Measurable residual disease by flow cytometry in acute myeloid leukemia is prognostic, independent of genomic profiling

Chezi Ganzel; Zhuoxin Sun; Timour Baslan; Yanming Zhang; Mithat Gönen; Omar I. Abdel-Wahab; Janis Racevskis; Francine Garrett-Bakelman; Scott W. Lowe; Hugo F. Fernandez; Rhett Ketterling; Selina M. Luger; Mark Litzow; Hillard M. Lazarus; Jacob M. Rowe; Martin S. Tallman; Ross L. Levine; Elisabeth Paietta

doi:10.1016/j.leukres.2022.106971

Measurable residual disease by flow cytometry in acute myeloid leukemia is prognostic, independent of genomic profiling

Chezi Ganzel^*, Zhuoxin Sun, Timour Baslan, Yanming Zhang, Mithat Gönen, Omar I. Abdel-Wahab, Janis Racevskis, Francine Garrett-Bakelman, Scott W. Lowe, Hugo F. Fernandez, Rhett Ketterling, Selina M. Luger, Mark Litzow, Hillard M. Lazarus, Jacob M. Rowe, Martin S. Tallman, Ross L. Levine, Elisabeth Paietta

^*Corresponding author for this work

Medicine, Hematology Oncology Division

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

3 Scopus citations

Abstract

Measurable residual disease (MRD) assessment provides a potent indicator of the efficacy of anti-leukemic therapy. It is unknown, however, whether integrating MRD with molecular profiling better identifies patients at risk of relapse. To investigate the clinical relevance of MRD in relation to a molecular-based prognostic schema, we measured MRD by flow cytometry in 189 AML patients enrolled in ECOG-ACRIN E1900 trial (NCT00049517) in morphologic complete remission (CR) (28.8 % of the original cohort) representing 44.4 % of CR patients. MRD positivity was defined as ≥ 0.1 % of leukemic bone marrow cells. Risk classification was based on standard cytogenetics, fluorescence-in-situ-hybridization, somatic gene analysis, and sparse whole genome sequencing for copy number ascertainment. At 84.6 months median follow-up of patients still alive at the time of analysis (range 47.0–120 months), multivariate analysis demonstrated that MRD status at CR (p = 0.001) and integrated molecular risk (p = 0.0004) independently predicted overall survival (OS). Among risk classes, MRD status significantly affected OS only in the favorable risk group (p = 0.002). Expression of CD25 (α-chain of the interleukin-2 receptor) by leukemic myeloblasts at diagnosis negatively affected OS independent of post-treatment MRD levels. These data suggest that integrating MRD with genetic profiling and pre-treatment CD25 expression may improve prognostication in AML.

Original language	English (US)
Article number	106971
Journal	Leukemia Research
Volume	123
DOIs	https://doi.org/10.1016/j.leukres.2022.106971
State	Published - Dec 2022

Funding

This study was conducted in part by the ECOG-ACRIN Cancer Research Group (Peter J. O'Dwyer, MD and Mitchell D. Schnall, MD, Ph.D. Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180820, U10CA180794, UG1CA189859, UG1CA233234, UG1CA232760 and UG1CA233290. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. government. This work was further supported by National Cancer Institute National Institutes of Health UG1 CA233332 (O.I.A.-W. and R.L.L.), P30 CA008748–55 (S.W.L.), P50 CA254838–01 (S.W.L.), and K08CA169055 (F.G.-B.), the American Society of Hematology (ASHAMFDP-20121) under the ASH-AMFDP partnership with The Robert Wood Johnson Foundation (F.G.-B.), U10 5U10CA180827 (subaward to F.G.-B), William C. and Joyce C. O′Neil Charitable Trust (T.B.), and the Memorial Sloan Kettering Single Cell Sequencing Initiative (T.B.). The authors acknowledge the use of the Integrated Genomics Operation Core, funded by the Memorial Sloan Kettering Cancer Center Support Grant NIH P30 CA008748. The authors also acknowledge the assistance of Xerxes Vevai and other members of the LTRL in the MRD analysis and the technical support of Tak Lee and Caroline Sheridan in the DNA analysis. This study was conducted in part by the ECOG-ACRIN Cancer Research Group (Peter J. O'Dwyer, MD and Mitchell D. Schnall, MD, Ph.D., Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180820 , U10CA180794 , UG1CA189859 , UG1CA233234 , UG1CA232760 and UG1CA233290 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. government. This work was further supported by National Cancer Institute National Institutes of Health UG1 CA233332 (O.I.A.-W. and R.L.L.), P30 CA008748–55 (S.W.L.), P50 CA254838–01 (S.W.L.), and K08CA169055 (F.G.-B.), the American Society of Hematology ( ASHAMFDP-20121 ) under the ASH-AMFDP partnership with The Robert Wood Johnson Foundation (F.G.-B.), U10 5U10CA180827 (subaward to F.G.-B), William C. and Joyce C. O′Neil Charitable Trust (T.B.), and the Memorial Sloan Kettering Single Cell Sequencing Initiative (T.B.). The authors acknowledge the use of the Integrated Genomics Operation Core, funded by the Memorial Sloan Kettering Cancer Center Support Grant NIH P30 CA008748 . The authors also acknowledge the assistance of Xerxes Vevai and other members of the LTRL in the MRD analysis and the technical support of Tak Lee and Caroline Sheridan in the DNA analysis.

Keywords

Acute myeloid leukemia
CD25
Flow cytometry
Genomic profiling
MRD
Measurable residual disease
Minimal residual disease

ASJC Scopus subject areas

Hematology
Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.leukres.2022.106971

Cite this

Ganzel, C., Sun, Z., Baslan, T., Zhang, Y., Gönen, M., Abdel-Wahab, O. I., Racevskis, J., Garrett-Bakelman, F., Lowe, S. W., Fernandez, H. F., Ketterling, R., Luger, S. M., Litzow, M., Lazarus, H. M., Rowe, J. M., Tallman, M. S., Levine, R. L., & Paietta, E. (2022). Measurable residual disease by flow cytometry in acute myeloid leukemia is prognostic, independent of genomic profiling. Leukemia Research, 123, Article 106971. https://doi.org/10.1016/j.leukres.2022.106971

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title = "Measurable residual disease by flow cytometry in acute myeloid leukemia is prognostic, independent of genomic profiling",

abstract = "Measurable residual disease (MRD) assessment provides a potent indicator of the efficacy of anti-leukemic therapy. It is unknown, however, whether integrating MRD with molecular profiling better identifies patients at risk of relapse. To investigate the clinical relevance of MRD in relation to a molecular-based prognostic schema, we measured MRD by flow cytometry in 189 AML patients enrolled in ECOG-ACRIN E1900 trial (NCT00049517) in morphologic complete remission (CR) (28.8 % of the original cohort) representing 44.4 % of CR patients. MRD positivity was defined as ≥ 0.1 % of leukemic bone marrow cells. Risk classification was based on standard cytogenetics, fluorescence-in-situ-hybridization, somatic gene analysis, and sparse whole genome sequencing for copy number ascertainment. At 84.6 months median follow-up of patients still alive at the time of analysis (range 47.0–120 months), multivariate analysis demonstrated that MRD status at CR (p = 0.001) and integrated molecular risk (p = 0.0004) independently predicted overall survival (OS). Among risk classes, MRD status significantly affected OS only in the favorable risk group (p = 0.002). Expression of CD25 (α-chain of the interleukin-2 receptor) by leukemic myeloblasts at diagnosis negatively affected OS independent of post-treatment MRD levels. These data suggest that integrating MRD with genetic profiling and pre-treatment CD25 expression may improve prognostication in AML.",

keywords = "Acute myeloid leukemia, CD25, Flow cytometry, Genomic profiling, MRD, Measurable residual disease, Minimal residual disease",

author = "Chezi Ganzel and Zhuoxin Sun and Timour Baslan and Yanming Zhang and Mithat G{\"o}nen and Abdel-Wahab, {Omar I.} and Janis Racevskis and Francine Garrett-Bakelman and Lowe, {Scott W.} and Fernandez, {Hugo F.} and Rhett Ketterling and Luger, {Selina M.} and Mark Litzow and Lazarus, {Hillard M.} and Rowe, {Jacob M.} and Tallman, {Martin S.} and Levine, {Ross L.} and Elisabeth Paietta",

note = "Publisher Copyright: {\textcopyright} 2022 Elsevier Ltd",

year = "2022",

month = dec,

doi = "10.1016/j.leukres.2022.106971",

language = "English (US)",

volume = "123",

journal = "Leukemia Research",

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Ganzel, C, Sun, Z, Baslan, T, Zhang, Y, Gönen, M, Abdel-Wahab, OI, Racevskis, J, Garrett-Bakelman, F, Lowe, SW, Fernandez, HF, Ketterling, R, Luger, SM, Litzow, M, Lazarus, HM, Rowe, JM, Tallman, MS, Levine, RL & Paietta, E 2022, 'Measurable residual disease by flow cytometry in acute myeloid leukemia is prognostic, independent of genomic profiling', Leukemia Research, vol. 123, 106971. https://doi.org/10.1016/j.leukres.2022.106971

TY - JOUR

T1 - Measurable residual disease by flow cytometry in acute myeloid leukemia is prognostic, independent of genomic profiling

AU - Ganzel, Chezi

AU - Sun, Zhuoxin

AU - Baslan, Timour

AU - Zhang, Yanming

AU - Gönen, Mithat

AU - Abdel-Wahab, Omar I.

AU - Racevskis, Janis

AU - Garrett-Bakelman, Francine

AU - Lowe, Scott W.

AU - Fernandez, Hugo F.

AU - Ketterling, Rhett

AU - Luger, Selina M.

AU - Litzow, Mark

AU - Lazarus, Hillard M.

AU - Rowe, Jacob M.

AU - Tallman, Martin S.

AU - Levine, Ross L.

AU - Paietta, Elisabeth

PY - 2022/12

Y1 - 2022/12

N2 - Measurable residual disease (MRD) assessment provides a potent indicator of the efficacy of anti-leukemic therapy. It is unknown, however, whether integrating MRD with molecular profiling better identifies patients at risk of relapse. To investigate the clinical relevance of MRD in relation to a molecular-based prognostic schema, we measured MRD by flow cytometry in 189 AML patients enrolled in ECOG-ACRIN E1900 trial (NCT00049517) in morphologic complete remission (CR) (28.8 % of the original cohort) representing 44.4 % of CR patients. MRD positivity was defined as ≥ 0.1 % of leukemic bone marrow cells. Risk classification was based on standard cytogenetics, fluorescence-in-situ-hybridization, somatic gene analysis, and sparse whole genome sequencing for copy number ascertainment. At 84.6 months median follow-up of patients still alive at the time of analysis (range 47.0–120 months), multivariate analysis demonstrated that MRD status at CR (p = 0.001) and integrated molecular risk (p = 0.0004) independently predicted overall survival (OS). Among risk classes, MRD status significantly affected OS only in the favorable risk group (p = 0.002). Expression of CD25 (α-chain of the interleukin-2 receptor) by leukemic myeloblasts at diagnosis negatively affected OS independent of post-treatment MRD levels. These data suggest that integrating MRD with genetic profiling and pre-treatment CD25 expression may improve prognostication in AML.

AB - Measurable residual disease (MRD) assessment provides a potent indicator of the efficacy of anti-leukemic therapy. It is unknown, however, whether integrating MRD with molecular profiling better identifies patients at risk of relapse. To investigate the clinical relevance of MRD in relation to a molecular-based prognostic schema, we measured MRD by flow cytometry in 189 AML patients enrolled in ECOG-ACRIN E1900 trial (NCT00049517) in morphologic complete remission (CR) (28.8 % of the original cohort) representing 44.4 % of CR patients. MRD positivity was defined as ≥ 0.1 % of leukemic bone marrow cells. Risk classification was based on standard cytogenetics, fluorescence-in-situ-hybridization, somatic gene analysis, and sparse whole genome sequencing for copy number ascertainment. At 84.6 months median follow-up of patients still alive at the time of analysis (range 47.0–120 months), multivariate analysis demonstrated that MRD status at CR (p = 0.001) and integrated molecular risk (p = 0.0004) independently predicted overall survival (OS). Among risk classes, MRD status significantly affected OS only in the favorable risk group (p = 0.002). Expression of CD25 (α-chain of the interleukin-2 receptor) by leukemic myeloblasts at diagnosis negatively affected OS independent of post-treatment MRD levels. These data suggest that integrating MRD with genetic profiling and pre-treatment CD25 expression may improve prognostication in AML.

KW - Acute myeloid leukemia

KW - CD25

KW - Flow cytometry

KW - Genomic profiling

KW - MRD

KW - Measurable residual disease

KW - Minimal residual disease

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JO - Leukemia Research

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Measurable residual disease by flow cytometry in acute myeloid leukemia is prognostic, independent of genomic profiling

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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