Blood Cancer Discovery最新文献_第5页

Transcriptional Plasticity Drives IMiD and p300 Inhibitor Resistance in Multiple Myeloma. 转录可塑性驱动多发性骨髓瘤的 IMiD 和 p300 抑制剂抗药性

IF 11.5

Blood Cancer Discovery Pub Date : 2024-01-08 DOI: 10.1158/2643-3230.BCD-23-0223

Seongseok Yun, John L Cleveland

引用次数: 0

Product Attributes of CAR T-cell Therapy Differentially Associate with Efficacy and Toxicity in Second-line Large B-cell Lymphoma (ZUMA-7). CAR - t细胞疗法的产品属性与二线大b细胞淋巴瘤(ZUMA-7)的疗效和毒性存在差异。

IF 11.2

Blood Cancer Discovery Pub Date : 2024-01-08 DOI: 10.1158/2643-3230.BCD-23-0112

Simone Filosto, Saran Vardhanabhuti, Miguel A Canales, Xavier Poiré, Lazaros J Lekakis, Sven de Vos, Craig A Portell, Zixing Wang, Christina To, Marco Schupp, Soumya Poddar, Tan Trinh, Carmen M Warren, Ethan G Aguilar, Justin Budka, Paul Cheng, Justin Chou, Adrian Bot, Rhine R Shen, Jason R Westin

{"title":"Product Attributes of CAR T-cell Therapy Differentially Associate with Efficacy and Toxicity in Second-line Large B-cell Lymphoma (ZUMA-7).","authors":"Simone Filosto, Saran Vardhanabhuti, Miguel A Canales, Xavier Poiré, Lazaros J Lekakis, Sven de Vos, Craig A Portell, Zixing Wang, Christina To, Marco Schupp, Soumya Poddar, Tan Trinh, Carmen M Warren, Ethan G Aguilar, Justin Budka, Paul Cheng, Justin Chou, Adrian Bot, Rhine R Shen, Jason R Westin","doi":"10.1158/2643-3230.BCD-23-0112","DOIUrl":"10.1158/2643-3230.BCD-23-0112","url":null,"abstract":"Treatment resistance and toxicities remain a risk following chimeric antigen receptor (CAR) T-cell therapy. Herein, we report pharmacokinetics, pharmacodynamics, and product and apheresis attributes associated with outcomes among patients with relapsed/refractory large B-cell lymphoma (LBCL) treated with axicabtagene ciloleucel (axi-cel) in ZUMA-7. Axi-cel peak expansion associated with clinical response and toxicity, but not response durability. In apheresis material and final product, a naive T-cell phenotype (CCR7+CD45RA+) expressing CD27 and CD28 associated with improved response durability, event-free survival, progression-free survival, and a lower number of prior therapies. This phenotype was not associated with high-grade cytokine release syndrome (CRS) or neurologic events. Higher baseline and postinfusion levels of serum inflammatory markers associated with differentiated/effector products, reduced efficacy, and increased CRS and neurologic events, thus suggesting targets for intervention. These data support better outcomes with earlier CAR T-cell intervention and may improve patient care by informing on predictive biomarkers and development of next-generation products.Significance: In ZUMA-7, the largest randomized CAR T-cell trial in LBCL, a naive T-cell product phenotype (CCR7+CD45RA+) expressing CD27 and CD28 associated with improved efficacy, decreased toxicity, and a lower number of prior therapies, supporting earlier intervention with CAR T-cell therapy. In addition, targets for improvement of therapeutic index are proposed. This article is featured in Selected Articles from This Issue, p. 4.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"21-33"},"PeriodicalIF":11.2,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10772511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138177480","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

Retraction: In Vivo Monitoring of Polycythemia Vera Development Reveals Carbonic Anhydrase 1 as a Potent Therapeutic Target. 撤回：体内监测多发性红细胞瘤的发展发现碳酸酐酶 1 是一个有效的治疗靶点

IF 11.2

Blood Cancer Discovery Pub Date : 2024-01-08 DOI: 10.1158/2643-3230.BCD-23-0218

引用次数: 0

Criteria for Diagnosis and Molecular Monitoring of NPM1-Mutated AML. NPM1突变AML的诊断和分子监测标准。

IF 11.5

Blood Cancer Discovery Pub Date : 2024-01-08 DOI: 10.1158/2643-3230.BCD-23-0144

Brunangelo Falini, Richard Dillon

{"title":"Criteria for Diagnosis and Molecular Monitoring of NPM1-Mutated AML.","authors":"Brunangelo Falini, Richard Dillon","doi":"10.1158/2643-3230.BCD-23-0144","DOIUrl":"10.1158/2643-3230.BCD-23-0144","url":null,"abstract":"NPM1-mutated acute myeloid leukemia (AML) represents the largest molecular subgroup of adult AML. NPM1-mutated AML is recognizable by molecular techniques and immunohistochemistry, which, when combined, can solve difficult diagnostic problems (including identification of myeloid sarcoma and NPM1 mutations outside exon 12). According to updated 2022 European LeukemiaNet (ELN) guidelines, determining the mutational status of NPM1 (and FLT3) is a mandatory step for the genetic-based risk stratification of AML. Monitoring of measurable residual disease (MRD) by qRT-PCR, combined with ELN risk stratification, can guide therapeutic decisions at the post-remission stage. Here, we review the criteria for appropriate diagnosis and molecular monitoring of NPM1-mutated AML.Significance: NPM1-mutated AML represents a distinct entity in the 2022 International Consensus Classification and 5th edition of World Health Organization classifications of myeloid neoplasms. The correct diagnosis of NPM1-mutated AML and its distinction from other AML entities is extremely important because it has clinical implications for the management of AML patients, such as genetic-based risk stratification according to 2022 ELN. Monitoring of MRD by qRT-PCR, combined with ELN risk stratification, can guide therapeutic decisions at the post-remission stage, e.g., whether or not to perform allogeneic hematopoietic stem cell transplantation.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"8-20"},"PeriodicalIF":11.5,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10772525/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71427418","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

Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma. 转录异质性克服了多发性骨髓瘤中破坏超级增强子的药物组合。

IF 11.5

Blood Cancer Discovery Pub Date : 2024-01-08 DOI: 10.1158/2643-3230.BCD-23-0062

Seth J Welsh, Benjamin G Barwick, Erin W Meermeier, Daniel L Riggs, Chang-Xin Shi, Yuan Xiao Zhu, Meaghen E Sharik, Megan T Du, Leslie D Abrego Rocha, Victoria M Garbitt, Caleb K Stein, Joachim L Petit, Nathalie Meurice, Yuliza Tafoya Alvarado, Rodrigo Fonseca, Kennedi T Todd, Sochilt Brown, Zachery J Hammond, Nicklus H Cuc, Courtney Wittenberg, Camille Herzog, Anna V Roschke, Yulia N Demchenko, Wei-Dong D Chen, Peng Li, Wei Liao, Warren J Leonard, Sagar Lonial, Nizar J Bahlis, Paola Neri, Lawrence H Boise, Marta Chesi, P Leif Bergsagel

{"title":"Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma.","authors":"Seth J Welsh, Benjamin G Barwick, Erin W Meermeier, Daniel L Riggs, Chang-Xin Shi, Yuan Xiao Zhu, Meaghen E Sharik, Megan T Du, Leslie D Abrego Rocha, Victoria M Garbitt, Caleb K Stein, Joachim L Petit, Nathalie Meurice, Yuliza Tafoya Alvarado, Rodrigo Fonseca, Kennedi T Todd, Sochilt Brown, Zachery J Hammond, Nicklus H Cuc, Courtney Wittenberg, Camille Herzog, Anna V Roschke, Yulia N Demchenko, Wei-Dong D Chen, Peng Li, Wei Liao, Warren J Leonard, Sagar Lonial, Nizar J Bahlis, Paola Neri, Lawrence H Boise, Marta Chesi, P Leif Bergsagel","doi":"10.1158/2643-3230.BCD-23-0062","DOIUrl":"10.1158/2643-3230.BCD-23-0062","url":null,"abstract":"Multiple myeloma (MM) is a malignancy that is often driven by MYC and that is sustained by IRF4, which are upregulated by super-enhancers. IKZF1 and IKZF3 bind to super-enhancers and can be degraded using immunomodulatory imide drugs (IMiD). Successful IMiD responses downregulate MYC and IRF4; however, this fails in IMiD-resistant cells. MYC and IRF4 downregulation can also be achieved in IMiD-resistant tumors using inhibitors of BET and EP300 transcriptional coactivator proteins; however, in vivo these drugs have a narrow therapeutic window. By combining IMiDs with EP300 inhibition, we demonstrate greater downregulation of MYC and IRF4, synergistic killing of myeloma in vitro and in vivo, and an increased therapeutic window. Interestingly, this potent combination failed where MYC and IRF4 expression was maintained by high levels of the AP-1 factor BATF. Our results identify an effective drug combination and a previously unrecognized mechanism of IMiD resistance.Significance: These results highlight the dependence of MM on IKZF1-bound super-enhancers, which can be effectively targeted by a potent therapeutic combination pairing IMiD-mediated degradation of IKZF1 and IKZF3 with EP300 inhibition. They also identify AP-1 factors as an unrecognized mechanism of IMiD resistance in MM. See related article by Neri, Barwick, et al., p. 56. See related commentary by Yun and Cleveland, p. 5. This article is featured in Selected Articles from This Issue, p. 4.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"34-55"},"PeriodicalIF":11.5,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10772542/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41170235","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

Acknowledgment to Reviewers. 感谢审稿人。

IF 11.2

Blood Cancer Discovery Pub Date : 2024-01-08 DOI: 10.1158/2643-3230.BCD-5-1-AR

引用次数: 0

Highlighted research articles 重点研究文章

IF 11.2

Blood Cancer Discovery Pub Date : 2024-01-08 DOI: 10.1158/2643-3230.bcd-5-1-iti

引用次数: 0

IDH1-mutant preleukemic hematopoietic stem cells can be eliminated by inhibition of oxidative phosphorylation. 抑制氧化磷酸化可消除 IDH1 突变的白血病前期造血干细胞。

IF 11.5

Blood Cancer Discovery Pub Date : 2023-12-13 DOI: 10.1158/2643-3230.BCD-23-0195

Niklas Landberg, Thomas Köhnke, Yang Feng, Yusuke Nakauchi, Amy C Fan, Miles H Linde, Daiki Karigane, Kelly Lim, Rahul Sinha, Luca Malcovati, Daniel Thomas, Ravindra Majeti

{"title":"IDH1-mutant preleukemic hematopoietic stem cells can be eliminated by inhibition of oxidative phosphorylation.","authors":"Niklas Landberg, Thomas Köhnke, Yang Feng, Yusuke Nakauchi, Amy C Fan, Miles H Linde, Daiki Karigane, Kelly Lim, Rahul Sinha, Luca Malcovati, Daniel Thomas, Ravindra Majeti","doi":"10.1158/2643-3230.BCD-23-0195","DOIUrl":"10.1158/2643-3230.BCD-23-0195","url":null,"abstract":"Rare preleukemic hematopoietic stem cells (pHSCs) harboring only the initiating mutations can be detected at the time of AML diagnosis. pHSCs are the origin of leukemia and a potential reservoir for relapse. Using primary human samples and gene-editing to model isocitrate dehydrogenase 1 (IDH1) mutant pHSCs, we show epigenetic, transcriptional, and metabolic differences between pHSCs and healthy hematopoietic stem cells (HSCs). We confirm that IDH1 driven clonal hematopoiesis is associated with cytopenia, suggesting an inherent defect to fully reconstitute hematopoiesis. Despite giving rise to multilineage engraftment, IDH1-mutant pHSCs exhibited reduced proliferation, blocked differentiation, downregulation of MHC Class II genes, and reprogramming of oxidative phosphorylation metabolism. Critically, inhibition of oxidative phosphorylation resulted in complete eradication of IDH1-mutant pHSCs but not IDH2-mutant pHSCs or wildtype HSCs. Our results indicate that IDH1-mutant preleukemic clones can be targeted with complex I inhibitors, offering a potential strategy to prevent development and relapse of leukemia.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2023-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10905513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138810547","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

Understanding Infection Risk with Anti-BCMA Bispecific Antibodies. 了解抗BCMA双特异性抗体的感染风险。

IF 11.2

Blood Cancer Discovery Pub Date : 2023-11-01 DOI: 10.1158/2643-3230.BCD-23-0157

Alfred L Garfall, Edward A Stadtmauer

引用次数: 0

An Embarrassment of Riches: Three FDA-Approved Bispecific Antibodies for Relapsed Refractory Multiple Myeloma. 财富的尴尬：三种美国食品药品监督管理局批准的用于复发性难治性多发性骨髓瘤的双特异性抗体。

IF 11.2

Blood Cancer Discovery Pub Date : 2023-11-01 DOI: 10.1158/2643-3230.BCD-23-0176

Ross Firestone, Alexander M Lesokhin, Saad Z Usmani

引用次数: 0