Qian Cheng

Background: Relapsed B-cell acute lymphoblastic leukemia (B-ALL) after allogeneic hematopoietic stem-cell transplantation (allo-HSCT), particularly with extramedullary disease (EMD), has a dismal prognosis. The efficacy and durability of allogeneic chimeric antigen receptor T cell (allo-CAR-T) therapy in this setting remain unclear. Methods: Fourteen patients with post-transplant relapsed B-ALL received allogeneic anti-CD19 CAR-T cells, including eight with EMD. Clinical responses, survival, CAR-T kinetics, and toxicities were evaluated. Results: With a median follow-up of 13.8 months (range, 4.4–52.9 months), the overall complete remission (CR) rate was 92.9% (13/14), with a median duration of remission (DOR) of 12.7 months (range, 3.5–50.3 months). Among patients with EMD, 87.5% (7/8) achieved CR, with a median DOR of 14.7 months (range, 3.5–50.3 months). Of the eight patients with EMD, four were Philadelphia chromosome-positive and received maintenance therapy with tyrosine kinase inhibitors after allo-CAR-T, including dasatinib ( n =1), ponatinib ( n =2), and olverembatinib ( n =1). Median overall survival and event-free survival were not reached in either the overall cohort or EMD subgroup. CAR-T cells persisted in vivo for a median of 5.9 months (range, 1.2–51.6 months). One patient experienced grade 3 cytokine release syndrome and grade 4 immune effector cell-associated neurotoxicity syndrome. One patient developed acute gastrointestinal graft-versus-host disease, followed by chronic graft-versus-host disease involving the skin and lungs. Conclusion: Allo-CAR-T therapy induces sustained remissions in patients with post-transplant relapsed B-ALL, including patients with EMD, and may serve as an effective backbone for tailored combination strategies. Trial registration: ChiCTR2000036350, registered on August 22, 2020; retrospectively registered.

Acute leukemia (AL) is an aggressive hematologic malignancy that often causes serious complications and requires intensive care unit (ICU) treatment. Identifying risk factors for mortality in AL patients during and post-ICU admission can improve prognosis. This retrospective study enrolled AL patients first admitted to the ICU of the Third Xiangya Hospital, Central South University, from November 2008 to October 2023. It analyzed risk factors associated with ICU mortality, 1-month mortality and 6-month mortality, and conducted a subgroup analysis of the prognosis of ICU survivors. A total of 126 patients were included in this study, with a median age of 42 years. Acute respiratory failure (46%) and sepsis (23%) were the main reasons for ICU admission. Overall, the mortality rates were 57.9% in the ICU, 67.5% at 1 month, and 69% at 6 months. Notably, among the ICU survivors, 26.4% (14/53) died within 6 months, with 85.7% (12/14) occurring within the first month. The time from hospital admission to ICU transfer >10 days and invasive mechanical ventilation were independent risk factors for ICU mortality, 1-month mortality and 6-month mortality. Relapsed or refractory leukemia (OR = 20.715) and low albumin levels (OR = 34.428) were independent risk factors for death within one month among ICU survivors. The risk factors for mortality in AL patients admitted to the ICU exhibit dynamic changes across different stages. For ICU survivors, optimizing nutritional support and initiating anti-tumor treatment as early as possible after discharge are crucial for improving prognosis.

Disease relapse is a major cause of treatment failure after allogeneic haematopoietic stem cell transplantation (allo-HSCT) in patients with acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). We retrospectively evaluated all patients (n = 145) with high-risk AML and MDS who underwent allo-HSCT between 2016 and 2022. Among them, 53 patients received maintenance therapy with azacitidine (AZA), and 10 of these patients received preemptive therapy. The rest of the 92 patients were in the control arm. The median follow-up time was 1215 days (103–3173 days). The median number of administered AZA cycles was 8. The 2-year relapse-free survival was 86.8% (46/53) in the AZA group compared with 76.1% (70/92) in the control group (P = 0.121). The 2-year overall survival in the AZA and control groups were 88.7% (47/53) and 82.6% (76/92), respectively (P = 0.326). Six patients (11.3%) in the AZA group experienced relapse, all of whom had a minimal residual disease (MRD)-positive status pre-HSCT. A total of 17 (32.1%) patients experienced grade 3–4 adverse events. In the preemptive therapy group, 70% (7/10) of the patients achieved complete remission after AZA treatment. AZA maintenance therapy following allo-HSCT is well tolerated and further follow-up and a larger group of patients will be necessary to confirm the potential to prevent relapse. The pre-transplant MRD status was identified as an important factor affecting the efficacy of AZA maintenance therapy.

The prognosis of multiple myeloma (MM) patients combined with renal insufficiency is poor. Renal fibrosis is an important pathological cause for MM patients combined with renal insufficiency. It is reported that epithelial–mesenchymal transition (EMT) of renal proximal tubular epithelial cells is an important mechanism in renal fibrosis. We speculated that EMT might play an important role in the renal insufficiency of MM with unclear mechanism. MM cells derived exosomes could affect the function of targeted cells by delivering microRNAs (miRNAs). Literature has shown that the expression of miR‐21 is closely related to EMT. In this research, we found that co‐culture of HK‐2 cells (human renal proximal tubular epithelial cells) and exosomes derived from MM cells promoted the EMT of HK‐2 cells, resulting in the down‐regulation of epithelial‐related marker (E‐cadherin), and up‐regulation of stroma‐related marker (Vimentin). Meanwhile, the expression of SMAD7, one of the downstream targets in the TGF‐β signalling pathway, was suppressed and the expression of TGF‐β was increased. After transfecting the inhibitor of miR‐21 in MM cells, the expression of miR‐21 in exosomes secreted by MM cells was significantly decreased, and the co‐culture of these treated exosomes and HK‐2 cells inhibited the EMT of HK‐2 cells. In conclusion, these findings showed that exosomal miR‐21 derived from MM cells could promote renal EMT through targeting TGF‐β/SMAD7 signalling pathway.

国内多发性骨髓瘤(multiple myeloma，MM)临床大数据较少，本研究旨在分析湖南省多中心1年期间新诊断多发性骨髓瘤(newly diagnosed multiple myeloma，NDMM)患者的临床资料，了解湖南省MM患者真实的临床特征和诊疗情况，加强对MM规范化诊疗流程和诊疗方案的认识。 收集湖南省12家大型综合性医院2019年1月1日至12月31日收治的共529例NDMM患者的临床资料，包括基线资料、治疗方案、疗程和不良反应等。采用SPSS 21.0统计软件分析患者的临床特征、治疗情况及安全性。 529例NDMM患者确诊年龄33~90(中位数64)岁，男女比为1.38꞉1；临床特征占比从高到低依次为骨痛(77.7%)、贫血(66.8%)、肾功能不全(40.6%)、高钙血症(15.1%)。分型：IgG型46.5%，IgA型24.6%，IgD型2.6%，IgM型0.8%，轻链型15.7%，双克隆型3.0%，不分泌0.6%，缺失6.2%。DS(Durie-Salmon)分期I期、II期、III期分别为4.5%、10.6%、77.3%，缺失40例(7.6%)；国际分期系统(International Staging System，ISS)分期I期、II、III期分别为10.4%、24.4%、47.6%，缺失93例(17.6%)；修订的国际分期系统(Revised International Staging System，R-ISS)分期I期、II、III期分别为5.5%、27.0%、23.1%，缺失235例(44.4%)，其中中南大学湘雅三医院单中心98例NDMM患者中DS分期缺失2.0%，ISS分期缺失12.3%，R-ISS分期缺失12.3%。治疗情况：529例患者中475例接受治疗，接受治疗率为89.8%；67.4%的患者能规范完成4个疗程诱导阶段的化学治疗(以下简称化疗)，其中90.3%的患者接受1次以上以蛋白酶体抑制剂为基础的化疗方案，67.2%接受1次以上以免疫调节剂为基础的化疗方案，59.8%的患者接受1次以上含蛋白酶体抑制剂与免疫调节剂的联合化疗方案。疗效：4个疗程组总缓解率(overall response rate，ORR)及高质量缓解率(high quality response rate，HQR)均优于2个疗程组(ORR为85% vs 65%，P=0.006；HQR为68.3% vs 24.0%，PP=0.035)。治疗期间出现的不良反应：血液学毒性17.5%、外周神经病变24.8%、胃肠道不良反应23.8%、肺部感染25.9%、带状疱疹4.6%、静脉血栓1.7%。 2019年期间湖南省NDMM的漏诊率较高，中位确诊年龄较大；诊断精准度不高，特别是在分期及危险分层上各医疗中心差异较大，将近一半的NDMM患者诊断时没有作出R-ISS分期；细胞遗传学数据缺失，需在后续研究中跟进。NDMM患者就诊时骨痛、贫血症状占比较高；接受治疗的患者中蛋白酶体抑制剂和/或免疫调节剂化疗方案使用率较高，但各医疗中心差距明显，规范化治疗尚待加强；化疗期间的安全性总体可控。

To analyze the pathogenic distribution, antibiotic susceptibility and prognostic factors for acute leukemia (AL) patients with Gram negative (G-) bacterial bloodstream infection (BSI), in order to provide theoretical basis for reducing the infection-related mortality of AL patients. The clinical data of 1 055 AL patients with BSI admitted to the hematology ward of three large-scale hospitals in Hunan Province from January 2010 to December 2018 were collected. The etiology, antibiotic susceptibility data and clinical features of patients with G- bacterial infection were analyzed. G- bacterial infection accounted for 622 AL patients with BSI, and the main pathogens were Escherichia coli (277 strains, 44.53%), Klebsiella pneumoniae (138 strains, 22.19%), and Pseudomonas aeruginosa (81 strains, 13.02%). Most G- bacteria were highly sensitive to carbapenems and β-lactam/β-lactamase inhibitor. State of disease, Pitt score ≥4, treatment with vasoactive agents and sensitive antibiotic >48 h were independent risk factors of 30-day mortality. Rational antibacterial treatment of G- bacterial BSI in AL patients requires adequate acquaintance of the local pathogenic epidemiology and antibiotic susceptibility-monitored data. Broad-spectrum antibiotics covering the most common and more virulent pathogens should be timely applicated and adjusted according to antibiotic susceptibility results and efficacy.

Background: The increased bone marrow angiogenesis is involved in the progression of multiple myeloma (MM) with the underlying mechanism poorly understood. Cancer-released exosomes could play an important role in the pathological angiogenesis through exosomal microRNAs (miRs) delivery. It is reported that miR-29b played an important role in regulating the tumor angiogenesis. Methods: In this study, we explored the role of C6-ceramide (C6-cer, a Ceramide pathway activator) in the angiogenic effect of MM exosomes and its potential mechanism. MM cells (OPM2 and RPMI-8226) treated with C6-cer were studied for its effects on the endothelial cell (EC) functions. Results: Our results showed that exosomes released from MM cells treated by C6-cer (Exo^C6-cer) significantly inhibited the proliferation, migration and tube formation of ECs. For mechanism studies, we found that the level of miR-29b was increased in ECs treated by Exo^C6-cer, while mRNA and protein expressions of Akt3, PI3K and VEGFA were decreased in ECs, indicating the involvement of Akt pathway. Furthermore, downregulation of miR-29b by inhibitor administration could prevent the Exo^C6-cer-induced cell proliferation, migration and angiogenesis of ECs, accompanied with the increased expressions of Akt3, PI3K and VEGFA. Conclusions: Collectively, our data suggest that Exo^C6-cer-mediated miR-29b expression participates in the progression of MM through suppressing the proliferation, migration and angiogenesis of ECs by targeting Akt signal pathway.

Background: The increased bone marrow angiogenesis is involved in the progression of multiple myeloma (MM) with the underlying mechanism poorly understood. Cancer-released exosomes could play an important role in the pathological angiogenesis through exosomal microRNAs (miRs) delivery. MiR-29b has been reported in regulating the tumor angiogenesis. Methods: In this study, we explored the role of C6-ceramide (C6-cer, a Ceramide pathway activator) in the angiogenic effect of MM exosomes and its potential mechanism. MM cells (OPM2 and RPMI-8226) treated with C6-cer were studied for its effects on the endothelial cell (EC) functions . Results: Our results showed that exosomes released from MM cells treated by C6-cer ( Exo C6-cer ) significantly inhibited the proliferation, migration and tube formation of ECs. For mechanism studies, we found that the level of miR-29b was increased in ECs treated by exo C6-cer , while mRNA and protein expressions of Akt3, PI3K and VEGFA were decreased in ECs, indicating the involvement of Akt pathway. Furthermore, downregulation of miR-29b by inhibitor administration could prevent the exo C6-cer -induced cell proliferation, migration and angiogenesis of ECs, accompanied with the increased expressions of Akt3, PI3K and VEGFA. Conclusions: Collectively, our data suggest that exo C6-cer -mediated miR-29b expression participates in the progression of MM through suppressing the proliferation, migration and angiogenesis of ECs by targeting Akt signal pathway.