Improving the prediction of acute myeloid leukaemia outcomes by complementing mutational profiling with ex vivo chemosensitivity.
acute myeloid leukaemia
ex vivo sensitivity test
sequencing
Journal
British journal of haematology
ISSN: 1365-2141
Titre abrégé: Br J Haematol
Pays: England
ID NLM: 0372544
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
02
09
2019
revised:
31
10
2019
accepted:
01
11
2019
pubmed:
19
2
2020
medline:
13
1
2021
entrez:
19
2
2020
Statut:
ppublish
Résumé
Refractoriness to induction therapy and relapse after complete remission are the leading causes of death in patients with acute myeloid leukaemia (AML). This study focussed on the prediction of response to standard induction therapy and outcome of patients with AML using a combined strategy of mutational profiling by next-generation sequencing (NGS, n = 190) and ex vivo PharmaFlow testing (n = 74) for the 10 most widely used drugs for AML induction therapy, in a cohort of adult patients uniformly treated according to Spanish PETHEMA guidelines. We identified an adverse mutational profile (EZH2, KMT2A, U2AF1 and/or TP53 mutations) that carries a greater risk of death [hazard ratio (HR): 3·29, P < 0·0001]. A high correlation was found between the ex vivo PharmaFlow results and clinical induction response (69%). Clinical correlation analysis showed that the pattern of multiresistance revealed by ex vivo PharmaFlow identified patients with a high risk of death (HR: 2·58). Patients with mutation status also ran a high risk (HR 4·19), and the risk was increased further in patients with both adverse profiles (HR 4·82). We have developed a new score based on NGS and ex vivo drug testing for AML patients that improves upon current prognostic risk stratification and allows clinicians to tailor treatments to minimise drug resistance.
Types de publication
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
672-683Subventions
Organisme : Instituto de Salud Carlos III
ID : PI13/02387
Pays : International
Organisme : Instituto de Salud Carlos III
ID : PI16/01530
Pays : International
Organisme : CRIS
ID : 2014/0120
Pays : International
Organisme : Spanish Ministry of Economy and Competitiveness
ID : 2013-16409
Pays : International
Organisme : Spanish of Instituto de salud Carlos III: Contratos Predoctorales de Formación en Investigación en Salud i-PFIS
ID : IFI 14/00008
Pays : International
Informations de copyright
© 2020 British Society for Haematology and John Wiley & Sons Ltd.
Références
Adzhubei, I., Jordan, D.M. & Sunyaev, S.R. (2013) 'Predicting functional effect of human missense mutations using PolyPhen-2', Curr Protoc Hum Genet, Chapter 7, pp. Unit 7 20.
Bennett, T.A., Montesinos, P., Moscardo, F., Martinez-Cuadron, D., Martinez, J., Sierra, J., Garcia, R., de Oteyza, J.P., Fernandez, P., Serrano, J., Fernandez, A., Herrera, P., Gonzalez, A., Bethancourt, C., Rodriguez-Macias, G., Alonso, A., Vera, J.A., Navas, B., Lavilla, E., Lopez, J.A., Jimenez, S., Simiele, A., Vidriales, B., Gonzalez, B.J., Burgaleta, C., Hernandez Rivas, J.A., Mascunano, R.C., Bautista, G., Perez Simon, J.A., Fuente Ade, L., Rayon, C., Troconiz, I.F., Janda, A., Bosanquet, A.G., Hernandez-Campo, P., Primo, D., Lopez, R., Liebana, B., Rojas, J.L., Gorrochategui, J., Sanz, M.A. & Ballesteros, J. (2014) Pharmacological profiles of acute myeloid leukemia treatments in patient samples by automated flow cytometry: a bridge to individualized medicine. Clinical Lymphoma Myeloma and Leukemia, 14, 305-318.
Burge, C. & Karlin, S. (1997) Prediction of complete gene structures in human genomic DNA. Journal of Molecular Biology, 268, 78-94.
Cedena, M.T., Rapado, I., Santos-Lozano, A., Ayala, R., Onecha, E., Abaigar, M., Such, E., Ramos, F., Cervera, J., Diez-Campelo, M., Sanz, G., Rivas, J.H., Lucia, A. & Martinez-Lopez, J. (2017) Mutations in the DNA methylation pathway and number of driver mutations predict response to azacitidine in myelodysplastic syndromes. Oncotarget, 8, 106948-106961.
Dohner, H., Estey, E., Grimwade, D., Amadori, S., Appelbaum, F.R., Buchner, T., Dombret, H., Ebert, B.L., Fenaux, P., Larson, R.A., Levine, R.L., Lo-Coco, F., Naoe, T., Niederwieser, D., Ossenkoppele, G.J., Sanz, M., Sierra, J., Tallman, M.S., Tien, H.F., Wei, A.H., Lowenberg, B. & Bloomfield, C.D. (2017) Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood, 129, 424-447.
van Dongen, J.J., Lhermitte, L., Bottcher, S., Almeida, J., van der Velden, V.H., Flores-Montero, J., Rawstron, A., Asnafi, V., Lecrevisse, Q., Lucio, P., Mejstrikova, E., Szczepanski, T., Kalina, T., de Tute, R., Bruggemann, M., Sedek, L., Cullen, M., Langerak, A.W., Mendonca, A., Macintyre, E., Martin-Ayuso, M., Hrusak, O., Vidriales, M.B., Orfao, A. & EuroFlow, C. (2012) EuroFlow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes. Leukemia, 26, 1908-1975.
Gale, R.E., Green, C., Allen, C., Mead, A.J., Burnett, A.K., Hills, R.K. & Linch, D.C., and Medical Research Council Adult Leukaemia Working, P (2008) The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood, 111, 2776-2784.
Gorello, P., Cazzaniga, G., Alberti, F., Dell'Oro, M.G., Gottardi, E., Specchia, G., Roti, G., Rosati, R., Martelli, M.F., Diverio, D., Lo Coco, F., Biondi, A., Saglio, G., Mecucci, C. & Falini, B. (2006) Quantitative assessment of minimal residual disease in acute myeloid leukemia carrying nucleophosmin (NPM1) gene mutations. Leukemia, 20, 1103-1108.
Hernandez, P., Gorrochategui, J., Primo, D., Robles, A., Rojas, J.L., Espinosa, A.B., Gomez, C., Martinez-Lopez, J., Bennett, T.A. & Ballesteros, J. (2017) Drug discovery testing compounds in patient samples by automated flow cytometry. SLAS Technol, 22, 325-337.
Itzykson, R., Kosmider, O., Cluzeau, T., Mansat-De Mas, V., Dreyfus, F., Beyne-Rauzy, O., Quesnel, B., Vey, N., Gelsi-Boyer, V., Raynaud, S., Preudhomme, C., Ades, L., Fenaux, P. & Fontenay, M., and Groupe Francophone des, M (2011) Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia, 25, 1147-1152.
Jun, K.R., Jang, S., Chi, H.S., Lee, K.H., Lee, J.H., Choi, S.J., Seo, J.J., Moon, H.N., Im, H.J. & Park, C.J. (2007) Relationship between in vitro chemosensitivity assessed with MTT assay and clinical outcomes in 103 patients with acute leukemia. Korean Journal of Laboratory Medicine, 27, 89-95.
Kalina, T., Flores-Montero, J., van der Velden, V.H., Martin-Ayuso, M., Bottcher, S., Ritgen, M., Almeida, J., Lhermitte, L., Asnafi, V., Mendonca, A., de Tute, R., Cullen, M., Sedek, L., Vidriales, M.B., Perez, J.J., te Marvelde, J.G., Mejstrikova, E., Hrusak, O., Szczepanski, T., van Dongen, J.J., Orfao, A. & EuroFlow, C. (2012) EuroFlow standardization of flow cytometer instrument settings and immunophenotyping protocols. Leukemia, 26, 1986-2010.
Klaeger, S., Heinzlmeir, S., Wilhelm, M., Polzer, H., Vick, B., Koenig, P.A., Reinecke, M., Ruprecht, B., Petzoldt, S., Meng, C., Zecha, J., Reiter, K., Qiao, H., Helm, D., Koch, H., Schoof, M., Canevari, G., Casale, E., Depaolini, S.R., Feuchtinger, A., Wu, Z., Schmidt, T., Rueckert, L., Becker, W., Huenges, J., Garz, A.K., Gohlke, B.O., Zolg, D.P., Kayser, G., Vooder, T., Preissner, R., Hahne, H., Tonisson, N., Kramer, K., Gotze, K., Bassermann, F., Schlegl, J., Ehrlich, H.C., Aiche, S., Walch, A., Greif, P.A., Schneider, S., Felder, E.R., Ruland, J., Medard, G., Jeremias, I., Spiekermann, K. & Kuster, B. (2017) The target landscape of clinical kinase drugs. Science, 358, https://doi.org/10.1126/science.aan4368
Martinez-Cuadron, D., Boluda, B., Martinez, P., Bergua, J., Rodriguez-Veiga, R., Esteve, J., Vives, S., Serrano, J., Vidriales, B., Salamero, O., Cordon, L., Sempere, A., Jimenez-Ubieto, A., Prieto-Delgado, J., Diaz-Beya, M., Garrido, A., Benavente, C., Perez-Simon, J.A., Moscardo, F., Sanz, M.A., Montesinos, P. & Cetlam and groups, P (2018) Correction to: A phase I-II study of plerixafor in combination with fludarabine, idarubicin, cytarabine, and G-CSF (PLERIFLAG regimen) for the treatment of patients with the first early-relapsed or refractory acute myeloid leukemia. Annals of Hematology, 97, 923.
Martinez-Cuadron, D., Gil, C., Serrano, J., Rodriguez, G., Perez-Oteyza, J., Garcia-Boyero, R., Jimenez-Bravo, S., Vives, S., Vidriales, M.B., Lavilla, E., Perez-Simon, J.A., Tormo, M., Colorado, M., Bergua, J., Lopez, J.A., Herrera, P., Hernandez-Campo, P., Gorrochategui, J., Primo, D., Rojas, J.L., Villoria, J., Moscardo, F., Troconiz, I., Linares Gomez, M., Martinez-Lopez, J., Ballesteros, J., Sanz, M., Montesinos, P., Spanish, P. g (2019) A precision medicine test predicts clinical response after idarubicin and cytarabine induction therapy in AML patients. Leukemia Research, 76, 1-10.
Mollgard, L., Deneberg, S., Nahi, H., Bengtzen, S., Jonsson-Videsater, K., Fioretos, T., Andersson, A., Paul, C. & Lehmann, S. (2008) The FLT3 inhibitor PKC412 in combination with cytostatic drugs in vitro in acute myeloid leukemia. Cancer Chemotherapy and Pharmacology, 62, 439-448.
Naulaerts, S., Dang, C.C. & Ballester, P.J. (2017) Precision and recall oncology: combining multiple gene mutations for improved identification of drug-sensitive tumours. Oncotarget, 8, 97025-97040.
Ng, P.C. & Henikoff, S. (2003) SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Research, 31, 3812-3814.
Onecha, E., Linares, M., Rapado, I., Ruiz-Heredia, Y., Martinez-Sanchez, P., Cedena, T., Pratcorona, M., Perez Oteyza, J., Herrera, P., Barragan, E., Montesinos, P., Garcia Vela, J.A., Magro, E., Anguita, E., Figuera, A., Riaza, R., Martinez-Barranco, P., Sanchez-Vega, B., Nomdedeu, J., Gallardo, M., Martinez-Lopez, J. & Ayala, R. (2018) Novel deep targeted sequencing method for minimal residual disease monitoring in acute myeloid leukemia. Haematologica, 104, 288-296.
Papaemmanuil, E., Gerstung, M., Bullinger, L., Gaidzik, V.I., Paschka, P., Roberts, N.D., Potter, N.E., Heuser, M., Thol, F., Bolli, N., Gundem, G., Van Loo, P., Martincorena, I., Ganly, P., Mudie, L., McLaren, S., O'Meara, S., Raine, K., Jones, D.R., Teague, J.W., Butler, A.P., Greaves, M.F., Ganser, A., Dohner, K., Schlenk, R.F., Dohner, H. & Campbell, P.J. (2016) Genomic classification and prognosis in acute myeloid leukemia. New England Journal of Medicine, 374, 2209-2221.
Patel, J.P., Gonen, M., Figueroa, M.E., Fernandez, H., Sun, Z., Racevskis, J., Van Vlierberghe, P., Dolgalev, I., Thomas, S., Aminova, O., Huberman, K., Cheng, J., Viale, A., Socci, N.D., Heguy, A., Cherry, A., Vance, G., Higgins, R.R., Ketterling, R.P., Gallagher, R.E., Litzow, M., van den Brink, M.R., Lazarus, H.M., Rowe, J.M., Luger, S., Ferrando, A., Paietta, E., Tallman, M.S., Melnick, A., Abdel-Wahab, O. & Levine, R.L. (2012) Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. New England Journal of Medicine, 366, 1079-1089.
Pemovska, T., Kontro, M., Yadav, B., Edgren, H., Eldfors, S., Szwajda, A., Almusa, H., Bespalov, M.M., Ellonen, P., Elonen, E., Gjertsen, B.T., Karjalainen, R., Kulesskiy, E., Lagstrom, S., Lehto, A., Lepisto, M., Lundan, T., Majumder, M.M., Marti, J.M., Mattila, P., Murumagi, A., Mustjoki, S., Palva, A., Parsons, A., Pirttinen, T., Ramet, M.E., Suvela, M., Turunen, L., Vastrik, I., Wolf, M., Knowles, J., Aittokallio, T., Heckman, C.A., Porkka, K., Kallioniemi, O. & Wennerberg, K. (2013a) 'c', Cancer Discov, 3, 1416-1429.
Pemovska, T., Kontro, M., Yadav, B., Edgren, H., Eldfors, S., Szwajda, A., Almusa, H., Bespalov, M.M., Ellonen, P., Elonen, E., Gjertsen, B.T., Karjalainen, R., Kulesskiy, E., Lagstrom, S., Lehto, A., Lepisto, M., Lundan, T., Majumder, M.M., Marti, J.M., Mattila, P., Murumagi, A., Mustjoki, S., Palva, A., Parsons, A., Pirttinen, T., Ramet, M.E., Suvela, M., Turunen, L., Vastrik, I., Wolf, M., Knowles, J., Aittokallio, T., Heckman, C.A., Porkka, K., Kallioniemi, O. & Wennerberg, K. (2013b) Individualized systems medicine strategy to tailor treatments for patients with chemorefractory acute myeloid leukemia. Cancer Discovery, 3, 1416-1429.
Rowe, J.M. & Tallman, M.S. (2010) How I treat acute myeloid leukemia. Blood, 116, 3147-3156.
Sato, T., Yang, X., Knapper, S., White, P., Smith, B.D., Galkin, S., Small, D., Burnett, A. & Levis, M. (2011) FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo. Blood, 117, 3286-3293.
Staib, P., Staltmeier, E., Neurohr, K., Cornely, O., Reiser, M. & Schinkothe, T. (2005) Prediction of individual response to chemotherapy in patients with acute myeloid leukaemia using the chemosensitivity index Ci. British Journal of Haematology, 128, 783-791.
Swords, R.T., Azzam, D., Al-Ali, H., Lohse, I., Volmar, C.H., Watts, J.M., Perez, A., Rodriguez, A., Vargas, F., Elias, R., Vega, F., Zelent, A., Brothers, S.P., Abbasi, T., Trent, J., Rangwala, S., Deutsch, Y., Conneally, E., Drusbosky, L., Cogle, C.R. & Wahlestedt, C. (2018) Ex-vivo sensitivity profiling to guide clinical decision making in acute myeloid leukemia: A pilot study. Leukemia Research, 64, 34-41.
Tate, J.G., Bamford, S., Jubb, H.C., Sondka, Z., Beare, D.M., Bindal, N., Boutselakis, H., Cole, C.G., Creatore, C., Dawson, E., Fish, P., Harsha, B., Hathaway, C., Jupe, S.C., Kok, C.Y., Noble, K., Ponting, L., Ramshaw, C.C., Rye, C.E., Speedy, H.E., Stefancsik, R., Thompson, S.L., Wang, S., Ward, S., Campbell, P.J. & Forbes, S.A. (2019) COSMIC: the Catalogue Of Somatic Mutations In Cancer. Nucleic Acids Research, 47, D941-D947.
Tyner, J.W., Tognon, C.E., Bottomly, D., Wilmot, B., Kurtz, S.E., Savage, S.L., Long, N., Schultz, A.R., Traer, E., Abel, M., Agarwal, A., Blucher, A., Borate, U., Bryant, J., Burke, R., Carlos, A., Carpenter, R., Carroll, J., Chang, B.H., Coblentz, C., d'Almeida, A., Cook, R., Danilov, A., Dao, K.T., Degnin, M., Devine, D., Dibb, J., Edwards, D.K.t., Eide, C.A., English, I., Glover, J., Henson, R., Ho, H., Jemal, A., Johnson, K., Johnson, R., Junio, B., Kaempf, A., Leonard, J., Lin, C., Liu, S.Q., Lo, P., Loriaux, M.M., Luty, S., Macey, T., MacManiman, J., Martinez, J., Mori, M., Nelson, D., Nichols, C., Peters, J., Ramsdill, J., Rofelty, A., Schuff, R., Searles, R., Segerdell, E., Smith, R.L., Spurgeon, S.E., Sweeney, T., Thapa, A., Visser, C., Wagner, J., Watanabe-Smith, K., Werth, K., Wolf, J., White, L., Yates, A., Zhang, H., Cogle, C.R., Collins, R.H., Connolly, D.C., Deininger, M.W., Drusbosky, L., Hourigan, C.S., Jordan, C.T., Kropf, P., Lin, T.L., Martinez, M.E., Medeiros, B.C., Pallapati, R.R., Pollyea, D.A., Swords, R.T., Watts, J.M., Weir, S.J., Wiest, D.L., Winters, R.M., McWeeney, S.K. & Druker, B.J. (2018) Functional genomic landscape of acute myeloid leukaemia. Nature, 562, 526-531.
Walter, R.B., Othus, M., Burnett, A.K., Lowenberg, B., Kantarjian, H.M., Ossenkoppele, G.J., Hills, R.K., Ravandi, F., Pabst, T., Evans, A., Pierce, S.R., Vekemans, M.C., Appelbaum, F.R. & Estey, E.H. (2015) Resistance prediction in AML: analysis of 4601 patients from MRC/NCRI, HOVON/SAKK, SWOG and MD Anderson Cancer Center. Leukemia, 29, 312-320.
Welch, J.S., Petti, A.A. & Ley, T.J. (2017) Decitabine in TP53-Mutated AML. New England Journal of Medicine, 376, 797-798.