Pub Date : 2024-07-10eCollection Date: 2024-07-01DOI: 10.1097/BS9.0000000000000192
Cheng Zhou, Jue Li, Xiaofan Sun, Liang Zhao, Huien Zhan, Hui Liang, Peng Fang, Tuo Zhang, Qiongzhi He, Juan Du, Hui Zeng
Acute myeloid leukemia (AML) is a common hematological malignancy with overall poor prognosis. Exploring novel targets is urgent and necessary to improve the clinical outcome of relapsed and refractory (RR) AML patients. Through clinical specimens, animal models and cell-level studies, we explored the specific mechanism of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1 (HMGCS1) in AML and the mechanism of targeting HMGCS1 to attenuate cell proliferation, increase chemotherapy sensitivity and improve the occurrence and development of AML. Here, we reveal that HMGCS1 is overexpressed in RR patients and negatively related to overall survival (OS). Knocking out HMGCS1 in AML cells attenuated cell proliferation and increased chemotherapy sensitivity, while stable overexpression of HMGCS1 had the opposite effects. Mechanistically, we identified that knockout of HMGCS1 suppressed mitogen-activated protein kinase (MAPK) pathway activity, while overexpression of HMGCS1 could remarkably enhance the pathway. U0126, a MEK1 inhibitor, offset the effects of HMGCS1 overexpression, indicating that HMGCS1 promotes RR AML through the MAPK pathway. Further, we verified that hymeglusin, a specific inhibitor of HMGCS1, decreases cell growth both in AML cell lines and primary bone marrow cells of AML patients. Furthermore, combination of hymeglusin and the common chemotherapeutic drug cytarabine and adriamycin (ADR) had synergistic toxic effects on AML cells. Our study demonstrates the important role of HMGCS1 in AML, and targeting this protein is promising for the treatment of RR AML.
{"title":"Targeting HMGCS1 restores chemotherapy sensitivity in acute myeloid leukemia.","authors":"Cheng Zhou, Jue Li, Xiaofan Sun, Liang Zhao, Huien Zhan, Hui Liang, Peng Fang, Tuo Zhang, Qiongzhi He, Juan Du, Hui Zeng","doi":"10.1097/BS9.0000000000000192","DOIUrl":"10.1097/BS9.0000000000000192","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) is a common hematological malignancy with overall poor prognosis. Exploring novel targets is urgent and necessary to improve the clinical outcome of relapsed and refractory (RR) AML patients. Through clinical specimens, animal models and cell-level studies, we explored the specific mechanism of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1 (HMGCS1) in AML and the mechanism of targeting HMGCS1 to attenuate cell proliferation, increase chemotherapy sensitivity and improve the occurrence and development of AML. Here, we reveal that HMGCS1 is overexpressed in RR patients and negatively related to overall survival (OS). Knocking out HMGCS1 in AML cells attenuated cell proliferation and increased chemotherapy sensitivity, while stable overexpression of HMGCS1 had the opposite effects. Mechanistically, we identified that knockout of HMGCS1 suppressed mitogen-activated protein kinase (MAPK) pathway activity, while overexpression of HMGCS1 could remarkably enhance the pathway. U0126, a MEK1 inhibitor, offset the effects of HMGCS1 overexpression, indicating that HMGCS1 promotes RR AML through the MAPK pathway. Further, we verified that hymeglusin, a specific inhibitor of HMGCS1, decreases cell growth both in AML cell lines and primary bone marrow cells of AML patients. Furthermore, combination of hymeglusin and the common chemotherapeutic drug cytarabine and adriamycin (ADR) had synergistic toxic effects on AML cells. Our study demonstrates the important role of HMGCS1 in AML, and targeting this protein is promising for the treatment of RR AML.</p>","PeriodicalId":67343,"journal":{"name":"血液科学(英文)","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11239175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141592251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
An accurate prognostic model for acute myeloid leukemia (AML) can guide personalized treatment. In our prospective cohort of 591 patients newly diagnosed with AML, we evaluated the prognostic significance of serum albumin levels. We recognized baseline serum albumin as a prognostic factor by univariate Cox regression analysis (albumin-high vs albumin-low: overall survival [OS]: hazard ratio [HR]: 0.679, 95% confidence interval [CI]: 0.529-0.870, P = .002; cumulative incidence of relapse [CIR]: HR: 0.705, 95% CI: 0.530-0.938, P = .017) and multivariate Cox regression analysis (OS: HR per g/L: 0.966, 95% CI: 0.940-0.993, P = .014; CIR: HR per g/L: 0.959, 95% CI: 0.927-0.993, P = .017). In the subgroup analysis, serum albumin was prognostic significant in patients who received intermediate-dose cytarabine combined with daunorubicin and omacetaxine mepesuccinate induction (albumin-high vs albumin-low: OS: HR: 0.585, 95% CI: 0.397-0.863, P = .007; CIR: HR: 0.551, 95% CI: 0.353-0.861, P = .009) rather than those receiving conventional-dose induction regimens. In addition, the impact of baseline serum albumin level was evident in patients with intermediate European LeukemiaNet risk (albumin-high vs albumin-low: OS: HR: 0.617, 95% CI: 0.424-0.896, P = .011; CIR: HR: 0.617, 95% CI: 0.388-0.979, P = .040). Gene set enrichment analysis revealed that leukemia stem cell signatures were enriched in patients with low serum albumin levels. Our study suggested that baseline serum albumin level was associated with the inherent properties of AML and correlated with patient outcomes.
{"title":"Serum albumin is associated with the inherent property of acute myeloid leukemia and correlates with patient outcomes.","authors":"Jiayuan Chen, Yan Hui, Yujia Zhai, Miao Yang, Xue Zhang, Yingchang Mi, Jianxiang Wang, Hui Wei","doi":"10.1097/BS9.0000000000000189","DOIUrl":"10.1097/BS9.0000000000000189","url":null,"abstract":"<p><p>An accurate prognostic model for acute myeloid leukemia (AML) can guide personalized treatment. In our prospective cohort of 591 patients newly diagnosed with AML, we evaluated the prognostic significance of serum albumin levels. We recognized baseline serum albumin as a prognostic factor by univariate Cox regression analysis (albumin-high vs albumin-low: overall survival [OS]: hazard ratio [HR]: 0.679, 95% confidence interval [CI]: 0.529-0.870, <i>P</i> = .002; cumulative incidence of relapse [CIR]: HR: 0.705, 95% CI: 0.530-0.938, <i>P</i> = .017) and multivariate Cox regression analysis (OS: HR per g/L: 0.966, 95% CI: 0.940-0.993, <i>P</i> = .014; CIR: HR per g/L: 0.959, 95% CI: 0.927-0.993, <i>P</i> = .017). In the subgroup analysis, serum albumin was prognostic significant in patients who received intermediate-dose cytarabine combined with daunorubicin and omacetaxine mepesuccinate induction (albumin-high vs albumin-low: OS: HR: 0.585, 95% CI: 0.397-0.863, <i>P</i> = .007; CIR: HR: 0.551, 95% CI: 0.353-0.861, <i>P</i> = .009) rather than those receiving conventional-dose induction regimens. In addition, the impact of baseline serum albumin level was evident in patients with intermediate European LeukemiaNet risk (albumin-high vs albumin-low: OS: HR: 0.617, 95% CI: 0.424-0.896, <i>P</i> = .011; CIR: HR: 0.617, 95% CI: 0.388-0.979, <i>P</i> = .040). Gene set enrichment analysis revealed that leukemia stem cell signatures were enriched in patients with low serum albumin levels. Our study suggested that baseline serum albumin level was associated with the inherent properties of AML and correlated with patient outcomes.</p>","PeriodicalId":67343,"journal":{"name":"血液科学(英文)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11090624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140917215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Acute myeloid leukemia (AML) with t(16;21)(p11;q22)/FUS::ERG is a rare AML subtype associated with poor prognosis. However, its clinical and molecular features remain poorly defined. We determined the clinicopathological, genomic, and transcriptomic characteristics and outcomes of patients with AML harboring FUS::ERG at our center. Thirty-six AML patients harboring FUS::ERG were identified, with an incidence rate of 0.3%. These patients were characterized by high lactate dehydrogenase levels (median: 838.5 U/L), elevated bone marrow blast counts (median: 71.5%), and a CD56-positive immunophenotype (94.3%). Notably, we found that RTK-RAS GTPase (RAS) pathway genes, including NRAS (33%) and PTPN11 (24%), were frequently mutated in this subtype. Transcriptome analysis revealed enrichment of the phosphatidylinositol-3-kinase-Akt (PI3K-Akt), mitogen-activated protein kinase (MAPK), and RAS signaling pathways and upregulation of BCL2, the target of venetoclax, in FUS::ERG AML compared to RUNX1::RUNX1T1 AML, a more common AML subtype with good prognosis. The median event-free survival in patients with FUS::ERG AML was 11.9 (95% confidence interval [CI]: 9.0-not available [NA]) months and the median overall survival was 18.2 (95% CI: 12.4-NA) months. Allogeneic hematopoietic stem cell transplantation failed to improve outcomes. Overall, the high incidence of RTK-RAS pathway mutations and high expression of BCL2 may indicate promising therapeutic targets in this high-risk AML subset.
{"title":"The RTK-RAS signaling pathway is enriched in patients with rare acute myeloid leukemia harboring t(16;21)(p11;q22)/<i>FUS::ERG</i>.","authors":"Anli Lai, Wenbing Liu, Hui Wei, Ying Wang, Dong Lin, Chunlin Zhou, Bingcheng Liu, Runxia Gu, Yan Li, Shuning Wei, Benfa Gong, Kaiqi Liu, Xiaoyuan Gong, Yuntao Liu, Guangji Zhang, Junping Zhang, Yingchang Mi, Jianxiang Wang, Shaowei Qiu","doi":"10.1097/BS9.0000000000000188","DOIUrl":"10.1097/BS9.0000000000000188","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) with t(16;21)(p11;q22)/<i>FUS::ERG</i> is a rare AML subtype associated with poor prognosis. However, its clinical and molecular features remain poorly defined. We determined the clinicopathological, genomic, and transcriptomic characteristics and outcomes of patients with AML harboring <i>FUS::ERG</i> at our center. Thirty-six AML patients harboring <i>FUS::ERG</i> were identified, with an incidence rate of 0.3%. These patients were characterized by high lactate dehydrogenase levels (median: 838.5 U/L), elevated bone marrow blast counts (median: 71.5%), and a CD56-positive immunophenotype (94.3%). Notably, we found that RTK-RAS GTPase (RAS) pathway genes, including <i>NRAS</i> (33%) and <i>PTPN11</i> (24%), were frequently mutated in this subtype. Transcriptome analysis revealed enrichment of the phosphatidylinositol-3-kinase-Akt (PI3K-Akt), mitogen-activated protein kinase (MAPK), and RAS signaling pathways and upregulation of <i>BCL2</i>, the target of venetoclax, in <i>FUS::ERG</i> AML compared to <i>RUNX1::RUNX1T1</i> AML, a more common AML subtype with good prognosis. The median event-free survival in patients with <i>FUS::ERG</i> AML was 11.9 (95% confidence interval [CI]: 9.0-not available [NA]) months and the median overall survival was 18.2 (95% CI: 12.4-NA) months. Allogeneic hematopoietic stem cell transplantation failed to improve outcomes. Overall, the high incidence of RTK-RAS pathway mutations and high expression of <i>BCL2</i> may indicate promising therapeutic targets in this high-risk AML subset.</p>","PeriodicalId":67343,"journal":{"name":"血液科学(英文)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11090622/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140917132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-07eCollection Date: 2024-04-01DOI: 10.1097/BS9.0000000000000187
Zixian Liu, Jinhong Wang, Yao Ma, Miner Xie, Peng Wu, Sen Zhang, Xiaofang Wang, Fang Dong, Hui Cheng, Ping Zhu, Mingzhe Han, Hideo Ema
Hematopoietic stem cells (HSCs) have been considered to progressively lose their self-renewal and differentiation potentials prior to the commitment to each blood lineage. However, recent studies have suggested that megakaryocyte progenitors (MkPs) are generated at the level of HSCs. In this study, we newly identified early megakaryocyte lineage-committed progenitors (MgPs) mainly in CD201-CD48- cells and CD48+ cells separated from the CD150+CD34-Kit+Sca-1+Lin- HSC population of the bone marrow in adult mice. Single-cell colony assay and single-cell transplantation showed that MgPs, unlike platelet-biased HSCs, had little repopulating potential in vivo, but formed larger megakaryocyte colonies in vitro (on average 8 megakaryocytes per colony) than did previously reported MkPs. Single-cell RNA sequencing supported that HSCs give rise to MkPs through MgPs along a Mk differentiation pathway. Single-cell reverse transcription polymerase chain reaction (RT-PCR) analysis showed that MgPs expressed Mk-related genes, but were transcriptionally heterogenous. Clonal culture of HSCs suggested that MgPs are not direct progeny of HSCs. We propose a differentiation model in which HSCs give rise to MgPs which then give rise to MkPs, supporting a classic model in which Mk-lineage commitment takes place at a late stage of differentiation.
{"title":"Early megakaryocyte lineage-committed progenitors in adult mouse bone marrow.","authors":"Zixian Liu, Jinhong Wang, Yao Ma, Miner Xie, Peng Wu, Sen Zhang, Xiaofang Wang, Fang Dong, Hui Cheng, Ping Zhu, Mingzhe Han, Hideo Ema","doi":"10.1097/BS9.0000000000000187","DOIUrl":"10.1097/BS9.0000000000000187","url":null,"abstract":"<p><p>Hematopoietic stem cells (HSCs) have been considered to progressively lose their self-renewal and differentiation potentials prior to the commitment to each blood lineage. However, recent studies have suggested that megakaryocyte progenitors (MkPs) are generated at the level of HSCs. In this study, we newly identified early megakaryocyte lineage-committed progenitors (MgPs) mainly in CD201<sup>-</sup>CD48<sup>-</sup> cells and CD48<sup>+</sup> cells separated from the CD150<sup>+</sup>CD34<sup>-</sup>Kit<sup>+</sup>Sca-1<sup>+</sup>Lin<sup>-</sup> HSC population of the bone marrow in adult mice. Single-cell colony assay and single-cell transplantation showed that MgPs, unlike platelet-biased HSCs, had little repopulating potential in vivo, but formed larger megakaryocyte colonies in vitro (on average 8 megakaryocytes per colony) than did previously reported MkPs. Single-cell RNA sequencing supported that HSCs give rise to MkPs through MgPs along a Mk differentiation pathway. Single-cell reverse transcription polymerase chain reaction (RT-PCR) analysis showed that MgPs expressed Mk-related genes, but were transcriptionally heterogenous. Clonal culture of HSCs suggested that MgPs are not direct progeny of HSCs. We propose a differentiation model in which HSCs give rise to MgPs which then give rise to MkPs, supporting a classic model in which Mk-lineage commitment takes place at a late stage of differentiation.</p>","PeriodicalId":67343,"journal":{"name":"血液科学(英文)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11078525/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140890630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-30eCollection Date: 2024-04-01DOI: 10.1097/BS9.0000000000000191
Fatih Ikiz, Ahmet Ak
This study, which included patients over the age of 18 who were diagnosed with coronavirus disease 2019 (COVID-19) in the emergency clinic, aims to determine the relationship between coagulation parameters and mortality. Epidemiologic data such as age, gender, medical history, vital parameters at emergency department admission, clinical findings, coagulation parameters such as d-dimer, prothrombin time (PT), active partial thromboplastin time (aPTT), international normalized ration (INR), fibrinogen, and platelet were evaluated. Patients with positive computerized tomography (CT) findings and positive polymerase chain reaction (PCR) together were included in the study. It was revealed that d-dimer, fibrinogen, INR, and PT values were higher in the elderly group. It was shown that there was a significant relationship between hospitalization days (ward or intensive care unit) and d-dimer levels. It was observed that d-dimer, fibrinogen elevation was significantly associated with prognosis by increasing mortality, and that platelet and aPTT values were also associated with prognosis and were lower in the mortality group. On the other hand, in receiver operating characteristic (ROC) analysis, the sensitivity and specificity data were 80.3%/80.0% for d-dimer, 70.5%/72.2% for fibrinogen, 58.2%/59.4% for aPTT, and 59.7%/59.2% for platelet, respectively. The overall classification success was 88.6% and mortality prediction success was 37.7% in the regression model of some coagulation parameters (d-dimer, fibrinogen, aPTT, and platelet) which were effective on prognosis. In conclusion, it was determined that d-dimer, fibrinogen, aPTT, and platelet parameters were directly associated with mortality and when these coagulation parameters were used together with the clinical, vital, and demographic data of the patients, the success of mortality prediction increased significantly.
{"title":"Investigation of the relationship between coagulation parameters and mortality in COVID-19 infection.","authors":"Fatih Ikiz, Ahmet Ak","doi":"10.1097/BS9.0000000000000191","DOIUrl":"https://doi.org/10.1097/BS9.0000000000000191","url":null,"abstract":"<p><p>This study, which included patients over the age of 18 who were diagnosed with coronavirus disease 2019 (COVID-19) in the emergency clinic, aims to determine the relationship between coagulation parameters and mortality. Epidemiologic data such as age, gender, medical history, vital parameters at emergency department admission, clinical findings, coagulation parameters such as d-dimer, prothrombin time (PT), active partial thromboplastin time (aPTT), international normalized ration (INR), fibrinogen, and platelet were evaluated. Patients with positive computerized tomography (CT) findings and positive polymerase chain reaction (PCR) together were included in the study. It was revealed that d-dimer, fibrinogen, INR, and PT values were higher in the elderly group. It was shown that there was a significant relationship between hospitalization days (ward or intensive care unit) and d-dimer levels. It was observed that d-dimer, fibrinogen elevation was significantly associated with prognosis by increasing mortality, and that platelet and aPTT values were also associated with prognosis and were lower in the mortality group. On the other hand, in receiver operating characteristic (ROC) analysis, the sensitivity and specificity data were 80.3%/80.0% for d-dimer, 70.5%/72.2% for fibrinogen, 58.2%/59.4% for aPTT, and 59.7%/59.2% for platelet, respectively. The overall classification success was 88.6% and mortality prediction success was 37.7% in the regression model of some coagulation parameters (d-dimer, fibrinogen, aPTT, and platelet) which were effective on prognosis. In conclusion, it was determined that d-dimer, fibrinogen, aPTT, and platelet parameters were directly associated with mortality and when these coagulation parameters were used together with the clinical, vital, and demographic data of the patients, the success of mortality prediction increased significantly.</p>","PeriodicalId":67343,"journal":{"name":"血液科学(英文)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11062700/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140874254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-17eCollection Date: 2024-01-01DOI: 10.1097/BS9.0000000000000179
Ying Yu, Wenjie Xiong, Tingyu Wang, Yuting Yan, Rui Lyu, Qi Wang, Wei Liu, Gang An, Weiwei Sui, Yan Xu, Wenyang Huang, Dehui Zou, Jianxiang Wang, Lugui Qiu, Shuhua Yi
Waldenstrom macroglobulinemia (WM) is a type of incurable, indolent B-cell lymphoma that is prone to relapse. Over time, treatment strategies have progressed from cytotoxic drugs to rituximab (R)- or bortezomib (V)-based regimens, and have now entered into an era of Bruton tyrosine kinase inhibitor (BTKi)-based regimens. However, the optimal treatment for the relapsed patients is still unclear. Herein, we analyzed the outcomes of the first- and second-line therapies in 377 patients with WM to illustrate the optimal choices for second-line therapy. After a median follow-up of 45.4 months, 89 patients received second-line therapy, and 53 patients were evaluated for response. The major response rates (MRR) of first- and second-line treatment were 65.1% and 67.9% (P = 0.678). The median progression-free survival (PFS) for the second-line therapy (PFS2) was shorter than that for the first-line therapy (PFS1) (56.3 vs 40.7 months, P = 0.03). However, PFS2 in targeted drugs group (R-/V-/BTKi-based regimens) was comparable to PFS1 (60.7 months vs 44.7 months, respectively, P = 0.21). Regarding second-line therapy, patients who underwent sequential treatment escalation-such as transitioning from cytotoxic drugs to R-/V-/BTKi-based regimens or from R-/V-based to BTKi-based regimens (escalation group) -had higher MRR (80.6% vs 47.1%, respectively, P = 0.023) and longer PFS2 (50.4 vs 23.5 months, respectively, P < 0.001) compared to the non-escalation group. Patients in the escalation group also had longer post-relapse overall survival compared with the non-escalation group (median, 50.4 vs 23.5 months, respectively, P = 0.039). Our findings indicate that sequential treatment escalation may improve the survival of patients with WM.
Waldenstrom巨球蛋白血症(WM)是一种难以治愈、易复发的不显性B细胞淋巴瘤。随着时间的推移,治疗策略已从细胞毒药物发展到以利妥昔单抗(R)或硼替佐米(V)为基础的方案,目前已进入以布鲁顿酪氨酸激酶抑制剂(BTKi)为基础的方案时代。然而,复发患者的最佳治疗方案仍不明确。在此,我们分析了377例WM患者的一线和二线治疗结果,以说明二线治疗的最佳选择。中位随访45.4个月后,89名患者接受了二线治疗,53名患者接受了反应评估。一线和二线治疗的主要反应率(MRR)分别为65.1%和67.9%(P = 0.678)。二线治疗的中位无进展生存期(PFS2)比一线治疗的中位无进展生存期(PFS1)短(56.3 个月对 40.7 个月,P = 0.03)。然而,靶向药物组(基于R-/V-/BTKi的方案)的PFS2与PFS1相当(分别为60.7个月 vs 44.7个月,P = 0.21)。在二线治疗方面,与未升级治疗组相比,进行了序贯治疗升级(如从细胞毒性药物过渡到基于R-/V-/BTKi的方案或从基于R-/V-方案过渡到基于BTKi的方案(升级组))的患者具有更高的MRR(分别为80.6% vs 47.1%,P = 0.023)和更长的PFS2(分别为50.4个月 vs 23.5个月,P 0.001)。与非升级治疗组相比,升级治疗组患者的复发后总生存期也更长(中位数分别为50.4个月和23.5个月,P = 0.039)。我们的研究结果表明,循序渐进的治疗可提高WM患者的生存率。
{"title":"Sequential treatment escalation improves survival in patients with Waldenstrom macroglobulinemia.","authors":"Ying Yu, Wenjie Xiong, Tingyu Wang, Yuting Yan, Rui Lyu, Qi Wang, Wei Liu, Gang An, Weiwei Sui, Yan Xu, Wenyang Huang, Dehui Zou, Jianxiang Wang, Lugui Qiu, Shuhua Yi","doi":"10.1097/BS9.0000000000000179","DOIUrl":"10.1097/BS9.0000000000000179","url":null,"abstract":"<p><p>Waldenstrom macroglobulinemia (WM) is a type of incurable, indolent B-cell lymphoma that is prone to relapse. Over time, treatment strategies have progressed from cytotoxic drugs to rituximab (R)- or bortezomib (V)-based regimens, and have now entered into an era of Bruton tyrosine kinase inhibitor (BTKi)-based regimens. However, the optimal treatment for the relapsed patients is still unclear. Herein, we analyzed the outcomes of the first- and second-line therapies in 377 patients with WM to illustrate the optimal choices for second-line therapy. After a median follow-up of 45.4 months, 89 patients received second-line therapy, and 53 patients were evaluated for response. The major response rates (MRR) of first- and second-line treatment were 65.1% and 67.9% (<i>P</i> = 0.678). The median progression-free survival (PFS) for the second-line therapy (PFS2) was shorter than that for the first-line therapy (PFS1) (56.3 vs 40.7 months, <i>P</i> = 0.03). However, PFS2 in targeted drugs group (R-/V-/BTKi-based regimens) was comparable to PFS1 (60.7 months vs 44.7 months, respectively, <i>P</i> = 0.21). Regarding second-line therapy, patients who underwent sequential treatment escalation-such as transitioning from cytotoxic drugs to R-/V-/BTKi-based regimens or from R-/V-based to BTKi-based regimens (escalation group) -had higher MRR (80.6% vs 47.1%, respectively, <i>P</i> = 0.023) and longer PFS2 (50.4 vs 23.5 months, respectively, <i>P <</i> 0.001) compared to the non-escalation group. Patients in the escalation group also had longer post-relapse overall survival compared with the non-escalation group (median, 50.4 vs 23.5 months, respectively, <i>P</i> = 0.039). Our findings indicate that sequential treatment escalation may improve the survival of patients with WM.</p>","PeriodicalId":67343,"journal":{"name":"血液科学(英文)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10796142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139492810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amyloid light chain (AL) amyloidosis is a rare plasma cell dyscrasia with dismal prognosis. This study aims to investigate the T-cell immune checkpoint expression patterns in systemic AL amyloidosis and its relationship with clinicobiological traits. We examined the frequencies of V-domain immunoglobulin suppressor of T cell activation+ (VISTA+), programmed cell death 1+ (PD-1+), T cell immunoglobulin and mucin-domain-containing-3+ (Tim-3+), T cell immunoreceptor with Ig and ITIM domains+ (TIGIT+) T cells in peripheral blood (PB) and bone marrow (BM) from 19 patients with newly diagnosed AL amyloidosis. Patients with AL amyloidosis had significantly higher percentages of VISTA+ and PD-1+ T cells in PB than healthy individuals (HIs), with no statistical differences in BM. The percentages of some double-positive T cells in PB were also considerably higher in AL amyloidosis than those in HIs. Additionally, the patients with renal involvement had more PD-1+ and TIGIT+ T cells than the patients without, and PD-1+CD3+%, PD-1+CD4+%, PD-1+Treg% were positively correlated with 24-hour proteinuria levels. Furthermore, the AL amyloidosis patients had higher counts of PD-1+ Treg in PB than multiple myeloma (MM) patients, while the MM patients had higher counts of TIGIT+ T cells than AL amyloidosis patients. Collectively, this is the first report of elevated proportions of VISTA+ and PD-1+ T cells in PB of AL amyloidosis patients, indicating an immunosuppressive milieu, and the increased PD-1+ and TIGIT+ T cells were associated with renal damage. VISTA, PD-1, and TIGIT may be potential targets for reversing T-cell exhaustion in AL amyloidosis.
{"title":"Immune checkpoint expression patterns on T cell subsets in light-chain amyloidosis: VISTA, PD-1, and TIGIT as potential therapeutic targets.","authors":"Jinghua Wang, Yujie Zhao, Pengjun Liao, Shuxin Huang, Youxue Huang, Shaohua Chen, Yangqiu Li, Liye Zhong","doi":"10.1097/BS9.0000000000000181","DOIUrl":"10.1097/BS9.0000000000000181","url":null,"abstract":"<p><p>Amyloid light chain (AL) amyloidosis is a rare plasma cell dyscrasia with dismal prognosis. This study aims to investigate the T-cell immune checkpoint expression patterns in systemic AL amyloidosis and its relationship with clinicobiological traits. We examined the frequencies of V-domain immunoglobulin suppressor of T cell activation<sup>+</sup> (VISTA<sup>+</sup>), programmed cell death 1<sup>+</sup> (PD-1<sup>+</sup>), T cell immunoglobulin and mucin-domain-containing-3<sup>+</sup> (Tim-3<sup>+</sup>), T cell immunoreceptor with Ig and ITIM domains<sup>+</sup> (TIGIT<sup>+</sup>) T cells in peripheral blood (PB) and bone marrow (BM) from 19 patients with newly diagnosed AL amyloidosis. Patients with AL amyloidosis had significantly higher percentages of VISTA<sup>+</sup> and PD-1<sup>+</sup> T cells in PB than healthy individuals (HIs), with no statistical differences in BM. The percentages of some double-positive T cells in PB were also considerably higher in AL amyloidosis than those in HIs. Additionally, the patients with renal involvement had more PD-1<sup>+</sup> and TIGIT<sup>+</sup> T cells than the patients without, and PD-1<sup>+</sup>CD3<sup>+</sup>%, PD-1<sup>+</sup>CD4<sup>+</sup>%, PD-1<sup>+</sup>Treg% were positively correlated with 24-hour proteinuria levels. Furthermore, the AL amyloidosis patients had higher counts of PD-1<sup>+</sup> Treg in PB than multiple myeloma (MM) patients, while the MM patients had higher counts of TIGIT<sup>+</sup> T cells than AL amyloidosis patients. Collectively, this is the first report of elevated proportions of VISTA<sup>+</sup> and PD-1<sup>+</sup> T cells in PB of AL amyloidosis patients, indicating an immunosuppressive milieu, and the increased PD-1<sup>+</sup> and TIGIT<sup>+</sup> T cells were associated with renal damage. VISTA, PD-1, and TIGIT may be potential targets for reversing T-cell exhaustion in AL amyloidosis.</p>","PeriodicalId":67343,"journal":{"name":"血液科学(英文)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10789457/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139473109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Numerous studies have discussed the therapeutic outcomes of using cell therapy or acupuncture to treat peripheral artery disease (PAD). However, there are no long-term studies on the safety and efficacy of transplanting peripheral blood mononuclear cells (PBMNCs) via acupoints to treat PAD. We first reviewed the short-term and long-term clinical results of PAD patients treated with PBMNCs through intramuscular non-acupoint transplantation (control group; n = 45) or intramuscular acupoint transplantation (acupoint group; n = 45) at a single university hospital general medical center between December 2002 and September 2022. Pain intensity (assessed with the verbal rating scale [VRS] score) in the acupoint group was considerably lower than that in the control group at month 1 (mean ± standard deviation [SD]: 1.29 ± 0.96 vs 1.76 ± 0.82; P = 0.016) and month 3 (mean ± SD: 1.27 ± 0.90 vs 1.61 ± 0.86; P = 0.042). We observed significant improvement of VRS score (P < .001 for all) and ankle-brachial index (ABI; P < .001 for all) from baseline in both groups at months 1, 3, 6, 12, 36, and 60. The 10-year cumulative rate of major amputation-free survival (MAFS) was higher in the acupoint group as compared to the control group (81.9%, 95% confidence interval [CI]: 71.3%-94.1% vs 78.5%, 95% CI: 66.7%-92.3%; P = 0.768). Compared with the routine injection method, intramuscular transplantation of PBMNCs via selected acupoints could significantly decrease the short-term pain intensity in patients with PAD, which remains an option for consideration.
许多研究讨论了使用细胞疗法或针灸治疗外周动脉疾病(PAD)的疗效。然而,目前还没有关于通过穴位移植外周血单核细胞(PBMNC)治疗 PAD 的安全性和有效性的长期研究。我们首先回顾了2002年12月至2022年9月期间在一家大学医院综合医疗中心通过肌肉注射非穴位移植(对照组;n = 45)或肌肉注射穴位移植(穴位组;n = 45)用PBMNCs治疗PAD患者的短期和长期临床结果。在第 1 个月(平均值±标准差[SD]:1.29±0.96 vs 1.76±0.82;P = 0.016)和第 3 个月(平均值±标准差:1.27±0.90 vs 1.61±0.86;P = 0.042),穴位组的疼痛强度(用口头评分量表[VRS]评分评估)明显低于对照组。我们观察到,在第 1、3、6、12、36 和 60 个月时,两组患者的 VRS 评分(P < .001)和踝肱指数(ABI;P < .001)均较基线有明显改善。与对照组相比,穴位组的 10 年无截肢累积存活率(MAFS)更高(81.9%,95% 置信区间 [CI]: 71.3%-94.1% vs 78.5%,95% CI: 66.7%-92.3%; P = 0.768)。与常规注射方法相比,通过选定穴位肌肉移植 PBMNCs 可显著降低 PAD 患者的短期疼痛强度,仍是一个值得考虑的选择。
{"title":"Acupoint transplantation versus non-acupoint transplantation using autologous peripheral blood mononuclear cells in treating peripheral arterial disease.","authors":"Wenjing Guo, Ling Pan, Ruiyu Yang, Jiali Sun, Qinglin Hu, Pingping Huang","doi":"10.1097/BS9.0000000000000175","DOIUrl":"10.1097/BS9.0000000000000175","url":null,"abstract":"<p><p>Numerous studies have discussed the therapeutic outcomes of using cell therapy or acupuncture to treat peripheral artery disease (PAD). However, there are no long-term studies on the safety and efficacy of transplanting peripheral blood mononuclear cells (PBMNCs) via acupoints to treat PAD. We first reviewed the short-term and long-term clinical results of PAD patients treated with PBMNCs through intramuscular non-acupoint transplantation (control group; n = 45) or intramuscular acupoint transplantation (acupoint group; n = 45) at a single university hospital general medical center between December 2002 and September 2022. Pain intensity (assessed with the verbal rating scale [VRS] score) in the acupoint group was considerably lower than that in the control group at month 1 (mean ± standard deviation [SD]: 1.29 ± 0.96 vs 1.76 ± 0.82; <i>P</i> = 0.016) and month 3 (mean ± SD: 1.27 ± 0.90 vs 1.61 ± 0.86; <i>P</i> = 0.042). We observed significant improvement of VRS score (<i>P</i> < .001 for all) and ankle-brachial index (ABI; <i>P</i> < .001 for all) from baseline in both groups at months 1, 3, 6, 12, 36, and 60. The 10-year cumulative rate of major amputation-free survival (MAFS) was higher in the acupoint group as compared to the control group (81.9%, 95% confidence interval [CI]: 71.3%-94.1% vs 78.5%, 95% CI: 66.7%-92.3%; <i>P</i> = 0.768). Compared with the routine injection method, intramuscular transplantation of PBMNCs via selected acupoints could significantly decrease the short-term pain intensity in patients with PAD, which remains an option for consideration.</p>","PeriodicalId":67343,"journal":{"name":"血液科学(英文)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10789451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139473104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-10eCollection Date: 2024-01-01DOI: 10.1097/BS9.0000000000000177
Kailin Xu
{"title":"Sequential infusion of two different chimeric antigen receptor T cells: induction of a deep and durable remission.","authors":"Kailin Xu","doi":"10.1097/BS9.0000000000000177","DOIUrl":"10.1097/BS9.0000000000000177","url":null,"abstract":"","PeriodicalId":67343,"journal":{"name":"血液科学(英文)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10781117/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139426189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}