Pub Date : 2023-12-09DOI: 10.1101/2023.12.06.23299616
Yaqi Zhao, Nicholas J Short, Hagop M Kantarjian, Ti-Cheng Chang, Pankaj S Ghate, Chunxu Qu, Walid Macaron, Nitin Jain, Beenu Thakral, Aaron H Phillips, Joseph Khoury, Guillermo Garcia-Manero, Wenchao Zhang, Yiping Fan, Hui Yang, Rebecca S Garris, Lewis F Nasr, Richard W Kriwacki, Kathryn G Roberts, Marina Konopleva, Elias J Jabbour, Charles G Mullighan
Inotuzumab ozogamicin (InO) is an antibody-drug conjugate that delivers calicheamicin to CD22-expressing cells. In a retrospective cohort of InO treated patients with B-cell acute lymphoblastic leukemia, we sought to understand the genomic determinants of response to InO. Acquired CD22 mutations were observed in 11% (3/27) of post-InO relapsed tumor samples. There were multiple CD22 mutations per sample and the mechanisms of CD22 escape included protein truncation, protein destabilization, and epitope alteration. Hypermutation by error-prone DNA damage repair (alternative end-joining, mismatch repair deficiency) drove CD22 escape. Acquired loss-of-function mutations in TP53, ATM and CDKN2A were observed, suggesting compromise of the G1/S DNA damage checkpoint as a mechanism of evading InO-induced apoptosis. In conclusion, genetic alterations modulating CD22 expression and DNA damage response influence InO efficacy. The escape strategies within and beyond antigen loss to CD22-targeted therapy elucidated in this study provide insights into improving therapeutic approaches and overcoming resistance.
伊诺珠单抗-奥佐加米星（InO）是一种抗体-药物共轭物，能将卡利昔明传递给表达 CD22 的细胞。在一组接受过 InO 治疗的 B 细胞急性淋巴细胞白血病患者的回顾性队列中，我们试图了解对 InO 反应的基因组决定因素。在11%（3/27）的InO治疗后复发肿瘤样本中观察到获得性CD22突变。每个样本都有多个CD22突变，CD22逃逸的机制包括蛋白截短、蛋白失稳和表位改变。容易出错的DNA损伤修复（替代性末端连接、错配修复缺陷）导致的高突变推动了CD22的逃逸。观察到TP53、ATM和CDKN2A的获得性功能缺失突变，表明G1/S DNA损伤检查点的损害是逃避InO诱导的细胞凋亡的一种机制。总之，调节 CD22 表达和 DNA 损伤反应的基因改变会影响 InO 的疗效。本研究阐明的抗原丢失内外的CD22靶向治疗逃逸策略为改进治疗方法和克服耐药性提供了启示。
{"title":"Genomic determinants of response and resistance to inotuzumab ozogamicin in B-cell ALL","authors":"Yaqi Zhao, Nicholas J Short, Hagop M Kantarjian, Ti-Cheng Chang, Pankaj S Ghate, Chunxu Qu, Walid Macaron, Nitin Jain, Beenu Thakral, Aaron H Phillips, Joseph Khoury, Guillermo Garcia-Manero, Wenchao Zhang, Yiping Fan, Hui Yang, Rebecca S Garris, Lewis F Nasr, Richard W Kriwacki, Kathryn G Roberts, Marina Konopleva, Elias J Jabbour, Charles G Mullighan","doi":"10.1101/2023.12.06.23299616","DOIUrl":"https://doi.org/10.1101/2023.12.06.23299616","url":null,"abstract":"Inotuzumab ozogamicin (InO) is an antibody-drug conjugate that delivers calicheamicin to CD22-expressing cells. In a retrospective cohort of InO treated patients with B-cell acute lymphoblastic leukemia, we sought to understand the genomic determinants of response to InO. Acquired <em>CD22</em> mutations were observed in 11% (3/27) of post-InO relapsed tumor samples. There were multiple <em>CD22</em> mutations per sample and the mechanisms of CD22 escape included protein truncation, protein destabilization, and epitope alteration. Hypermutation by error-prone DNA damage repair (alternative end-joining, mismatch repair deficiency) drove CD22 escape. Acquired loss-of-function mutations in <em>TP53</em>, <em>ATM</em> and <em>CDKN2A</em> were observed, suggesting compromise of the G1/S DNA damage checkpoint as a mechanism of evading InO-induced apoptosis. In conclusion, genetic alterations modulating CD22 expression and DNA damage response influence InO efficacy. The escape strategies within and beyond antigen loss to CD22-targeted therapy elucidated in this study provide insights into improving therapeutic approaches and overcoming resistance.","PeriodicalId":501203,"journal":{"name":"medRxiv - Hematology","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138576654","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 : 2023-11-29DOI: 10.1101/2023.11.27.23299081
Renee Higgins, Nicholas Haase, Patrick Desmond, Ian Levine, Clara Romero, Brian Fernández, Eumene Lee, Mike Adams, Derek Arndt,, Greg Grabarek, Ju Young Kim, Rachel Krupa, Ginger Mina, Ryan Morgan, John Poland, Galen Reed, Robin Richardson, Kelline Rodems, Astrid Schroeder, Maike Zimmermann, Florence Lee, Dena Marrinucci
Introduction - Routine blood tests play an essential role in modern healthcare, but their administration, processing, and reporting under the current centralized testing model is slow, inefficient, and cumbersome for patients and providers especially in outpatient settings. Truvian's benchtop blood testing platform, in late-stage development, aims to decentralize and streamline routine blood testing, replacing traditional send-outs to a central laboratory with a compact, easy-to-use benchtop platform at the point-of-action™ to ensure timely and actionable results between a patient and healthcare provider. Using only a small amount of blood from a single heparinized sample, the Truvian platform can simultaneously provide results for a full panel of routine blood tests spanning clinical chemistry, hematology, and immunoassays. Evaluation of the Truvian platform in independent external studies is important to understand its performance in real world settings and to identify opportunities for improvement to complete development. To assess the performance of a comprehensive wellness panel on the Truvian platform, a multi-site study was completed at Truvian's headquarters in San Diego, California, and at an independent clinical trial site in the Pacific Northwest. The study evaluated the panel's precision and accuracy against central laboratory analyzers. Methods - Precision and accuracy studies were performed with a panel of 32 routine blood tests including immunoassay, clinical chemistry and hematology assays on the Truvian platform. Precision studies were run across multiple days and instruments to assess repeatability and reproducibility for each test in the panel. A method comparison study included 237 patients and compared the Truvian platform to best-in-class FDA cleared central laboratory analyzers - the Roche Cobas and Sysmex analyzers. Bland-Altman and either Passing-Bablok, or Deming regression analyses were used to determine agreement for each analyte in the panel. Additionally, linearity, sensitivity, and endogenous interfering substance studies were carried out for tests within the panel. Results - Overall, the Truvian platform had a run reliability rate of > 95%. In the precision and detection capability studies, the evaluated tests successfully satisfied all predefined criteria for precision, linearity, and sensitivity. Moreover, the method comparison study revealed concordance with central laboratory analyzers. Conclusions - This multi-site study demonstrated that the Truvian platform, currently in late-stage development, is capable of delivering the clinical performance and reliability needed for decentralized blood testing. The study also provided additional areas of focus to complete development.
{"title":"Concordance of Truvian's Benchtop Blood Testing Platform to Central Laboratory Testing","authors":"Renee Higgins, Nicholas Haase, Patrick Desmond, Ian Levine, Clara Romero, Brian Fernández, Eumene Lee, Mike Adams, Derek Arndt,, Greg Grabarek, Ju Young Kim, Rachel Krupa, Ginger Mina, Ryan Morgan, John Poland, Galen Reed, Robin Richardson, Kelline Rodems, Astrid Schroeder, Maike Zimmermann, Florence Lee, Dena Marrinucci","doi":"10.1101/2023.11.27.23299081","DOIUrl":"https://doi.org/10.1101/2023.11.27.23299081","url":null,"abstract":"Introduction - Routine blood tests play an essential role in modern healthcare, but their administration, processing, and reporting under the current centralized testing model is slow, inefficient, and cumbersome for patients and providers especially in outpatient settings.\u0000Truvian's benchtop blood testing platform, in late-stage development, aims to decentralize and streamline routine blood testing, replacing traditional send-outs to a central laboratory with a compact, easy-to-use benchtop platform at the point-of-action™ to ensure timely and actionable results between a patient and healthcare provider. Using only a small amount of blood from a single heparinized sample, the Truvian platform can simultaneously provide results for a full panel of routine blood tests spanning clinical chemistry, hematology, and immunoassays.\u0000Evaluation of the Truvian platform in independent external studies is important to understand its performance in real world settings and to identify opportunities for improvement to complete development. To assess the performance of a comprehensive wellness panel on the Truvian platform, a multi-site study was completed at Truvian's headquarters in San Diego, California, and at an independent clinical trial site in the Pacific Northwest. The study evaluated the panel's precision and accuracy against central laboratory analyzers.\u0000Methods - Precision and accuracy studies were performed with a panel of 32 routine blood tests including immunoassay, clinical chemistry and hematology assays on the Truvian platform. Precision studies were run across multiple days and instruments to assess repeatability and reproducibility for each test in the panel. A method comparison study included 237 patients and compared the Truvian platform to best-in-class FDA cleared central laboratory analyzers - the Roche Cobas and Sysmex analyzers. Bland-Altman and either Passing-Bablok, or Deming regression analyses were used to determine agreement for each analyte in the panel. Additionally, linearity, sensitivity, and endogenous interfering substance studies were carried out for tests within the panel.\u0000Results - Overall, the Truvian platform had a run reliability rate of > 95%. In the precision and detection capability studies, the evaluated tests successfully satisfied all predefined criteria for precision, linearity, and sensitivity. Moreover, the method comparison study revealed concordance with central laboratory analyzers.\u0000Conclusions - This multi-site study demonstrated that the Truvian platform, currently in late-stage development, is capable of delivering the clinical performance and reliability needed for decentralized blood testing. The study also provided additional areas of focus to complete development.","PeriodicalId":501203,"journal":{"name":"medRxiv - Hematology","volume":"433 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138511315","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 : 2023-11-23DOI: 10.1101/2023.11.23.23298558
Sophie Reed, Charlie Diamond, Samiya Mahmood, Soubera Rymell, Michael Smith, Michele Pansini, Bethan Psaila, Adam J. Mead, Helena Thomaides-Brears, Onima Chowdhury
Assessment of organ impairment in patients with chronic myeloid neoplasms is pivotal in selecting treatments and for accurate prognostication of patient outcomes. In order to determine the multi-organ health of patients with chronic myeloid neoplasms, we conducted a prospective, observational study utilising a novel MRI technology which quantitatively assesses the health of multiple organs in one scan. Organ impairment was significantly higher in the patient cohort compared to healthy controls, most notably with increased rates of kidney fibroinflammation 28% vs 0% (p-value = 0.002). MRI-defined kidney impairment was prevalent in patients with normal serum biomarkers of kidney disease, demonstrating the added value of MRI as a tool to identify occult organ impairment. This has wider implications for enhancing the assessment of organ health in patients with a variety of blood cancers at diagnosis and throughout treatment, guiding more personalised strategies and improving patient outcomes.
{"title":"Multiparametric MRI detects multi-organ impairment in patients with chronic myeloid neoplasms with normal serum biomarkers","authors":"Sophie Reed, Charlie Diamond, Samiya Mahmood, Soubera Rymell, Michael Smith, Michele Pansini, Bethan Psaila, Adam J. Mead, Helena Thomaides-Brears, Onima Chowdhury","doi":"10.1101/2023.11.23.23298558","DOIUrl":"https://doi.org/10.1101/2023.11.23.23298558","url":null,"abstract":"Assessment of organ impairment in patients with chronic myeloid neoplasms is pivotal in selecting treatments and for accurate prognostication of patient outcomes. In order to determine the multi-organ health of patients with chronic myeloid neoplasms, we conducted a prospective, observational study utilising a novel MRI technology which quantitatively assesses the health of multiple organs in one scan. Organ impairment was significantly higher in the patient cohort compared to healthy controls, most notably with increased rates of kidney fibroinflammation 28% vs 0% (p-value = 0.002). MRI-defined kidney impairment was prevalent in patients with normal serum biomarkers of kidney disease, demonstrating the added value of MRI as a tool to identify occult organ impairment. This has wider implications for enhancing the assessment of organ health in patients with a variety of blood cancers at diagnosis and throughout treatment, guiding more personalised strategies and improving patient outcomes.","PeriodicalId":501203,"journal":{"name":"medRxiv - Hematology","volume":"449 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138511313","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 : 2023-07-26DOI: 10.1101/2023.07.21.23292515
Arutyun Bagramyan, Charles P. Lin
We present a miniature oblique back-illumination microscope (mOBM) for imaging the microcirculation of human oral mucosa, enabling real-time, label-free phase contrast imaging of leukocyte rolling and adhesion, the initial steps in leukocyte recruitment that is a hallmark of inflammation. Imaging cell motion can provide new diagnostic information (time course of disease progression, response to therapy, etc.) that is not available using traditional static diagnostic parameters such as cell number and morphology.
{"title":"Miniaturized microscope for non-invasive imaging of leukocyte-endothelial interactions in human microcirculation","authors":"Arutyun Bagramyan, Charles P. Lin","doi":"10.1101/2023.07.21.23292515","DOIUrl":"https://doi.org/10.1101/2023.07.21.23292515","url":null,"abstract":"We present a miniature oblique back-illumination microscope (mOBM) for imaging the microcirculation of human oral mucosa, enabling real-time, label-free phase contrast imaging of leukocyte rolling and adhesion, the initial steps in leukocyte recruitment that is a hallmark of inflammation. Imaging cell motion can provide new diagnostic information (time course of disease progression, response to therapy, etc.) that is not available using traditional static diagnostic parameters such as cell number and morphology.","PeriodicalId":501203,"journal":{"name":"medRxiv - Hematology","volume":"448 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138511314","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 : 2023-04-20DOI: 10.1101/2021.12.22.21268233
Salvador Chulián, Bernadette J. Stolz, Álvaro Martínez-Rubio, Cristina Blázquez Goñi, Juan F. Rodríguez Gutiérrez, Teresa Caballero Velázquez, Águeda Molinos Quintana, Manuel Ramírez Orellana, Ana Castillo Robleda, José Luis Fuster Soler, Alfredo Minguela Puras, María V. Martínez Sánchez, María Rosa, Víctor M. Pérez-García, Helen M. Byrne
Although children and adolescents with acute lymphoblastic leukaemia (ALL) have high survival rates, approximately 15-20% of patients relapse. Risk of relapse is routinely estimated at diagnosis by biological factors, including flow cytometry data. This high-dimensional data is typically manually assessed by projecting it onto a subset of biomarkers. Cell density and “empty spaces” in 2D projections of the data, i.e. regions devoid of cells, are then used for qualitative assessment. Here, we use topological data analysis (TDA), which quantifies shapes, including empty spaces, in data, to analyse pre-treatment ALL datasets with known patient outcomes. We combine these fully unsupervised analyses with Machine Learning (ML) to identify significant shape characteristics and demonstrate that they accurately predict risk of relapse, particularly for patients previously classified as ‘low risk’. We independently confirm the predictive power of CD10, CD20, CD38, and CD45 as biomarkers for ALL diagnosis. Based on our analyses, we propose three increasingly detailed prognostic pipelines for analysing flow cytometry data from ALL patients depending on technical and technological availability: 1. Visual inspection of specific biological features in biparametric projections of the data; 2. Computation of quantitative topological descriptors of such projections; 3. A combined analysis, using TDA and ML, in the four-parameter space defined by CD10, CD20, CD38 and CD45. Our analyses readily extend to other haematological malignancies.
{"title":"The shape of cancer relapse: Topological data analysis predicts recurrence in paediatric acute lymphoblastic leukaemia","authors":"Salvador Chulián, Bernadette J. Stolz, Álvaro Martínez-Rubio, Cristina Blázquez Goñi, Juan F. Rodríguez Gutiérrez, Teresa Caballero Velázquez, Águeda Molinos Quintana, Manuel Ramírez Orellana, Ana Castillo Robleda, José Luis Fuster Soler, Alfredo Minguela Puras, María V. Martínez Sánchez, María Rosa, Víctor M. Pérez-García, Helen M. Byrne","doi":"10.1101/2021.12.22.21268233","DOIUrl":"https://doi.org/10.1101/2021.12.22.21268233","url":null,"abstract":"Although children and adolescents with acute lymphoblastic leukaemia (ALL) have high survival rates, approximately 15-20% of patients relapse. Risk of relapse is routinely estimated at diagnosis by biological factors, including flow cytometry data. This high-dimensional data is typically manually assessed by projecting it onto a subset of biomarkers. Cell density and “empty spaces” in 2D projections of the data, i.e. regions devoid of cells, are then used for qualitative assessment. Here, we use topological data analysis (TDA), which quantifies shapes, including empty spaces, in data, to analyse pre-treatment ALL datasets with known patient outcomes. We combine these fully unsupervised analyses with Machine Learning (ML) to identify significant shape characteristics and demonstrate that they accurately predict risk of relapse, particularly for patients previously classified as ‘low risk’. We independently confirm the predictive power of CD10, CD20, CD38, and CD45 as biomarkers for ALL diagnosis. Based on our analyses, we propose three increasingly detailed prognostic pipelines for analysing flow cytometry data from ALL patients depending on technical and technological availability: 1. Visual inspection of specific biological features in biparametric projections of the data; 2. Computation of quantitative topological descriptors of such projections; 3. A combined analysis, using TDA and ML, in the four-parameter space defined by CD10, CD20, CD38 and CD45. Our analyses readily extend to other haematological malignancies.","PeriodicalId":501203,"journal":{"name":"medRxiv - Hematology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138531439","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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