Meng-Xiao Luo, Tania Tan, Marie Trussart, Annika Poch, Minh-Hanh Thi Nguyen, Terence P Speed, Damien G Hicks, Esther Bandala-Sanchez, Hongke Peng, Stephane Chappaz, Charlotte Slade, Daniel T Utzschneider, Rachel M Koldej, David Ritchie, Andreas Strasser, Rachel Thijssen, Matthew E Ritchie, Constantine Si Lun Tam, Geoffrey J Lindeman, David Ching Siang Huang, Thomas E Lew, Mary Ann Anderson, Andrew W Roberts, Charis E Teh, Daniel H D Gray
{"title":"Venetoclax剂量递增可快速激活慢性淋巴细胞白血病的BAFF/BCL-2生存轴","authors":"Meng-Xiao Luo, Tania Tan, Marie Trussart, Annika Poch, Minh-Hanh Thi Nguyen, Terence P Speed, Damien G Hicks, Esther Bandala-Sanchez, Hongke Peng, Stephane Chappaz, Charlotte Slade, Daniel T Utzschneider, Rachel M Koldej, David Ritchie, Andreas Strasser, Rachel Thijssen, Matthew E Ritchie, Constantine Si Lun Tam, Geoffrey J Lindeman, David Ching Siang Huang, Thomas E Lew, Mary Ann Anderson, Andrew W Roberts, Charis E Teh, Daniel H D Gray","doi":"10.1182/blood.2024024341","DOIUrl":null,"url":null,"abstract":"<p><p>Venetoclax, a first-in-class BH3 mimetic drug targeting BCL-2, has improved outcomes for patients with chronic lymphocytic leukemia (CLL). Early measurements of the depth of the venetoclax treatment response, assessed by minimal residual disease, are strong predictors of long-term clinical outcomes. Yet, there are limited data concerning the early changes induced by venetoclax treatment that might inform strategies to improve responses. To address this gap, we conducted longitudinal mass cytometric profiling of blood cells from patients with CLL during the first five weeks of venetoclax monotherapy. At baseline, we resolved CLL heterogeneity at the single-cell level to define multiple subpopulations in all patients distinguished by proliferative, metabolic and cell survival proteins. Venetoclax induced significant reduction in all CLL subpopulations coincident with rapid upregulation of pro-survival BCL-2, BCL-XL and MCL-1 proteins in surviving cells, which had reduced sensitivity to the drug. Mouse models recapitulated the venetoclax-induced elevation of survival proteins in B cells and CLL-like cells that persisted in vivo, with genetic models demonstrating that extensive apoptosis and access to the B cell cytokine, BAFF, were essential. Accordingly, analysis of patients with CLL that were treated with venetoclax or the anti-CD20 antibody obinutuzumab exhibited marked elevation of BAFF and increased pro-survival proteins in leukemic cells that persisted. Overall, these data highlight the rapid adaptation of CLL cells to targeted therapies via homeostatic factors and support co-targeting of cytokine signals to achieve deeper and more durable long-term responses.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":null,"pages":null},"PeriodicalIF":21.0000,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Venetoclax Dose Escalation Rapidly Activates a BAFF/BCL-2 Survival Axis in Chronic Lymphocytic Leukemia.\",\"authors\":\"Meng-Xiao Luo, Tania Tan, Marie Trussart, Annika Poch, Minh-Hanh Thi Nguyen, Terence P Speed, Damien G Hicks, Esther Bandala-Sanchez, Hongke Peng, Stephane Chappaz, Charlotte Slade, Daniel T Utzschneider, Rachel M Koldej, David Ritchie, Andreas Strasser, Rachel Thijssen, Matthew E Ritchie, Constantine Si Lun Tam, Geoffrey J Lindeman, David Ching Siang Huang, Thomas E Lew, Mary Ann Anderson, Andrew W Roberts, Charis E Teh, Daniel H D Gray\",\"doi\":\"10.1182/blood.2024024341\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Venetoclax, a first-in-class BH3 mimetic drug targeting BCL-2, has improved outcomes for patients with chronic lymphocytic leukemia (CLL). Early measurements of the depth of the venetoclax treatment response, assessed by minimal residual disease, are strong predictors of long-term clinical outcomes. Yet, there are limited data concerning the early changes induced by venetoclax treatment that might inform strategies to improve responses. To address this gap, we conducted longitudinal mass cytometric profiling of blood cells from patients with CLL during the first five weeks of venetoclax monotherapy. At baseline, we resolved CLL heterogeneity at the single-cell level to define multiple subpopulations in all patients distinguished by proliferative, metabolic and cell survival proteins. Venetoclax induced significant reduction in all CLL subpopulations coincident with rapid upregulation of pro-survival BCL-2, BCL-XL and MCL-1 proteins in surviving cells, which had reduced sensitivity to the drug. Mouse models recapitulated the venetoclax-induced elevation of survival proteins in B cells and CLL-like cells that persisted in vivo, with genetic models demonstrating that extensive apoptosis and access to the B cell cytokine, BAFF, were essential. Accordingly, analysis of patients with CLL that were treated with venetoclax or the anti-CD20 antibody obinutuzumab exhibited marked elevation of BAFF and increased pro-survival proteins in leukemic cells that persisted. Overall, these data highlight the rapid adaptation of CLL cells to targeted therapies via homeostatic factors and support co-targeting of cytokine signals to achieve deeper and more durable long-term responses.</p>\",\"PeriodicalId\":9102,\"journal\":{\"name\":\"Blood\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":21.0000,\"publicationDate\":\"2024-10-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Blood\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1182/blood.2024024341\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Blood","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1182/blood.2024024341","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
Venetoclax Dose Escalation Rapidly Activates a BAFF/BCL-2 Survival Axis in Chronic Lymphocytic Leukemia.
Venetoclax, a first-in-class BH3 mimetic drug targeting BCL-2, has improved outcomes for patients with chronic lymphocytic leukemia (CLL). Early measurements of the depth of the venetoclax treatment response, assessed by minimal residual disease, are strong predictors of long-term clinical outcomes. Yet, there are limited data concerning the early changes induced by venetoclax treatment that might inform strategies to improve responses. To address this gap, we conducted longitudinal mass cytometric profiling of blood cells from patients with CLL during the first five weeks of venetoclax monotherapy. At baseline, we resolved CLL heterogeneity at the single-cell level to define multiple subpopulations in all patients distinguished by proliferative, metabolic and cell survival proteins. Venetoclax induced significant reduction in all CLL subpopulations coincident with rapid upregulation of pro-survival BCL-2, BCL-XL and MCL-1 proteins in surviving cells, which had reduced sensitivity to the drug. Mouse models recapitulated the venetoclax-induced elevation of survival proteins in B cells and CLL-like cells that persisted in vivo, with genetic models demonstrating that extensive apoptosis and access to the B cell cytokine, BAFF, were essential. Accordingly, analysis of patients with CLL that were treated with venetoclax or the anti-CD20 antibody obinutuzumab exhibited marked elevation of BAFF and increased pro-survival proteins in leukemic cells that persisted. Overall, these data highlight the rapid adaptation of CLL cells to targeted therapies via homeostatic factors and support co-targeting of cytokine signals to achieve deeper and more durable long-term responses.
期刊介绍:
Blood, the official journal of the American Society of Hematology, published online and in print, provides an international forum for the publication of original articles describing basic laboratory, translational, and clinical investigations in hematology. Primary research articles will be published under the following scientific categories: Clinical Trials and Observations; Gene Therapy; Hematopoiesis and Stem Cells; Immunobiology and Immunotherapy scope; Myeloid Neoplasia; Lymphoid Neoplasia; Phagocytes, Granulocytes and Myelopoiesis; Platelets and Thrombopoiesis; Red Cells, Iron and Erythropoiesis; Thrombosis and Hemostasis; Transfusion Medicine; Transplantation; and Vascular Biology. Papers can be listed under more than one category as appropriate.