A novel deep targeted sequencing method for minimal residual disease monitoring in acute myeloid leukemia
Por:
Onecha, E, Linares, M, Rapado, I, Ruiz-Heredia, Y, Martinez-Sanchez, P, Cedena, T, Pratcorona, M, Oteyza, JP, Herrera, P, Barragan, E, Montesinos, P, Vela, JAG, Magro, E, Anguita, E, Figuera, A, Riaza, R, Martinez-Barranco, P, Sanchez-Vega, B, Nomdedeu, J, Gallardo, M, Martinez-Lopez, J, Ayala, R
Publicada:
1 feb 2019
Resumen:
Abhigh proportion of patients with acute myeloid leukemia who achieve minimal residual disease negative status ultimately relapse ecause a fraction of pathological clones remains undetected by standard methods. We designed and validated a high-throughput sequencing method for minimal residual disease assessment of cell clonotypes with mutations of NPAP, IDH1/2, and/or Fa3-single nucleotide variants. For clinical validation, 106 follow-up samples from 63 patients in complete remission were studied by sequencing, evaluating the level of mutations detected at diagnosis. The predictive value of minimal residual disease status by sequencing, multiparameter flow cytometry, or quantitative polymerase chain reaction analysis was determined by survival analysis. The sequencing method achieved a sensitivity of 10 for single nucleotide variants and 10' for insertions/deletions and could be used in acute myeloid leukemia patients who carry any mutation (86% in our diagnostic data set). Sequencing determined minimal residual disease positive status was associated with lower disease-free survival (hazard ratio 3.4, P=0.005) and lower overall survival (hazard ratio 4.2, P<0.001). Multivariate analysis showed that minimal residual disease positive status determined by sequencing was an independent factor associated with risk of death (hazard ratio 4.54, P=0.005) and the only independent factor conferring risk of relapse (hazard ratio 3.76, P=0.012). This sequencing-based method simplifies and standardizes minimal residual disease evaluation, with high applicability in acute myeloid leukemia. It is also an improvement upon flow cytometry- and quantitative polymerase chain reaction-based prediction of outcomes of patients with acute myeloid leukemia and could be incorporated in clinical settings and clinical trials.
Filiaciones:
Onecha, E:
Hosp Univ 12 Octubre, Hematol Dept, Madrid, Spain
CNIO, Hematol Malignancies Clin Res Unit, Madrid, Spain
Linares, M:
Hosp Univ 12 Octubre, Hematol Dept, Madrid, Spain
CNIO, Hematol Malignancies Clin Res Unit, Madrid, Spain
Rapado, I:
Hosp Univ 12 Octubre, Hematol Dept, Madrid, Spain
CNIO, Hematol Malignancies Clin Res Unit, Madrid, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Ruiz-Heredia, Y:
Hosp Univ 12 Octubre, Hematol Dept, Madrid, Spain
CNIO, Hematol Malignancies Clin Res Unit, Madrid, Spain
Martinez-Sanchez, P:
Hosp Univ 12 Octubre, Hematol Dept, Madrid, Spain
Cedena, T:
Hosp Univ 12 Octubre, Hematol Dept, Madrid, Spain
CNIO, Hematol Malignancies Clin Res Unit, Madrid, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Univ Complutense Madrid, Madrid, Spain
Pratcorona, M:
Hosp Santa Creu & Sant Pau, Hematol Dept, Barcelona, Spain
Oteyza, JP:
Hosp Univ Sanchinarro, Hematol Dept, Madrid, Spain
Herrera, P:
Hosp Univ Ramon y Cajal, Hematol Dept, Madrid, Spain
Barragan, E:
Univ Complutense Madrid, Madrid, Spain
Hosp Univ La Fe, Hematol Dept, Valencia, Spain
Montesinos, P:
Univ Complutense Madrid, Madrid, Spain
Hosp Univ La Fe, Hematol Dept, Valencia, Spain
Vela, JAG:
Hosp Univ Getafe, Dept Hematol, Madrid, Spain
Magro, E:
Hosp Univ Principe Asturias, Hematol Dept, Madrid, Spain
Anguita, E:
UCM, IdISSC, Hosp Clinico San Carlos, Hematol Dept, Madrid, Spain
Figuera, A:
Hosp Univ Princesa, Hematol Dept, Madrid, Spain
Riaza, R:
Hosp Univ Severo Ochoa, Hematol Dept, Madrid, Spain
Martinez-Barranco, P:
Hosp Univ Fdn Alcorcon, Hematol Dept, Madrid, Spain
Sanchez-Vega, B:
CNIO, Hematol Malignancies Clin Res Unit, Madrid, Spain
Nomdedeu, J:
Hosp Santa Creu & Sant Pau, Hematol Dept, Barcelona, Spain
Gallardo, M:
CNIO, Hematol Malignancies Clin Res Unit, Madrid, Spain
Martinez-Lopez, J:
Hosp Univ 12 Octubre, Hematol Dept, Madrid, Spain
CNIO, Hematol Malignancies Clin Res Unit, Madrid, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Univ Complutense Madrid, Madrid, Spain
Ayala, R:
Hosp Univ 12 Octubre, Hematol Dept, Madrid, Spain
CNIO, Hematol Malignancies Clin Res Unit, Madrid, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Univ Complutense Madrid, Madrid, Spain
Gold, Green Published
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