George Mo, Sang Y Lee, David G Coffey, Valentin Voillet, Ilan R Kirsch, Raphael Gottardo, Kimberly S Smythe, Cecilia C S Yeung, Adam Greenbaum, Damian J Green, David G Maloney, Brian G Till
{"title":"Long-term Remissions Following CD20-Directed Chimeric Antigen Receptor-Adoptive T-cell Therapy.","authors":"George Mo, Sang Y Lee, David G Coffey, Valentin Voillet, Ilan R Kirsch, Raphael Gottardo, Kimberly S Smythe, Cecilia C S Yeung, Adam Greenbaum, Damian J Green, David G Maloney, Brian G Till","doi":"10.1158/2643-3230.BCD-23-0263","DOIUrl":"10.1158/2643-3230.BCD-23-0263","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T-cell therapy produces high response rates in refractory B-cell non-Hodgkin lymphoma, but long-term data are minimal to date. In this study, we present long-term follow-up of a pilot trial testing a CD20-targeting third-generation CAR in patients with relapsed B-cell lymphomas following cyclophosphamide-only lymphodepletion. Two of the three patients in the trial, with mantle cell lymphoma and follicular lymphoma, had remissions lasting more than 7 years, though they ultimately relapsed. The absence of B-cell aplasia in both patients suggested a lack of functional CAR T-cell persistence, leading to the hypothesis that endogenous immune responses were responsible for these long-term remissions. Correlative immunologic analyses supported this hypothesis, with evidence of new humoral and cellular antitumor immune responses proximal to clinical response time points. Collectively, our results suggest that CAR T-cell therapy may facilitate epitope spreading and endogenous immune response formation in lymphomas. Significance: Two of three patients treated with CD20-targeted CAR T-cell therapy had long-term remissions, with evidence of endogenous antitumor immune response formation. Further investigation is warranted to develop conditions that promote epitope spreading in lymphomas.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"258-266"},"PeriodicalIF":11.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11215399/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140923532","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}
{"title":"The Fate(s) of CAR T-Cell Therapy: Navigating the Risks of CAR+ T-Cell Malignancy.","authors":"Mohamed Abou-El-Enein","doi":"10.1158/2643-3230.BCD-23-0272","DOIUrl":"10.1158/2643-3230.BCD-23-0272","url":null,"abstract":"<p><p>The introduction of chimeric antigen receptor (CAR) T-cell therapy represents a landmark advancement in treating resistant forms of cancer such as leukemia, lymphoma, and myeloma. However, concerns about long-term safety have emerged following an FDA investigation into reports of second primary malignancies (SPM) after CAR-T cell treatment. This review offers a thorough examination of how genetically modified T cells might transform into CAR+ SPM. It explores genetic and molecular pathways leading to T-cell lymphomagenesis, the balance between CAR T-cell persistence, stemness, and oncogenic risk, and the trade-off of T-cell exhaustion, which may limit therapy efficacy but potentially reduce lymphomagenesis risk. Significance: An FDA probe into 22 cases of second primary T-cell malignancies following CAR T-cell therapy stresses the need to investigate their origins. Few may arise from preexisting genetic and epigenetic alterations and those introduced during therapeutic engineering. Technological advances, regulatory oversight, and patient monitoring are essential to mitigate potential risks.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"249-257"},"PeriodicalIF":11.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11215381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140877473","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}
Nicole D Vincelette, Xiaoqing Yu, Andrew T Kuykendall, Jungwon Moon, Siyuan Su, Chia-Ho Cheng, Rinzine Sammut, Tiffany N Razabdouski, Hai V Nguyen, Erika A Eksioglu, Onyee Chan, Najla Al Ali, Parth C Patel, Dae H Lee, Shima Nakanishi, Renan B Ferreira, Elizabeth Hyjek, Qianxing Mo, Suzanne Cory, Harshani R Lawrence, Ling Zhang, Daniel J Murphy, Rami S Komrokji, Daesung Lee, Scott H Kaufmann, John L Cleveland, Seongseok Yun
{"title":"Trisomy 8 Defines a Distinct Subtype of Myeloproliferative Neoplasms Driven by the MYC-Alarmin Axis.","authors":"Nicole D Vincelette, Xiaoqing Yu, Andrew T Kuykendall, Jungwon Moon, Siyuan Su, Chia-Ho Cheng, Rinzine Sammut, Tiffany N Razabdouski, Hai V Nguyen, Erika A Eksioglu, Onyee Chan, Najla Al Ali, Parth C Patel, Dae H Lee, Shima Nakanishi, Renan B Ferreira, Elizabeth Hyjek, Qianxing Mo, Suzanne Cory, Harshani R Lawrence, Ling Zhang, Daniel J Murphy, Rami S Komrokji, Daesung Lee, Scott H Kaufmann, John L Cleveland, Seongseok Yun","doi":"10.1158/2643-3230.BCD-23-0210","DOIUrl":"10.1158/2643-3230.BCD-23-0210","url":null,"abstract":"<p><p>Despite advances in understanding the genetic abnormalities in myeloproliferative neoplasms (MPN) and the development of JAK2 inhibitors, there is an urgent need to devise new treatment strategies, particularly for patients with triple-negative (TN) myelofibrosis (MF) who lack mutations in the JAK2 kinase pathway and have very poor clinical outcomes. Here we report that MYC copy number gain and increased MYC expression frequently occur in TN-MF and that MYC-directed activation of S100A9, an alarmin protein that plays pivotal roles in inflammation and innate immunity, is necessary and sufficient to drive development and progression of MF. Notably, the MYC-S100A9 circuit provokes a complex network of inflammatory signaling that involves numerous hematopoietic cell types in the bone marrow microenvironment. Accordingly, genetic ablation of S100A9 or treatment with small molecules targeting the MYC-S100A9 pathway effectively ameliorates MF phenotypes, highlighting the MYC-alarmin axis as a novel therapeutic vulnerability for this subgroup of MPNs. Significance: This study establishes that MYC expression is increased in TN-MPNs via trisomy 8, that a MYC-S100A9 circuit manifest in these cases is sufficient to provoke myelofibrosis and inflammation in diverse hematopoietic cell types in the BM niche, and that the MYC-S100A9 circuit is targetable in TN-MPNs.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"276-297"},"PeriodicalIF":11.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11215389/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140853706","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}
Cecilia Restelli, Marco Ruella, Luca Paruzzo, Corrado Tarella, Pier Giuseppe Pelicci, Emanuela Colombo
{"title":"Recent Advances in Immune-Based Therapies for Acute Myeloid Leukemia.","authors":"Cecilia Restelli, Marco Ruella, Luca Paruzzo, Corrado Tarella, Pier Giuseppe Pelicci, Emanuela Colombo","doi":"10.1158/2643-3230.BCD-23-0202","DOIUrl":"10.1158/2643-3230.BCD-23-0202","url":null,"abstract":"<p><p>Despite advancements, acute myeloid leukemia (AML) remains unconquered by current therapies. Evidence of immune evasion during AML progression, such as HLA loss and T-cell exhaustion, suggests that antileukemic immune responses contribute to disease control and could be harnessed by immunotherapy. In this review, we discuss a spectrum of AML immunotherapy targets, encompassing cancer cell-intrinsic and surface antigens as well as targeting in the leukemic milieu, and how they can be tailored for personalized approaches. These targets are overviewed across major immunotherapy modalities applied to AML: immune checkpoint inhibitors, antibody-drug conjugates, therapeutic vaccines, bispecific/trispecific antibodies, and chimeric antigen receptor (CAR)-T and CAR-NK cells. Significance: Immune therapies in AML treatment show evolving promise. Ongoing research aims to customize approaches for varied patient profiles and clinical scenarios. This review covers immune surveillance mechanisms, therapy options like checkpoint inhibitors, antibodies, CAR-T/NK cells, and vaccines, as well as resistance mechanisms and microenvironment considerations.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"234-248"},"PeriodicalIF":11.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11215380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141432956","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}
Andrew L Young, Hannah C Davis, Maggie J Cox, Tyler M Parsons, Samantha C Burkart, Diane E Bender, Lulu Sun, Stephen T Oh, Grant A Challen
{"title":"Spatial Mapping of Hematopoietic Clones in Human Bone Marrow.","authors":"Andrew L Young, Hannah C Davis, Maggie J Cox, Tyler M Parsons, Samantha C Burkart, Diane E Bender, Lulu Sun, Stephen T Oh, Grant A Challen","doi":"10.1158/2643-3230.BCD-23-0110","DOIUrl":"10.1158/2643-3230.BCD-23-0110","url":null,"abstract":"<p><p>Clonal hematopoiesis (CH) is the expansion of somatically mutated cells in the hematopoietic compartment of individuals without hematopoietic dysfunction. Large CH clones (i.e., >2% variant allele fraction) predispose to hematologic malignancy, but CH is detected at lower levels in nearly all middle-aged individuals. Prior work has extensively characterized CH in peripheral blood, but the spatial distribution of hematopoietic clones in human bone marrow is largely undescribed. To understand CH at this level, we developed a method for spatially aware somatic mutation profiling and characterized the bone marrow of a patient with polycythemia vera. We identified the complex clonal distribution of somatic mutations in the hematopoietic compartment, the restriction of somatic mutations to specific subpopulations of hematopoietic cells, and spatial constraints of these clones in the bone marrow. This proof of principle paves the way to answering fundamental questions regarding CH spatial organization and factors driving CH expansion and malignant transformation in the bone marrow.</p><p><strong>Significance: </strong>CH occurs commonly in humans and can predispose to hematologic malignancy. Although well characterized in blood, it is poorly understood how clones are spatially distributed in the bone marrow. To answer this, we developed methods for spatially aware somatic mutation profiling to describe clonal heterogeneity in human bone marrow. See related commentary by Austin and Aifantis, p. 139.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"153-163"},"PeriodicalIF":11.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11062237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139991301","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}
Caner Saygin, Pu Zhang, Jacob Stauber, Ibrahim Aldoss, Adam S Sperling, Lachelle D Weeks, Marlise R Luskin, Todd C Knepper, Pankhuri Wanjari, Peng Wang, Angela M Lager, Carrie Fitzpatrick, Jeremy P Segal, Mehdi Gharghabi, Sandeep Gurbuxani, Girish Venkataraman, Jason X Cheng, Bart J Eisfelder, Oliver Bohorquez, Anand A Patel, Sheethal Umesh Nagalakshmi, Savita Jayaram, Olatoyosi M Odenike, Richard A Larson, Lucy A Godley, Daniel A Arber, Christopher J Gibson, Nikhil C Munshi, Guido Marcucci, Benjamin L Ebert, John M Greally, Ulrich Steidl, Rosa Lapalombella, Bijal D Shah, Wendy Stock
{"title":"Acute Lymphoblastic Leukemia with Myeloid Mutations Is a High-Risk Disease Associated with Clonal Hematopoiesis.","authors":"Caner Saygin, Pu Zhang, Jacob Stauber, Ibrahim Aldoss, Adam S Sperling, Lachelle D Weeks, Marlise R Luskin, Todd C Knepper, Pankhuri Wanjari, Peng Wang, Angela M Lager, Carrie Fitzpatrick, Jeremy P Segal, Mehdi Gharghabi, Sandeep Gurbuxani, Girish Venkataraman, Jason X Cheng, Bart J Eisfelder, Oliver Bohorquez, Anand A Patel, Sheethal Umesh Nagalakshmi, Savita Jayaram, Olatoyosi M Odenike, Richard A Larson, Lucy A Godley, Daniel A Arber, Christopher J Gibson, Nikhil C Munshi, Guido Marcucci, Benjamin L Ebert, John M Greally, Ulrich Steidl, Rosa Lapalombella, Bijal D Shah, Wendy Stock","doi":"10.1158/2643-3230.BCD-23-0106","DOIUrl":"10.1158/2643-3230.BCD-23-0106","url":null,"abstract":"<p><p>Myeloid neoplasms arise from preexisting clonal hematopoiesis (CH); however, the role of CH in the pathogenesis of acute lymphoblastic leukemia (ALL) is unknown. We found that 18% of adult ALL cases harbored TP53, and 16% had myeloid CH-associated gene mutations. ALL with myeloid mutations (MyM) had distinct genetic and clinical characteristics, associated with inferior survival. By using single-cell proteogenomic analysis, we demonstrated that myeloid mutations were present years before the diagnosis of ALL, and a subset of these clones expanded over time to manifest as dominant clones in ALL. Single-cell RNA sequencing revealed upregulation of genes associated with cell survival and resistance to apoptosis in B-ALL with MyM, which responds better to newer immunotherapeutic approaches. These findings define ALL with MyM as a high-risk disease that can arise from antecedent CH and offer new mechanistic insights to develop better therapeutic and preventative strategies.</p><p><strong>Significance: </strong>CH is a precursor lesion for lymphoblastic leukemogenesis. ALL with MyM has distinct genetic and clinical characteristics, associated with adverse survival outcomes after chemotherapy. CH can precede ALL years before diagnosis, and ALL with MyM is enriched with activated T cells that respond to immunotherapies such as blinatumomab. See related commentary by Iacobucci, p. 142.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"164-179"},"PeriodicalIF":11.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11061587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139040498","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}
Thomas Köhnke, Kevin A Nuno, Catherine C Alder, Eric J Gars, Paul Phan, Amy C Fan, Ravindra Majeti
{"title":"Human ASXL1-Mutant Hematopoiesis Is Driven by a Truncated Protein Associated with Aberrant Deubiquitination of H2AK119.","authors":"Thomas Köhnke, Kevin A Nuno, Catherine C Alder, Eric J Gars, Paul Phan, Amy C Fan, Ravindra Majeti","doi":"10.1158/2643-3230.BCD-23-0235","DOIUrl":"10.1158/2643-3230.BCD-23-0235","url":null,"abstract":"<p><p>Mutations in additional sex combs like 1 (ASXL1) confer poor prognosis both in myeloid malignancies and in premalignant clonal hematopoiesis (CH). However, the mechanisms by which these mutations contribute to disease initiation remain unresolved, and mutation-specific targeting has remained elusive. To address this, we developed a human disease model that recapitulates the disease trajectory from ASXL1-mutant CH to lethal myeloid malignancy. We demonstrate that mutations in ASXL1 lead to the expression of a functional, truncated protein and determine that truncated ASXL1 leads to global redistribution of the repressive chromatin mark H2AK119Ub, increased transposase-accessible chromatin, and activation of both myeloid and stem cell gene-expression programs. Finally, we demonstrate that H2AK119Ub levels are tied to truncated ASXL1 expression levels and leverage this observation to demonstrate that inhibition of the PRC1 complex might be an ASXL1-mutant-specific therapeutic vulnerability in both premalignant CH and myeloid malignancy.</p><p><strong>Significance: </strong>Mutant ASXL1 is a common driver of CH and myeloid malignancy. Using primary human HSPCs, we determine that truncated ASXL1 leads to redistribution of H2AK119Ub and may affect therapeutic vulnerability to PRC1 inhibition.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"202-223"},"PeriodicalIF":11.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11061584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139742184","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}
Elyse A Olesinski, Karanpreet Singh Bhatia, Chuqi Wang, Marissa S Pioso, Xiao Xian Lin, Ahmed M Mamdouh, Shu Xuan Ng, Vedant Sandhu, Shaista Shabbir Jasdanwala, Binyam Yilma, Stephan Bohl, Jeremy A Ryan, Disha Malani, Marlise R Luskin, Olli Kallioniemi, Kimmo Porkka, Sophia Adamia, Wee Joo Chng, Motomi Osato, David M Weinstock, Jacqueline S Garcia, Anthony Letai, Shruti Bhatt
{"title":"Acquired Multidrug Resistance in AML Is Caused by Low Apoptotic Priming in Relapsed Myeloblasts.","authors":"Elyse A Olesinski, Karanpreet Singh Bhatia, Chuqi Wang, Marissa S Pioso, Xiao Xian Lin, Ahmed M Mamdouh, Shu Xuan Ng, Vedant Sandhu, Shaista Shabbir Jasdanwala, Binyam Yilma, Stephan Bohl, Jeremy A Ryan, Disha Malani, Marlise R Luskin, Olli Kallioniemi, Kimmo Porkka, Sophia Adamia, Wee Joo Chng, Motomi Osato, David M Weinstock, Jacqueline S Garcia, Anthony Letai, Shruti Bhatt","doi":"10.1158/2643-3230.BCD-24-0001","DOIUrl":"10.1158/2643-3230.BCD-24-0001","url":null,"abstract":"<p><p>In many cancers, mortality is associated with the emergence of relapse with multidrug resistance (MDR). Thus far, the investigation of cancer relapse mechanisms has largely focused on acquired genetic mutations. Using acute myeloid leukemia (AML) patient-derived xenografts (PDX), we systematically elucidated a basis of MDR and identified drug sensitivity in relapsed AML. We derived pharmacologic sensitivity for 22 AML PDX models using dynamic BH3 profiling (DBP), together with genomics and transcriptomics. Using in vivo acquired resistant PDXs, we found that resistance to unrelated, narrowly targeted agents in distinct PDXs was accompanied by broad resistance to drugs with disparate mechanisms. Moreover, baseline mitochondrial apoptotic priming was consistently reduced regardless of the class of drug-inducing selection. By applying DBP, we identified drugs showing effective in vivo activity in resistant models. This study implies evasion of apoptosis drives drug resistance and demonstrates the feasibility of the DBP approach to identify active drugs for patients with relapsed AML.</p><p><strong>Significance: </strong>Acquired resistance to targeted therapy remains challenging in AML. We found that reduction in mitochondrial priming and common transcriptomic signatures was a conserved mechanism of acquired resistance across different drug classes in vivo. Drugs active in vivo can be identified even in the multidrug resistant state by DBP.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"180-201"},"PeriodicalIF":11.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11061585/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140040506","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}
Irene M Ghobrial, Nicole Gormley, Shaji K Kumar, Maria-Victoria Mateos, P Leif Bergsagel, Marta Chesi, Madhav V Dhodapkar, Angela Dispenzieri, Rafael Fonseca, Gad Getz, Efstathios Kastritis, Sigurdur Y Kristinsson, Jose Angel Martinez-Climent, Salomon Manier, Catherine R Marinac, Francesco Maura, Gareth J Morgan, Faith E Davies, Omar Nadeem, Mario Nuvolone, Bruno Paiva, Elizabeth O'Donnell, Felipe Prosper, Urvi A Shah, Romanos Sklavenitis-Pistofidis, Adam S Sperling, George S Vassiliou, Nikhil C Munshi, Philip E Castle, Kenneth C Anderson, Jesus F San Miguel
{"title":"Round Table Discussion on Optimal Clinical Trial Design in Precursor Multiple Myeloma.","authors":"Irene M Ghobrial, Nicole Gormley, Shaji K Kumar, Maria-Victoria Mateos, P Leif Bergsagel, Marta Chesi, Madhav V Dhodapkar, Angela Dispenzieri, Rafael Fonseca, Gad Getz, Efstathios Kastritis, Sigurdur Y Kristinsson, Jose Angel Martinez-Climent, Salomon Manier, Catherine R Marinac, Francesco Maura, Gareth J Morgan, Faith E Davies, Omar Nadeem, Mario Nuvolone, Bruno Paiva, Elizabeth O'Donnell, Felipe Prosper, Urvi A Shah, Romanos Sklavenitis-Pistofidis, Adam S Sperling, George S Vassiliou, Nikhil C Munshi, Philip E Castle, Kenneth C Anderson, Jesus F San Miguel","doi":"10.1158/2643-3230.BCD-24-0022","DOIUrl":"10.1158/2643-3230.BCD-24-0022","url":null,"abstract":"<p><strong>Summary: </strong>While the current approach to precursor hematologic conditions is to \"watch and wait,\" this may change with the development of therapies that are safe and extend survival or delay the onset of symptomatic disease. The goal of future therapies in precursor hematologic conditions is to improve survival and prevent or delay the development of symptomatic disease while maximizing safety. Clinical trial considerations in this field include identifying an appropriate at-risk population, safety assessments, dose selection, primary and secondary trial endpoints including surrogate endpoints, control arms, and quality-of-life metrics, all of which may enable more precise benefit-risk assessment.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"146-152"},"PeriodicalIF":11.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11061588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140029182","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}
{"title":"\"Myeloid\" Mutations in ALL Are Not Uncommon: Implications for Etiology and Therapies.","authors":"Ilaria Iacobucci","doi":"10.1158/2643-3230.BCD-24-0015","DOIUrl":"10.1158/2643-3230.BCD-24-0015","url":null,"abstract":"<p><strong>Summary: </strong>In Blood Cancer Discovery, Saygin and colleagues report that somatic variants that are recurrent in myeloid malignancies can also occur with high frequency (16%) in adult acute lymphoblastic leukemia (ALL) where they correlate with older age, diagnosis following genotoxic therapy for a prior malignancy and worse outcome to chemotherapy. Mutations in these \"myeloid\" genes can precede ALL diagnosis and arise in hematopoietic stem or progenitor cells that clonally expand and differentiate into both lymphoblasts and nonmalignant myeloid cells, supporting a role for clonal hematopoiesis as premalignant state outside the context of myeloid malignancies and providing implications for both ALL etiology and therapeutic intervention. See related article by Saygin et al., p. 164 (4).</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":"5 3","pages":"142-145"},"PeriodicalIF":11.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11061583/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140865548","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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