Jie Jin revised the manuscript. All authors have read and approved the final manuscript. We would like to thank Hongyan Tong, Wenjuan Yu, and Yanan Zhu from the Department of Hematology, the First Affiliated Hospital, Zhejiang University College of Medicine, as well as Jianmin Wang, Jianmin Yang and Lei Gao from the Department of Hematology, Institute of Hematology, Changhai Hospital, for managing patients and supporting our work. We also thanked Jiewen Sun from Women's Hospital and Institute of Genetics, Zhejiang University School of Medicine for providing advices on English language writing. This study was funded by the Natural Science Foundation of Zhejiang Province (LY21H080003), Zhejiang Provincial Key Research and Development Program (2021C03123), and National Natural Science Foundation of China (82370163, 82170144, 81771779). This study was approved by the ethical review committees of the First Affiliated Hospital of Zhejiang University School of Medicine (IIT20220659A) and Changhai Hospital (B2022-035). All procedures in studies involving human participants were performed in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments. Written informed consent was obtained from these patients. The authors declare no conflicts of interest. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Acute graft-versus-host disease (aGvHD) is the main cause of non-relapse mortality in the early stage after allogeneic hematopoietic cell transplantation (alloHCT). 40-60% of aGvHD cases were identified as steroid refractory (SR)-aGvHD, which has a fulminant prognosis. However, the underlying associations between immune reconstitution and SR-aGvHD remain unclear. To address this knowledge gap, samples of steroid-naïve aGvHD and non-aGvHD patients were analyzed with multi-omics approaches. Peripheral blood mononucleated cells (PBMCs) isolated from 26 non-aGvHD, 17 steroid-sensitive (SS)-aGvHD and 19 SR-aGvHD patients at d16 (one week before aGvHD fully brown) were analyzed by mass cytometry (CyTOF). The proportions of CD28high CD8+ effector memory T cells (Tem), Th1-like CD4+ memory T cells, and CD56high NK cells were significantly expanded in SR-aGvHD samples. CD28high CD8+ Tem cells from SR-aGvHD samples showed higher expressions of ICOS, HLA-DR, IL2RB and IL27RA. However, the proportions of monocyticdendritic cells (DCs), plasmacytoid DCs, CD15- monocytes and CCR4+ monocytes were decreased. Inflammatory factors related to T-cell activation (such as IL-2, IL-27, IL15RA), co-stimulation (CD40), and chemotaxis were elevated in the plasma of SR-aGvHD patients. Taken the increased proportions of T-cell subsets and elevated levels of T-cell related inflammatory factors of SR-aGvHD, we further characterized the functional status of peripheral CD3+ T cells by single-cell RNA sequencing. The GZMK+ CD8+ Tem cells were characterized by co-stimulation (CD27), expansion (MKI67, MCM5) and inflammation (HMGB1, HMGB2) from SR-aGvHD samples. GZMK+ CD8+ Tem cells of SR-aGvHD samples received increased amounts of interactions between HLA-I molecules and CD8A/B, which reflected an immune active status. The results were validated with external cohort. PBMCs of 144 alloHCT recipients were analyzed by flow-cytometric analysis at a median time of 16 days. The absolute number of peripheral CD28high CD8+ Tem cells were significantly higher in SR-aGvHD group, compared with non-aGvHD and SS-aGvHD groups (90.8/ul vs. 19.7/ul and 7.2/ul, P ＜0.001). The area under ROC curve of 0.914 identified 11.078/ul of peripheral CD28high CD8+ Tem as the optimal cutoff value predicting SR-aGvHD with 100% sensitivity and 82.7% specificity. Functional defect of glucocorticoid receptor (GR) pathway is one of the major mechanisms for glucocorticoid resistance. We observed the decreased activity score of GR pathway in GZMK+ CD8+ Tem cells from SR-aGvHD samples. Among the genes of GR pathway, we found that NR3C1 gene, which encoding GR, was lower expressed in CD8+ Tem cells from SR-aGvHD samples. We investigated the expression of GR in PBMCs by flow-cytometric analysis. CD8+ Tem cells isolated from SR-aGvHD patients showed a significant lower expression of GR compared with CD8- cells from SR-aGvHD patients (median fluorescence intensity [MFI]: 1214 vs. 3020, P ＜0.001), CD8+ Tem cells from non-aGvHD and SS-aGvHD patients (MFI: 1214 vs. 3092 and 2292, P = 0.001). To characterize the mechanism underlying GR reduction, we analyzed the overlap of SR-associated differentially expressed genes in the comparison of SR-aGvHD with SS-aGvHD and non-aGvHD. A total of 297 common upregulated and downregulated genes showed the enrichment of immune regulation and cytokine signaling pathways. Cytokine receptors, including IL27RA, IL15RA, and IL2RB and co-stimulation molecules including TNFRSF9 and CD27 were increased in CD8+ Tem cells of SR-aGvHD samples. The protein kinase profilers demonstrated that STAT1, STAT3, PYK2, and AKT1/2/3 were significantly phosphorylated in CD8+ T cells from SR-aGvHD samples. The activities of STAT1, JUNB and FOSB regulons which regulate GR expression were significantly enriched in steroid-refractory CD8+ Tem cells. Furthermore, the higher phosphorylation of STAT1 was confirmed in SR-aGvHD samples by flow-cytometric analysis and western-blot. Primary CD8+ T cells treated with IL-2, IL-15 or IL-27 showed resistant to dexamethasone-induced apoptotic effects. For the first time, our data showed that cytokine pathways of IL-2, IL-15 or IL-27 promoted overactivation of CD28high CD8+ Tem cells, and the following phosphorylation of STAT1 reduced GR expression contributed to SR. Overactivated STAT1 in CD8+ Tem in the peri-engraftment phase might be a reliable indicator for SR-aGvHD.

Acute myeloid leukaemia(AML)is characterized mainly by an increase in the number of myeloid cells in the bone marrow and a decrease in the number of mature cells;AML accounts for 28％of leukaemia cases,and it has a five-year survival rate of only 30.5％[1].

AbstractBackgroundTo explore the effects of monitoring measurable residual disease and post‐remission treatment selection on the clinical outcomes of B‐cell acute lymphoblastic leukemia (B‐ALL) in adults.MethodsBetween September 2010 and January 2022, adult patients with B‐ALL who received combination chemotherapy, with or without allogeneic hematopoietic stem cell transplantation (allo‐HSCT), were included in the retrospective study, which was approved by the Ethics Committee and the observation of Declaration of Helsinki conditions.ResultsOne hundred and forty‐three B‐ALL patients achieved complete remission (CR) were included in the study, of whom 94 patients (65.7%) received allo‐HSCT in first complete remission (CR1).Multivariate analysis showed that the most powerful factors affecting OS were transplantation (hazard ratio [HR] = 0.540, p = 0.037) and sustained measurable residue disease (MRD) negativity (HR = 0.508, p = 0.037). The subgroup analysis showed that the prognosis of the allo‐HSCT group was better than that of the chemotherapy group, regardless of whether MRD was negative or positive after two courses of consolidation therapy. After consolidation therapy, the prognosis of patients with positive MRD remained significantly better in the allo‐HSCT group than in the chemotherapy group. However, no significant difference was observed in the prognosis between the allo‐HSCT and chemotherapy groups with negative MRD after consolidation therapy.ConclusionsB‐ALL patients who achieve sustained MRD negativity during consolidation therapy have excellent long‐term outcomes even without allo‐HSCT. Allo‐HSCT is associated with a significant benefit in terms of OS and DFS for patients who were with positive MRD during consolidation therapy.

Objective: The outbreak of COVID-19 not only raised public health concerns but also caused tremendous psychological distress. Deficits in fear played a role in the development and maintenance of posttraumatic stress symptoms (PTSS). We aimed to investigate the relationship between fear and PTSS during COVID-19 at two points. Method: The questionnaire at the first time of investigation (T1) was conducted through WeChat or phone from January 30, 2020 to February 25, 2020 as part of the psychological trauma recover project-5-6 in China. And the questionnaire at the second time of investigation (T2) was collected from March 17, 2021 to June 17, 2021. After 12 months, data from 150 participants were included in the final analysis. Fear was measured by a self-reported question. Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5) was designed to assess PTSS. Pearson correlation, multivariate regression analysis, and multiple mediator model were used as statistical analyses. Results: Fear reduced significantly over time. Participants with higher fear presented worse PTSS in both T1 and T2. Positive correlations between fear and PTSS of participants were found over time. Occupation and change of fear are significant predictors in the severity of PTSS over time. Change of fear partially mediated the relationship between the PCL-5 total score in T1 and the development of PTSS. Conclusion: Fear reduction was beneficial to trauma resilience. Future interventions could be developed to reduce excessive fear in facing natural disasters or following epidemics.

BackgroundChronic graft-versus-host disease (cGVHD) manifests with characteristics of autoimmune disease with organs attacked by pathogenic helper T cells. Recent studies have highlighted the role of T cells in cGVHD pathogenesis. Due to limited understanding of underlying mechanisms, preventing cGVHD after allogenic hematopoietic cell transplantation (HCT) has become a major challenge.Materials and methodsHere, we used a representative cGVHD model with the donor C57BL/6 to recipient BALB/c combination. Post-HCT, mice were treated with IgG or anti-CD4 monoclonal antibody. The severity of cGVHD was assessed by evaluating symptoms of cGVHD and histopathology examination (H&E) of target organs. Thymus gland damage and defects of the negative selection were assessed by analyzing the CD4+CD8+ double-positive thymocytes, cortical thymic epithelial cells and medullary thymic epithelial cells (mTECs). Immunotolerance of CD8+ T cells was assessed by detecting the expression of CD80, PD-1, GRAIL and IL-7Rα. Long-term cellular and humoral immunity associated with graft-versus-leukemia (GVL) effects were evaluated through detecting the percentage of CD4+ T cells, IgG, IgM and IgA concentrations, and performing tumor challenge experiment.ResultsDonor CD8+ T cells caused thymic epithelial cells damage and impaired negative selection in recipients, leading to generation of autoreactive T cells and causing cGVHD. Anti-CD4 mAb treatment promoted immune incompetence of thymus-infiltrating CD8+ T cells, facilitated recovery of CD4+CD8+ thymocytes and regeneration mTECs, and preserved negative-selection, but had no effects on the long-term cellular immunity and humoral immunity, resulting in preservation of GVL effect.ConclusionOur results indicate that anti-CD4 mAb therapy early post-HCT allows thymus recovery by inducing the immune tolerance of thymus infiltrated CD8+ T cells, thereby alleviating thymic epithelial cells damage, preserving negative selection, and preserving long-term GVL effect at the same time.

Primary plasma cell leukemia (pPCL) is a rare and aggressive form of plasma cell disorder, which accounts for ~70% of all PCL. Survival of pPCL remains poor, and is related with early mortality. There is no standard therapy for patients with pPCL. In the present study, a 26-year-old man who was diagnosed with pPCL was reported. The patient achieved stringent complete remission to the successful treatment of intensive chemotherapy combined with sequential autologous and allogeneic stem cell transplantation (SCT) followed by maintenance therapy with oral administration of ixazomib, thalidomide and dexamethasone (IRD regimen). Development of complex treatment algorithms that combine novel agents, SCT and post-transplantation remission strategies may translate into survival in patients with pPCL.

As reported, SETD2 is recurrently mutated in acute myeloid leukaemia (AML), but knowledge about the specifics is limited. We enrolled 530 consecutive newly diagnosed AML patients in our study, and we analysed the distribution pattern and prognostic role of SETD2 mutation in AML. SETD2 mutation was found to affect 6.3% of AML patients, and it frequently co-occurred with IDH2, NRAS and CEBPA mutations. SETD2-mutated patients saw excellent therapeutic responses but failed to gain better survival time than other patients. This could be because of the high recurrence and mortality in SETD2-mutated patients who have additional mutations, such as NRAS mutation.

The preferred donor (haploidentical donor [HID] versus matched unrelated donor [URD]) choice in patients with acquired severe aplastic anemia (SAA) who lack an HLA-matched sibling donor (MSD) and fail upfront immunosuppressive treatment (IST) therapy is unknown. We retrospectively investigated SAA patients (n = 58) who underwent allogeneic stem cell transplantation (allo-SCT) between January 2012 and October 2022. The 5-year overall survival (OS) and 5-year failure-free survival (FFS) were comparable among the URD (n = 8), HID (n = 25), and MSD (n = 25) cohorts (OS: mean, 87.5 ± 11.7% versus 98.0 ± 6.5% versus 83.3 ± 7.6% [P = .926]; FFS: mean, 60.0 ± 18.2% versus 87.0 ± 7.0% versus 78.3 ± 8.6% [P = .222]). Multivariate analysis revealed that primary engraftment failure independently predicted OS and secondary graft failure predicted FFS among SAA patients who underwent allo-SCT, but donor type and age were not predictive of these outcomes. An urgent second SCT for patients with engraftment failure may be an effective salvage treatment. Our findings show that an alternative donor SCT is indicated for eligible SAA patients without an MSD even if age ≥40 years.

Autologous stem cell transplantation (ASCT) is a salvage therapy for relapsed or refractory diffuse large B-cell lymphoma (DLBCL). We have developed a novel conditioning regimen called CEAC (oral semustine 250 mg/m2 d-6, etoposide 300 mg/m2 d-5 d-2, cytarabine 500 mg/m2 d-5 d-2, and cyclophosphamide 1200 mg/m2 d-5 d-2) In lymphoma patients in China. Here, we conducted a study to compare the conventional BEAM regimen with the CEAC regimen in 110 DLBCL patients. Propensity-score matching was performed in a 1:4 ratio (22 patients received BEAM and 88 received CEAC). Our results showed no significant difference in the overall response rate (95

Genetic heterogeneity poses a great challenge to the understanding and management of acute myeloid leukemia (AML). Knowledge of the IKZF1 mutation in AML specifically is extremely limited. In a previous work, we described the distribution pattern of IKZF1 mutation in AML, but its clinical impact has remained undefined due to the limited number of cases. Herein, we attempt to answer this question in one relatively large cohort covering 522 newly diagnosed AML patients. A total of 26 IKZF1 mutations were found in 20 AML patients (20/522, 3.83%). This condition has a young median age of onset of morbidity (P = 0.032). The baseline characteristics of IKZF1-mutated and wild-type patients were comparable. IKZF1 mutation showed significant co-occurrences with CEBPA (P < 0.001), SF3B1 (P < 0.001), and CSF3R (P = 0.005) mutations, and it was mutually exclusive with NPM1 mutation (P = 0.033). Although IKZF1-mutated AML was more preferably classified into the intermediate-risk group (P = 0.004), it showed one inferior complete remission rate (P = 0.032). AML with high burden of IKZF1 mutation (variant allele frequency > 0.20) showed relatively short overall survival period (P = 0.012), and it was an independent factor for the increased risk of death (hazard ratio, 6.101; 95% CI 2.278-16.335; P = 0.0003). In subgroup analysis, our results showed that IKZF1 mutation conferred poor therapeutic response and prognosis for SF3B1-mutated AML (P = 0.0017). We believe this work improves our knowledge of IKZF1 mutation.

A standard salvage regimen for patients with acute myeloid leukemia (AML) who are not in complete remission (CR) after initial induction therapy does not exist. We retrospectively investigated re-induction therapy for 151 patients with AML who did not achieve CR after the initial course between January 2014 and March 2021. The re-induction regimen did not correlate with the CR rate after the second course, whereas patients had similar 5-year overall survival (OS) and event-free survival (EFS) based on different re-induction regimens. Multivariable analysis revealed that International European Leukaemia Net (ELN) risk stratification independently predicted both OS and EFS among patients not in CR after the first course, although the re-induction regimen did not predict prognosis. Urgent salvage alloHSCT may improve the prognosis of patients with refractory AML. In summary, our study showed that the re-induction regimen did not significantly predict the prognosis of patients with AML not in CR after the first course of treatment. The development and selection of an efficient treatment algorithm for the treatment of AML remains a pressing research challenge.

Background: Extranodal involvement is recognized as a poor prognostic factor for diffuse large B-cell lymphoma (DLBCL). However, the prognostic differences of patients with refractory/relapsed (R/R) nodal and extranodal DLBCL in the chimeric antigen receptor T cell (CART) therapy era are still unclear. Materials and methods: In this study, 18 R/R nodal DLBCL (R/R N-DLBCL) and 19 R/R extranodal DLBCL (R/R EN-DLBCL) were enrolled to compare clinical outcomes. Results: The median follow-up time was 13 (range, 1-47) months and one-year progression-free survival (PFS; 83.3% vs. 42.1%, P = 0.008) and one-year overall survival (OS; 94.4% vs. 63.2%, P = 0.020) were significantly different between nodal and extranodal patients. In the multivariable Cox regression analysis, R/R EN-DLBCL was associated with worse PFS (hazard ratio [HR] = 4.263, P = 0.018) and OS (HR = 9.589, P = 0.034) compared to R/R N-DLBCL. Additionally, autologous hematopoietic stem cell transplantation (ASCT) combined with CART therapy (ASCT + CART) was correlated with better PFS (HR = 0.164, P = 0.003) compared to CART treatment alone. Conclusions: The clinical outcomes of R/R EN-DLBCL were worse than R/R N-DLBCL in patients receiving CART therapy and ASCT + CART therapy is a promising alternative treatment for patients with R/R EN-DLBCL.

Acute myeloid leukemia (AML) patients relapsing after allogeneic hematopoietic stem cell transplantation (allo-HSCT) have a poor prognosis. Cytogenetic evolution (CGE) has been investigated and found to have an important impact on the prognosis of relapsed leukemia, but its impact on AML patients relapsing after transplantation remains controversial. In this study, we analyzed 34 AML patients relapsing after allo-HSCT, among whom 14 developed additional abnormalities in chromosomal karyotype after leukemia recurrence (CGE group) and 20 patients did not (non-CGE group). We found that the cytogenetic characteristics were much more complex at relapse in the CGE group, and the acquisition of aberrations at relapse most commonly involved chromosome 11. The 6-month post-relapse overall survival (PROS) of the CGE group was significantly lower than that of the non-CGE group (21.4