Pub Date : 2024-10-24DOI: 10.1016/j.bneo.2024.100052
Anne P. de Groot , Chelsea R. Wilson , Ellen Weersing , Jacobine S. Pouw , Albertina Dethmers-Ausema , Huong Nguyen , Evan F. W. Chen , Alok Shaurya , Linda Smit , Fraser Hof , Gerald de Haan
Abstract
Self-renewal of leukemic cells results in the accumulation of dysfunctional blood cells and suppression of normal hematopoiesis. The polycomb group protein chromobox 7 (CBX7) is an epigenetic regulator that represses genes required for differentiation and cell cycle arrest and thereby promotes self-renewal. Because leukemic cells are highly self-renewing, we tested whether pharmacological targeting of CBX7 would reduce self-renewal and induce differentiation of human leukemic cells. We found that existing and newly developed CBX7 inhibitors derepress the epigenome, resulting in reduced ubiquitination of histone 2A and reduced binding of CBX7 to its target genes. This led to reduced cell growth, increased differentiation of leukemic cells in vitro, and delayed engraftment of primary leukemic cells in xenotransplant models. Therefore, pharmacological targeting of CBX7 constitutes a novel therapeutic approach for leukemia.
{"title":"Pharmacological targeting of CBX7 alters the epigenetic landscape and induces differentiation of leukemic cells","authors":"Anne P. de Groot , Chelsea R. Wilson , Ellen Weersing , Jacobine S. Pouw , Albertina Dethmers-Ausema , Huong Nguyen , Evan F. W. Chen , Alok Shaurya , Linda Smit , Fraser Hof , Gerald de Haan","doi":"10.1016/j.bneo.2024.100052","DOIUrl":"10.1016/j.bneo.2024.100052","url":null,"abstract":"<div><h3>Abstract</h3><div>Self-renewal of leukemic cells results in the accumulation of dysfunctional blood cells and suppression of normal hematopoiesis. The polycomb group protein chromobox 7 (CBX7) is an epigenetic regulator that represses genes required for differentiation and cell cycle arrest and thereby promotes self-renewal. Because leukemic cells are highly self-renewing, we tested whether pharmacological targeting of CBX7 would reduce self-renewal and induce differentiation of human leukemic cells. We found that existing and newly developed CBX7 inhibitors derepress the epigenome, resulting in reduced ubiquitination of histone 2A and reduced binding of CBX7 to its target genes. This led to reduced cell growth, increased differentiation of leukemic cells in vitro, and delayed engraftment of primary leukemic cells in xenotransplant models. Therefore, pharmacological targeting of CBX7 constitutes a novel therapeutic approach for leukemia.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"1 4","pages":"Article 100052"},"PeriodicalIF":0.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142707090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-14DOI: 10.1016/j.bneo.2024.100049
Rudra P. Dutta , Santiago Thibaud , Violetta Leshchenko , Meghana Ram , David T. Melnekoff , Sherry Bhalla , Paula Restrepo , Vikas A. Gupta , Benjamin G. Barwick , Scott Newman , Jonathan McCafferty , Feras Hantash , Ajay K. Nooka , Hearn J. Cho , Shambavi Richard , Cesar Rodriguez , Adriana Rossi , Larysa Sanchez , Ajai Chari , Lawrence H. Boise , Alessandro Laganà
Abstract
Venetoclax, a selective B-cell lymphoma 2 (BCL2) inhibitor, has emerged as a promising therapeutic agent for multiple myeloma (MM), particularly in patients harboring the t(11;14) translocation. In this study, we set out to identify markers of sensitivity and resistance to venetoclax in a real-world patient population, aiming to facilitate the development of personalized therapeutic strategies. Through the analysis of RNA sequencing (RNA-seq) data from relapsed/refractory patients treated with venetoclax, either as a single agent or in combination with other drugs, we unveiled a novel 6-gene signature that significantly stratified patients into risk groups for relapse and further validated its clinical relevance in 2 independent clinical and ex vivo data sets. Our analysis also highlighted the negative impact of chromosome 1q gain, which harbors the myeloid cell leukemia-1 (MCL1) gene, on progression-free survival, even in t(11;14)-positive patients. Encouraged by the well-documented role of MCL1 in resistance to venetoclax in various malignancies and the prognostic importance of the BCL2/MCL1 ratio in our cohort, we explored Cyclin-Dependent Kinase 7 (CDK7) inhibition as a potential strategy to overcome venetoclax resistance. In vitro experiments demonstrated that CRISPR-Cas9–mediated CDK7 depletion led to decreased MCL1 levels, enhancing the sensitivity of MM cells to venetoclax. Moreover, the combination of the CDK7 inhibitor THZ1 with venetoclax markedly induced cell death in venetoclax-resistant MM cells harboring 1q gain, thus offering a rational therapeutic approach, particularly for patients with this aberration. Overall, these findings provide important insights for optimizing venetoclax-based therapeutic strategies in MM.
{"title":"Predictors of response to venetoclax and therapeutic potential of CDK7 inhibition in multiple myeloma","authors":"Rudra P. Dutta , Santiago Thibaud , Violetta Leshchenko , Meghana Ram , David T. Melnekoff , Sherry Bhalla , Paula Restrepo , Vikas A. Gupta , Benjamin G. Barwick , Scott Newman , Jonathan McCafferty , Feras Hantash , Ajay K. Nooka , Hearn J. Cho , Shambavi Richard , Cesar Rodriguez , Adriana Rossi , Larysa Sanchez , Ajai Chari , Lawrence H. Boise , Alessandro Laganà","doi":"10.1016/j.bneo.2024.100049","DOIUrl":"10.1016/j.bneo.2024.100049","url":null,"abstract":"<div><h3>Abstract</h3><div>Venetoclax, a selective B-cell lymphoma 2 (BCL2) inhibitor, has emerged as a promising therapeutic agent for multiple myeloma (MM), particularly in patients harboring the t(11;14) translocation. In this study, we set out to identify markers of sensitivity and resistance to venetoclax in a real-world patient population, aiming to facilitate the development of personalized therapeutic strategies. Through the analysis of RNA sequencing (RNA-seq) data from relapsed/refractory patients treated with venetoclax, either as a single agent or in combination with other drugs, we unveiled a novel 6-gene signature that significantly stratified patients into risk groups for relapse and further validated its clinical relevance in 2 independent clinical and ex vivo data sets. Our analysis also highlighted the negative impact of chromosome 1q gain, which harbors the myeloid cell leukemia-1 (MCL1) gene, on progression-free survival, even in t(11;14)-positive patients. Encouraged by the well-documented role of MCL1 in resistance to venetoclax in various malignancies and the prognostic importance of the BCL2/MCL1 ratio in our cohort, we explored Cyclin-Dependent Kinase 7 (CDK7) inhibition as a potential strategy to overcome venetoclax resistance. In vitro experiments demonstrated that CRISPR-Cas9–mediated CDK7 depletion led to decreased MCL1 levels, enhancing the sensitivity of MM cells to venetoclax. Moreover, the combination of the CDK7 inhibitor THZ1 with venetoclax markedly induced cell death in venetoclax-resistant MM cells harboring 1q gain, thus offering a rational therapeutic approach, particularly for patients with this aberration. Overall, these findings provide important insights for optimizing venetoclax-based therapeutic strategies in MM.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"1 4","pages":"Article 100049"},"PeriodicalIF":0.0,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142706954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-13DOI: 10.1016/j.bneo.2024.100048
Lawrence A. Stern ∗ , Vibhuti Vyas ∗ , Laura Lim , Christian Huynh , Ryan Urak , Ruby Espinosa , Zhiqiang Wang , Michalina Silva Thiel , John C. Williams , Stephen J. Forman , Christine E. Brown † , Xiuli Wang †
Abstract
In this study, we aim to develop a humanized CD19 chimeric antigen receptor (CAR) that matches the potency of the FMC63 CAR and potentially reduces the risk of immunogenicity. The murine FMC63 single-chain variable fragment (scFv) was humanized yielding 2 lead candidate scFvs, VH4vκ1 and 4D5, which exhibit weaker binding affinity than FMC63 scFv. These humanized CD19-scFvs were incorporated into CAR constructs to generate huCD19R(VH4Vκ1) and huCD19R(4D5) CARs, both containing the 41BB costimulatory domain. The antitumor activity of the CAR T cells was assessed against CD19+ and CD19 low-expressing tumors. FMC63 CAR T cells with the same backbone in all studies were used as controls. The results showed that the huCD19R(VH4vκ1) CAR T cells exhibited similar expansion, phenotype, and effector function to the FMC63 CAR upon stimulation with CD19 targets. When the CAR T cells were challenged with CD19-bearing tumors, the huCD19R(VH4vκ1) CAR T cells showed similar proliferation to the FMC63 CAR T cells, whereas the huCD19R(4D5) CAR T cells essentially failed to proliferate. Moreover, the huCD19R(VH4vκ1) CAR T cells exhibited significantly better in vivo antitumor activity than the huCD19R(4D5) CAR T cells when tested against tumors expressing a range of CD19 antigens. Finally, using a hybrid model, we found that the huCD19R(VH4vκ1) T cells had a comparable cytokine secretion profile to that of FMC63 CAR T cells. Furthermore, the huCD19R(VH4vκ1) CAR T cells exhibited efficacy against both CD19+ and engineered CD19 low-expressing tumors. These findings suggest that huCD19R(VH4vκ1) CAR T cells may offer enhanced persistence and represent a promising candidate for clinical translation as a therapy for CD19+ tumors.
摘要 在本研究中，我们旨在开发一种人源化 CD19 嵌合抗原受体（CAR），其效力与 FMC63 CAR 相当，并可能降低免疫原性风险。对小鼠 FMC63 单链可变片段（scFv）进行了人源化处理，得到了两个主要候选 scFv：VH4vκ1 和 4D5，它们的结合亲和力比 FMC63 scFv 弱。这些人源化 CD19-scFv 被整合到 CAR 构建物中，生成了 huCD19R(VH4Vκ1) 和 huCD19R(4D5)CAR，这两种 CAR 都含有 41BB costimulatory domain。评估了 CAR T 细胞对 CD19+ 和 CD19 低表达肿瘤的抗肿瘤活性。所有研究中使用相同骨架的 FMC63 CAR T 细胞作为对照。结果显示，huCD19R(VH4vκ1) CAR T细胞在受到CD19靶点刺激时，表现出与FMC63 CAR相似的扩增、表型和效应功能。当 CAR T 细胞受到 CD19 肿瘤的挑战时，huCD19R(VH4vκ1) CAR T 细胞表现出与 FMC63 CAR T 细胞相似的增殖，而 huCD19R(4D5) CAR T 细胞基本上没有增殖。此外，在对表达一系列 CD19 抗原的肿瘤进行测试时，huCD19R(VH4vκ1) CAR T 细胞的体内抗肿瘤活性明显优于 huCD19R(4D5) CAR T 细胞。最后，我们利用混合模型发现，huCD19R(VH4vκ1) T细胞的细胞因子分泌情况与FMC63 CAR T细胞相当。此外，huCD19R(VH4vκ1) CAR T细胞对CD19+和低表达CD19的工程肿瘤都有疗效。这些研究结果表明，huCD19R(VH4vκ1)CAR T细胞可能具有更强的持久性，有望作为CD19+肿瘤的治疗方法应用于临床。
{"title":"Development and characterization of a low-affinity humanized CD19 chimeric antigen receptor for B-cell malignancies","authors":"Lawrence A. Stern ∗ , Vibhuti Vyas ∗ , Laura Lim , Christian Huynh , Ryan Urak , Ruby Espinosa , Zhiqiang Wang , Michalina Silva Thiel , John C. Williams , Stephen J. Forman , Christine E. Brown † , Xiuli Wang †","doi":"10.1016/j.bneo.2024.100048","DOIUrl":"10.1016/j.bneo.2024.100048","url":null,"abstract":"<div><h3>Abstract</h3><div>In this study, we aim to develop a humanized CD19 chimeric antigen receptor (CAR) that matches the potency of the FMC63 CAR and potentially reduces the risk of immunogenicity. The murine FMC63 single-chain variable fragment (scFv) was humanized yielding 2 lead candidate scFvs, VH4vκ1 and 4D5, which exhibit weaker binding affinity than FMC63 scFv. These humanized CD19-scFvs were incorporated into CAR constructs to generate huCD19R(VH4Vκ1) and huCD19R(4D5) CARs, both containing the 41BB costimulatory domain. The antitumor activity of the CAR T cells was assessed against CD19<sup>+</sup> and CD19 low-expressing tumors. FMC63 CAR T cells with the same backbone in all studies were used as controls. The results showed that the huCD19R(VH4vκ1) CAR T cells exhibited similar expansion, phenotype, and effector function to the FMC63 CAR upon stimulation with CD19 targets. When the CAR T cells were challenged with CD19-bearing tumors, the huCD19R(VH4vκ1) CAR T cells showed similar proliferation to the FMC63 CAR T cells, whereas the huCD19R(4D5) CAR T cells essentially failed to proliferate. Moreover, the huCD19R(VH4vκ1) CAR T cells exhibited significantly better in vivo antitumor activity than the huCD19R(4D5) CAR T cells when tested against tumors expressing a range of CD19 antigens. Finally, using a hybrid model, we found that the huCD19R(VH4vκ1) T cells had a comparable cytokine secretion profile to that of FMC63 CAR T cells. Furthermore, the huCD19R(VH4vκ1) CAR T cells exhibited efficacy against both CD19<sup>+</sup> and engineered CD19 low-expressing tumors. These findings suggest that huCD19R(VH4vκ1) CAR T cells may offer enhanced persistence and represent a promising candidate for clinical translation as a therapy for CD19<sup>+</sup> tumors.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"1 4","pages":"Article 100048"},"PeriodicalIF":0.0,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142707091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-12DOI: 10.1016/j.bneo.2024.100046
Hamed Bashiri , Ahad Khalilnezhad , Haruhito Totani , Joe Yeong , Tae-Hoon Chung , Felicia Wee , Yuezhen Xue , Zhen Wei Neo , Li Yen Chong , Wee Joo Chng , Atsushi Watanabe , Siok-Bian Ng , The Phyu , Toshio Suda
Abstract
Multiple myeloma (MM) stands as a formidable blood malignancy, necessitating innovative therapeutic approaches. Excessive immunoglobulin production within myeloma cells leads to a buildup of toxic proteins, and autophagy plays a crucial role in their survival by degrading toxic aggregates and generating energy. Membrane-associated RING finger protein 5 (MARCH5) is an E3-ligase positioned at the outer mitochondrial membrane and has been shown to regulate autophagy by competing for MicroRNA 30a (MIR30A). Given the fundamental significance of autophagy in promoting the survival of myeloma cells, coupled with the regulatory role of MARCH5 in autophagic activity, we hypothesized that MARCH5 plays an essential function in MM and holds a pivotal position in the pathogenesis and progression of MM. We identified MARCH5’s unique dependencies in MM cells by analyzing the Cancer Dependency Map, thereby establishing its significance in MM biology. Examining various data sets, including CoMMpass (Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile Study) and HOVON (Haemato-Oncology Foundation for Adults in the Netherlands), demonstrated a correlation between MARCH5 expression and patient outcomes. Knockdown of MARCH5 revealed a substantial reduction in MM cell viability, which was associated with a decrease in autophagic activity. Mechanistically, we unraveled a novel MARCH5/AKT/FOXO3 axis, wherein MARCH5 regulates autophagy through the Protein Kinase B (AKT)-mediated degradation of Forkhead Box O3 (FOXO3). Compromised MM cell viability observed with MARCH5 knockdown was recapitulated in FOXO3 knockdown experiments, validating the pivotal role of FOXO3 in mediating MARCH5’s effects. In conclusion, this research highlights the crucial role of MARCH5 in MM, and the identified MARCH5/AKT/FOXO3 axis enhances our understanding of MM biology and provides a foundation for developing targeted therapies.
摘要多发性骨髓瘤（MM）是一种可怕的血液恶性肿瘤，需要创新的治疗方法。骨髓瘤细胞内过量的免疫球蛋白生成会导致有毒蛋白质的堆积，而自噬则通过降解有毒的聚集体并产生能量，在骨髓瘤细胞的存活过程中发挥着至关重要的作用。膜相关 RING 手指蛋白 5（MARCH5）是一种位于线粒体外膜的 E3 连接酶，已被证明可通过竞争 MicroRNA 30a (MIR30A)来调节自噬。鉴于自噬在促进骨髓瘤细胞存活方面的重要意义，以及 MARCH5 在自噬活动中的调控作用，我们推测 MARCH5 在 MM 中发挥着重要功能，并在 MM 的发病机制和进展中占据关键地位。我们通过分析癌症依赖性图谱（Cancer Dependency Map）确定了MARCH5在MM细胞中的独特依赖性，从而确立了它在MM生物学中的重要地位。通过研究各种数据集，包括CoMMpass（多发性骨髓瘤临床结果与遗传特征个人评估研究）和HOVON（荷兰成人血液肿瘤基金会），证明了MARCH5的表达与患者预后之间的相关性。敲除MARCH5后，MM细胞的存活率大大降低，这与自噬活性降低有关。从机理上讲，我们发现了一个新的MARCH5/AKT/FOXO3轴，其中MARCH5通过蛋白激酶B（AKT）介导的叉头框O3（FOXO3）降解来调节自噬。FOXO3敲除实验再现了MARCH5敲除时观察到的MM细胞活力下降，验证了FOXO3在介导MARCH5效应中的关键作用。总之，这项研究强调了 MARCH5 在 MM 中的关键作用，所确定的 MARCH5/AKT/FOXO3 轴增强了我们对 MM 生物学的了解，并为开发靶向疗法奠定了基础。
{"title":"Deciphering MARCH5’s impact on multiple myeloma: insights into autophagy regulation and AKT-FOXO3 signaling","authors":"Hamed Bashiri , Ahad Khalilnezhad , Haruhito Totani , Joe Yeong , Tae-Hoon Chung , Felicia Wee , Yuezhen Xue , Zhen Wei Neo , Li Yen Chong , Wee Joo Chng , Atsushi Watanabe , Siok-Bian Ng , The Phyu , Toshio Suda","doi":"10.1016/j.bneo.2024.100046","DOIUrl":"10.1016/j.bneo.2024.100046","url":null,"abstract":"<div><h3>Abstract</h3><div>Multiple myeloma (MM) stands as a formidable blood malignancy, necessitating innovative therapeutic approaches. Excessive immunoglobulin production within myeloma cells leads to a buildup of toxic proteins, and autophagy plays a crucial role in their survival by degrading toxic aggregates and generating energy. Membrane-associated RING finger protein 5 (MARCH5) is an E3-ligase positioned at the outer mitochondrial membrane and has been shown to regulate autophagy by competing for MicroRNA 30a (MIR30A). Given the fundamental significance of autophagy in promoting the survival of myeloma cells, coupled with the regulatory role of MARCH5 in autophagic activity, we hypothesized that MARCH5 plays an essential function in MM and holds a pivotal position in the pathogenesis and progression of MM. We identified MARCH5’s unique dependencies in MM cells by analyzing the Cancer Dependency Map, thereby establishing its significance in MM biology. Examining various data sets, including CoMMpass (Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile Study) and HOVON (Haemato-Oncology Foundation for Adults in the Netherlands), demonstrated a correlation between MARCH5 expression and patient outcomes. Knockdown of <em>MARCH5</em> revealed a substantial reduction in MM cell viability, which was associated with a decrease in autophagic activity. Mechanistically, we unraveled a novel MARCH5/AKT/FOXO3 axis, wherein MARCH5 regulates autophagy through the Protein Kinase B (AKT)-mediated degradation of Forkhead Box O3 (FOXO3). Compromised MM cell viability observed with <em>MARCH5</em> knockdown was recapitulated in <em>FOXO3</em> knockdown experiments, validating the pivotal role of FOXO3 in mediating MARCH5’s effects. In conclusion, this research highlights the crucial role of MARCH5 in MM, and the identified MARCH5/AKT/FOXO3 axis enhances our understanding of MM biology and provides a foundation for developing targeted therapies.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"1 4","pages":"Article 100046"},"PeriodicalIF":0.0,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142706556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-08DOI: 10.1016/j.bneo.2024.100044
Joshua W. D. Tobin , Venkata A. Chikatamarla , Marko Matic , Alison Griffin , Rakin Chowdhury , Ross Salvaris , Amanda Goh , Harrison Black , Tsz Hung Tong , Callum Birks , Sanjiv Jain , Elizabeth Goodall , Shreerang Sirdesai , Thomas Trevis , Elizabeth Steinepreis , Yiyang Chen , Li Li , Glenn Broadby , Naadir Gutta , Kirk Morris , Greg Hapgood
Abstract
Progression of follicular lymphoma (FL) or transformation (TFL) within 24 months of immunochemotherapy (ICT) represent high-risk defining events (HRDE) with poor overall survival (OS). We examined baseline clinical characteristics, imaging, and outcomes for patients experiencing HRDE with newly diagnosed FL requiring ICT. HRDE groups were: relapse or progression of FL within 24 months (FL24), early TFL (transformation <24 months of ICT), late TFL (transformation >24 months of ICT).433 patients were categorized as reference FL (Ref FL), n = 352 (no HRDE); FL24, n = 43; early TFL, n = 29; late TFL, n = 9. Chemotherapy included bendamustine (63%), CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone) (27%), or CVP (cyclophosphamide, vincristine, prednisone) (10%); 85% received rituximab/15% obinutuzumab and 48% received maintenance therapy. Compared with Ref FL group, OS from HRDE was inferior for FL24 (hazard ratio [HR], 3.93; 95% confidence interval [CI], 2.14-7.23), early TFL (HR, 8.16; 95% CI, 4.38-15.2), and late TFL (HR, 8.23; 95% CI, 3.18-21.25). OS from HRDE was inferior for early TFL compared with FL24 (HR, 2.08; 95% CI, 1.02-4.21). In multivariable analysis, performance status, lactate dehydrogenase, beta-2-microglobulin and grade 3A were associated with early TFL. Clinical characteristics did not differentiate early TFL from FL24. Maximum standardized uptake value was higher in early TFL but not FL24 compared to Ref FL. Early TFL and FL24 represent different HRDEs and are associated with inferior OS. Distinguishing early TFL from FL24 is important for biomarker development, management and to develop and interpret trials in this area of unmet need.
{"title":"Outcomes for high-risk defining events in follicular lymphoma following frontline immunochemotherapy","authors":"Joshua W. D. Tobin , Venkata A. Chikatamarla , Marko Matic , Alison Griffin , Rakin Chowdhury , Ross Salvaris , Amanda Goh , Harrison Black , Tsz Hung Tong , Callum Birks , Sanjiv Jain , Elizabeth Goodall , Shreerang Sirdesai , Thomas Trevis , Elizabeth Steinepreis , Yiyang Chen , Li Li , Glenn Broadby , Naadir Gutta , Kirk Morris , Greg Hapgood","doi":"10.1016/j.bneo.2024.100044","DOIUrl":"10.1016/j.bneo.2024.100044","url":null,"abstract":"<div><h3>Abstract</h3><div>Progression of follicular lymphoma (FL) or transformation (TFL) within 24 months of immunochemotherapy (ICT) represent high-risk defining events (HRDE) with poor overall survival (OS). We examined baseline clinical characteristics, imaging, and outcomes for patients experiencing HRDE with newly diagnosed FL requiring ICT. HRDE groups were: relapse or progression of FL within 24 months (FL24), early TFL (transformation <24 months of ICT), late TFL (transformation >24 months of ICT).433 patients were categorized as reference FL (Ref FL), n = 352 (no HRDE); FL24, n = 43; early TFL, n = 29; late TFL, n = 9. Chemotherapy included bendamustine (63%), CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone) (27%), or CVP (cyclophosphamide, vincristine, prednisone) (10%); 85% received rituximab/15% obinutuzumab and 48% received maintenance therapy. Compared with Ref FL group, OS from HRDE was inferior for FL24 (hazard ratio [HR], 3.93; 95% confidence interval [CI], 2.14-7.23), early TFL (HR, 8.16; 95% CI, 4.38-15.2), and late TFL (HR, 8.23; 95% CI, 3.18-21.25). OS from HRDE was inferior for early TFL compared with FL24 (HR, 2.08; 95% CI, 1.02-4.21). In multivariable analysis, performance status, lactate dehydrogenase, beta-2-microglobulin and grade 3A were associated with early TFL. Clinical characteristics did not differentiate early TFL from FL24. Maximum standardized uptake value was higher in early TFL but not FL24 compared to Ref FL. Early TFL and FL24 represent different HRDEs and are associated with inferior OS. Distinguishing early TFL from FL24 is important for biomarker development, management and to develop and interpret trials in this area of unmet need.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"1 4","pages":"Article 100044"},"PeriodicalIF":0.0,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142652453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-18DOI: 10.1016/j.bneo.2024.100043
Amrita Y. Krishnan , Krina K. Patel , Meera Mohan , Sundar Jagannath , Ruben Niesvizky , Rebecca W. Silbermann , Ziji Yu , Tao Long , Scott R. P. McDonnell , Deborah Berg , Keith E. Stockerl-Goldstein
Abstract
This phase 1b trial aimed to determine the safety, tolerability, and preliminary efficacy of mezagitamab, a subcutaneously administered anti-CD38 monoclonal antibody, in patients with relapsed/refractory multiple myeloma (RRMM). Eligible patients had received ≥3 prior lines of treatment, including an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and a steroid, or ≥2 prior lines in which 1 included a PI + IMiD, and were refractory or intolerant to ≥1 IMiD and ≥1 PI. Fifty patients were enrolled: 44 received mezagitamab monotherapy (dose-escalating cohorts at 45-1200 mg) and 6 received mezagitamab 300 mg in combination with pomalidomide plus dexamethasone. Patients received mezagitamab weekly for 8 doses, every other week for 8 doses, and monthly thereafter. No dose-limiting toxicities were reported with single-agent mezagitamab, and the recommended phase 2 dose was determined as 600 mg. The most common drug-related treatment-emergent adverse events (TEAEs) were fatigue in the monotherapy cohort (9/44 patients) and neutropenia in the combination cohort (4/6 patients); neutropenia was the only drug-related grade ≥3 TEAE to occur in >1 patient. No infusion reactions occurred, and 4 injection-site reactions were reported. Three patients discontinued treatment due to TEAEs. Among the 22 patients receiving 600 mg mezagitamab, the overall response rate was 47%, and the median duration of response was 22.1 months. Mezagitamab outcomes were comparable to those reported with other anti-CD38 therapies in patients with advanced RRMM. Further development of mezagitamab in myeloma is not planned, but studies are underway in autoimmune conditions. This trial was registered at www.ClinicalTrials.gov as #NCT03439280.
{"title":"Phase 1b study of the anti-CD38 antibody mezagitamab in patients with relapsed/refractory multiple myeloma","authors":"Amrita Y. Krishnan , Krina K. Patel , Meera Mohan , Sundar Jagannath , Ruben Niesvizky , Rebecca W. Silbermann , Ziji Yu , Tao Long , Scott R. P. McDonnell , Deborah Berg , Keith E. Stockerl-Goldstein","doi":"10.1016/j.bneo.2024.100043","DOIUrl":"10.1016/j.bneo.2024.100043","url":null,"abstract":"<div><h3>Abstract</h3><div>This phase 1b trial aimed to determine the safety, tolerability, and preliminary efficacy of mezagitamab, a subcutaneously administered anti-CD38 monoclonal antibody, in patients with relapsed/refractory multiple myeloma (RRMM). Eligible patients had received ≥3 prior lines of treatment, including an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and a steroid, or ≥2 prior lines in which 1 included a PI + IMiD, and were refractory or intolerant to ≥1 IMiD and ≥1 PI. Fifty patients were enrolled: 44 received mezagitamab monotherapy (dose-escalating cohorts at 45-1200 mg) and 6 received mezagitamab 300 mg in combination with pomalidomide plus dexamethasone. Patients received mezagitamab weekly for 8 doses, every other week for 8 doses, and monthly thereafter. No dose-limiting toxicities were reported with single-agent mezagitamab, and the recommended phase 2 dose was determined as 600 mg. The most common drug-related treatment-emergent adverse events (TEAEs) were fatigue in the monotherapy cohort (9/44 patients) and neutropenia in the combination cohort (4/6 patients); neutropenia was the only drug-related grade ≥3 TEAE to occur in >1 patient. No infusion reactions occurred, and 4 injection-site reactions were reported. Three patients discontinued treatment due to TEAEs. Among the 22 patients receiving 600 mg mezagitamab, the overall response rate was 47%, and the median duration of response was 22.1 months. Mezagitamab outcomes were comparable to those reported with other anti-CD38 therapies in patients with advanced RRMM. Further development of mezagitamab in myeloma is not planned, but studies are underway in autoimmune conditions. This trial was registered at <span><span>www.ClinicalTrials.gov</span><svg><path></path></svg></span> as #NCT03439280.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"1 4","pages":"Article 100043"},"PeriodicalIF":0.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142652452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-16DOI: 10.1016/j.bneo.2024.100042
Eunice Lai ∗ , Yu Yang Soon ∗ , Ainsley Ryan Yan Bin Lee , Shi Yin Wong , Cinnie Yentia Soekojo , Melissa Ooi , Wee Joo Chng , Sanjay de Mel
Abstract
Lenalidomide, ixazomib, and daratumumab have been proposed as maintenance therapies for patients with newly diagnosed multiple myeloma (MM; NDMM). There are, however, no randomized controlled trials (RCTs) comparing them. We conducted a network meta-analysis (NMA) of RCTs comparing these agents against placebo in NDMM. A Bayesian NMA model was used to assess the relative effects of competing treatments on progression-free survival (PFS) and overall survival (OS) in 9 studies including 4115 patients with transplant-eligible MM (TEMM) and 1689 patients with non–transplant-eligible MM (NTEMM). Lenalidomide and daratumumab but not ixazomib were associated with improved PFS compared with placebo in patients with TEMM (lenalidomide [hazard ratio (HR), 0.46; 95% credible interval (CrI), 0.36-0.56]; daratumumab [HR, 0.49; 95% Crl, 0.32-0.76]; and ixazomib [HR, 0.72; 95% CrI, 0.46-1.12]) and those with NTEMM (lenalidomide [HR, 0.46; 95% CrI, 0.29-0.75] and ixazomib [HR, 0.69; 95% CrI, 0.43-1.18]). The PFS benefit for daratumumab was present regardless of whether daratumumab-based induction therapy was received. None of the agents showed an OS benefit, and PFS benefits were not seen in patients with high-risk cytogenetics. Lenalidomide was associated with second malignancies, ixazomib with thrombocytopenia, and daratumumab with pneumonia. We propose that lenalidomide remains the maintenance therapy of choice for NDMM.
{"title":"Lenalidomide, ixazomib, or daratumumab maintenance therapy in multiple myeloma","authors":"Eunice Lai ∗ , Yu Yang Soon ∗ , Ainsley Ryan Yan Bin Lee , Shi Yin Wong , Cinnie Yentia Soekojo , Melissa Ooi , Wee Joo Chng , Sanjay de Mel","doi":"10.1016/j.bneo.2024.100042","DOIUrl":"10.1016/j.bneo.2024.100042","url":null,"abstract":"<div><h3>Abstract</h3><div>Lenalidomide, ixazomib, and daratumumab have been proposed as maintenance therapies for patients with newly diagnosed multiple myeloma (MM; NDMM). There are, however, no randomized controlled trials (RCTs) comparing them. We conducted a network meta-analysis (NMA) of RCTs comparing these agents against placebo in NDMM. A Bayesian NMA model was used to assess the relative effects of competing treatments on progression-free survival (PFS) and overall survival (OS) in 9 studies including 4115 patients with transplant-eligible MM (TEMM) and 1689 patients with non–transplant-eligible MM (NTEMM). Lenalidomide and daratumumab but not ixazomib were associated with improved PFS compared with placebo in patients with TEMM (lenalidomide [hazard ratio (HR), 0.46; 95% credible interval (CrI), 0.36-0.56]; daratumumab [HR, 0.49; 95% Crl, 0.32-0.76]; and ixazomib [HR, 0.72; 95% CrI, 0.46-1.12]) and those with NTEMM (lenalidomide [HR, 0.46; 95% CrI, 0.29-0.75] and ixazomib [HR, 0.69; 95% CrI, 0.43-1.18]). The PFS benefit for daratumumab was present regardless of whether daratumumab-based induction therapy was received. None of the agents showed an OS benefit, and PFS benefits were not seen in patients with high-risk cytogenetics. Lenalidomide was associated with second malignancies, ixazomib with thrombocytopenia, and daratumumab with pneumonia. We propose that lenalidomide remains the maintenance therapy of choice for NDMM.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"1 4","pages":"Article 100042"},"PeriodicalIF":0.0,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142573253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-05DOI: 10.1016/j.bneo.2024.100040
Wangisa Dunuwille , William C. Wilson , Hassan Bjeije , Nancy Issa , Wentao Han , Tyler M. Parsons , Andrew L. Young , Infencia Xavier Raj , Aishwarya Krishnan , Tarang Gaur , Eunice S. Wang , Andrew P. Weng , Matthew C. Stubbs , Hamza Celik , Amanda F. Cashen , John R. Edwards , Grant A. Challen
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm. Although the prognosis of pediatric T-ALL has improved with intensified chemotherapy regimens, this benefit has largely not translated to the adult T-ALL population. Development of new treatments requires understanding the mechanisms driven by specific mutations. DNMT3A mutations are identified in ∼10% to 18% of adult patients with T-ALL and are associated with poor clinical outcomes. Here, using primary human specimens, we show that cells from patients with T-ALL with DNMT3A mutations are resistant to apoptosis and certain chemotherapies. Elevated JAK/STAT signaling drove prosurvival programs in patients with mutant DNMT3A, and JAK/STAT inhibition restored sensitivity to chemotherapy. The prosurvival gene BIRC5 was upregulated in patients with DNMT3A-mutant T-ALL, and these cells were specifically sensitive to the Baculoviral IAP Repeat Containing 5 (BIRC5) inhibitor YM155. Genetic inhibition of BIRC5 in vivo lead to rapid depletion of DNMT3A-mutant T-ALL cells in patient-derived xenografts, positioning BIRC5 as a precision medicine target for these patients.
{"title":"BIRC5 upregulation enhances DNMT3A-mutant T-ALL cell survival and pathogenesis","authors":"Wangisa Dunuwille , William C. Wilson , Hassan Bjeije , Nancy Issa , Wentao Han , Tyler M. Parsons , Andrew L. Young , Infencia Xavier Raj , Aishwarya Krishnan , Tarang Gaur , Eunice S. Wang , Andrew P. Weng , Matthew C. Stubbs , Hamza Celik , Amanda F. Cashen , John R. Edwards , Grant A. Challen","doi":"10.1016/j.bneo.2024.100040","DOIUrl":"10.1016/j.bneo.2024.100040","url":null,"abstract":"<div><h3>Abstract</h3><div>T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm. Although the prognosis of pediatric T-ALL has improved with intensified chemotherapy regimens, this benefit has largely not translated to the adult T-ALL population. Development of new treatments requires understanding the mechanisms driven by specific mutations. <em>DNMT3A</em> mutations are identified in ∼10% to 18% of adult patients with T-ALL and are associated with poor clinical outcomes. Here, using primary human specimens, we show that cells from patients with T-ALL with <em>DNMT3A</em> mutations are resistant to apoptosis and certain chemotherapies. Elevated JAK/STAT signaling drove prosurvival programs in patients with mutant <em>DNMT3A</em>, and JAK/STAT inhibition restored sensitivity to chemotherapy. The prosurvival gene <em>BIRC5</em> was upregulated in patients with <em>DNMT3A</em>-mutant T-ALL, and these cells were specifically sensitive to the Baculoviral IAP Repeat Containing 5 (BIRC5) inhibitor YM155. Genetic inhibition of <em>BIRC5</em> in vivo lead to rapid depletion of <em>DNMT3A</em>-mutant T-ALL cells in patient-derived xenografts, positioning BIRC5 as a precision medicine target for these patients.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"1 4","pages":"Article 100040"},"PeriodicalIF":0.0,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01DOI: 10.1016/j.bneo.2024.100034
Natalia Timofeeva , Nitin Jain , Varsha Gandhi
Abstract
The combination of ibrutinib and venetoclax has emerged as a promising therapeutic strategy for patients with chronic lymphocytic leukemia (CLL). Preclinical investigations demonstrated a synergistic antitumor effect through multiple mechanisms, providing a robust foundation for translating this regimen into clinical trials. Beyond the dual inhibition by 2 small molecules, another innovative concept being tested with this combination is the use of measurable residual disease (MRD)–driven treatment vs fixed-duration treatment to meet the escalating demand for oral, convenient, cost-effective, and time-limited therapeutic approaches. The clinical translation of this combination has yielded remarkable outcomes with significant improvements in the progression-free survival and overall survival rates for both treatment-naïve patients and those with relapsed/refractory CLL. Notably, a substantial proportion of patients achieved undetectable MRD. Clinical trial updates following the initial published results have shown consistency and durability of responses over time. In this review, the initial investigator-initiated trial results for ibrutinib and venetoclax are discussed, several multicenter clinical trial designs and outcomes are examined, variables such as chromosome 17p deletion that influence treatment responses are addressed, and the safety of the regimen is discussed. In addition, we reviewed the usage of this combination in other B-cell malignancies and discussed how current knowledge can be used for shaping the future CLL treatment regimens.
{"title":"Ibrutinib and venetoclax in combination for chronic lymphocytic leukemia: synergy in practice","authors":"Natalia Timofeeva , Nitin Jain , Varsha Gandhi","doi":"10.1016/j.bneo.2024.100034","DOIUrl":"10.1016/j.bneo.2024.100034","url":null,"abstract":"<div><h3>Abstract</h3><p>The combination of ibrutinib and venetoclax has emerged as a promising therapeutic strategy for patients with chronic lymphocytic leukemia (CLL). Preclinical investigations demonstrated a synergistic antitumor effect through multiple mechanisms, providing a robust foundation for translating this regimen into clinical trials. Beyond the dual inhibition by 2 small molecules, another innovative concept being tested with this combination is the use of measurable residual disease (MRD)–driven treatment vs fixed-duration treatment to meet the escalating demand for oral, convenient, cost-effective, and time-limited therapeutic approaches. The clinical translation of this combination has yielded remarkable outcomes with significant improvements in the progression-free survival and overall survival rates for both treatment-naïve patients and those with relapsed/refractory CLL. Notably, a substantial proportion of patients achieved undetectable MRD. Clinical trial updates following the initial published results have shown consistency and durability of responses over time. In this review, the initial investigator-initiated trial results for ibrutinib and venetoclax are discussed, several multicenter clinical trial designs and outcomes are examined, variables such as chromosome 17p deletion that influence treatment responses are addressed, and the safety of the regimen is discussed. In addition, we reviewed the usage of this combination in other B-cell malignancies and discussed how current knowledge can be used for shaping the future CLL treatment regimens.</p></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"1 3","pages":"Article 100034"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2950328024000347/pdfft?md5=6d685af44e4971629738466491360299&pid=1-s2.0-S2950328024000347-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142095128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01DOI: 10.1016/j.bneo.2024.100033
Koji Nagafuji , Toshihiro Miyamoto , Tetsuya Eto , Tomohiko Kamimura , Koji Kato , Yasuhiko Miyazaki , Atsushi Wake , Kentaro Kohno , Ken Takase , Yutaka Imamura , Naoyuki Uchida , Kazuki Tanimoto , Noriaki Kawano , Toshiro Kurokawa , Yukio Kondo , Yoshikiyo Ito , Tomoaki Fujisaki , Junichi Tsukada , Koji Yonemoto , Toshinori Hori , Koichi Akashi
Abstract
The enhanced utilization of native L-asparaginase (L-Asp) aims to improve treatment outcomes for adult patients with non-Philadelphia chromosome (Ph) acute lymphoblastic leukemia (ALL). In this measurable residual disease 2014 (MRD2014) study, we modified our protocol to include an augmented dose of native L-Asp. Compared with former MRD2008, the total dose of L-Asp was raised from 36 000 U/m2 to 232 000 U/m2 in patients aged 16 to 35 and from 36 000 U/m2 to 132 000 U/m2 in patients aged 36 to 65 years. Adult patients with ALL were enrolled between January 2014 and December 2019 based on the following eligibility criteria: non-L3 ALL, age 16 to 65 years, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate liver and kidney functions (serum bilirubin ≤ 2.0 mg/dL; serum creatinine ≤ 2.0 mg/dL). The median follow-up time was 1128 days (range, 35-2400). A total of 81 patients with non-Ph ALL (40 males and 41 females; median age, 39 years [range, 16-64]) in whom MRD status was assessed were included. Complete remission was achieved in 72 patients (89%). The probability of 3-year event-free survival (EFS) and overall survival (OS) in these patients were 55% and 72%, respectively. The outcomes for patients aged 16 to 35 years demonstrated remarkable improvement. The 3-year EFS of MRD2008 at 45% significantly increased to 71% for MRD2014. Our study unequivocally demonstrated the beneficial effects of augmented use of L-Asp in this adolescent and young adult population. This trial was registered at UMIN Clinical Trials Registry as #UMIN000012382.
{"title":"Augmented use of L-asparaginase markedly improves AYA ALL outcomes: FBMTG prospective MRD2014 study","authors":"Koji Nagafuji , Toshihiro Miyamoto , Tetsuya Eto , Tomohiko Kamimura , Koji Kato , Yasuhiko Miyazaki , Atsushi Wake , Kentaro Kohno , Ken Takase , Yutaka Imamura , Naoyuki Uchida , Kazuki Tanimoto , Noriaki Kawano , Toshiro Kurokawa , Yukio Kondo , Yoshikiyo Ito , Tomoaki Fujisaki , Junichi Tsukada , Koji Yonemoto , Toshinori Hori , Koichi Akashi","doi":"10.1016/j.bneo.2024.100033","DOIUrl":"10.1016/j.bneo.2024.100033","url":null,"abstract":"<div><h3>Abstract</h3><p>The enhanced utilization of native L-asparaginase (L-Asp) aims to improve treatment outcomes for adult patients with non-Philadelphia chromosome (Ph) acute lymphoblastic leukemia (ALL). In this measurable residual disease 2014 (MRD2014) study, we modified our protocol to include an augmented dose of native L-Asp. Compared with former MRD2008, the total dose of L-Asp was raised from 36 000 U/m<sup>2</sup> to 232 000 U/m<sup>2</sup> in patients aged 16 to 35 and from 36 000 U/m<sup>2</sup> to 132 000 U/m<sup>2</sup> in patients aged 36 to 65 years. Adult patients with ALL were enrolled between January 2014 and December 2019 based on the following eligibility criteria: non-L3 ALL, age 16 to 65 years, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate liver and kidney functions (serum bilirubin ≤ 2.0 mg/dL; serum creatinine ≤ 2.0 mg/dL). The median follow-up time was 1128 days (range, 35-2400). A total of 81 patients with non-Ph ALL (40 males and 41 females; median age, 39 years [range, 16-64]) in whom MRD status was assessed were included. Complete remission was achieved in 72 patients (89%). The probability of 3-year event-free survival (EFS) and overall survival (OS) in these patients were 55% and 72%, respectively. The outcomes for patients aged 16 to 35 years demonstrated remarkable improvement. The 3-year EFS of MRD2008 at 45% significantly increased to 71% for MRD2014. Our study unequivocally demonstrated the beneficial effects of augmented use of L-Asp in this adolescent and young adult population. This trial was registered at UMIN Clinical Trials Registry as #UMIN000012382.</p></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"1 3","pages":"Article 100033"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2950328024000335/pdfft?md5=bbf499ae9c9b69c23bb21aa6d69f4833&pid=1-s2.0-S2950328024000335-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142095183","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}
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