Pub Date : 2026-02-01Epub Date: 2025-10-24DOI: 10.1016/j.bneo.2025.100176
Julio C. Chavez , Ellen Napier , Attilio Bondanza , Andrew Lewandowski , Jennifer Mataraza , David Quinn , Paul Kwon , Frederick L. Locke , Boris Engels , Rakesh Awasthi , Petrina Georgala , Malgorzata Leyk , David Hynds , Michele Moschetta , Stephen J. Schuster
Abstract
The mechanisms underlying chimeric antigen receptor (CAR) T-cell failure are not fully understood; however, T-cell differentiation and presence of an immunosuppressive tumor microenvironment are thought to contribute. Ibrutinib, a Bruton tyrosine kinase inhibitor, has been shown to modify both T-cell phenotype and tumor microenvironment. Preliminary data suggest that combining ibrutinib with tisagenlecleucel may improve efficacy of CAR T-cell therapy; however, it is unknown whether the timing of ibrutinib treatment affects clinical outcomes. This phase 1b exploratory study assessed tisagenlecleucel in combination with ibrutinib for safety, efficacy, and feasibility in adult patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Ibrutinib (560 mg/d) was started ≥21 days before apheresis (preapheresis arm, n = 4) or after apheresis for ≥21 days before tisagenlecleucel infusion (postapheresis arm, n = 6). Both arms received ibrutinib continuously thereafter for up to 24 months after infusion. As of study termination (1 November 2021), 10 patients were treated and underwent posttisagenlecleucel response assessment. Final product manufactured from patients in the preapheresis arm had higher interferon gamma and interleukin-2 release and a reduction in senescent T cells. Fewer patients in the preapheresis arm vs the postapheresis arm experienced cytokine release syndrome (1/4 vs 5/6) or death (1/4 vs 4/6). Although increased tisagenlecleucel expansion was observed in the postapheresis arm, a higher response rate was observed in the preapheresis arm (4/4 vs 3/6). Altogether, these findings suggest administering ibrutinib before leukapheresis may modify T-cell characteristics in the collected material, thereby improving final CAR T-cell product quality and clinical outcomes for patients with R/R LBLC treated with tisagenlecleucel. This trial was registered at www.clinicaltrials.gov as #NCT03876028.
嵌合抗原受体（CAR） t细胞衰竭的机制尚不完全清楚；然而，t细胞分化和免疫抑制肿瘤微环境的存在被认为是原因之一。Ibrutinib是一种布鲁顿酪氨酸激酶抑制剂，已被证明可以改变t细胞表型和肿瘤微环境。初步数据表明，依鲁替尼联合tisagenlecleucel可提高CAR - t细胞治疗的疗效；然而，目前尚不清楚伊鲁替尼治疗的时机是否会影响临床结果。这项1b期探索性研究评估了tisagenlecleucel联合依鲁替尼治疗复发/难治性（R/R）大b细胞淋巴瘤（LBCL）成人患者的安全性、有效性和可行性。伊鲁替尼（560mg /d）在采前≥21天（采前组，n = 4）或采后≥21天（采后组，n = 6）开始使用。此后，两组患者在输注后连续接受伊鲁替尼治疗长达24个月。截至研究终止（2021年11月1日），10名患者接受了治疗并进行了tisagenagenle后反应评估。采前组患者生产的最终产品具有更高的干扰素γ和白细胞介素-2释放，衰老T细胞减少。与采后组相比，采前组较少患者出现细胞因子释放综合征（1/4 vs 5/6）或死亡（1/4 vs 4/6）。虽然在采后组观察到增加的组织白细胞扩张，但采前组观察到更高的反应率（4/4 vs 3/6）。总之，这些研究结果表明，在白细胞分离前给予依鲁替尼可能会改变收集材料中的t细胞特征，从而改善最终的CAR - t细胞产品质量，并改善经tisagenlecucel治疗的R/R LBLC患者的临床结果。该试验在www.clinicaltrials.gov注册为#NCT03876028。
{"title":"Tisagenlecleucel in combination with ibrutinib in adults with relapsed and/or refractory large B-cell lymphomas","authors":"Julio C. Chavez , Ellen Napier , Attilio Bondanza , Andrew Lewandowski , Jennifer Mataraza , David Quinn , Paul Kwon , Frederick L. Locke , Boris Engels , Rakesh Awasthi , Petrina Georgala , Malgorzata Leyk , David Hynds , Michele Moschetta , Stephen J. Schuster","doi":"10.1016/j.bneo.2025.100176","DOIUrl":"10.1016/j.bneo.2025.100176","url":null,"abstract":"<div><h3>Abstract</h3><div>The mechanisms underlying chimeric antigen receptor (CAR) T-cell failure are not fully understood; however, T-cell differentiation and presence of an immunosuppressive tumor microenvironment are thought to contribute. Ibrutinib, a Bruton tyrosine kinase inhibitor, has been shown to modify both T-cell phenotype and tumor microenvironment. Preliminary data suggest that combining ibrutinib with tisagenlecleucel may improve efficacy of CAR T-cell therapy; however, it is unknown whether the timing of ibrutinib treatment affects clinical outcomes. This phase 1b exploratory study assessed tisagenlecleucel in combination with ibrutinib for safety, efficacy, and feasibility in adult patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Ibrutinib (560 mg/d) was started ≥21 days before apheresis (preapheresis arm, n = 4) or after apheresis for ≥21 days before tisagenlecleucel infusion (postapheresis arm, n = 6). Both arms received ibrutinib continuously thereafter for up to 24 months after infusion. As of study termination (1 November 2021), 10 patients were treated and underwent posttisagenlecleucel response assessment. Final product manufactured from patients in the preapheresis arm had higher interferon gamma and interleukin-2 release and a reduction in senescent T cells. Fewer patients in the preapheresis arm vs the postapheresis arm experienced cytokine release syndrome (1/4 vs 5/6) or death (1/4 vs 4/6). Although increased tisagenlecleucel expansion was observed in the postapheresis arm, a higher response rate was observed in the preapheresis arm (4/4 vs 3/6). Altogether, these findings suggest administering ibrutinib before leukapheresis may modify T-cell characteristics in the collected material, thereby improving final CAR T-cell product quality and clinical outcomes for patients with R/R LBLC treated with tisagenlecleucel. This trial was registered at <span><span>www.clinicaltrials.gov</span><svg><path></path></svg></span> as #<span><span>NCT03876028</span><svg><path></path></svg></span>.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"3 1","pages":"Article 100176"},"PeriodicalIF":0.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145840564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-12-15DOI: 10.1016/j.bneo.2025.100188
Steven Tessier , Jithma P. Abeykoon , Gordon Ruan , N. Nora Bennani , Mithun V. Shah , Karen L. Rech , Aishwarya Ravindran , Jay H. Ryu , Robert Vassallo , Matthew J. Koster , Caroline J. Davidge-Pitts , Lucinda M. Gruber , W. Oliver Tobin , Julio C. Sartori-Valinotti , Talal Hilal , Liuyan Jiang , Muhammad Alhaj Moustafa , Asra Z. Ahmed , Corrie R. Bach , Jason R. Young , Ronald S. Go
{"title":"Epidemiology of Erdheim-Chester disease in the United States: a SEER-based analysis","authors":"Steven Tessier , Jithma P. Abeykoon , Gordon Ruan , N. Nora Bennani , Mithun V. Shah , Karen L. Rech , Aishwarya Ravindran , Jay H. Ryu , Robert Vassallo , Matthew J. Koster , Caroline J. Davidge-Pitts , Lucinda M. Gruber , W. Oliver Tobin , Julio C. Sartori-Valinotti , Talal Hilal , Liuyan Jiang , Muhammad Alhaj Moustafa , Asra Z. Ahmed , Corrie R. Bach , Jason R. Young , Ronald S. Go","doi":"10.1016/j.bneo.2025.100188","DOIUrl":"10.1016/j.bneo.2025.100188","url":null,"abstract":"","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"3 1","pages":"Article 100188"},"PeriodicalIF":0.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145977232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-11-25DOI: 10.1016/j.bneo.2025.100186
Nicholas Dunham ∗ , Zhenjia Wang ∗ , Yaseswini Neelamraju , Yan Guo , B. Bishal Paudel , Cem Meydan , Jorge A. Gandara , Fady A Abdelmalak , Hao Fan , Joyce Hardwick , Justin H. Layer , Tak Lee , Bernhard Maier , W. Hayes McDonald , Isaani Patnaik , Subhash Prajapati , Franck Rapaport , Caroline Sheridan , Gloria Sheynkman , Paul Zumbo , Francine E. Garrett-Bakelman †
Abstract
Relapsed acute myeloid leukemia (relAML) remains a clinical challenge. We have shown that epigenetic heterogeneity may contribute to transcriptional dysregulation and disease progression in AML, but the specific aberrant transcriptional programs have not been identified. We analyzed molecular profiles from patient-matched diagnostic and relapse AML specimens. A subset of differentially expressed genes (DEG) that were disparate in direction of expression change identified 2 patient subtypes. We predicted that transcriptional regulators (TR) might regulate the expression patterns observed. The expression patterns of the top TR predicted for the disparate genes associated with clinical outcomes. The top TR predicted for the disparate DEG and DEG identified in a patient-derived xenograft model of relAML included members of the LIM domain only 2 - LIM domain binding 1 - TAL BHLH TF1, erythroid differentiation factor (LMO2-LDB1-TAL1) multisubunit complex (LTMC). Analysis of DepMap data identified LMO2-dependent cells with a subset highly expressing TAL1, suggesting coordinated regulation. TAL1 copurified in immunoprecipitation for LMO2 and LDB1 followed by tandem mass spectrometry analysis in HEL and K562 cells, and results from chromatin immunoprecipitation experiments suggest significant co-occupancy of TAL1 and LDB1. Loss-of-function experiments targeting LMO2, LDB1, and TAL1 in AML cell lines associated with reduced cell growth, downregulation of cell cycle genes, and a negative association with gene expression patterns observed in relapsed patients with increased TAL1 expression. Our results from primary AML specimens and functional analyses of AML cell lines supports an essential role for the LTMC in AML. Targeting the complex or downstream effectors could provide novel therapeutic considerations for a subset of patients with AML.
{"title":"The LMO2-LDB1-TAL1 complex regulates transcription networks in acute myeloid leukemia","authors":"Nicholas Dunham ∗ , Zhenjia Wang ∗ , Yaseswini Neelamraju , Yan Guo , B. Bishal Paudel , Cem Meydan , Jorge A. Gandara , Fady A Abdelmalak , Hao Fan , Joyce Hardwick , Justin H. Layer , Tak Lee , Bernhard Maier , W. Hayes McDonald , Isaani Patnaik , Subhash Prajapati , Franck Rapaport , Caroline Sheridan , Gloria Sheynkman , Paul Zumbo , Francine E. Garrett-Bakelman †","doi":"10.1016/j.bneo.2025.100186","DOIUrl":"10.1016/j.bneo.2025.100186","url":null,"abstract":"<div><h3>Abstract</h3><div>Relapsed acute myeloid leukemia (relAML) remains a clinical challenge. We have shown that epigenetic heterogeneity may contribute to transcriptional dysregulation and disease progression in AML, but the specific aberrant transcriptional programs have not been identified. We analyzed molecular profiles from patient-matched diagnostic and relapse AML specimens. A subset of differentially expressed genes (DEG) that were disparate in direction of expression change identified 2 patient subtypes. We predicted that transcriptional regulators (TR) might regulate the expression patterns observed. The expression patterns of the top TR predicted for the disparate genes associated with clinical outcomes. The top TR predicted for the disparate DEG and DEG identified in a patient-derived xenograft model of relAML included members of the LIM domain only 2 - LIM domain binding 1 - TAL BHLH TF1, erythroid differentiation factor (LMO2-LDB1-TAL1) multisubunit complex (LTMC). Analysis of DepMap data identified LMO2-dependent cells with a subset highly expressing TAL1, suggesting coordinated regulation. TAL1 copurified in immunoprecipitation for LMO2 and LDB1 followed by tandem mass spectrometry analysis in HEL and K562 cells, and results from chromatin immunoprecipitation experiments suggest significant co-occupancy of TAL1 and LDB1. Loss-of-function experiments targeting LMO2, LDB1, and TAL1 in AML cell lines associated with reduced cell growth, downregulation of cell cycle genes, and a negative association with gene expression patterns observed in relapsed patients with increased TAL1 expression. Our results from primary AML specimens and functional analyses of AML cell lines supports an essential role for the LTMC in AML. Targeting the complex or downstream effectors could provide novel therapeutic considerations for a subset of patients with AML.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"3 1","pages":"Article 100186"},"PeriodicalIF":0.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145977231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-10-27DOI: 10.1016/j.bneo.2025.100177
François-Xavier Mahon , Stéphanie Dulucq , Delphine Réa , Franck-Emmanuel Nicolini , Françoise Rigal-Huguet , Katerina Machova Polakova , Viviane Dubruille , Marie-Pierre Noel , Jean-Christophe Ianotto , Bruno Villemagne , Émilie Cayssials , Sophie Park , Philippe Rousselot , Gabriel Etienne
Abstract
The French Stop Imatinib study (STIM1) was one of the first trials to explore the possibility of discontinuing imatinib in patients with chronic myeloid leukemia (CML) who had achieved a sustained molecular response (at least a 4.5-log reduction). The stringent criteria for molecular recurrence (MRec) were defined as BCR::ABL1 transcript positivity confirmed by a second test showing either a 1-log increase or loss of major molecular response across consecutive assessments. This comprehensive update presents long-term follow-up data from the STIM1 study, with a median molecular follow-up of 12.8 years (range, 0.8-15). Results showed a molecular recurrence-free survival rate of 37% (95% confidence interval [CI], 28-48) at 120 months, and 35% (95% CI, 26-46) at 156 months after imatinib discontinuation. Importantly, no patients experienced CML progression during the follow-up. Overall survival rates were 97% (95% CI, 94-100) at 10 years and 88% (95% CI, 81-96) at 20 years. A case of late MRec, confirmed through DNA BCR::ABL1 breakpoint analysis and comparison at diagnosis and recurrence, indicated the persistence of the original disease rather than the onset of new CML. This study offers valuable insights into the safety and feasibility of imatinib discontinuation for patients with CML, supporting long-term remission while maintaining survival. This study was registered at ClinicalTrials.gov as #NCT00478985.
{"title":"Extended long-term follow-up and the survival of Stop Imatinib study","authors":"François-Xavier Mahon , Stéphanie Dulucq , Delphine Réa , Franck-Emmanuel Nicolini , Françoise Rigal-Huguet , Katerina Machova Polakova , Viviane Dubruille , Marie-Pierre Noel , Jean-Christophe Ianotto , Bruno Villemagne , Émilie Cayssials , Sophie Park , Philippe Rousselot , Gabriel Etienne","doi":"10.1016/j.bneo.2025.100177","DOIUrl":"10.1016/j.bneo.2025.100177","url":null,"abstract":"<div><h3>Abstract</h3><div>The French Stop Imatinib study (STIM1) was one of the first trials to explore the possibility of discontinuing imatinib in patients with chronic myeloid leukemia (CML) who had achieved a sustained molecular response (at least a 4.5-log reduction). The stringent criteria for molecular recurrence (MRec) were defined as <em>BCR</em>::<em>ABL1</em> transcript positivity confirmed by a second test showing either a 1-log increase or loss of major molecular response across consecutive assessments. This comprehensive update presents long-term follow-up data from the STIM1 study, with a median molecular follow-up of 12.8 years (range, 0.8-15). Results showed a molecular recurrence-free survival rate of 37% (95% confidence interval [CI], 28-48) at 120 months, and 35% (95% CI, 26-46) at 156 months after imatinib discontinuation. Importantly, no patients experienced CML progression during the follow-up. Overall survival rates were 97% (95% CI, 94-100) at 10 years and 88% (95% CI, 81-96) at 20 years. A case of late MRec, confirmed through DNA <em>BCR</em>::<em>ABL1</em> breakpoint analysis and comparison at diagnosis and recurrence, indicated the persistence of the original disease rather than the onset of new CML. This study offers valuable insights into the safety and feasibility of imatinib discontinuation for patients with CML, supporting long-term remission while maintaining survival. This study was registered at <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> as #NCT00478985.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"3 1","pages":"Article 100177"},"PeriodicalIF":0.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145884588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2026-02-10DOI: 10.1016/j.bneo.2026.100192
{"title":"Dührsen U, Bockisch A, Hertenstein B, et al. Response-guided first-line therapy and treatment of relapse in aggressive lymphoma: 10-year follow-up of the PETAL trial. Blood Neoplasia. 2024;1(3):100018.","authors":"","doi":"10.1016/j.bneo.2026.100192","DOIUrl":"10.1016/j.bneo.2026.100192","url":null,"abstract":"","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"3 1","pages":"Article 100192"},"PeriodicalIF":0.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146215445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-11-17DOI: 10.1016/j.bneo.2025.100185
Jonny Mendoza-Castrejon , Wei Yang , Elisabeth Denby , Rohini Muthukumar , Emily B. Casey , Riddhi M. Patel , Sarah K. Tasian , Jeffrey A. Magee
Abstract
Infant leukemias arise as B-cell acute lymphoblastic or acute myeloid leukemia. Most are driven by chromosomal rearrangements of the MLL/KMT2A gene (MLLr) and arise in utero, implying a fetal cell of origin. Fetal and neonatal hematopoietic progenitors have unique transcriptomes and epigenomes, raising the question of whether MLL fusion proteins activate distinct target genes during these early stages of life. In this study, we used a transgenic mouse model of MLL::ENL-driven leukemia to identify Skida1 as a target gene that is more highly induced in fetal and neonatal progenitors than in adult progenitors. SKIDA1 is highly expressed in human MLLr leukemias, and the encoded protein associates with the polycomb repressive complex 2. We show that Skida1 is dispensable for normal hematopoiesis, but it promotes B-cell priming and maintains MLL::ENL-expressing hematopoietic stem cells (HSCs) and multipotent progenitor cells during neonatal development. Conditional deletion of Skida1 has no effect on normal HSC function, yet it impairs B-cell production from neonatal MLL::ENL-expressing HSCs while leaving myeloid leukemogenesis unaffected. Temporally restricted targets of MLL fusion proteins, such as SKIDA1, can therefore tune cell fates at different ages, potentially influencing the types MLLr leukemias that arise at different ages.
{"title":"SKIDA1 sustains MLL::ENL-expressing hematopoietic progenitors during neonatal stages and promotes B-lineage priming","authors":"Jonny Mendoza-Castrejon , Wei Yang , Elisabeth Denby , Rohini Muthukumar , Emily B. Casey , Riddhi M. Patel , Sarah K. Tasian , Jeffrey A. Magee","doi":"10.1016/j.bneo.2025.100185","DOIUrl":"10.1016/j.bneo.2025.100185","url":null,"abstract":"<div><h3>Abstract</h3><div>Infant leukemias arise as B-cell acute lymphoblastic or acute myeloid leukemia. Most are driven by chromosomal rearrangements of the <em>MLL</em>/<em>KMT2A</em> gene (MLLr) and arise in utero, implying a fetal cell of origin. Fetal and neonatal hematopoietic progenitors have unique transcriptomes and epigenomes, raising the question of whether MLL fusion proteins activate distinct target genes during these early stages of life. In this study, we used a transgenic mouse model of MLL::ENL-driven leukemia to identify <em>Skida1</em> as a target gene that is more highly induced in fetal and neonatal progenitors than in adult progenitors. <em>SKIDA1</em> is highly expressed in human MLLr leukemias, and the encoded protein associates with the polycomb repressive complex 2. We show that <em>Skida1</em> is dispensable for normal hematopoiesis, but it promotes B-cell priming and maintains MLL::ENL-expressing hematopoietic stem cells (HSCs) and multipotent progenitor cells during neonatal development. Conditional deletion of <em>Skida1</em> has no effect on normal HSC function, yet it impairs B-cell production from neonatal MLL::ENL-expressing HSCs while leaving myeloid leukemogenesis unaffected. Temporally restricted targets of MLL fusion proteins, such as <em>SKIDA1</em>, can therefore tune cell fates at different ages, potentially influencing the types MLLr leukemias that arise at different ages.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"3 1","pages":"Article 100185"},"PeriodicalIF":0.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145884025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-11-06DOI: 10.1016/j.bneo.2025.100181
Andrew F. Berdel ∗ , Julian Ronnacker ∗ , Daniela V. Wenge , Lina J. Kolloch , Philipp Berning , Linus Angenendt , Tobias J. Brix , Annette Westermann , Klaus Wethmar , Torsten Kessler , Andrea Kerkhoff , Rolf M. Mesters , Christian Reicherts , Jan-Henrik Mikesch , Wolfgang E. Berdel , Georg Lenz , Christoph Schliemann , Matthias Stelljes
Abstract
The European LeukemiaNet (ELN) classification for acute myeloid leukemia (AML) incorporates cytogenetic and mutational risk profiles of AML to define separate risk groups that correlate with survival outcomes. Recommendations for postremission treatment (PRT) intensity, mainly allogeneic hematopoietic stem cell transplant, are based on these risk groups. In-depth genetically defined cohorts of registries or clinical trials, often reported as retrospective real-world validation cohorts, contain an inherent bias as patients were not treated according to recommendations matching time intervals of the respective ELN classification. We analyzed 662 patients with AML who received intensive induction therapy at our center between 2010 and 2022. Patients were classified according to ELN 2010 if treated between 2010 and 2016, and ELN 2017 if treated between 2017 and 2022. Overall survival (OS) and relapse-free survival (RFS) significantly improved for patients treated between 2017 and 2022 compared with those treated between 2010 and 2016 (4-year OS, 60% vs 40%; 4-year RFS, 54% vs 35%). To eliminate treatment bias, patients treated between 2017 and 2022 were retrospectively reclassified for genetic risk according to ELN 2010 and compared with regularly classified patients treated between 2010 and 2016. The improved outcome was particularly evident for intermediate-risk (IR) patients, whereas favorable and adverse subgroups showed no significant difference. This is, to our knowledge, the first analysis examining the impact of ELN-guided PRT in the context of treatment algorithms applied in the respective ELN time period. We conclude that the shift of risk groups between ELN 2010 and 2017, along with the resulting intensified PRT, contributed to significantly improved survival of patients with AML, particularly those with IR.
{"title":"Impact of European LeukemiaNet–guided postremission therapy on outcomes of patients with AML from 2010 to 2022","authors":"Andrew F. Berdel ∗ , Julian Ronnacker ∗ , Daniela V. Wenge , Lina J. Kolloch , Philipp Berning , Linus Angenendt , Tobias J. Brix , Annette Westermann , Klaus Wethmar , Torsten Kessler , Andrea Kerkhoff , Rolf M. Mesters , Christian Reicherts , Jan-Henrik Mikesch , Wolfgang E. Berdel , Georg Lenz , Christoph Schliemann , Matthias Stelljes","doi":"10.1016/j.bneo.2025.100181","DOIUrl":"10.1016/j.bneo.2025.100181","url":null,"abstract":"<div><h3>Abstract</h3><div>The European LeukemiaNet (ELN) classification for acute myeloid leukemia (AML) incorporates cytogenetic and mutational risk profiles of AML to define separate risk groups that correlate with survival outcomes. Recommendations for postremission treatment (PRT) intensity, mainly allogeneic hematopoietic stem cell transplant, are based on these risk groups. In-depth genetically defined cohorts of registries or clinical trials, often reported as retrospective real-world validation cohorts, contain an inherent bias as patients were not treated according to recommendations matching time intervals of the respective ELN classification. We analyzed 662 patients with AML who received intensive induction therapy at our center between 2010 and 2022. Patients were classified according to ELN 2010 if treated between 2010 and 2016, and ELN 2017 if treated between 2017 and 2022. Overall survival (OS) and relapse-free survival (RFS) significantly improved for patients treated between 2017 and 2022 compared with those treated between 2010 and 2016 (4-year OS, 60% vs 40%; 4-year RFS, 54% vs 35%). To eliminate treatment bias, patients treated between 2017 and 2022 were retrospectively reclassified for genetic risk according to ELN 2010 and compared with regularly classified patients treated between 2010 and 2016. The improved outcome was particularly evident for intermediate-risk (IR) patients, whereas favorable and adverse subgroups showed no significant difference. This is, to our knowledge, the first analysis examining the impact of ELN-guided PRT in the context of treatment algorithms applied in the respective ELN time period. We conclude that the shift of risk groups between ELN 2010 and 2017, along with the resulting intensified PRT, contributed to significantly improved survival of patients with AML, particularly those with IR.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"3 1","pages":"Article 100181"},"PeriodicalIF":0.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145791009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-11-07DOI: 10.1016/j.bneo.2025.100179
Chad C. Bjorklund , Marta Larrayoz , Jian Kang , Hsiling Chiu , Natasha Shtraizent , Lei Wu , Shirong Li , Chih-Chao Hsu , Junfei Zhao , Michael Amatangelo , Tracy T. Chow , Krista Wollerman , Ram Kumar Singh , Sneha Sridhara , Shailesh Dudhgaonkar , Prakash Subramanyam , Kaushik Ghosh , Paul G. Richardson , Nizar J. Bahlis , Anjan Thakurta , Patrick R. Hagner
Abstract
Triplet regimens that include an immunomodulatory agent, proteasome inhibitor, and dexamethasone are widely used in newly diagnosed and relapsed/refractory (R/R) multiple myeloma (MM). Mezigdomide (MEZI; CC-92480) is a cereblon E3 ubiquitin ligase modulator that is being clinically investigated in combination with bortezomib (BTZ) and low-dose dexamethasone (DEX) for safety and efficacy in pretreated R/RMM. The single-agent mechanism of action (MOA) of MEZI has been defined by the recruitment and degradation of essential MM transcription factors Ikaros and Aiolos, leading to cell autonomous antitumor effects and immune modulation. These effects were confirmed in patients based on pharmacodynamic measurements of Ikaros/Aiolos degradation in biomarker evaluations of immune subsets. However, the MOA of triplet regimens, including that of MEZI/BTZ/DEX remain poorly defined. To better understand the MOA of this triplet combination, we compared the mechanistic contributions of MEZI, BTZ, or DEX alone, or in combination, in preclinical MM models in vitro and in vivo. Additionally, we have compared these results with similar combinations with the immunomodulatory agent pomalidomide (POM). Our studies indicate that the MEZI/BTZ/DEX triplet is superior to all single agents and POM/BTZ/DEX in terms of potency of antiproliferative and proapoptotic activities, substrate degradation depth and kinetics in the presence of BTZ, and in vivo efficacy. We show that the combination of MEZI with BTZ increases cell death through disruption of multiple phases of the cell cycle and this thereby enhances the direct cytotoxic effects of the combination treatment.
{"title":"Mezigdomide combined with bortezomib disrupts the cell cycle and elicits superior antitumor effects in multiple myeloma","authors":"Chad C. Bjorklund , Marta Larrayoz , Jian Kang , Hsiling Chiu , Natasha Shtraizent , Lei Wu , Shirong Li , Chih-Chao Hsu , Junfei Zhao , Michael Amatangelo , Tracy T. Chow , Krista Wollerman , Ram Kumar Singh , Sneha Sridhara , Shailesh Dudhgaonkar , Prakash Subramanyam , Kaushik Ghosh , Paul G. Richardson , Nizar J. Bahlis , Anjan Thakurta , Patrick R. Hagner","doi":"10.1016/j.bneo.2025.100179","DOIUrl":"10.1016/j.bneo.2025.100179","url":null,"abstract":"<div><h3>Abstract</h3><div>Triplet regimens that include an immunomodulatory agent, proteasome inhibitor, and dexamethasone are widely used in newly diagnosed and relapsed/refractory (R/R) multiple myeloma (MM). Mezigdomide (MEZI; CC-92480) is a cereblon E3 ubiquitin ligase modulator that is being clinically investigated in combination with bortezomib (BTZ) and low-dose dexamethasone (DEX) for safety and efficacy in pretreated R/RMM. The single-agent mechanism of action (MOA) of MEZI has been defined by the recruitment and degradation of essential MM transcription factors Ikaros and Aiolos, leading to cell autonomous antitumor effects and immune modulation. These effects were confirmed in patients based on pharmacodynamic measurements of Ikaros/Aiolos degradation in biomarker evaluations of immune subsets. However, the MOA of triplet regimens, including that of MEZI/BTZ/DEX remain poorly defined. To better understand the MOA of this triplet combination, we compared the mechanistic contributions of MEZI, BTZ, or DEX alone, or in combination, in preclinical MM models in vitro and in vivo. Additionally, we have compared these results with similar combinations with the immunomodulatory agent pomalidomide (POM). Our studies indicate that the MEZI/BTZ/DEX triplet is superior to all single agents and POM/BTZ/DEX in terms of potency of antiproliferative and proapoptotic activities, substrate degradation depth and kinetics in the presence of BTZ, and in vivo efficacy. We show that the combination of MEZI with BTZ increases cell death through disruption of multiple phases of the cell cycle and this thereby enhances the direct cytotoxic effects of the combination treatment.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"3 1","pages":"Article 100179"},"PeriodicalIF":0.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146037614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2026-01-14DOI: 10.1016/j.bneo.2026.100197
Alok Swaroop , Natasha L. Johnson , Michelle C. Tophkhane , Courtnee Rodgers , Michelle Pogrebetskaya , Ashwin Koppayi , Salina Dominguez , Eric Padron , Jessica K. Altman , Lucy A. Godley
{"title":"FLT3 as a germ line driver in AML: expanding the landscape of leukemia predisposition","authors":"Alok Swaroop , Natasha L. Johnson , Michelle C. Tophkhane , Courtnee Rodgers , Michelle Pogrebetskaya , Ashwin Koppayi , Salina Dominguez , Eric Padron , Jessica K. Altman , Lucy A. Godley","doi":"10.1016/j.bneo.2026.100197","DOIUrl":"10.1016/j.bneo.2026.100197","url":null,"abstract":"","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"3 1","pages":"Article 100197"},"PeriodicalIF":0.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146184111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-11-06DOI: 10.1016/j.bneo.2025.100180
Hao-Yuan Wang , Fu-Chen Yang , Ching-Fen Yang , Chun-Kuang Tsai , Po-Chun Liu , Po-Shen Ko , Yao-Chung Liu , Jyh-Pyng Gau , Jin-Hwang Liu , Po-Min Chen , Nien-Jung Chen
Abstract
CD8 and CD4 T lymphocytes play critical roles in antitumor immunity and are central to immune-based therapies for diffuse large B-cell lymphoma (DLBCL). Conversely, monocytic myeloid-derived suppressor cells (M-MDSCs) promote immunosuppression and tumor progression. This study investigates the prognostic value of the ratios of CD8 and CD4 T lymphocytes to M-MDSCs, referred to as CD8MMR and CD4MMR, in patients with untreated DLBCL. In a prospective observational study, 160 patients newly diagnosed with DLBCL were enrolled and randomized into training (n = 120) and validation (n = 40) cohorts. Circulating immune cells were assessed from fresh peripheral blood using flow cytometry, and cutoff values for CD8MMR and CD4MMR were determined by receiver operating characteristic curve and area under the curve analysis. Patients with high-risk International Prognostic Index (IPI), double-expressor lymphoma, or Epstein-Barr virus–positive DLBCL had significantly lower CD8MMR and CD4MMR. Low CD8MMR (<3.56) or CD4MMR (<3.79) was significantly associated with inferior progression-free survival (PFS) and overall survival (OS). When combining both ratios, patients with high levels of CD8MMR and CD4MMR had the most favorable survival, whereas those with low levels of both had the poorest outcomes; discordant levels corresponded to intermediate survival. Multivariate analysis revealed CD8MMR as an independent predictor of PFS and OS, with greater predictive strength than CD4MMR. Furthermore, CD8MMR stratified survival outcomes across different IPI risk categories and cell-of-origin subtypes, consistently identifying patients with poor prognosis. These findings suggest that CD8MMR is a novel and independent prognostic biomarker in DLBCL, offering additional value for risk stratification in clinical practice.
{"title":"Ratios of CD8 T lymphocytes to M-MDSCs (CD8MMR) predict prognosis in patients with untreated DLBCL","authors":"Hao-Yuan Wang , Fu-Chen Yang , Ching-Fen Yang , Chun-Kuang Tsai , Po-Chun Liu , Po-Shen Ko , Yao-Chung Liu , Jyh-Pyng Gau , Jin-Hwang Liu , Po-Min Chen , Nien-Jung Chen","doi":"10.1016/j.bneo.2025.100180","DOIUrl":"10.1016/j.bneo.2025.100180","url":null,"abstract":"<div><h3>Abstract</h3><div>CD8 and CD4 T lymphocytes play critical roles in antitumor immunity and are central to immune-based therapies for diffuse large B-cell lymphoma (DLBCL). Conversely, monocytic myeloid-derived suppressor cells (M-MDSCs) promote immunosuppression and tumor progression. This study investigates the prognostic value of the ratios of CD8 and CD4 T lymphocytes to M-MDSCs, referred to as CD8MMR and CD4MMR, in patients with untreated DLBCL. In a prospective observational study, 160 patients newly diagnosed with DLBCL were enrolled and randomized into training (n = 120) and validation (n = 40) cohorts. Circulating immune cells were assessed from fresh peripheral blood using flow cytometry, and cutoff values for CD8MMR and CD4MMR were determined by receiver operating characteristic curve and area under the curve analysis. Patients with high-risk International Prognostic Index (IPI), double-expressor lymphoma, or Epstein-Barr virus–positive DLBCL had significantly lower CD8MMR and CD4MMR. Low CD8MMR (<3.56) or CD4MMR (<3.79) was significantly associated with inferior progression-free survival (PFS) and overall survival (OS). When combining both ratios, patients with high levels of CD8MMR and CD4MMR had the most favorable survival, whereas those with low levels of both had the poorest outcomes; discordant levels corresponded to intermediate survival. Multivariate analysis revealed CD8MMR as an independent predictor of PFS and OS, with greater predictive strength than CD4MMR. Furthermore, CD8MMR stratified survival outcomes across different IPI risk categories and cell-of-origin subtypes, consistently identifying patients with poor prognosis. These findings suggest that CD8MMR is a novel and independent prognostic biomarker in DLBCL, offering additional value for risk stratification in clinical practice.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"3 1","pages":"Article 100180"},"PeriodicalIF":0.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145840565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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