Erythroblastic sarcoma is a rare and aggressive hematologic malignancy presenting as a mass-forming extramedullary proliferation of immature erythroid cells. Myeloid/lymphoid neoplasms with JAK2 rearrangement, most often PCM1::JAK2, may show eosinophilia, myelofibrosis, and expansion of immature erythroid precursors. NUTM1 rearrangements, initially recognized as defining alterations of NUT carcinoma, have subsequently been identified in selected hematologic malignancies but remain exceptionally rare in myeloid neoplasms. Here, we report an adult erythroblastic sarcoma harbouring concurrent PCM1::JAK2 and a novel NOP10::NUTM1 fusion, accompanied by partial chromosome 8p deletion and complicated by secondary hemophagocytic lymphohistiocytosis. To our knowledge, this is the first reported adult erythroblastic sarcoma with concurrent PCM1::JAK2 and NOP10::NUTM1 fusions. This case extends the molecular spectrum of erythroblastic sarcoma and underscores the value of integrated morphologic, immunophenotypic, cytogenetic, and genomic assessment in diagnostically challenging erythroid neoplasms.

The tumor necrosis factor (TNF) receptor superfamily member, transmembrane activator and CAML interactor (TACI) encoded by TNFRSF13B, are extensively involved in immune responses. In our previous work, TNFRSF13B exon 2 variants were recurrently identified in chronic active Epstein-Barr virus disease (CAEBV). Here we aim to reveal the roles of TNFRSF13B variants in CAEBV, and investigate the feasibility of targeting TNFRSF13B/TACI as a new approach to control EBV infection. The lymphoblastoid cell lines (LCL) models carrying homozygous TNFRSF13B exon 2 frameshift mutations were constructed using CRISPR/Cas9. Immunological assays, transcriptomic analysis, and gene silencing experiments were performed on LCL models to measure the effect of TNFRSF13B exon 2 variants and explore the underlying mechanisms. TACI ligands and a TLR9 agonist were applied to modulate TACI signaling and EBV activities. Frameshift mutations in exon 2 of TNFRSF13B significantly up-regulated the short isoforms of TACI (TACI-S) at the expense of its long isoforms (TACI-L) in LCLs. The up-regulated TACI-S induced more intense activation of NF-κB, MAPK, and Rho signaling pathways, leading to the switch of EBV activities to lytic reactivation. The subsequent increased viral load and viral IL-10 provide a rational for the susceptibility of variant carriers to CAEBV. The BAFF trimer, an indirect TACI-signaling inhibitor, also significantly suppressed the EBV lytic program. Gene silencing experiments indicated that XBP-1 might be involved in the TACI-mediated regulation of EBV lytic activities in EBV-immortalized B cells. This study underscores the impact of TNFRSF13B variants on EBV infection and host immune responses, offering insights into CAEBV pathogenesis and potential therapeutic strategies.

Background:Advanced bulky tumors cause pain, hemorrhage, and functional impairment, but their volume, hypoxic core, and proximity to organs at risk limit dose escalation with conventional radiotherapy. Lattice radiotherapy (LRT) delivers ablative doses to intratumoral vertices while sparing peripheral tissue. We evaluated personalized LRT on standard flattening-filter (FF) linacs, alone or with radiotherapy. Methods:Seven patients (8 sites) with advanced bulky tumors treated February-November 2025 using 6 MV VMAT in FF mode were retrospectively reviewed. LRT (1-5 fractions of 6-15 Gy) was individualized by performance status, prior therapy, and tumor geometry; additional radiotherapy was at physician discretion. Co-primary endpoints were symptom relief (NRS, analgesic use, tumor-related symptoms) and local disease control; acute toxicity was secondary. Results:Median age was 69 years, median ECOG 2 (1-3), and mean tumor volume 370.7 cc (101.8-792.4 cc). All patients completed planned LRT. Symptom improvement occurred in 6 of 8 sites (75%), usually within two weeks. At median follow-up of 8 months (4-12), partial response (PR) was achieved in 5 of 8 sites (62.5%), stable disease (SD) in 2 (25.0%), and progressive disease (PD) in 1 (12.5%); the disease control rate (DCR = CR + PR + SD) was 7/8 (87.5%), with no complete response (CR) observed. Acute toxicity occurred in 3 patients (all grade 1-2, mainly fatigue and mild dermatitis); no grade ≥3 events occurred. Conclusion:Personalized LRT on FF linacs was feasible and well tolerated, with encouraging early palliative benefit in this small, heterogeneous cohort, supporting prospective evaluation with standardized symptom-assessment tools.

We report a case of a 30-year-old male patient with a germline heterozygous TET2 R1354fs mutation, who successively developed three distinct lymphoid malignancies: mixed cellularity classical Hodgkin lymphoma (MCCHL), angioimmunoblastic T-cell lymphoma (AITL), and T-cell acute lymphoblastic leukemia (T-ALL). Sequencing analysis of the oral mucosa and bone marrow specimens during the remission phase confirmed the germline origin of the TET2 mutation. This represents the first documented case of the sequential transformation across three distinct lymphoid malignancies attributable to a germline TET2 mutation, underscoring its pivotal role in lymphomagenesis and clonal evolution.

Although BRAF/MEK inhibitor (BRAFi/MEKi) therapy initially shows high efficacy in patients with BRAF V600 E/K cutaneous melanoma, resistance develops in over 75% of cases. We tested robustness of the umbrella trial strategy in this population by analyzing relationships between genomic status of a gene and associated downstream consequences at the protein level. The results revealed weak relationships among mutations, copy-number amplification, and protein expression and activation. An in vivo compound repurposing screen using 11 clinically relevant agents from an NCI-portfolio with pan-RTK, non-RTK, and/or PI3K-mTOR specificity identified dasatinib as most capable of restoring sensitivity to BRAFi/MEKi in patient-derived xenograft (PDX) models originating from tumors that had progressed on BRAFi ± MEKi. High baseline expression of BRAFi/MEKi resistance-associated proteins (e.g., AXL, YAP, HSP70, and phospho-AKT) was predictive of the response to BRAFi/MEKi + dasatinib combination therapy. These findings suggest that adding dasatinib may help overcome resistance and restore anti-tumor activity in patients with BRAFi/MEKi-refractory cutaneous melanoma.

Chemotherapy resistance represents a major challenge in relapsed and refractory acute myeloid leukemia (AML). Therefore, it is necessary to investigate the mechanisms underlying chemotherapy resistance in AML. INSR not only highly expressed in AML cells treated with chidamide, but also elevated in AML patients. Subsequent overexpression and knockdown experiments of INSR in AML cells demonstrated that INSR facilitates cell cycle transition from G1 to S phase and promotes AML cell proliferation. Furthermore, INSR upregulates vimentin and N-cadherin expression, thereby enhancing cell invasion and migration. By integrating transcriptome sequencing data with gene expression profile interactive analysis, we discovered that AKT1 expression levels were positively correlated with INSR expression, while AKT1 expression exhibited a negative correlation with the prognosis of AML patients. AKT1 expression inhibition reduced the proliferation and migratory activity of AML cells. Additionally, suppressing AKT1 expression diminished the impact of INSR on promoting AML cells proliferation, invasion, and migration. This study indicates that INSR expression is elevated in AML cells after treating with chidamide and that INSR promotes AML cells proliferation and migration by upregulating AKT1 expression.

AAV-based gene therapy targeting adipose tissue has been underdeveloped due to lack of adipose-tropic AAV vectors with sufficient transduction efficiency. We previously demonstrated that an engineered capsid variant of Rec2 capsid with F503Y, Y708D and K709I substitution (named V7 capsid) exhibited highly selective adipo-tropism while ablating liver transduction upon intraperitoneal injection or intravenous injection. In this study, we investigated the feasibility of subcutaneous administration of V7 vector harboring human leptin (V7-LEP) in a congenital leptin deficiency model ob/ob mice. Subcutaneous administration of V7-LEP vector at a low dose of 4×1010 viral genome per mouse restored circulating leptin levels and completely normalized metabolic abnormalities associated with leptin deficiency. In an ongoing long-term experiment, one-time subcutaneous administration of V7-LEP to extreme obese ob/ob mice has led to sustained weight loss at least up to 9 months post injection associated with stable circulating human leptin levels throughout the long-term study. These data indicate subcutaneous injection is a feasible and relevant administration route for gene therapy targeting adipose tissue, and V7-LEP is highly efficacious for congenital leptin deficiency and potentially other lipodystrophy disorders with leptin deficiency.

The subjectivity of morphological assessment and the overlapping pathological features of different subtypes of myeloproliferative neoplasms (MPNs) make accurate diagnosis challenging. To improve the pathological assessment of MPNs, we developed a diagnosis model (fusion model) based on the combination of bone marrow whole-slide images (deep learning [DL] model) and clinical parameters (clinical model). Thousand and fifty-one MPN and non-MPN patients were divided into the training, internal testing and one internal and two external validation cohorts (the combined validation cohort). In the combined validation cohort, fusion model achieved higher areas under curve (AUCs) than clinical or DL model or both for MPNs and subtype identification. Compared with haematopathologists with different experience, clinical model achieved AUC which was comparable to seniors and higher than juniors ( p  = 0.0208) for polycythaemia vera. The AUCs of fusion model were comparable to seniors and higher than juniors for essential thrombocytosis ( p  = 0.0141), prefibrotic primary myelofibrosis ( p  = 0.0085) and overt primary myelofibrosis ( p  = 0.0330) identification. In conclusion, the performances of our proposed models are equivalent to senior haematopathologists and better than juniors, providing a new perspective on the utilization of DL algorithms in MPN morphological assessment.

Background While chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment landscape for certain hematologic malignancies, therapeutic resistance and disease relapse highlight the critical need to improve the durability of clinical responses. The limited in vivo persistence and antitumor efficacy of CAR-T cells remain major barriers to achieving sustained therapeutic outcomes. Although CD5 has been extensively studied as a therapeutic target in cancers, particularly T-cell malignancies, its role as an immunomodulatory molecule in T cell-based immunotherapy remains poorly understood. Here, we developed a CD5-deficient T cell-based immunotherapy using the CRISPR-Cas9 system to address these limitations and enhance antitumor potency.Methods Employing green fluorescent protein knock-in murine models alongside clinical specimens, we examined the in vivo persistence of CD5-deficient T cells and their influence on T-cell receptor (TCR) clonality diversity. The antitumor efficacy of CD5-deficient engineered T cells was assessed in tumor cell line-derived xenograft murine models. To elucidate underlying mechanisms, we performed a comprehensive evaluation of the activation, expansion and infiltration of CD5-deficient engineered T cells in response to antigen stimulation, as well as their exhaustion dynamics under conditions of repeated antigen exposure.Results Our study identifies CD5 as a bona fide inhibitory immunomodulatory molecule. CD5 ablation significantly enhances T cell functionality by enhancing the activation level, mitigating exhaustion, promoting CD8+ T cell expansion, and improving in vivo persistence. Single-cell transcriptomic profiling of patient-derived CD5-deficient T cells revealed distinct effector subsets with elevated cytotoxicity markers and cell cycle regulators, such as STMN1, which correlate with enhanced expansion while preserving clonal diversity, as evidenced by TCR repertoire analysis.Conclusions These collective findings establish CD5 ablation as a viable strategy to circumvent the intrinsic limitations of current T cell-based therapies, providing a mechanistic rationale for clinical translation.

UNC13D, which encodes the Munc13-4 protein, is a critical gene implicated in type 3 familial hemophagocytic lymphohistiocytosis (HLH). While biallelic nucleotide variants in HLH-related genes, including UNC13D, are traditionally linked to recessive inheritance patterns in HLH, emerging evidence suggests that heterozygous variants may also contribute to the onset of adult-onset HLH. However, the pathogenicity of heterozygous UNC13D variants is still not fully understood. Here, we present a 29-year-old male patient with Epstein-Barr virus (EBV)-triggered adult-onset HLH, who was found to carry compound heterozygous variants in the UNC13D gene (c.2588G>A and c.1978_1979insATTACCG) with complete T/NK cytotoxicity dysfunction. We conducted NK-cell function assay in this pedigree to link the genotype to phenotype and demonstrated that the monoallelic UNC13D c.2588G>A variant could partially impair NK cell cytotoxicity, in contrast to the completely recessive inheritance observed with UNC13D c.1978_1979insATTACCG and other familial HLH-related variants. In addition, to explore the implication of UNC13D c.2588G>A variant in various diseases, we reviewed 16 published studies, including data on 35 patients carrying this variant. Data showed the heterozygous variant of UNC13D c.2588G>A might act as a genetic risk factor predisposing carriers to conditions like HLH, lymphoma, etc. This study underscores the pathogenic role of the UNC13D c.2588G>A variant and expands our understanding of the genetic basis of adult-onset HLH.

Acute myeloid leukemia (AML) is a highly heterogeneous disease, and molecular events such as DNMT3A gene mutations are associated with poor prognosis in AML patients. Consequently, there is an urgent need for a novel therapeutic approach for AML. DNMT3A mRNA and protein expression were confirmed in DNMT3A-mutant AML cells via RT-qPCR and Western blotting. Cell proliferation and apoptosis were assessed via CCK-8 and Annexin V/PI staining, respectively. Flow cytometry was used to analyze surface antigens and CD44v6 CAR-T-cell transfection efficiency. CD44v6-directed CAR plasmids were constructed, and lentiviruses were packaged. Methylation-specific PCR was used to evaluate differences in promoter methylation, whereas ELISA was used to measure cytokine secretion. In this study, we found that the DNMT3A-mutant group presented significantly increased expression of CD44v6 on the cell surface. Methylation of the CD44 promoter region was lower in the mutant group than in the control group. CD44v6 CAR-T cells exhibited specific cytotoxicity against DNMT3A-mutant AML cells. Furthermore, pretreatment with low concentrations of decitabine significantly enhanced the killing effect of CD44v6 CAR-T cells on DNMT3A-mutant AML cells (P < 0.05). Additionally, decitabine treatment upregulated the expression of CD44v6 on the surface of DNMT3A-mutant AML cells (P < 0.05). CD44v6 is a promising CAR-T-cell therapy target in AML patients with DNMT3A mutations. Notably, treatment with decitabine resulted in increased CD44v6 expression on the cell surface of DNMT3A-mutant AML cells. This increase in CD44v6 expression facilitates improved recognition and targeting by CD44v6 CAR-T cells.

Although most cases of Burkitt lymphoma (BL) respond well to chemotherapy, relapsed or refractory BL, particularly in the presence of TP53 aberrations, presents a significant therapeutic challenge. TP53 germline or mosaic mutations, though rare, are clinically relevant in lymphomas as they persist in both lymphoma cells and autologous chimeric antigen receptor (CAR)-T cells, potentially influencing treatment outcomes. Here, we report the first documented case of a TP53 mosaic mutation and a 17p deletion in an adult patient with refractory BL. After four cycles of unsuccessful standard induction chemotherapy, the patient received CAR-T cell therapy combined with autologous stem cell transplantation. The comprehensive treatment plan included radiotherapy bridging, sequential infusions of CD19 and CD22 CAR-T cells, and maintenance therapy with chidamide, obinutuzumab, sintilimab, and azacitidine. Two months postinfusion, the patient achieved complete remission, which has been sustained for 24 months to date. This case indicates that, despite the challenges posed by multiple-hit TP53 aberrations in refractory BL, a multifaceted therapeutic approach can achieve positive outcomes. Furthermore, based on previous studies and our findings, we speculate that TP53 alterations may play a biphasic role in this patient's CAR-T therapy: in lymphoma cells, TP53 alterations impair CAR-T cell cytotoxicity, while in CAR-T cells, they may promote enhanced expansion and persistence. This potential dual role might help explain why TP53 deficiency does not universally affect the efficacy of CAR-T therapy in certain studies.

Expanding the repertoire of CAR therapies to include intracellular antigens holds promise for treating a broad spectrum of malignancies. TCR-like T cells, capable of recognizing intracellular antigen-derived peptides in complex with HLA molecules (pHLA), represent a promising strategy in the field of engineered cellular therapy. This study introduced antibody-like TCR (abTCR) T cells that specifically targeted HLA-A*02:01-restricted LMP2426 peptides, a typical Epstein-Barr virus (EBV) latency II protein, for the treatment of EBV-associated lymphoproliferative diseases (EBV-LPDs). Compared with classic CAR T cells targeting the same epitope, abTCR T cells demonstrated superior efficiency, including increased CD107A expression, enhanced cytotoxicity, and elevated IFN-γ secretion, even when engaging with target cells that naturally present antigens. Moreover, a costimulatory signal-armed abTCR (Co-abTCR), which integrated a costimulatory structure with the abTCR, further enhanced the proliferation and in vivo tumoricidal efficacy of transfected T cells. Collectively, our study developed a potentially novel TCR-like T cell therapy that targets HLA-A*02/LMP2426 for the treatment of EBV-LPDs, providing a potential therapeutic solution for targeting of intracellular antigens in cancer immunotherapy.

Background: There is no consensus on treatment strategies for relapsed or refractory acute myeloid leukemia (R/R AML) and myelodysplastic syndrome (MDS). Non-chemotherapy strategies such as the “XAB” regimen, which combines selinexor, an inhibitor of exportin-1 (XPO1), with azacitidine (A) and venetoclax, a BCL-2 inhibitor (B), are currently widely studied. However, considerable heterogeneity among patients results in varying treatment efficacy. Our study aimed to explore the application of early assessment in AML and MDS patients receiving the XAB regimen. Methods: This study was conducted at Tongji Hospital. Patients aged 18-70 years diagnosed with AML and MDS were included. The specific XAB regimen consisted of selinexor 35mg/m2 twice weekly for two consecutive weeks, azacitidine 75mg/m2/d on days 1-5, and venetoclax 100mg on day 1, 200mg on day 2, followed by 400mg daily. Patients underwent bone marrow (BM) examinations on days 7 and 14. Based on BM examination on day 7, patients were categorized into early response (≥50% decrease in BM blast percentage compared to baseline), early minimal response (<50% decrease), and early non-response (no change or increase). If the patient exhibits an early response, the current course of treatment will continue. In cases of early minimal response, 50mg per day of cytarabine will be added for 5 days. For patients showing early non-response, the current treatment will stop. Patients who did not achieve complete remission (CR)/CR with incomplete hematologic recovery (CRi) but partial remission (PR) after the initial course will receive an additional cycle of treatment. Patients achieving CR/CRi can subsequently undergo hematopoietic stem cell transplantation (HSCT) or receive consolidation and maintenance therapy based on the XAB regimen, while those with persistent non-remission (NR) will stop the XAB regimen and receive alternative therapy. Results: As of July 22, 2024, 23 patients receiving the XAB regimen enrolled. Baseline characteristics included: median age of 51; Male: Female =13:8; R/R AML and MDS incidences were 14 and 1, respectively, while newly diagnosed AML and MDS were 6 and 2, respectively. Of the 23 patients, 18 showed an early response, 4 early minimal response, and 1 early non-response. After one course of treatment, 13 (56.5%) patients achieved CR/CRi, and 3 patients achieved PR, 2 of whom received another cycle of the XAB regimen, resulting in 1 patient achieving CR. Additionally, 7 patients were NR. Based on changes in BM blast percentage on days 7 and 14, patients were classified into four groups: (1) early decrease to ≤5% with no subsequent increase. (2) gradual early decrease >5% with continued decrease. (3) early decrease followed by increase. (4) early increase. Among the 23 patients, 10 belonged to Group 1, all achieving CR/CRi. By the end of follow-up, 1 patient died from severe infection. 6 patients belonged to Group 2, of whom 3 achieved CR/CRi, 1 died from disease progression, and 2 died from transplant-related complications. 6 patients belonged to Group 3, of whom 2 died from disease progression. 1 patient belonged to Group 4, who died from disease progression. None of the patients in Group 3 and Group 4 achieved CR/CRi. Patients in Group 1 showed the best response to the XAB regimen, indicating potential for subsequent HSCT or consolidation and maintenance therapy based on the XAB regimen. Patients who did not achieve early CR/CRi showed a gradual decrease in BM blast percentage (Group 2), even achieving CR eventually, while other patients experienced subsequent elevation of BM blast percentage (Group 3), indicating resistance to the XAB regimen. For these patients in Group 2 and Group 3, an early comprehensive evaluation system is imperative to establish, incorporating methods such as minimal residual disease detection and risk stratification to evaluate and intervene promptly, thereby improving prognosis. Patients with an early increase in BM blast percentage (Group 4) showed poor response to the XAB regimen and should be promptly discontinued for alternative therapies. Conclusion: Early assessment has predictive value for efficacy and prognosis in patients who received an XAB regimen, helping us make prompt decisions to select the most effective treatment for patients.

Background: Refractoriness and relapse after chimeric antigen receptor T-cell therapy have emerged as major challenges for immunotherapy of aggressive large B-cell lymphoma. Thus far, there is no consensus on how to address treatment failure and whether to administer maintenance therapy following CAR-T cell therapy. Methods: From August 2017 through November 2022, 52 patients with refractory/relapsed aggressive LBCL who had a high risk of resistance to CAR-T cell therapy were given chidamide in combination with a PD-1 inhibitor as maintenance therapy following either CAR19/22 T-cell cocktail therapy or CAR19/22 T-cell cocktail therapy plus autologous stem cell transplantation (ASCT). Another 52 aggressive LBCL patients who had comparable baseline characteristics and received similar therapeutic regimens but did not receive any interventions following CAR-T cell therapy or CAR-T cell therapy plus ASCT were regarded as the control group to evaluate the efficacy and safety of the combination of chidamide and a PD-1 inhibitor. Results: Among the 52 patients who received chidamide and a PD-1 inhibitor as maintenance therapy, with a median follow-up of 26.5 months (range: 1.1-53.8), neither the median progression-free survival (PFS) nor overall survival (OS) was reached, and the expected 2-year OS and PFS rates were 89 % and 77 %, respectively, which were superior to those of the control group (p < 0.001). Long-term chidamide administration and a specific genetic subtype of EZB were strongly associated with a better response after chidamide plus PD-1 blockade therapy. Additionally, long-term chidamide administration was significantly associated with prolonged persistence and reactivation of CD19-directed CAR-T cells in the peripheral blood. Adverse effects (AEs) were moderate and reversible, and no treatment-related deaths occurred. Conclusion: Our results indicate that the combination of chidamide and PD-1 blockade as maintenance therapy could improve the outcomes of aggressive LBCL patients at high risk of failing CAR-T cell therapy.

Hyperbilirubinaemia is a prevalent condition during the neonatal period, and if not promptly and effectively managed, it can lead to severe bilirubin-induced neurotoxicity. Sunflower seeds are a nutrient-rich food source, particularly abundant in linoleic acid. Here, we provide compelling evidence that lactating maternal mice fed a sunflower seed diet experience enhanced neurological outcomes and increased survival rates in hyperbilirubinemic offspring. We assessed histomorphological indices, including cerebellar Nissl staining, and Calbindin staining, and hippocampal hematoxylin and eosin staining. Furthermore, we observed the transmission of linoleic acid, enriched in sunflower seeds, to offspring through lactation. The oral administration of linoleic acid-rich sunflower seed oil by lactating mothers significantly prolonged the survival time of hyperbilirubinemic offspring mice. Mechanistically, linoleic acid counteracts the bilirubin-induced accumulation of ubiquitinated proteins and neuronal cell death by activating autophagy. Collectively, these findings elucidate the novel role of a maternal linoleic acid-supplemented diet in promoting child health.

TET2 is a critical gene that regulates DNA methylation, encoding a dioxygenase protein that plays a vital role in the regulation of genomic methylation and other epigenetic modifications, as well as in hematopoiesis. Mutations in TET2 are present in 7

Background: MCD (MYD88(L265P)/CD79B(mut)) diffuse large B-cell lymphoma has a poor prognosis. There is no published clinical research conclusion regarding zanubrutinib or orelabrutinib for the initial treatment of MCD DLBCL. Aims: This study aimed to analyse the efficacy and safety of Bruton's tyrosine kinase inhibitor (BTKi) (zanubrutinib or orelabrutinib) therapy for newly diagnosed DLBCL patients with MYD88(mut) and/or CD79B(mut). Materials and Methods: Twenty-three newly diagnosed DLBCL patients with MYD88(mut) and/or CD79B(mut) from June 2020 to June 2022 received BTKi combined with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or rituximab + lenalidomide (R-2). A control group of 17 patients with MYD88(mut) and/or CD79B(mut) DLBCL who received the standard R-CHOP therapy was also assessed. We retrospectively analysed clinical characteristics, safety, overall response rate (ORR), complete response (CR) rate and progression-free survival (PFS) of the two groups. Results: The main clinical features were a high International Prognostic Index (IPI) score (>= 3, 22/40, 55%) and a high rate of extranodal involvement (27/40,67.5%). Among the 23 DLBCL patients, 18 received BTKi + R-CHOP, and five elderly DLBCL patients were treated with BTKi + R-2. Compared with those in the control group (ORR 70.6%, CRR 52.9%, 1-year PFS rate 41.2%), improved ORR, CRR and PFS results were observed in the BTKi + R-CHOP group (100%, 94.4% and 88.9%, p = 0.019, 0.007, and 0.0001). In subgroup analyses based on genetic subtypes, cell origin, dual expression or IPI score, patients in the BTKi + R-CHOP group had better PFS than patients in the control group. In the BTKi + R-CHOP group, no significant difference was found in ORR, CRR and PFS based on subtype analysis, while BTKi-type subgroups exhibited statistically significant differences in 1-year PFS (p = 0.028). There were no significant differences in grade 3-4 haematological toxicity (p = 1) and grade 3-4 non-haematological toxicity (p = 0.49) between the BTKi + R-CHOP and R-CHOP treatment groups. In the BTKi + R-2 group, the ORR was 100%, the CRR was 80%, and the 1-year PFS rate was 80%. The incidences of grade 3-4 haematologic toxicity and non-haematological toxicity were both 40%. No bleeding or cardiovascular events of grade 3 or higher occurred in any patients. Discussion: The efficacy of BTKi combined with R-CHOP was similar to previous reports, which was significantly better than R-CHOP alone. It is necessary to fully consider that 14 patients in the BTKi + R-CHOP group received a BTKi as maintenance therapy when evaluating efficacy. Meanwhile, the addition of a BTKi may improve the prognosis of non-GCB, DEL or high-IPI-score DLBCL patients with MYD88(mut) and/or CD79B(mut). In our study, five elderly DLBCL patients with MYD88(mut) and/or CD79B(mut) were achieved better ORR, CRR, PFS than the historical data of R-miniCHOP treatment and Ibrutinib + R-2 treatment. However, the efficacy and benefit of BTKis for this type of DLBCL need to be further analysed using a larger sample size. Conclusion: This study suggests that newly diagnosed DLBCL patients with MYD88(mut) and/or CD79B(mut) may benefit from BTKis according to real-world clinical data.

Key Clinical Message Immune checkpoint inhibitors are a very popular method of treating malignant tumors. But its side effects cannot be ignored. This study revealed obstructive complications during immune consolidation therapy following sequential chimeric antigen receptor T cell therapy with autologous hematopoietic stem cell transplantation in two patients with diffuse large b cell lymphoma (DLBCL). Both our patients had the same symptoms of vomiting and inability to eat due to pyloric obstruction, it should be highlighted that this is a relatively rare and irreversible complication of upper gastrointestinal caused by immune consolidation therapy. Abstract Immune checkpoint inhibitors (ICIs) have become the standard therapy for many malignant tumors.However, ICIs are associated with unique immune‐related adverse events (irAEs) caused by dysregulated immune activation and associated complications have been observed in patients. Here, we report two cases of patients with pyloric obstruction and duodenal ulcers induced by the use of sintilimab, which provides some guidance for the widely used anti‐programmed death‐1 therapy. During the entire treatment progression for such patients, the correct differential diagnosis of adverse effects and the use of immunosuppressive agents such as glucocorticoids are essential to facilitate early prevention and intervention of irAEs.