Abstract
The impact of ten-eleven-translocation 2 (TET2) mutations on response to azacitidine (AZA) in MDS has not been reported. We sequenced the TET2 gene in 86 MDS and acute myeloid leukemia (AML) with 20–30% blasts treated by AZA, that is disease categories wherein this drug is approved by Food and Drug Administration (FDA). Thirteen patients (15%) carried TET2 mutations. Patients with mutated and wild-type (WT) TET2 had mostly comparable pretreatment characteristics, except for lower hemoglobin, better cytogenetic risk and longer MDS duration before AZA in TET2 mutated patients (P=0.03, P=0.047 and P=0.048, respectively). The response rate (including hematological improvement) was 82% in MUT versus 45% in WT patients (P=0.007). Mutated TET2 (P=0.04) and favorable cytogenetic risk (intermediate risk: P=0.04, poor risk: P=0.048 compared with good risk) independently predicted a higher response rate. Response duration and overall survival were, however, comparable in the MUT and WT groups. In higher risk MDS and AML with low blast count, TET2 status may be a genetic predictor of response to AZA, independently of karyotype.
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References
Ito S, D’Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y . Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 2010; 466: 1129–1133.
Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 2009; 324: 930–935.
Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 2010; 468: 839–843.
Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Masse A et al. Mutation in TET2 in myeloid cancers. N Engl J Med 2009; 360: 2289–2301.
Kosmider O, Gelsi-Boyer V, Cheok M, Grabar S, Della-Valle V, Picard F et al. TET2 mutation is an independent favorable prognostic factor in myelodysplastic syndromes (MDS). Blood 2009; 114: 3285–3291.
Langemeijer SM, Kuiper RP, Berends M, Knops R, Aslanyan MG, Massop M et al. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet 2009; 41: 838–842.
Nibourel O, Kosmider O, Cheok M, Boissel N, Renneville A, Philippe N et al. Incidence and prognostic value of TET2 alterations in de novo acute myeloid leukemia (AML) achieving complete remission. Blood 2010; 116: 1132–1135.
Smith AE, Mohamedali AM, Kulasekararaj A, Lim Z, Gaken J, Lea NC et al. Next-generation sequencing of the TET2 gene in 355 MDS and CMML patients reveals low abundance mutant clones with early origins, but indicates no definite prognostic value. Blood 2010; 116: 3923–3932.
Jankowska AM, Szpurka H, Tiu RV, Makishima H, Afable M, Huh J et al. Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms. Blood 2009; 113: 6403–6410.
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009; 10: 223–232.
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Gattermann N, Germing U et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol 2010; 28: 562–569.
Kantarjian HM, O’Brien S, Shan J, Aribi A, Garcia-Manero G, Jabbour E et al. Update of the decitabine experience in higher risk myelodysplastic syndrome and analysis of prognostic factors associated with outcome. Cancer 2007; 109: 265–273.
Itzykson R, Thepot S, Quesnel B, Dreyfus F, Beyne-Rauzy O, Turlure P et al. Prognostic factors of response and overall survival in 282 higher-risk myelodysplastic syndromes treated with azacitidine. Blood 2011; 117: 403–411.
Moon JH, Kim SN, Kang BW, Chae YS, Kim JG, Baek JH et al. Predictive value of pretreatment risk group and baseline LDH levels in MDS patients receiving azacitidine treatment. Ann Hematol 2010; 89: 681–689.
Wijermans P, Lubbert M, Verhoef G, Bosly A, Ravoet C, Andre M et al. Low-dose 5-aza-2′-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients. J Clin Oncol 2000; 18: 956–962.
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982; 51: 189–199.
Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 2006; 108: 419–425.
Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89: 2079–2088.
Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 2002; 20: 2429–2440.
Silverman LR, McKenzie DR, Peterson BL, Holland JF, Backstrom JT, Beach CL et al. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol 2006; 24: 3895–3903.
Silverman LR, Fenaux P, Mufti GJ, Santini V, Hellstrom-Lindberg E, Gattermann N et al. Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes. Cancer 2011; E-pub ahead of print 10 January 2011.
Blum W, Garzon R, Klisovic RB, Schwind S, Walker A, Geyer S et al. Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc Natl Acad Sci USA 2010; 107: 7473–7478.
Lubbert M, Wijermans P, Kunzmann R, Verhoef G, Bosly A, Ravoet C et al. Cytogenetic responses in high-risk myelodysplastic syndrome following low-dose treatment with the DNA methylation inhibitor 5-aza-2′-deoxycytidine. Br J Haematol 2001; 114: 349–357.
Raj K, John A, Ho A, Chronis C, Khan S, Samuel J et al. CDKN2B methylation status and isolated chromosome 7 abnormalities predict responses to treatment with 5-azacytidine. Leukemia 2007; 21: 1937–1944.
Fandy TE, Herman JG, Kerns P, Jiemjit A, Sugar EA, Choi SH et al. Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies. Blood 2009; 114: 2764–2773.
Shen L, Kantarjian H, Guo Y, Lin E, Shan J, Huang X et al. DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes. J Clin Oncol 2010; 28: 605–613.
Follo MY, Finelli C, Mongiorgi S, Clissa C, Bosi C, Testoni N et al. Reduction of phosphoinositide-phospholipase C beta1 methylation predicts the responsiveness to azacitidine in high-risk MDS. Proc Natl Acad Sci USA 2009; 106: 16811–16816.
Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C, Jones AV et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet 2010; 42: 722–726.
Walter MJ, Shen D, Shao J, Ding L, Grillot M, McLellan M et al. Recurrent DNMT3A mutations in patients with myelodysplastic syndrome. ASH Annu Meeting Abstr 2010; 116: 608.
Acknowledgements
We would like to thank Lamya Slama, Gaelle Herledan, Julien Brard for technical assistance, Rosa Sapena from the GFM for recording data. This work was supported in part by an unrestricted research grant from Celgene.
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RI and OK contributed equally to this paper as first author. MF and PF designed the research. OK collected biological samples and performed sequencing analyses. RI collected clinical data and performed statistical analyses. RI, OK, PF and MF drafted the manuscript. TC, FD, OBR, BQ, NV and LA enrolled the patients, collected clinical data and wrote the manuscript. VD, VGB, SR and CP collected and qualified biological samples, and wrote the manuscript.
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Itzykson, R., Kosmider, O., Cluzeau, T. et al. Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia 25, 1147–1152 (2011). https://doi.org/10.1038/leu.2011.71
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DOI: https://doi.org/10.1038/leu.2011.71