首页 > 最新文献

Leukemia Research Reports最新文献

英文 中文
Real-world treatments and clinical outcomes in unfit AML patients receiving first-line treatment or best supportive care in Italy (CURRENT study) 意大利接受一线治疗或最佳支持治疗的不适合急性髓细胞白血病患者的实际治疗情况和临床结果(CURRENT 研究)
Q4 Medicine Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100453
Maria Paola Martelli , Nicola Di Renzo , Antonio Curti , Nicola Stefano Fracchiolla , Luca Maurillo , Morena Caira , Paola Finsinger , Giuliana Gualberti , Felicetto Ferrara , Attilio Olivieri

Real-world data on treatment patterns and outcomes of patients with acute myeloid leukemia unfit for intensive chemotherapy are lacking before the advent of precision medicine in this setting.

Herein, we present the Italian sub-analysis of the CURRENT study in AML patients unfit for first line intensive chemotherapy, evaluating patients’ outcomes between 2015 and 2018.

Among 74 evaluable patients, 62 received systemic treatments (most used therapy was hypomethylating agents), while 12 best supportive care.

Key results include both efficacy and safety data, as well as HCRU and treatment patterns. In first-line therapy cohort median OS was 13.4 months vs. 2.7 months for BSC.

在精准医疗出现之前,有关不适合接受强化化疗的急性髓性白血病患者的治疗模式和疗效的真实世界数据十分缺乏。在此,我们介绍了CURRENT研究的意大利子分析,该研究针对不适合接受一线强化化疗的急性髓性白血病患者,评估了患者在2015年至2018年期间的疗效。在74名可评估患者中,62人接受了系统治疗(最常用的疗法是低甲基化药物),12人接受了最佳支持治疗。主要结果包括疗效和安全性数据,以及HCRU和治疗模式。在一线治疗队列中,中位OS为13.4个月,而BSC为2.7个月。
{"title":"Real-world treatments and clinical outcomes in unfit AML patients receiving first-line treatment or best supportive care in Italy (CURRENT study)","authors":"Maria Paola Martelli ,&nbsp;Nicola Di Renzo ,&nbsp;Antonio Curti ,&nbsp;Nicola Stefano Fracchiolla ,&nbsp;Luca Maurillo ,&nbsp;Morena Caira ,&nbsp;Paola Finsinger ,&nbsp;Giuliana Gualberti ,&nbsp;Felicetto Ferrara ,&nbsp;Attilio Olivieri","doi":"10.1016/j.lrr.2024.100453","DOIUrl":"https://doi.org/10.1016/j.lrr.2024.100453","url":null,"abstract":"<div><p>Real-world data on treatment patterns and outcomes of patients with acute myeloid leukemia unfit for intensive chemotherapy are lacking before the advent of precision medicine in this setting.</p><p>Herein, we present the Italian sub-analysis of the CURRENT study in AML patients unfit for first line intensive chemotherapy, evaluating patients’ outcomes between 2015 and 2018.</p><p>Among 74 evaluable patients, 62 received systemic treatments (most used therapy was hypomethylating agents), while 12 best supportive care.</p><p>Key results include both efficacy and safety data, as well as HCRU and treatment patterns. In first-line therapy cohort median OS was 13.4 months vs. 2.7 months for BSC.</p></div>","PeriodicalId":38435,"journal":{"name":"Leukemia Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213048924000438/pdfft?md5=f5c1ed3740748c30eca95f71c3a15eda&pid=1-s2.0-S2213048924000438-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140063297","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}
引用次数: 0
A META-ANALYSIS OF COMPLICATED CASES OF INFLAMMATORY BOWEL DISEASE AND BONE MARROW FAILURE SYNDROME IN JAPAN 日本炎症性肠病和骨髓衰竭综合征复杂病例的荟萃分析
Q4 Medicine Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100421
T. Yagi , H. Kumagai , A. Shimada

Introduction

Inflammatory bowel disease (IBD) is characterized by chronic inflammation within the digestive tract. In myelodysplastic syndrome (MDS) and aplastic anemia (AA), inflammation in the bone marrow is thought to be one of the causes. There are case reports of MDS or AA combined with IBD. Among these patients, there were several cases who improved hematopoietic function and IBD symptoms after treatment for MDS or AA. However, there are no summarized reports of cases of IBD combined with MDS or AA in Japan. We retrospectively reviewed the reports of IBD combined with MDS or AA in Japan.

Methods

We collected reports on cases of IBD combined with MDS or AA in Japan using Igaku Chuo Zasshi [Ichushi] and PubMed, and reviewed those cases.

Results

We collected 45 cases of IBD combined with MDS or AA. There were 28 and 19 cases of IBD combined with MDS and AA, respectively. Two cases progressed from AA to MDS. Seven cases occurred in the same period. In 21 cases, MDS or AA occurred prior to IBD. In 5 cases, hematopoietic stem cell transplantation restored both IBD and hematopoietic function.

Conclusions

We performed the first literature review of combined cases of IBD and MDS or AA in Japan. Considering the timing of onset and treatment response, there may be common pathologies in IBD and MDS or AA. However, we could not collect treatment details. We plan to construct a nationwide database of complicated cases and elucidate the pathophysiology of these cases.

导言炎症性肠病(IBD)的特征是消化道内的慢性炎症。在骨髓增生异常综合征(MDS)和再生障碍性贫血(AA)中,骨髓炎症被认为是病因之一。有 MDS 或 AA 合并 IBD 的病例报告。在这些患者中,有几例患者在接受 MDS 或 AA 治疗后,造血功能和 IBD 症状得到改善。然而,在日本还没有 IBD 合并 MDS 或 AA 病例的总结报告。我们回顾性地回顾了日本关于 IBD 合并 MDS 或 AA 的报告。方法我们通过 Igaku Chuo Zasshi [Ichushi] 和 PubMed 收集了日本关于 IBD 合并 MDS 或 AA 的病例报告,并对这些病例进行了回顾。IBD 合并 MDS 和 AA 的病例分别为 28 例和 19 例。2例从AA发展为MDS。7例发生在同一时期。21例患者的MDS或AA发生在IBD之前。结论我们首次对日本的 IBD 和 MDS 或 AA 合并病例进行了文献综述。考虑到发病时间和治疗反应,IBD 和 MDS 或 AA 可能存在共同病理。但是,我们无法收集治疗细节。我们计划建立一个全国性的复杂病例数据库,并阐明这些病例的病理生理学。
{"title":"A META-ANALYSIS OF COMPLICATED CASES OF INFLAMMATORY BOWEL DISEASE AND BONE MARROW FAILURE SYNDROME IN JAPAN","authors":"T. Yagi ,&nbsp;H. Kumagai ,&nbsp;A. Shimada","doi":"10.1016/j.lrr.2024.100421","DOIUrl":"https://doi.org/10.1016/j.lrr.2024.100421","url":null,"abstract":"<div><h3>Introduction</h3><p>Inflammatory bowel disease (IBD) is characterized by chronic inflammation within the digestive tract. In myelodysplastic syndrome (MDS) and aplastic anemia (AA), inflammation in the bone marrow is thought to be one of the causes. There are case reports of MDS or AA combined with IBD. Among these patients, there were several cases who improved hematopoietic function and IBD symptoms after treatment for MDS or AA. However, there are no summarized reports of cases of IBD combined with MDS or AA in Japan. We retrospectively reviewed the reports of IBD combined with MDS or AA in Japan.</p></div><div><h3>Methods</h3><p>We collected reports on cases of IBD combined with MDS or AA in Japan using Igaku Chuo Zasshi [Ichushi] and PubMed, and reviewed those cases.</p></div><div><h3>Results</h3><p>We collected 45 cases of IBD combined with MDS or AA. There were 28 and 19 cases of IBD combined with MDS and AA, respectively. Two cases progressed from AA to MDS. Seven cases occurred in the same period. In 21 cases, MDS or AA occurred prior to IBD. In 5 cases, hematopoietic stem cell transplantation restored both IBD and hematopoietic function.</p></div><div><h3>Conclusions</h3><p>We performed the first literature review of combined cases of IBD and MDS or AA in Japan. Considering the timing of onset and treatment response, there may be common pathologies in IBD and MDS or AA. However, we could not collect treatment details. We plan to construct a nationwide database of complicated cases and elucidate the pathophysiology of these cases.</p></div>","PeriodicalId":38435,"journal":{"name":"Leukemia Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213048924000116/pdfft?md5=eed8f5705846a42368e187499e377e4d&pid=1-s2.0-S2213048924000116-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140103265","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}
引用次数: 0
DIAGNOSTIC UTILITY OF ALDEHYDE DEGRADATION DEFICIENCY SYNDROME USING PROTEOMIC ANALYSIS 利用蛋白质组分析诊断醛降解缺乏综合征的实用性
Q4 Medicine Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100418
M. Wakamatsu , H. Muramatsu , H. Sato , M. Ishikawa , D. Nakajima , R. Konno , Y. Kawashima , M. Hamada , Y. Okuno , O. Ohara , Y. Takahashi

Introduction

Inherited bone marrow failure syndrome (IBMFS) is characterized by a heterogeneous group of disorders with marked cytopenia in one hematopoietic cell lineage. Aldehyde Degradation Deficiency Syndrome (ADDS) is one of the newly discovered IBMFS, caused by a combined deficiency of ADH5 and ALDH2, which are important for the degradation of endogenously produced formaldehyde. Here, we utilized recent technological advances in data-independent proteomic analysis to establish a diagnostic testing for IBMFS, including ADDS.

Methods

We performed a multi-omics analysis of in-depth proteomic analysis, targeted capture DNA sequencing, and RNA sequencing among patients with IBMFS.

Results

In-depth non-targeted proteomic analysis was performed on 74 samples obtained from 60 patients with IBMFS and 14 healthy controls. We identified eight independent proteomic clusters (C1-C8), with ribosome pathway-related proteins specifically downregulated in C1 and C2, enriched for Diamond-Blackfan anemia and Schwachman-Diamond syndrome, respectively. In the 74 samples, four patients with ADDS showed significantly reduced ADH5 protein expression, whereas the remaining samples showed normal expression. To provide a large-scale rapid screening system in a practical clinical setting, targeted proteomic analysis was performed using a small panel, including ADH5 proteins, in a developmental cohort of 417 samples with hematological malignancies and healthy controls. ADH5 protein expression levels were significantly reduced in ADDS, and its sensitivity and specificity values were 100.0% and 97.5%, respectively.

Conclusions

We have performed the first integrated multi-omics analysis for IBMFS, and demonstrated that clinical applications of targeted proteomic assays would be useful in diagnosing for IBMFS, including ADDS.

导言遗传性骨髓衰竭综合征(IBMFS)是一组异质性疾病,其特征是一个造血细胞系出现明显的全血细胞减少。醛降解缺陷综合征(ADDS)是新发现的骨髓衰竭综合征之一,由 ADH5 和 ALDH2 共同缺乏引起,而这两种物质对降解内源性产生的甲醛非常重要。方法我们对 IBMFS 患者进行了深度蛋白质组分析、靶向捕获 DNA 测序和 RNA 测序等多组学分析。结果我们对来自 60 名 IBMFS 患者和 14 名健康对照者的 74 份样本进行了深度非靶向蛋白质组分析。我们发现了八个独立的蛋白质组群(C1-C8),其中核糖体通路相关蛋白质在C1和C2中特异性下调,分别富集于菱形-巴拉克范贫血症和施瓦赫曼-钻石综合征。在74个样本中,4名ADDS患者的ADH5蛋白表达明显降低,而其余样本表达正常。为了在实际临床环境中提供一个大规模的快速筛查系统,研究人员在一个由417个血液恶性肿瘤样本和健康对照组样本组成的发育队列中,使用一个包括ADH5蛋白在内的小面板进行了靶向蛋白质组分析。ADDS患者的ADH5蛋白表达水平明显降低,其灵敏度和特异度分别为100.0%和97.5%。结论我们首次对IBMFS进行了多组学综合分析,并证明了靶向蛋白质组测定的临床应用将有助于诊断包括ADDS在内的IBMFS。
{"title":"DIAGNOSTIC UTILITY OF ALDEHYDE DEGRADATION DEFICIENCY SYNDROME USING PROTEOMIC ANALYSIS","authors":"M. Wakamatsu ,&nbsp;H. Muramatsu ,&nbsp;H. Sato ,&nbsp;M. Ishikawa ,&nbsp;D. Nakajima ,&nbsp;R. Konno ,&nbsp;Y. Kawashima ,&nbsp;M. Hamada ,&nbsp;Y. Okuno ,&nbsp;O. Ohara ,&nbsp;Y. Takahashi","doi":"10.1016/j.lrr.2024.100418","DOIUrl":"https://doi.org/10.1016/j.lrr.2024.100418","url":null,"abstract":"<div><h3>Introduction</h3><p>Inherited bone marrow failure syndrome (IBMFS) is characterized by a heterogeneous group of disorders with marked cytopenia in one hematopoietic cell lineage. Aldehyde Degradation Deficiency Syndrome (ADDS) is one of the newly discovered IBMFS, caused by a combined deficiency of ADH5 and ALDH2, which are important for the degradation of endogenously produced formaldehyde. Here, we utilized recent technological advances in data-independent proteomic analysis to establish a diagnostic testing for IBMFS, including ADDS.</p></div><div><h3>Methods</h3><p>We performed a multi-omics analysis of in-depth proteomic analysis, targeted capture DNA sequencing, and RNA sequencing among patients with IBMFS.</p></div><div><h3>Results</h3><p>In-depth non-targeted proteomic analysis was performed on 74 samples obtained from 60 patients with IBMFS and 14 healthy controls. We identified eight independent proteomic clusters (C1-C8), with ribosome pathway-related proteins specifically downregulated in C1 and C2, enriched for Diamond-Blackfan anemia and Schwachman-Diamond syndrome, respectively. In the 74 samples, four patients with ADDS showed significantly reduced ADH5 protein expression, whereas the remaining samples showed normal expression. To provide a large-scale rapid screening system in a practical clinical setting, targeted proteomic analysis was performed using a small panel, including ADH5 proteins, in a developmental cohort of 417 samples with hematological malignancies and healthy controls. ADH5 protein expression levels were significantly reduced in ADDS, and its sensitivity and specificity values were 100.0% and 97.5%, respectively.</p></div><div><h3>Conclusions</h3><p>We have performed the first integrated multi-omics analysis for IBMFS, and demonstrated that clinical applications of targeted proteomic assays would be useful in diagnosing for IBMFS, including ADDS.</p></div>","PeriodicalId":38435,"journal":{"name":"Leukemia Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213048924000086/pdfft?md5=210b5b55130fba593fda02ab4629f2e9&pid=1-s2.0-S2213048924000086-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140103419","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}
引用次数: 0
MOLECULAR INTERNATIONAL PROGNOSTIC SCORING SYSTEM FOR MYELODYSPLASTIC SYNDROMES: A MONOCENTRIC EXPERIENCE 骨髓增生异常综合征分子国际预后评分系统:单中心经验
Q4 Medicine Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100431
E. Diral, G. Bergonzi, S. Mastaglio, C. Tresoldi, P. Ronchi, M. Ponzoni, M. Cristante, D. Clerici, L. Vago, M. Bernardi, F. Ciceri

Introduction

Allogeneic HSCT (aHSCT) is the only curative treatment, reserved for IPSS-R higher risk (HR, > 3.5) MDS. Molecular data have been integrated within the recently validated IPSS-Mol score system, in order to better predict clinical outcome. However, IPSS-Mol is not still used to guide clinical decisions. We aim to investigate IPSS-Mol significance in a cohort of MDS patients transplanted at our center.

Methods

We retrospectively analyzed a cohort of 74 MDS patients undergoing aHSCT between 2010-2022 at our center according to IPSS-R risk score. All patients received treosulfan-based conditioning regimens and PBSC as stem cell source from matched related/unrelated or haploidentical donors. NGS testing for somatic myeloid mutations was performed retrospectively on cryopreserved marrow cells at diagnosis and MDS risk score was then re-calculated according to IPSS-Mol.

Results

27 patients (36%) were lower risk (LR) at diagnosis and underwent aHSCT for disease progression. All the other patients were HR (IPSS-R > 3.5) and received aHSCT as upfront or consolidation treatment. At least one oncogenic mutation was found in 86.5% of cases by NGS testing. With IPSS-Mol 10 LR patients (37%) were re-stratified as HR (of note, 6/12 patients with intermediate IPSS-R ≤ 3.5), while 7 HR patients (15%) were re-stratified as LR.

Conclusions

aHSCT remains the only curative strategy in HR MDS. NGS testing and application of IPSS-Mol allow to better prognosticate MDS, mostly in patients with LR MDS and specifically in intermediate risk (≤3.5) group. This could help in guiding treatment and specifically optimizing the use of aHSCT in MDS.

导言同种异体造血干细胞移植(aHSCT)是唯一可治愈的治疗方法,适用于 IPSS-R 高风险(HR, > 3.5)MDS。为了更好地预测临床结果,分子数据已被整合到最近通过验证的 IPSS-Mol 评分系统中。然而,IPSS-Mol 仍未被用于指导临床决策。我们旨在研究 IPSS-Mol 在本中心接受移植的一组 MDS 患者中的意义。所有患者均接受了以曲硫烷为基础的调理方案,并以匹配的亲缘/非亲缘或单倍体供者的PBSC作为干细胞来源。对诊断时冷冻保存的骨髓细胞进行体细胞骨髓突变的NGS检测,然后根据IPSS-Mol重新计算MDS风险评分。其他患者均为HR(IPSS-R >3.5),接受了aHSCT作为前期或巩固治疗。86.5%的病例通过NGS检测发现了至少一种致癌突变。通过IPSS-Mol,10例LR患者(37%)被重新分层为HR(值得注意的是,6/12例患者的中间IPSS-R≤3.5),而7例HR患者(15%)被重新分层为LR。NGS检测和IPSS-Mol的应用可以更好地预测MDS的预后,主要针对LR MDS患者,尤其是中危(≤3.5)组患者。这有助于指导治疗,特别是优化 MDS 患者的 aHSCT 的使用。
{"title":"MOLECULAR INTERNATIONAL PROGNOSTIC SCORING SYSTEM FOR MYELODYSPLASTIC SYNDROMES: A MONOCENTRIC EXPERIENCE","authors":"E. Diral,&nbsp;G. Bergonzi,&nbsp;S. Mastaglio,&nbsp;C. Tresoldi,&nbsp;P. Ronchi,&nbsp;M. Ponzoni,&nbsp;M. Cristante,&nbsp;D. Clerici,&nbsp;L. Vago,&nbsp;M. Bernardi,&nbsp;F. Ciceri","doi":"10.1016/j.lrr.2024.100431","DOIUrl":"https://doi.org/10.1016/j.lrr.2024.100431","url":null,"abstract":"<div><h3>Introduction</h3><p>Allogeneic HSCT (aHSCT) is the only curative treatment, reserved for IPSS-R higher risk (HR, &gt; 3.5) MDS. Molecular data have been integrated within the recently validated IPSS-Mol score system, in order to better predict clinical outcome. However, IPSS-Mol is not still used to guide clinical decisions. We aim to investigate IPSS-Mol significance in a cohort of MDS patients transplanted at our center.</p></div><div><h3>Methods</h3><p>We retrospectively analyzed a cohort of 74 MDS patients undergoing aHSCT between 2010-2022 at our center according to IPSS-R risk score. All patients received treosulfan-based conditioning regimens and PBSC as stem cell source from matched related/unrelated or haploidentical donors. NGS testing for somatic myeloid mutations was performed retrospectively on cryopreserved marrow cells at diagnosis and MDS risk score was then re-calculated according to IPSS-Mol.</p></div><div><h3>Results</h3><p>27 patients (36%) were lower risk (LR) at diagnosis and underwent aHSCT for disease progression. All the other patients were HR (IPSS-R &gt; 3.5) and received aHSCT as upfront or consolidation treatment. At least one oncogenic mutation was found in 86.5% of cases by NGS testing. With IPSS-Mol 10 LR patients (37%) were re-stratified as HR (of note, 6/12 patients with intermediate IPSS-R ≤ 3.5), while 7 HR patients (15%) were re-stratified as LR.</p></div><div><h3>Conclusions</h3><p>aHSCT remains the only curative strategy in HR MDS. NGS testing and application of IPSS-Mol allow to better prognosticate MDS, mostly in patients with LR MDS and specifically in intermediate risk (≤3.5) group. This could help in guiding treatment and specifically optimizing the use of aHSCT in MDS.</p></div>","PeriodicalId":38435,"journal":{"name":"Leukemia Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213048924000219/pdfft?md5=1c5b2853f0f0334709793e7375ff3b13&pid=1-s2.0-S2213048924000219-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140103597","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}
引用次数: 0
A STAT3 DEGRADER DEMONSTRATES PRE-CLINICAL EFFICACY IN VENETOCLAX RESISTANT MDS & AML 一种Stat3降解剂显示出对耐药MDS和AML的临床前疗效
Q4 Medicine Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100445
A. Shastri, S. Chakraborty, C. Morganti, H. Zhang, B. Rivera-Pena, K. Ito, M. Konopleva

Introduction

High-risk MDS & AML are the result of malignant transformation of an immature hematopoietic precursor. Venetoclax (Ven) is a selective inhibitor of the anti-apoptotic BCL2 protein that is FDA approved for the treatment of AML, despite which, the overall cure rates in HR-MDS and AML are dismal. Signal transducer and activator of transcription 3 (STAT3) is de-methylation and overexpression in MDS & AML stem cells. It is associated with an adverse prognosis in a large cohort of patients. We have also demonstrated that STAT3 controls several important leukemic drivers such as the anti-apoptotic protein MCL1, which is the central mechanism of venetoclax resistance.

Methods

Ven resistant AML cell lines (MOLM-13, MV-4-11) demonstrated an increased expression of STAT3/ Phospho-STAT3 and the down-stream effector MCL1 when compared to parental cell lines. Data from > 90 AML patients treated with prior venetoclax show that high expression of STAT3 correlated with worse overall survival and remission duration.

Results

A clinical degrader of STAT3 resulted in degradation of STAT3 in both parental and ven resistant cancer cell lines. STAT3 degradation also resulted in increased apoptosis in parental & Ven resistant MOLM-13 cell line. In primary patient colony assays, there was increased erythroid and myeloid differentiation on treatment with a STAT3 degrader. Furthermore, murine model of venetoclax resistance showed significant reduction in STAT3 & MCL1 on treatment with the STAT3 degrader.

Conclusions

Targeting STAT3 and downstream MCL1 is novel strategy in MDS/AML that can spur clinical development of the STAT3 degraders especially given the significant side profile of direct MCL1 inhibitors.

导言高危骨髓增生异常综合征(MDS)和急性髓细胞性白血病(AML)是未成熟造血前体恶性转化的结果。Venetoclax(Ven)是一种抗凋亡BCL2蛋白的选择性抑制剂,已被FDA批准用于治疗急性髓细胞性白血病,尽管如此,HR-MDS和急性髓细胞性白血病的总体治愈率仍然令人沮丧。信号转导和激活转录 3(STAT3)在 MDS 和 AML 干细胞中存在去甲基化和过表达现象。它与大量患者的不良预后有关。我们还证明,STAT3 控制着几种重要的白血病驱动因子,如抗凋亡蛋白 MCL1,而这正是 Venetoclax 耐药的核心机制。方法与亲代细胞系相比,Ven 耐药的 AML 细胞系(MOLM-13、MV-4-11)显示出 STAT3/磷酸化 STAT3 和下行效应因子 MCL1 的表达增加。结果 STAT3的一种临床降解剂导致STAT3在亲代细胞系和对Venetoclax耐药的癌细胞系中降解。STAT3降解还导致亲代和对Ven耐药的MOLM-13细胞系的细胞凋亡增加。在原发性患者集落试验中,使用 STAT3 降解剂处理后,红细胞和骨髓分化增加。结论靶向 STAT3 和下游 MCL1 是治疗 MDS/AML 的新策略,可以促进 STAT3 降解剂的临床开发,特别是考虑到直接 MCL1 抑制剂的副作用很大。
{"title":"A STAT3 DEGRADER DEMONSTRATES PRE-CLINICAL EFFICACY IN VENETOCLAX RESISTANT MDS & AML","authors":"A. Shastri,&nbsp;S. Chakraborty,&nbsp;C. Morganti,&nbsp;H. Zhang,&nbsp;B. Rivera-Pena,&nbsp;K. Ito,&nbsp;M. Konopleva","doi":"10.1016/j.lrr.2024.100445","DOIUrl":"https://doi.org/10.1016/j.lrr.2024.100445","url":null,"abstract":"<div><h3>Introduction</h3><p>High-risk MDS &amp; AML are the result of malignant transformation of an immature hematopoietic precursor. Venetoclax (Ven) is a selective inhibitor of the anti-apoptotic BCL2 protein that is FDA approved for the treatment of AML, despite which, the overall cure rates in HR-MDS and AML are dismal. Signal transducer and activator of transcription 3 (STAT3) is de-methylation and overexpression in MDS &amp; AML stem cells. It is associated with an adverse prognosis in a large cohort of patients. We have also demonstrated that STAT3 controls several important leukemic drivers such as the anti-apoptotic protein MCL1, which is the central mechanism of venetoclax resistance.</p></div><div><h3>Methods</h3><p>Ven resistant AML cell lines (MOLM-13, MV-4-11) demonstrated an increased expression of STAT3/ Phospho-STAT3 and the down-stream effector MCL1 when compared to parental cell lines. Data from &gt; 90 AML patients treated with prior venetoclax show that high expression of STAT3 correlated with worse overall survival and remission duration.</p></div><div><h3>Results</h3><p>A clinical degrader of STAT3 resulted in degradation of STAT3 in both parental and ven resistant cancer cell lines. STAT3 degradation also resulted in increased apoptosis in parental &amp; Ven resistant MOLM-13 cell line. In primary patient colony assays, there was increased erythroid and myeloid differentiation on treatment with a STAT3 degrader. Furthermore, murine model of venetoclax resistance showed significant reduction in STAT3 &amp; MCL1 on treatment with the STAT3 degrader.</p></div><div><h3>Conclusions</h3><p>Targeting STAT3 and downstream MCL1 is novel strategy in MDS/AML that can spur clinical development of the STAT3 degraders especially given the significant side profile of direct MCL1 inhibitors.</p></div>","PeriodicalId":38435,"journal":{"name":"Leukemia Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213048924000359/pdfft?md5=34565d0330b117d488c84b68d03049c3&pid=1-s2.0-S2213048924000359-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140103894","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}
引用次数: 0
IL-2/CD25 axis mediates cellular networks promoting the growth of CD25+ acute myeloid leukemia cells IL-2/CD25 轴介导促进 CD25+ 急性髓性白血病细胞生长的细胞网络
Q4 Medicine Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100454
Kazunori Nakase , Kenkichi Kita

Although the expression of interleukin-2 receptor α-chain (IL-2Rα, CD25) has been provided prognostic significance independent of known biomarkers in acute myeloid leukemia (AML), the functional role of CD25 molecule remains unknown. Since IL-2 can be trans-presented via CD25 to another cell, CD25+AML cells may deliver environmental IL-2 to surrounding immune cells to produce myeloid growth factors for their proliferation. We hypothesize that cellular interactions via IL-2/CD25 axis in the bone marrow microenvironment contributes to the growth advantage of these AML cells and affects the clinical outcome of those AML patients.

虽然白细胞介素-2受体α-链(IL-2Rα,CD25)的表达在急性髓性白血病(AML)中具有独立于已知生物标志物的预后意义,但CD25分子的功能作用仍然未知。由于IL-2可通过CD25转呈到另一个细胞,CD25+AML细胞可能将环境中的IL-2传递给周围的免疫细胞,以产生髓系生长因子促进其增殖。我们推测,骨髓微环境中通过 IL-2/CD25 轴的细胞相互作用促成了这些急性髓细胞白血病细胞的生长优势,并影响了这些急性髓细胞白血病患者的临床预后。
{"title":"IL-2/CD25 axis mediates cellular networks promoting the growth of CD25+ acute myeloid leukemia cells","authors":"Kazunori Nakase ,&nbsp;Kenkichi Kita","doi":"10.1016/j.lrr.2024.100454","DOIUrl":"https://doi.org/10.1016/j.lrr.2024.100454","url":null,"abstract":"<div><p>Although the expression of interleukin-2 receptor α-chain (IL-2Rα, CD25) has been provided prognostic significance independent of known biomarkers in acute myeloid leukemia (AML), the functional role of CD25 molecule remains unknown. Since IL-2 can be trans-presented via CD25 to another cell, CD25<sup>+</sup>AML cells may deliver environmental IL-2 to surrounding immune cells to produce myeloid growth factors for their proliferation. We hypothesize that cellular interactions via IL-2/CD25 axis in the bone marrow microenvironment contributes to the growth advantage of these AML cells and affects the clinical outcome of those AML patients.</p></div>","PeriodicalId":38435,"journal":{"name":"Leukemia Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S221304892400044X/pdfft?md5=e87d3fc5e5f5a9baca7d584fe77971e1&pid=1-s2.0-S221304892400044X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140134306","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}
引用次数: 0
Micro-transplantation in an elderly patient with very high risk MDS:A case report and literature review 一名高危 MDS 老年患者的微移植:病例报告和文献综述
IF 0.7 Q4 HEMATOLOGY Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100475

Introduction

The prognosis of patients with myelodysplastic syndromes (MDS) (very high risk) is poor.HLA-mismatched allogeneic T-cell infusion which is called micro-transplantation can not only shorten the time of bone marrow suppression, but also improve the treatment response of patients.

Case presentation

A 74-year-old woman presented with fatigue and showed pancytopenia on routine blood count. She was diagnosed with MDS (very high risk) after bone marrow examination,then she received 4 cycles of micro-transplantation. The progression-free survival was 22 months and overall survival was 33 months.

Discussion

The patient showed good tolerance to micro-transplantation with manageable toxicities and short myelosuppression time.

导言 骨髓增生异常综合征(MDS)(极高危)患者的预后很差。HLA 不匹配的异体 T 细胞输注(即微移植)不仅能缩短骨髓抑制时间,还能改善患者的治疗反应。病例介绍 一位 74 岁的女性患者因乏力前来就诊,血常规检查显示为全血细胞减少。经过骨髓检查,她被确诊为 MDS(极高危),随后接受了 4 个周期的微移植。讨论该患者对微量移植的耐受性良好,毒性反应可控,骨髓抑制时间短。
{"title":"Micro-transplantation in an elderly patient with very high risk MDS:A case report and literature review","authors":"","doi":"10.1016/j.lrr.2024.100475","DOIUrl":"10.1016/j.lrr.2024.100475","url":null,"abstract":"<div><h3>Introduction</h3><p>The prognosis of patients with myelodysplastic syndromes (MDS) (very high risk) is poor.HLA-mismatched allogeneic T-cell infusion which is called micro-transplantation can not only shorten the time of bone marrow suppression, but also improve the treatment response of patients.</p></div><div><h3>Case presentation</h3><p>A 74-year-old woman presented with fatigue and showed pancytopenia on routine blood count. She was diagnosed with MDS (very high risk) after bone marrow examination,then she received 4 cycles of micro-transplantation. The progression-free survival was 22 months and overall survival was 33 months.</p></div><div><h3>Discussion</h3><p>The patient showed good tolerance to micro-transplantation with manageable toxicities and short myelosuppression time.</p></div>","PeriodicalId":38435,"journal":{"name":"Leukemia Research Reports","volume":null,"pages":null},"PeriodicalIF":0.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213048924000657/pdfft?md5=cce42c4b377861e7392c209e22d0247a&pid=1-s2.0-S2213048924000657-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141841638","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}
引用次数: 0
Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia in Jehovah's witness patients 治疗耶和华见证人患者中的费城染色体阳性急性淋巴细胞白血病
IF 0.7 Q4 HEMATOLOGY Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100474
{"title":"Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia in Jehovah's witness patients","authors":"","doi":"10.1016/j.lrr.2024.100474","DOIUrl":"10.1016/j.lrr.2024.100474","url":null,"abstract":"","PeriodicalId":38435,"journal":{"name":"Leukemia Research Reports","volume":null,"pages":null},"PeriodicalIF":0.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213048924000645/pdfft?md5=3040d4d2694de947d12371d548eb36f2&pid=1-s2.0-S2213048924000645-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141849553","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}
引用次数: 0
Chronic myeloid leukemia with involvement of membranous labyrinth 慢性髓性白血病累及膜迷路
IF 0.7 Q4 HEMATOLOGY Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100471

This case report explains an extraordinary presentation of chronic myeloid leukemia (CML) in a 39-year-old male with a T315I mutation, presenting with acute bilateral hearing loss and imbalance secondary to myeloid blast crisis. Neurological involvement was confirmed through MRI brain and cerebrospinal fluid analysis. Initial treatment with ponatinib and FLAG (fludarabine, cytarabine, G-CSF) regimen showed promise, but complications necessitated discontinuation. The patient's complex clinical trajectory, marked by complications and intolerance to tyrosine kinase inhibitors, highlights the intricate nature of CML blast crisis with T315I mutation management. Recognizing atypical presentations and early mutation analysis are pivotal for tailored treatment strategies.

本病例报告解释了一名 39 岁男性慢性髓性白血病(CML)患者的特殊表现,该患者具有 T315I 突变,表现为急性双侧听力损失和失衡,继发于髓细胞暴发性危象。通过脑磁共振成像和脑脊液分析证实了神经系统受累。最初使用泊纳替尼和FLAG(氟达拉滨、阿糖胞苷、G-CSF)方案进行治疗,疗效显著,但因出现并发症而不得不停药。该患者的临床轨迹十分复杂,并发症和对酪氨酸激酶抑制剂的不耐受是其特点,这凸显了T315I突变的CML爆裂危象治疗的复杂性。识别非典型表现和早期突变分析对于定制治疗策略至关重要。
{"title":"Chronic myeloid leukemia with involvement of membranous labyrinth","authors":"","doi":"10.1016/j.lrr.2024.100471","DOIUrl":"10.1016/j.lrr.2024.100471","url":null,"abstract":"<div><p>This case report explains an extraordinary presentation of chronic myeloid leukemia (CML) in a 39-year-old male with a T315I mutation, presenting with acute bilateral hearing loss and imbalance secondary to myeloid blast crisis. Neurological involvement was confirmed through MRI brain and cerebrospinal fluid analysis. Initial treatment with ponatinib and FLAG (fludarabine, cytarabine, G-CSF) regimen showed promise, but complications necessitated discontinuation. The patient's complex clinical trajectory, marked by complications and intolerance to tyrosine kinase inhibitors, highlights the intricate nature of CML blast crisis with T315I mutation management. Recognizing atypical presentations and early mutation analysis are pivotal for tailored treatment strategies.</p></div>","PeriodicalId":38435,"journal":{"name":"Leukemia Research Reports","volume":null,"pages":null},"PeriodicalIF":0.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S221304892400061X/pdfft?md5=72e11a1ea336e7231d57c0f3856bed99&pid=1-s2.0-S221304892400061X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141849867","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}
引用次数: 0
Treatment of relapsed/refractory chronic lymphocytic leukemia with Zanubrutinib after progressing on other BTK inhibitors 使用其他 BTK 抑制剂治疗慢性淋巴细胞白血病进展后,使用 Zanubrutinib 治疗复发/难治性慢性淋巴细胞白血病
Q4 Medicine Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100459
Nkolika Nwankwo , Aswanth Reddy , Swarup Kumar , Maha Zafar

Chronic Lymphocytic Leukemia (CLL) is the most common type of leukemia in the US, representing approximately 1.1% of all new cancers diagnosed. Most patients with CLL can be monitored without treatment, and the indicated treatment options include a CD20 monoclonal antibody with or without bruton tyrosine kinase (BTK) inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, and B-cell lymphoma 2 (BCL2) antagonists. We review the case of a 77-year-old female with a long-standing history of CLL predominant lymphocytosis, transfusion -independent anemia, and thrombocytopenia. Patient responded to zanubrutinib after initial failure of idelalisib, rituximab, and acalabrutinib and venetoclax.

慢性淋巴细胞白血病(CLL)是美国最常见的白血病类型,约占所有新诊断癌症的 1.1%。大多数慢性淋巴细胞白血病患者无需治疗即可接受监测,适用的治疗方案包括 CD20 单克隆抗体与或不与布鲁顿酪氨酸激酶(BTK)抑制剂、磷脂酰肌醇 3-激酶(PI3K)抑制剂和 B 细胞淋巴瘤 2(BCL2)拮抗剂。我们回顾了一例 77 岁女性患者的病例,她长期以来以 CLL 淋巴细胞增多、输血依赖性贫血和血小板减少为主。患者在最初使用伊德拉利西、利妥昔单抗、阿卡布替尼和 Venetoclax 失败后,对扎鲁替尼产生了反应。
{"title":"Treatment of relapsed/refractory chronic lymphocytic leukemia with Zanubrutinib after progressing on other BTK inhibitors","authors":"Nkolika Nwankwo ,&nbsp;Aswanth Reddy ,&nbsp;Swarup Kumar ,&nbsp;Maha Zafar","doi":"10.1016/j.lrr.2024.100459","DOIUrl":"https://doi.org/10.1016/j.lrr.2024.100459","url":null,"abstract":"<div><p>Chronic Lymphocytic Leukemia (CLL) is the most common type of leukemia in the US, representing approximately 1.1% of all new cancers diagnosed. Most patients with CLL can be monitored without treatment, and the indicated treatment options include a CD20 monoclonal antibody with or without bruton tyrosine kinase (BTK) inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, and B-cell lymphoma 2 (BCL2) antagonists. We review the case of a 77-year-old female with a long-standing history of CLL predominant lymphocytosis, transfusion -independent anemia, and thrombocytopenia. Patient responded to zanubrutinib after initial failure of idelalisib, rituximab, and acalabrutinib and venetoclax.</p></div>","PeriodicalId":38435,"journal":{"name":"Leukemia Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213048924000499/pdfft?md5=a23718a3244f0f271e6dad162430fcf4&pid=1-s2.0-S2213048924000499-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140622167","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}
引用次数: 0
期刊
Leukemia Research Reports
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1