Clearance of somatic mutations at remission and the risk of relapse in acute myeloid leukemia

Kiyomi Morita, Hagop M. Kantarjian, Feng Wang, Yuanqing Yan, Carlos Bueso-Ramos, Koji Sasaki, Ghayas C. Issa, Sa Wang, Jeffrey Jorgensen, Xingzhi Song, Jianhua Zhang, Samantha Tippen, Rebecca Thornton, Marcus Coyle, Latasha Little, Curtis Gumbs, Naveen Pemmaraju, Naval Daver, Courtney D. DiNardo, Marina KonoplevaMichael Andreeff, Farhad Ravandi, Jorge E. Cortes, Tapan Kadia, Elias Jabbour, Guillermo Garcia-Manero, Keyur P. Patel, P. Andrew Futreal, Koichi Takahashi

Research output: Contribution to journalArticle

Abstract

Purpose The aim of the current study was to determine whether the degree of mutation clearance at remission predicts the risk of relapse in patients with acute myeloid leukemia (AML). Patients and Methods One hundred thirty-one previously untreated patients with AML who received intensive induction chemotherapy and attained morphologic complete remission (CR) at day 30 were studied. Pretreatment and CR bone marrow were analyzed using targeted capture DNA sequencing. We analyzed the association between mutation clearance (MC) on the basis of variant allele frequency (VAF) at CR (MC2.5: if the VAF of residual mutations was < 2.5%; MC1.0: if the VAF was < 1%; and complete MC [CMC]: if no detectable residual mutations) and event-free survival, overall survival (OS), and cumulative incidence of relapse (CIR). Results MC1.0 and CMC were associated with significantly better OS (2-year OS: 75% v 61% in MC1.0 v non-MC1.0; P = .0465; 2-year OS: 77% v 60% in CMC v non-CMC; P = .0303) and lower CIR (2-year CIR: 26% v 46% in MC1.0 v non-MC 1.0; P = .0349; 2 year-CIR: 24% v 46% in CMC v non-CMC; P = .03), whereas there was no significant difference in any of the above outcomes by MC2.5. Multivariable analysis adjusting for age, cytogenetic risk, allogeneic stem-cell transplantation, and flow cytometry–based minimal residual disease revealed that patients with CMC had significantly better event-free survival (hazard ratio [HR], 0.43; P = .0083), OS (HR, 0.47; P = .04), and CIR (HR, 0.27; P < .001) than did patients without CMC. These prognostic associations were stronger when preleukemic mutations, such as DNMT3A, TET2, and ASXL1, were removed from the analysis. Conclusion Clearance of somatic mutation at CR, particularly in nonpreleukemic genes, was associated with significantly better survival and less risk of relapse. Somatic mutations in nonpreleukemic genes may function as a molecular minimal residual disease marker in AML.

Original languageEnglish (US)
Pages (from-to)1788-1797
Number of pages10
JournalJournal of Clinical Oncology
Volume36
Issue number18
DOIs
StatePublished - Jun 20 2018
Externally publishedYes

Fingerprint

Acute Myeloid Leukemia
Recurrence
Mutation
Survival
Gene Frequency
Incidence
Residual Neoplasm
Disease-Free Survival
Induction Chemotherapy
Stem Cell Transplantation
DNA Sequence Analysis
Cytogenetics
Genes
Bone Marrow

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Morita, K., Kantarjian, H. M., Wang, F., Yan, Y., Bueso-Ramos, C., Sasaki, K., ... Takahashi, K. (2018). Clearance of somatic mutations at remission and the risk of relapse in acute myeloid leukemia. Journal of Clinical Oncology, 36(18), 1788-1797. https://doi.org/10.1200/JCO.2017.77.6757

Clearance of somatic mutations at remission and the risk of relapse in acute myeloid leukemia. / Morita, Kiyomi; Kantarjian, Hagop M.; Wang, Feng; Yan, Yuanqing; Bueso-Ramos, Carlos; Sasaki, Koji; Issa, Ghayas C.; Wang, Sa; Jorgensen, Jeffrey; Song, Xingzhi; Zhang, Jianhua; Tippen, Samantha; Thornton, Rebecca; Coyle, Marcus; Little, Latasha; Gumbs, Curtis; Pemmaraju, Naveen; Daver, Naval; DiNardo, Courtney D.; Konopleva, Marina; Andreeff, Michael; Ravandi, Farhad; Cortes, Jorge E.; Kadia, Tapan; Jabbour, Elias; Garcia-Manero, Guillermo; Patel, Keyur P.; Futreal, P. Andrew; Takahashi, Koichi.

In: Journal of Clinical Oncology, Vol. 36, No. 18, 20.06.2018, p. 1788-1797.

Research output: Contribution to journalArticle

Morita, K, Kantarjian, HM, Wang, F, Yan, Y, Bueso-Ramos, C, Sasaki, K, Issa, GC, Wang, S, Jorgensen, J, Song, X, Zhang, J, Tippen, S, Thornton, R, Coyle, M, Little, L, Gumbs, C, Pemmaraju, N, Daver, N, DiNardo, CD, Konopleva, M, Andreeff, M, Ravandi, F, Cortes, JE, Kadia, T, Jabbour, E, Garcia-Manero, G, Patel, KP, Futreal, PA & Takahashi, K 2018, 'Clearance of somatic mutations at remission and the risk of relapse in acute myeloid leukemia', Journal of Clinical Oncology, vol. 36, no. 18, pp. 1788-1797. https://doi.org/10.1200/JCO.2017.77.6757
Morita, Kiyomi ; Kantarjian, Hagop M. ; Wang, Feng ; Yan, Yuanqing ; Bueso-Ramos, Carlos ; Sasaki, Koji ; Issa, Ghayas C. ; Wang, Sa ; Jorgensen, Jeffrey ; Song, Xingzhi ; Zhang, Jianhua ; Tippen, Samantha ; Thornton, Rebecca ; Coyle, Marcus ; Little, Latasha ; Gumbs, Curtis ; Pemmaraju, Naveen ; Daver, Naval ; DiNardo, Courtney D. ; Konopleva, Marina ; Andreeff, Michael ; Ravandi, Farhad ; Cortes, Jorge E. ; Kadia, Tapan ; Jabbour, Elias ; Garcia-Manero, Guillermo ; Patel, Keyur P. ; Futreal, P. Andrew ; Takahashi, Koichi. / Clearance of somatic mutations at remission and the risk of relapse in acute myeloid leukemia. In: Journal of Clinical Oncology. 2018 ; Vol. 36, No. 18. pp. 1788-1797.
@article{5a834b8f39004d75a67bd143dd6d7a69,
title = "Clearance of somatic mutations at remission and the risk of relapse in acute myeloid leukemia",
abstract = "Purpose The aim of the current study was to determine whether the degree of mutation clearance at remission predicts the risk of relapse in patients with acute myeloid leukemia (AML). Patients and Methods One hundred thirty-one previously untreated patients with AML who received intensive induction chemotherapy and attained morphologic complete remission (CR) at day 30 were studied. Pretreatment and CR bone marrow were analyzed using targeted capture DNA sequencing. We analyzed the association between mutation clearance (MC) on the basis of variant allele frequency (VAF) at CR (MC2.5: if the VAF of residual mutations was < 2.5{\%}; MC1.0: if the VAF was < 1{\%}; and complete MC [CMC]: if no detectable residual mutations) and event-free survival, overall survival (OS), and cumulative incidence of relapse (CIR). Results MC1.0 and CMC were associated with significantly better OS (2-year OS: 75{\%} v 61{\%} in MC1.0 v non-MC1.0; P = .0465; 2-year OS: 77{\%} v 60{\%} in CMC v non-CMC; P = .0303) and lower CIR (2-year CIR: 26{\%} v 46{\%} in MC1.0 v non-MC 1.0; P = .0349; 2 year-CIR: 24{\%} v 46{\%} in CMC v non-CMC; P = .03), whereas there was no significant difference in any of the above outcomes by MC2.5. Multivariable analysis adjusting for age, cytogenetic risk, allogeneic stem-cell transplantation, and flow cytometry–based minimal residual disease revealed that patients with CMC had significantly better event-free survival (hazard ratio [HR], 0.43; P = .0083), OS (HR, 0.47; P = .04), and CIR (HR, 0.27; P < .001) than did patients without CMC. These prognostic associations were stronger when preleukemic mutations, such as DNMT3A, TET2, and ASXL1, were removed from the analysis. Conclusion Clearance of somatic mutation at CR, particularly in nonpreleukemic genes, was associated with significantly better survival and less risk of relapse. Somatic mutations in nonpreleukemic genes may function as a molecular minimal residual disease marker in AML.",
author = "Kiyomi Morita and Kantarjian, {Hagop M.} and Feng Wang and Yuanqing Yan and Carlos Bueso-Ramos and Koji Sasaki and Issa, {Ghayas C.} and Sa Wang and Jeffrey Jorgensen and Xingzhi Song and Jianhua Zhang and Samantha Tippen and Rebecca Thornton and Marcus Coyle and Latasha Little and Curtis Gumbs and Naveen Pemmaraju and Naval Daver and DiNardo, {Courtney D.} and Marina Konopleva and Michael Andreeff and Farhad Ravandi and Cortes, {Jorge E.} and Tapan Kadia and Elias Jabbour and Guillermo Garcia-Manero and Patel, {Keyur P.} and Futreal, {P. Andrew} and Koichi Takahashi",
year = "2018",
month = "6",
day = "20",
doi = "10.1200/JCO.2017.77.6757",
language = "English (US)",
volume = "36",
pages = "1788--1797",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "18",

}

TY - JOUR

T1 - Clearance of somatic mutations at remission and the risk of relapse in acute myeloid leukemia

AU - Morita, Kiyomi

AU - Kantarjian, Hagop M.

AU - Wang, Feng

AU - Yan, Yuanqing

AU - Bueso-Ramos, Carlos

AU - Sasaki, Koji

AU - Issa, Ghayas C.

AU - Wang, Sa

AU - Jorgensen, Jeffrey

AU - Song, Xingzhi

AU - Zhang, Jianhua

AU - Tippen, Samantha

AU - Thornton, Rebecca

AU - Coyle, Marcus

AU - Little, Latasha

AU - Gumbs, Curtis

AU - Pemmaraju, Naveen

AU - Daver, Naval

AU - DiNardo, Courtney D.

AU - Konopleva, Marina

AU - Andreeff, Michael

AU - Ravandi, Farhad

AU - Cortes, Jorge E.

AU - Kadia, Tapan

AU - Jabbour, Elias

AU - Garcia-Manero, Guillermo

AU - Patel, Keyur P.

AU - Futreal, P. Andrew

AU - Takahashi, Koichi

PY - 2018/6/20

Y1 - 2018/6/20

N2 - Purpose The aim of the current study was to determine whether the degree of mutation clearance at remission predicts the risk of relapse in patients with acute myeloid leukemia (AML). Patients and Methods One hundred thirty-one previously untreated patients with AML who received intensive induction chemotherapy and attained morphologic complete remission (CR) at day 30 were studied. Pretreatment and CR bone marrow were analyzed using targeted capture DNA sequencing. We analyzed the association between mutation clearance (MC) on the basis of variant allele frequency (VAF) at CR (MC2.5: if the VAF of residual mutations was < 2.5%; MC1.0: if the VAF was < 1%; and complete MC [CMC]: if no detectable residual mutations) and event-free survival, overall survival (OS), and cumulative incidence of relapse (CIR). Results MC1.0 and CMC were associated with significantly better OS (2-year OS: 75% v 61% in MC1.0 v non-MC1.0; P = .0465; 2-year OS: 77% v 60% in CMC v non-CMC; P = .0303) and lower CIR (2-year CIR: 26% v 46% in MC1.0 v non-MC 1.0; P = .0349; 2 year-CIR: 24% v 46% in CMC v non-CMC; P = .03), whereas there was no significant difference in any of the above outcomes by MC2.5. Multivariable analysis adjusting for age, cytogenetic risk, allogeneic stem-cell transplantation, and flow cytometry–based minimal residual disease revealed that patients with CMC had significantly better event-free survival (hazard ratio [HR], 0.43; P = .0083), OS (HR, 0.47; P = .04), and CIR (HR, 0.27; P < .001) than did patients without CMC. These prognostic associations were stronger when preleukemic mutations, such as DNMT3A, TET2, and ASXL1, were removed from the analysis. Conclusion Clearance of somatic mutation at CR, particularly in nonpreleukemic genes, was associated with significantly better survival and less risk of relapse. Somatic mutations in nonpreleukemic genes may function as a molecular minimal residual disease marker in AML.

AB - Purpose The aim of the current study was to determine whether the degree of mutation clearance at remission predicts the risk of relapse in patients with acute myeloid leukemia (AML). Patients and Methods One hundred thirty-one previously untreated patients with AML who received intensive induction chemotherapy and attained morphologic complete remission (CR) at day 30 were studied. Pretreatment and CR bone marrow were analyzed using targeted capture DNA sequencing. We analyzed the association between mutation clearance (MC) on the basis of variant allele frequency (VAF) at CR (MC2.5: if the VAF of residual mutations was < 2.5%; MC1.0: if the VAF was < 1%; and complete MC [CMC]: if no detectable residual mutations) and event-free survival, overall survival (OS), and cumulative incidence of relapse (CIR). Results MC1.0 and CMC were associated with significantly better OS (2-year OS: 75% v 61% in MC1.0 v non-MC1.0; P = .0465; 2-year OS: 77% v 60% in CMC v non-CMC; P = .0303) and lower CIR (2-year CIR: 26% v 46% in MC1.0 v non-MC 1.0; P = .0349; 2 year-CIR: 24% v 46% in CMC v non-CMC; P = .03), whereas there was no significant difference in any of the above outcomes by MC2.5. Multivariable analysis adjusting for age, cytogenetic risk, allogeneic stem-cell transplantation, and flow cytometry–based minimal residual disease revealed that patients with CMC had significantly better event-free survival (hazard ratio [HR], 0.43; P = .0083), OS (HR, 0.47; P = .04), and CIR (HR, 0.27; P < .001) than did patients without CMC. These prognostic associations were stronger when preleukemic mutations, such as DNMT3A, TET2, and ASXL1, were removed from the analysis. Conclusion Clearance of somatic mutation at CR, particularly in nonpreleukemic genes, was associated with significantly better survival and less risk of relapse. Somatic mutations in nonpreleukemic genes may function as a molecular minimal residual disease marker in AML.

UR - http://www.scopus.com/inward/record.url?scp=85049428523&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85049428523&partnerID=8YFLogxK

U2 - 10.1200/JCO.2017.77.6757

DO - 10.1200/JCO.2017.77.6757

M3 - Article

C2 - 29702001

AN - SCOPUS:85049428523

VL - 36

SP - 1788

EP - 1797

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 18

ER -