Unified classification and risk-stratification in Acute Myeloid Leukemia

Yanis Tazi; Juan E. Arango-Ossa; Yangyu Zhou; Elsa Bernard; Ian Thomas; Amanda Gilkes; Sylvie Freeman; Yoann Pradat; Sean J. Johnson; Robert Hills; Richard Dillon; Max F. Levine; Daniel Leongamornlert; Adam Butler; Arnold Ganser; Lars Bullinger; Konstanze Döhner; Oliver Ottmann; Richard Adams; Hartmut Döhner; Peter J. Campbell; Alan K. Burnett; Michael Dennis; Nigel H. Russell; Sean M. Devlin; Brian J.P. Huntly; Elli Papaemmanuil

doi:10.1038/s41467-022-32103-8

Unified classification and risk-stratification in Acute Myeloid Leukemia

Yanis Tazi, Juan E. Arango-Ossa, Yangyu Zhou, Elsa Bernard, Ian Thomas, Amanda Gilkes, Sylvie Freeman, Yoann Pradat, Sean J. Johnson, Robert Hills, Richard Dillon, Max F. Levine, Daniel Leongamornlert, Adam Butler, Arnold Ganser, Lars Bullinger, Konstanze Döhner, Oliver Ottmann, Richard Adams, Hartmut DöhnerPeter J. Campbell, Alan K. Burnett, Michael Dennis, Nigel H. Russell, Sean M. Devlin, Brian J.P. Huntly, Elli Papaemmanuil^*

^*Corresponding author for this work

Medical & Molecular Genetics

Research output: Contribution to journal › Article › peer-review

84 Citations (Scopus)

Abstract

Clinical recommendations for Acute Myeloid Leukemia (AML) classification and risk-stratification remain heavily reliant on cytogenetic findings at diagnosis, which are present in <50% of patients. Using comprehensive molecular profiling data from 3,653 patients we characterize and validate 16 molecular classes describing 100% of AML patients. Each class represents diverse biological AML subgroups, and is associated with distinct clinical presentation, likelihood of response to induction chemotherapy, risk of relapse and death over time. Secondary AML-2, emerges as the second largest class (24%), associates with high-risk disease, poor prognosis irrespective of flow Minimal Residual Disease (MRD) negativity, and derives significant benefit from transplantation. Guided by class membership we derive a 3-tier risk-stratification score that re-stratifies 26% of patients as compared to standard of care. This results in a unified framework for disease classification and risk-stratification in AML that relies on information from cytogenetics and 32 genes. Last, we develop an open-access patient-tailored clinical decision support tool.

Original language	English
Article number	4622
Journal	Nature Communications
Volume	13
Issue number	1
Early online date	8 Aug 2022
DOIs	https://doi.org/10.1038/s41467-022-32103-8
Publication status	Published - Dec 2022

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Tazi, Y., Arango-Ossa, J. E., Zhou, Y., Bernard, E., Thomas, I., Gilkes, A., Freeman, S., Pradat, Y., Johnson, S. J., Hills, R., Dillon, R., Levine, M. F., Leongamornlert, D., Butler, A., Ganser, A., Bullinger, L., Döhner, K., Ottmann, O., Adams, R., ... Papaemmanuil, E. (2022). Unified classification and risk-stratification in Acute Myeloid Leukemia. Nature Communications, 13(1), Article 4622. https://doi.org/10.1038/s41467-022-32103-8

@article{7e8571345ab74e7e89c1a39fc3b71b06,

title = "Unified classification and risk-stratification in Acute Myeloid Leukemia",

abstract = "Clinical recommendations for Acute Myeloid Leukemia (AML) classification and risk-stratification remain heavily reliant on cytogenetic findings at diagnosis, which are present in <50% of patients. Using comprehensive molecular profiling data from 3,653 patients we characterize and validate 16 molecular classes describing 100% of AML patients. Each class represents diverse biological AML subgroups, and is associated with distinct clinical presentation, likelihood of response to induction chemotherapy, risk of relapse and death over time. Secondary AML-2, emerges as the second largest class (24%), associates with high-risk disease, poor prognosis irrespective of flow Minimal Residual Disease (MRD) negativity, and derives significant benefit from transplantation. Guided by class membership we derive a 3-tier risk-stratification score that re-stratifies 26% of patients as compared to standard of care. This results in a unified framework for disease classification and risk-stratification in AML that relies on information from cytogenetics and 32 genes. Last, we develop an open-access patient-tailored clinical decision support tool.",

author = "Yanis Tazi and Arango-Ossa, {Juan E.} and Yangyu Zhou and Elsa Bernard and Ian Thomas and Amanda Gilkes and Sylvie Freeman and Yoann Pradat and Johnson, {Sean J.} and Robert Hills and Richard Dillon and Levine, {Max F.} and Daniel Leongamornlert and Adam Butler and Arnold Ganser and Lars Bullinger and Konstanze D{\"o}hner and Oliver Ottmann and Richard Adams and Hartmut D{\"o}hner and Campbell, {Peter J.} and Burnett, {Alan K.} and Michael Dennis and Russell, {Nigel H.} and Devlin, {Sean M.} and Huntly, {Brian J.P.} and Elli Papaemmanuil",

note = "Funding Information: E.P. is a Josie Robertson Investigator and is supported by the European Hematology Association, American Society of Hematology, Gabrielle{\textquoteright}s Angels Foundation, V Foundation and The Geoffrey Beene Foundation and is a Damon Runyon Rachleff Innovator fellow. Work in the B.J.P.H. lab is funded by Cancer Research UK (C18680/A25508), the European Research Council (647685), MRC (MR-R009708-1), the Kay Kendall Leukemia Fund (KKL1243), the Wellcome Trust (205254/Z/16/Z) and the Cancer Research UK Cambridge Major Centre (C49940/A25117). This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014), and was funded in part, by the Wellcome Trust who supported the Wellcome—MRC Cambridge Stem Cell Institute (203151/Z/16/Z). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. L.B., H.D. and B.J.P.H. are supported by the HARMONY Alliance (IMI Project No. 116026; https://www.harmony-alliance.eu/ ). The UK-NCRI AML working group trials were supported with research grants from the Medical Research Council (MRC), Cancer Research UK (CRUK), Blood Cancer UK and Cardiff University. We would like to thank all patients and investigators for their participation in the trials and the study. Funding Information: E.P. is a Josie Robertson Investigator and is supported by the European Hematology Association, American Society of Hematology, Gabrielle{\textquoteright}s Angels Foundation, V Foundation and The Geoffrey Beene Foundation and is a Damon Runyon Rachleff Innovator fellow. Work in the B.J.P.H. lab is funded by Cancer Research UK (C18680/A25508), the European Research Council (647685), MRC (MR-R009708-1), the Kay Kendall Leukemia Fund (KKL1243), the Wellcome Trust (205254/Z/16/Z) and the Cancer Research UK Cambridge Major Centre (C49940/A25117). This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014), and was funded in part, by the Wellcome Trust who supported the Wellcome—MRC Cambridge Stem Cell Institute (203151/Z/16/Z). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. L.B., H.D. and B.J.P.H. are supported by the HARMONY Alliance (IMI Project No. 116026; https://www.harmony-alliance.eu/). The UK-NCRI AML working group trials were supported with research grants from the Medical Research Council (MRC), Cancer Research UK (CRUK), Blood Cancer UK and Cardiff University. We would like to thank all patients and investigators for their participation in the trials and the study. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-32103-8",

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Tazi, Y, Arango-Ossa, JE, Zhou, Y, Bernard, E, Thomas, I, Gilkes, A, Freeman, S, Pradat, Y, Johnson, SJ, Hills, R, Dillon, R, Levine, MF, Leongamornlert, D, Butler, A, Ganser, A, Bullinger, L, Döhner, K, Ottmann, O, Adams, R, Döhner, H, Campbell, PJ, Burnett, AK, Dennis, M, Russell, NH, Devlin, SM, Huntly, BJP & Papaemmanuil, E 2022, 'Unified classification and risk-stratification in Acute Myeloid Leukemia', Nature Communications, vol. 13, no. 1, 4622. https://doi.org/10.1038/s41467-022-32103-8

TY - JOUR

T1 - Unified classification and risk-stratification in Acute Myeloid Leukemia

AU - Tazi, Yanis

AU - Arango-Ossa, Juan E.

AU - Zhou, Yangyu

AU - Bernard, Elsa

AU - Thomas, Ian

AU - Gilkes, Amanda

AU - Freeman, Sylvie

AU - Pradat, Yoann

AU - Johnson, Sean J.

AU - Hills, Robert

AU - Dillon, Richard

AU - Levine, Max F.

AU - Leongamornlert, Daniel

AU - Butler, Adam

AU - Ganser, Arnold

AU - Bullinger, Lars

AU - Döhner, Konstanze

AU - Ottmann, Oliver

AU - Adams, Richard

AU - Döhner, Hartmut

AU - Campbell, Peter J.

AU - Burnett, Alan K.

AU - Dennis, Michael

AU - Russell, Nigel H.

AU - Devlin, Sean M.

AU - Huntly, Brian J.P.

AU - Papaemmanuil, Elli

N1 - Funding Information: E.P. is a Josie Robertson Investigator and is supported by the European Hematology Association, American Society of Hematology, Gabrielle’s Angels Foundation, V Foundation and The Geoffrey Beene Foundation and is a Damon Runyon Rachleff Innovator fellow. Work in the B.J.P.H. lab is funded by Cancer Research UK (C18680/A25508), the European Research Council (647685), MRC (MR-R009708-1), the Kay Kendall Leukemia Fund (KKL1243), the Wellcome Trust (205254/Z/16/Z) and the Cancer Research UK Cambridge Major Centre (C49940/A25117). This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014), and was funded in part, by the Wellcome Trust who supported the Wellcome—MRC Cambridge Stem Cell Institute (203151/Z/16/Z). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. L.B., H.D. and B.J.P.H. are supported by the HARMONY Alliance (IMI Project No. 116026; https://www.harmony-alliance.eu/ ). The UK-NCRI AML working group trials were supported with research grants from the Medical Research Council (MRC), Cancer Research UK (CRUK), Blood Cancer UK and Cardiff University. We would like to thank all patients and investigators for their participation in the trials and the study. Funding Information: E.P. is a Josie Robertson Investigator and is supported by the European Hematology Association, American Society of Hematology, Gabrielle’s Angels Foundation, V Foundation and The Geoffrey Beene Foundation and is a Damon Runyon Rachleff Innovator fellow. Work in the B.J.P.H. lab is funded by Cancer Research UK (C18680/A25508), the European Research Council (647685), MRC (MR-R009708-1), the Kay Kendall Leukemia Fund (KKL1243), the Wellcome Trust (205254/Z/16/Z) and the Cancer Research UK Cambridge Major Centre (C49940/A25117). This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014), and was funded in part, by the Wellcome Trust who supported the Wellcome—MRC Cambridge Stem Cell Institute (203151/Z/16/Z). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. L.B., H.D. and B.J.P.H. are supported by the HARMONY Alliance (IMI Project No. 116026; https://www.harmony-alliance.eu/). The UK-NCRI AML working group trials were supported with research grants from the Medical Research Council (MRC), Cancer Research UK (CRUK), Blood Cancer UK and Cardiff University. We would like to thank all patients and investigators for their participation in the trials and the study. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - Clinical recommendations for Acute Myeloid Leukemia (AML) classification and risk-stratification remain heavily reliant on cytogenetic findings at diagnosis, which are present in <50% of patients. Using comprehensive molecular profiling data from 3,653 patients we characterize and validate 16 molecular classes describing 100% of AML patients. Each class represents diverse biological AML subgroups, and is associated with distinct clinical presentation, likelihood of response to induction chemotherapy, risk of relapse and death over time. Secondary AML-2, emerges as the second largest class (24%), associates with high-risk disease, poor prognosis irrespective of flow Minimal Residual Disease (MRD) negativity, and derives significant benefit from transplantation. Guided by class membership we derive a 3-tier risk-stratification score that re-stratifies 26% of patients as compared to standard of care. This results in a unified framework for disease classification and risk-stratification in AML that relies on information from cytogenetics and 32 genes. Last, we develop an open-access patient-tailored clinical decision support tool.

AB - Clinical recommendations for Acute Myeloid Leukemia (AML) classification and risk-stratification remain heavily reliant on cytogenetic findings at diagnosis, which are present in <50% of patients. Using comprehensive molecular profiling data from 3,653 patients we characterize and validate 16 molecular classes describing 100% of AML patients. Each class represents diverse biological AML subgroups, and is associated with distinct clinical presentation, likelihood of response to induction chemotherapy, risk of relapse and death over time. Secondary AML-2, emerges as the second largest class (24%), associates with high-risk disease, poor prognosis irrespective of flow Minimal Residual Disease (MRD) negativity, and derives significant benefit from transplantation. Guided by class membership we derive a 3-tier risk-stratification score that re-stratifies 26% of patients as compared to standard of care. This results in a unified framework for disease classification and risk-stratification in AML that relies on information from cytogenetics and 32 genes. Last, we develop an open-access patient-tailored clinical decision support tool.

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U2 - 10.1038/s41467-022-32103-8

DO - 10.1038/s41467-022-32103-8

M3 - Article

C2 - 35941135

AN - SCOPUS:85135551626

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4622

ER -

Unified classification and risk-stratification in Acute Myeloid Leukemia

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