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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2019

Open Access 01-12-2019 | Chronic Myeloid Leukemia | Review

Next-generation sequencing for BCR-ABL1 kinase domain mutation testing in patients with chronic myeloid leukemia: a position paper

Authors: Simona Soverini, Elisabetta Abruzzese, Monica Bocchia, Massimiliano Bonifacio, Sara Galimberti, Antonella Gozzini, Alessandra Iurlo, Luigiana Luciano, Patrizia Pregno, Gianantonio Rosti, Giuseppe Saglio, Fabio Stagno, Mario Tiribelli, Paolo Vigneri, Giovanni Barosi, Massimo Breccia

Published in: Journal of Hematology & Oncology | Issue 1/2019

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Abstract

BCR-ABL1 kinase domain (KD) mutation status is considered to be an important element of clinical decision algorithms for chronic myeloid leukemia (CML) patients who do not achieve an optimal response to tyrosine kinase inhibitors (TKIs). Conventional Sanger sequencing is the method currently recommended to test BCR-ABL1 KD mutations. However, Sanger sequencing has limited sensitivity and cannot always discriminate between polyclonal and compound mutations. The use of next-generation sequencing (NGS) is increasingly widespread in diagnostic laboratories and represents an attractive alternative. Currently available data on the clinical impact of NGS-based mutational testing in CML patients do not allow recommendations with a high grade of evidence to be prepared. This article reports the results of a group discussion among an ad hoc expert panel with the objective of producing recommendations on the appropriateness of clinical decisions about the indication for NGS, the performance characteristics of NGS platforms, and the therapeutic changes that could be applied based on the use of NGS in CML. Overall, these recommendations might be employed to inform clinicians about the practical use of NGS in CML.
Literature
1.
Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP, et al. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med. 2017;376(10):917–27.PubMedPubMedCentralCrossRef
2.
Hochhaus A, Saglio G, Hughes TP, Larson RA, Kim DW, Issaragrisil S, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30(5):1044–54.PubMedPubMedCentralCrossRef
3.
Cortes JE, Saglio G, Kantarjian HM, Baccarani M, Mayer J, Boque C, et al. Final 5-year study results of DASISION: the Dasatinib versus Imatinib study in treatment-naive chronic myeloid leukemia patients trial. J Clin Oncol. 2016;34(20):2333–40.PubMedPubMedCentralCrossRef
4.
Talati C, Pinilla-Ibarz J. Resistance in chronic myeloid leukemia: definitions and novel therapeutic agents. Curr Opin Hematol. 2018;25(2):154–61.PubMedCrossRef
5.
Soverini S, Mancini M, Bavaro L, Cavo M, Martinelli G. Chronic myeloid leukemia: the paradigm of targeting oncogenic tyrosine kinase signaling and counteracting resistance for successful cancer therapy. Mol Cancer. 2018;17(1):49.PubMedPubMedCentralCrossRef
6.
Soverini S, Branford S, Nicolini FE, Talpaz M, Deininger MW, Martinelli G, et al. Implications of BCR-ABL1 kinase domain-mediated resistance in chronic myeloid leukemia. Leuk Res. 2014;38(1):10–20.PubMedCrossRef
7.
Branford S, Rudzki Z, Walsh S, Parkinson I, Grigg A, Szer J, et al. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood. 2003;102(1):276–83.PubMedCrossRef
8.
Khorashad JS, de Lavallade H, Apperley JF, Milojkovic D, Reid AG, Bua M, et al. Finding of kinase domain mutations in patients with chronic phase chronic myeloid leukemia responding to imatinib may identify those at high risk of disease progression. J Clin Oncol. 2008;26(29):4806–13.PubMedCrossRef
9.
Nicolini FE, Corm S, Le QH, Sorel N, Hayette S, Bories D, et al. Mutation status and clinical outcome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients: a retrospective analysis from the French intergroup of CML (Fi(phi)-LMC GROUP). Leukemia. 2006;20(6):1061–6.PubMedCrossRef
10.
Nicolini FE, Ibrahim AR, Soverini S, Martinelli G, Muller MC, Hochhaus A, et al. The BCR-ABLT315I mutation compromises survival in chronic phase chronic myelogenous leukemia patients resistant to tyrosine kinase inhibitors, in a matched pair analysis. Haematologica. 2013;98(10):1510–6.PubMedPubMedCentralCrossRef
11.
Sharma P, Mohanty S, Kochupillai V, Kumar L. Mutations in ABL kinase domain are associated with inferior progression-free survival. Leuk Lymphoma. 2010;51(6):1072–8.PubMedCrossRef
12.
Soverini S, Martinelli G, Rosti G, Bassi S, Amabile M, Poerio A, et al. ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia. J Clin Oncol. 2005;23(18):4100–9.PubMedCrossRef
13.
Xue M, Cheng J, Zhao J, Zhang S, Jian J, Qiao Y, et al. Outcomes of 219 chronic myeloid leukaemia patients with additional chromosomal abnormalities and/or tyrosine kinase domain mutations. Int J Lab Hematol. 2019;41(1):94–101.PubMedCrossRef
14.
Etienne G, Dulucq S, Huguet F, Schmitt A, Lascaux A, Hayette S, et al. Incidence and outcome of BCR-ABL mutated chronic myeloid leukemia patients who failed to tyrosine kinase inhibitors. Cancer Med. 2019;8(11):5173–82.PubMedPubMedCentralCrossRef
15.
Redaelli S, Piazza R, Rostagno R, Magistroni V, Perini P, Marega M, et al. Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. J Clin Oncol. 2009;27(3):469–71.PubMedCrossRef
16.
Soverini S, Hochhaus A, Nicolini FE, Gruber F, Lange T, Saglio G, et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood. 2011;118(5):1208–15.PubMedCrossRef
17.
Alikian M, Gerrard G, Subramanian PG, Mudge K, Foskett P, Khorashad JS, et al. BCR-ABL1 kinase domain mutations: methodology and clinical evaluation. Am J Hematol. 2012;87(3):298–304.PubMedCrossRef
18.
Alikian M, Gale RP, Apperley JF, Foroni L. Molecular techniques for the personalised management of patients with chronic myeloid leukaemia. Biomol Detect Quantif. 2017;11:4–20.PubMedPubMedCentralCrossRef
19.
Bacher U, Shumilov E, Flach J, Porret N, Joncourt R, Wiedemann G, et al. Challenges in the introduction of next-generation sequencing (NGS) for diagnostics of myeloid malignancies into clinical routine use. Blood Cancer J. 2018;8(11):113.PubMedPubMedCentralCrossRef
20.
Kohlmann A, Grossmann V, Nadarajah N, Haferlach T. Next-generation sequencing - feasibility and practicality in haematology. Br J Haematol. 2013;160(6):736–53.PubMedCrossRef
21.
Yohe S, Thyagarajan B. Review of clinical next-generation sequencing. Arch Pathol Lab Med. 2017;141(11):1544–57.PubMedCrossRef
22.
23.
Williams PL, Webb C. The Delphi technique: a methodological discussion. J Adv Nurs. 1994;19(1):180–6.PubMedCrossRef
24.
Hughes T, Saglio G, Branford S, Soverini S, Kim DW, Muller MC, et al. Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. J Clin Oncol. 2009;27(25):4204–10.PubMedPubMedCentralCrossRef
25.
Muller MC, Cortes JE, Kim DW, Druker BJ, Erben P, Pasquini R, et al. Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. Blood. 2009;114(24):4944–53.PubMedPubMedCentralCrossRef
26.
Soverini S, Gnani A, Colarossi S, Castagnetti F, Abruzzese E, Paolini S, et al. Philadelphia-positive patients who already harbor imatinib-resistant Bcr-Abl kinase domain mutations have a higher likelihood of developing additional mutations associated with resistance to second- or third-line tyrosine kinase inhibitors. Blood. 2009;114(10):2168–71.PubMedCrossRef
27.
Schmitt MW, Pritchard JR, Leighow SM, Aminov BI, Beppu L, Kim DS, et al. Single-molecule sequencing reveals patterns of preexisting drug resistance that suggest treatment strategies in Philadelphia-positive leukemias. Clin Cancer Res. 2018;24(21):5321–34.PubMedPubMedCentralCrossRef
28.
Radich JP, Dai H, Mao M, Oehler V, Schelter J, Druker B, et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci U S A. 2006;103(8):2794–9.PubMedPubMedCentralCrossRef
29.
Machova Polakova K, Kulvait V, Benesova A, Linhartova J, Klamova H, Jaruskova M, et al. Next-generation deep sequencing improves detection of BCR-ABL1 kinase domain mutations emerging under tyrosine kinase inhibitor treatment of chronic myeloid leukemia patients in chronic phase. J Cancer Res Clin Oncol. 2015;141(5):887–99.PubMedCrossRef
30.
Baer C, Kern W, Koch S, Nadarajah N, Schindela S, Meggendorfer M, et al. Ultra-deep sequencing leads to earlier and more sensitive detection of the tyrosine kinase inhibitor resistance mutation T315I in chronic myeloid leukemia. Haematologica. 2016;101(7):830–8.PubMedPubMedCentralCrossRef
31.
Kizilors A, Crisa E, Lea N, Passera R, Mian S, Anwar J, et al. Effect of low-level BCR-ABL1 kinase domain mutations identified by next-generation sequencing in patients with chronic myeloid leukaemia: a population-based study. Lancet Haematol. 2019;6(5):e276–e84.PubMedCrossRef
32.
33.
Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872–84.PubMedPubMedCentralCrossRef
34.
Soverini S, De Benedittis C, Machova Polakova K, Brouckova A, Horner D, Iacono M, et al. Unraveling the complexity of tyrosine kinase inhibitor-resistant populations by ultra-deep sequencing of the BCR-ABL kinase domain. Blood. 2013;122(9):1634–48.PubMedCrossRef
35.
Soverini S, De Benedittis C, Polakova KM, Linhartova J, Castagnetti F, Gugliotta G, et al. Next-generation sequencing for sensitive detection of BCR-ABL1 mutations relevant to tyrosine kinase inhibitor choice in Imatinib-resistant patients. Oncotarget. 2016;7(16):21982–90.PubMedPubMedCentralCrossRef
36.
Parker WT, Ho M, Scott HS, Hughes TP, Branford S. Poor response to second-line kinase inhibitors in chronic myeloid leukemia patients with multiple low-level mutations, irrespective of their resistance profile. Blood. 2012;119(10):2234–8.PubMedCrossRef
37.
Parker WT, Lawrence RM, Ho M, Irwin DL, Scott HS, Hughes TP, et al. Sensitive detection of BCR-ABL1 mutations in patients with chronic myeloid leukemia after imatinib resistance is predictive of outcome during subsequent therapy. J Clin Oncol. 2011;29(32):4250–9.PubMedCrossRef
38.
Soverini S, De Benedittis C, Castagnetti F, Gugliotta G, Mancini M, Bavaro L, et al. In chronic myeloid leukemia patients on second-line tyrosine kinase inhibitor therapy, deep sequencing of BCR-ABL1 at the time of warning may allow sensitive detection of emerging drug-resistant mutants. BMC Cancer. 2016;16:572.PubMedPubMedCentralCrossRef
39.
Khorashad JS, Kelley TW, Szankasi P, Mason CC, Soverini S, Adrian LT, et al. BCR-ABL1 compound mutations in tyrosine kinase inhibitor-resistant CML: frequency and clonal relationships. Blood. 2013;121(3):489–98.PubMedPubMedCentralCrossRef
40.
Zabriskie MS, Eide CA, Tantravahi SK, Vellore NA, Estrada J, Nicolini FE, et al. BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia. Cancer Cell. 2014;26(3):428–42.PubMedPubMedCentralCrossRef
41.
Barrett J. Allogeneic stem cell transplantation for chronic myeloid leukemia. Semin Hematol. 2003;40(1):59–71.PubMedCrossRef
42.
Nicolini FE, Basak GW, Kim DW, Olavarria E, Pinilla-Ibarz J, Apperley JF, et al. Overall survival with Ponatinib versus allogeneic stem cell transplantation in Philadelphia chromosome-positive leukemias with the T315I mutation. Cancer. 2017;123(15):2875–80.PubMedCrossRef
43.
44.
Jabbour E, Cortes J, Santos FP, Jones D, O’Brien S, Rondon G, et al. Results of allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia patients who failed tyrosine kinase inhibitors after developing BCR-ABL1 kinase domain mutations. Blood. 2011;117(13):3641–7.PubMedPubMedCentralCrossRef
45.
Egan DN, Beppu L, Radich JP. Patients with Philadelphia-positive leukemia with BCR-ABL kinase mutations before allogeneic transplantation predominantly relapse with the same mutation. Biol Blood Marrow Transplant. 2015;21(1):184–9.PubMedCrossRef
46.
Hehlmann R, Saussele S, Voskanyan A, Silver RT. Management of CML-blast crisis. Best Pract Res Clin Haematol. 2016;29(3):295–307.PubMedCrossRef
47.
Saussele S, Silver RT. Management of chronic myeloid leukemia in blast crisis. Ann Hematol. 2015;94(Suppl 2):S159–65.PubMedCrossRef
48.
Branford S, Wang P, Yeung DT, Thomson D, Purins A, Wadham C, et al. Integrative genomic analysis reveals cancer-associated mutations at diagnosis of CML in patients with high-risk disease. Blood. 2018;132(9):948–61.PubMedCrossRef
49.
Chen Z, Shao C, Wang W, Zuo Z, Mou X, Hu SJ, et al. Cytogenetic landscape and impact in blast phase of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy. Leukemia. 2017;31(3):585–92.PubMedCrossRef
50.
Soverini S, de Benedittis C, Mancini M, Martinelli G. Mutations in the BCR-ABL1 kinase domain and elsewhere in chronic myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2015;15(Suppl):S120–8.PubMedCrossRef
51.
Soverini S, Colarossi S, Gnani A, Rosti G, Castagnetti F, Poerio A, et al. Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA Working Party on Chronic Myeloid Leukemia. Clin Cancer Res. 2006;12(24):7374–9.PubMedCrossRef
52.
Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J, et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell. 2002;2(2):117–25.PubMedCrossRef
53.
Roche-Lestienne C, Soenen-Cornu V, Grardel-Duflos N, Lai JL, Philippe N, Facon T, et al. Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment. Blood. 2002;100(3):1014–8.PubMedCrossRef
54.
Willis SG, Lange T, Demehri S, Otto S, Crossman L, Niederwieser D, et al. High-sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic evolution but not response to therapy. Blood. 2005;106(6):2128–37.PubMedCrossRef
55.
56.
Breccia M, Foa R. Current information and recommendations on the discontinuation of TKI inhibitors in chronic myeloid leukemia. Curr Oncol Rep. 2018;20(3):23.PubMedCrossRef
57.
Rea D, Mahon FX. How I manage relapse of chronic myeloid leukaemia after stopping tyrosine kinase inhibitor therapy. Br J Haematol. 2018;180(1):24–32.PubMedCrossRef
58.
Hochhaus A, Masszi T, Giles FJ, Radich JP, Ross DM, Gomez Casares MT, et al. Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study. Leukemia. 2017;31(7):1525–31.PubMedPubMedCentralCrossRef
59.
Deininger MW, Hodgson JG, Shah NP, Cortes JE, Kim DW, Nicolini FE, et al. Compound mutations in BCR-ABL1 are not major drivers of primary or secondary resistance to ponatinib in CP-CML patients. Blood. 2016;127(6):703–12.PubMedPubMedCentralCrossRef
60.
Erbilgin Y, Eskazan AE, Hatirnaz Ng O, Salihoglu A, Elverdi T, Firtina S, et al. Deep sequencing of BCR-ABL1 kinase domain mutations in chronic myeloid leukemia patients with resistance to tyrosine kinase inhibitors. Leuk Lymphoma. 2019;60(1):200–7.PubMedCrossRef
61.
Preuner S, Barna A, Frommlet F, Czurda S, Konstantin B, Alikian M, et al. Quantitative analysis of mutant subclones in chronic myeloid leukemia: comparison of different methodological approaches. Int J Mol Sci. 2016;17(5).PubMedCentralCrossRef
62.
Szankasi P, Schumacher JA, Kelley TW. Detection of BCR-ABL1 mutations that confer tyrosine kinase inhibitor resistance using massively parallel, next generation sequencing. Ann Hematol. 2016;95(2):201–10.PubMedCrossRef
63.
Soverini S, Bavaro L, De Benedittis C, Martelli M, Iurlo A, Orofino N, et al. Prospective assessment of NGS-detectable mutations in CML patients with non-optimal response: the NEXT-in-CML study. Blood. In press. 
64.
Sherbenou DW, Hantschel O, Kaupe I, Willis S, Bumm T, Turaga LP, et al. BCR-ABL SH3-SH2 domain mutations in chronic myeloid leukemia patients on imatinib. Blood. 2010;116(17):3278–85.PubMedPubMedCentralCrossRef
65.
Hochhaus A, Saussele S, Rosti G, Mahon FX, Janssen J, Hjorth-Hansen H, et al. Chronic myeloid leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Supplement_4):iv261.PubMedCrossRef
66.
Arsenic R, Treue D, Lehmann A, Hummel M, Dietel M, Denkert C, et al. Comparison of targeted next-generation sequencing and Sanger sequencing for the detection of PIK3CA mutations in breast cancer. BMC Clin Pathol. 2015;15:20.PubMedPubMedCentralCrossRef
67.
Baudhuin LM, Lagerstedt SA, Klee EW, Fadra N, Oglesbee D, Ferber MJ. Confirming variants in next-generation sequencing panel testing by Sanger sequencing. J Mol Diagn. 2015;17(4):456–61.PubMedCrossRef
68.
Hung SS, Meissner B, Chavez EA, Ben-Neriah S, Ennishi D, Jones MR, et al. Assessment of capture and amplicon-based approaches for the development of a targeted next-generation sequencing pipeline to personalize lymphoma management. J Mol Diagn. 2018;20(2):203–14.PubMedCrossRef
69.
Kohlmann A, Klein HU, Weissmann S, Bresolin S, Chaplin T, Cuppens H, et al. The Interlaboratory RObustness of Next-generation sequencing (IRON) study: a deep sequencing investigation of TET2, CBL and KRAS mutations by an international consortium involving 10 laboratories. Leukemia. 2011;25(12):1840–8.PubMedCrossRef
70.
Misyura M, Zhang T, Sukhai MA, Thomas M, Garg S, Kamel-Reid S, et al. Comparison of next-generation sequencing panels and platforms for detection and verification of somatic tumor variants for clinical diagnostics. J Mol Diagn. 2016;18(6):842–50.PubMedCrossRef
71.
Simen BB, Yin L, Goswami CP, Davis KO, Bajaj R, Gong JZ, et al. Validation of a next-generation-sequencing cancer panel for use in the clinical laboratory. Arch Pathol Lab Med. 2015;139(4):508–17.PubMedCrossRef
72.
Sutton LA, Ljungstrom V, Mansouri L, Young E, Cortese D, Navrkalova V, et al. Targeted next-generation sequencing in chronic lymphocytic leukemia: a high-throughput yet tailored approach will facilitate implementation in a clinical setting. Haematologica. 2015;100(3):370–6.PubMedPubMedCentralCrossRef
Metadata
Title
Next-generation sequencing for BCR-ABL1 kinase domain mutation testing in patients with chronic myeloid leukemia: a position paper
Authors
Simona Soverini
Elisabetta Abruzzese
Monica Bocchia
Massimiliano Bonifacio
Sara Galimberti
Antonella Gozzini
Alessandra Iurlo
Luigiana Luciano
Patrizia Pregno
Gianantonio Rosti
Giuseppe Saglio
Fabio Stagno
Mario Tiribelli
Paolo Vigneri
Giovanni Barosi
Massimo Breccia
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2019
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-019-0815-5

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