Skip to main content
Erschienen in:

01.12.2014 | Myelodsyplastic Syndromes (M Sekeres, Section Editor)

Stopping Higher-Risk Myelodysplastic Syndrome in Its Tracks

verfasst von: Daniel A. Pollyea, Jonathan A. Gutman

Erschienen in: Current Hematologic Malignancy Reports | Ausgabe 4/2014

Einloggen, um Zugang zu erhalten

Abstract

Higher-risk myelodysplastic syndromes (MDS) are a collection of diseases associated with poor outcomes from complications related to bone marrow failure and evolution to acute myeloid leukemia. While most patients receive epigenetic therapies, intensive chemotherapy or allogeneic stem cell transplantation, more tolerable and effective treatments are necessary to realize the goal of stopping this disease in its tracks. Recent efforts, building on decades of research exploring the pathogenesis of this disease, have revealed exciting clues that elucidate critical biological features that drive or contribute to MDS, and may serve as targets for selective and well-tolerated future therapies. Here, we review the current diagnostic, prognostic, and therapeutic approaches to higher-risk MDS.
Literatur
1.
Zurück zum Zitat Greenberg PL, Attar E, Bennett JM, et al. NCCN clinical practice guidelines in oncology: myelodysplastic syndromes. J Natl Compr Cancer Netw. 2011;9:30–56. Greenberg PL, Attar E, Bennett JM, et al. NCCN clinical practice guidelines in oncology: myelodysplastic syndromes. J Natl Compr Cancer Netw. 2011;9:30–56.
2.
Zurück zum Zitat Ma X, Does M, Raza A, Mayne ST. Myelodysplastic syndromes: incidence and survival in the United States. Cancer. 2007;109:1536–42.PubMed Ma X, Does M, Raza A, Mayne ST. Myelodysplastic syndromes: incidence and survival in the United States. Cancer. 2007;109:1536–42.PubMed
3.
Zurück zum Zitat Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114:937–51.PubMed Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114:937–51.PubMed
4.
Zurück zum Zitat Fenaux P, Bowen D, Gattermann N, et al. Practical use of azacitidine in higher-risk myelodysplastic syndromes: an expert panel opinion. Leuk Res. 2010;34:1410–6.PubMed Fenaux P, Bowen D, Gattermann N, et al. Practical use of azacitidine in higher-risk myelodysplastic syndromes: an expert panel opinion. Leuk Res. 2010;34:1410–6.PubMed
5.
Zurück zum Zitat Stone RM. How I treat patients with myelodysplastic syndromes. Blood. 2009;113:6296–303.PubMed Stone RM. How I treat patients with myelodysplastic syndromes. Blood. 2009;113:6296–303.PubMed
6.
Zurück zum Zitat Sekeres MA, Schoonen WM, Kantarjian H, et al. Characteristics of US patients with myelodysplastic syndromes: results of six cross-sectional physician surveys. J Natl Cancer Inst. 2008;100:1542–51.PubMedCentralPubMed Sekeres MA, Schoonen WM, Kantarjian H, et al. Characteristics of US patients with myelodysplastic syndromes: results of six cross-sectional physician surveys. J Natl Cancer Inst. 2008;100:1542–51.PubMedCentralPubMed
7.
Zurück zum Zitat Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 1982;51:189–99.PubMed Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 1982;51:189–99.PubMed
8.
Zurück zum Zitat Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002;100:2292–302.PubMed Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002;100:2292–302.PubMed
9.
Zurück zum Zitat Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:2079–88.PubMed Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:2079–88.PubMed
10.
Zurück zum Zitat Malcovati L, Germing U, Kuendgen A, et al. Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol. 2007;25:3503–10.PubMed Malcovati L, Germing U, Kuendgen A, et al. Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol. 2007;25:3503–10.PubMed
11.
Zurück zum Zitat Kantarjian H, O’Brien S, Ravandi F, et al. Proposal for a new risk model in myelodysplastic syndrome that accounts for events not considered in the original International Prognostic Scoring System. Cancer. 2008;113:1351–61.PubMedCentralPubMed Kantarjian H, O’Brien S, Ravandi F, et al. Proposal for a new risk model in myelodysplastic syndrome that accounts for events not considered in the original International Prognostic Scoring System. Cancer. 2008;113:1351–61.PubMedCentralPubMed
12.••
Zurück zum Zitat Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120:2454–65. This revision of the most common MDS prognostic scoring system enriches the prognostic power of the IPSS by adding detail to the clinical variables required.PubMed Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120:2454–65. This revision of the most common MDS prognostic scoring system enriches the prognostic power of the IPSS by adding detail to the clinical variables required.PubMed
13.
Zurück zum Zitat Gergis U, Wissa U. High-risk myelodysplastic syndromes: chemotherapy, transplantation, and beyond. Curr Hematol Malignant Rep. 2010;5:1–8. Gergis U, Wissa U. High-risk myelodysplastic syndromes: chemotherapy, transplantation, and beyond. Curr Hematol Malignant Rep. 2010;5:1–8.
14.
Zurück zum Zitat Bally C, Thepot S, Quesnel B, et al. Azacitidine in the treatment of therapy related myelodysplastic syndrome and acute myeloid leukemia (tMDS/AML): a report on 54 patients by the Groupe Francophone Des Myelodysplasies (GFM). Leuk Res. 2013;37:637–40.PubMed Bally C, Thepot S, Quesnel B, et al. Azacitidine in the treatment of therapy related myelodysplastic syndrome and acute myeloid leukemia (tMDS/AML): a report on 54 patients by the Groupe Francophone Des Myelodysplasies (GFM). Leuk Res. 2013;37:637–40.PubMed
15.
Zurück zum Zitat Gore SD, Hermes-DeSantis ER. Enhancing survival outcomes in the management of patients with higher-risk myelodysplastic syndromes. Cancer Control. 2009;16(Suppl):2–10.PubMed Gore SD, Hermes-DeSantis ER. Enhancing survival outcomes in the management of patients with higher-risk myelodysplastic syndromes. Cancer Control. 2009;16(Suppl):2–10.PubMed
16.
Zurück zum Zitat Figueroa ME, Skrabanek L, Li Y, et al. MDS and secondary AML display unique patterns and abundance of aberrant DNA methylation. Blood. 2009;114:3448–58.PubMedCentralPubMed Figueroa ME, Skrabanek L, Li Y, et al. MDS and secondary AML display unique patterns and abundance of aberrant DNA methylation. Blood. 2009;114:3448–58.PubMedCentralPubMed
17.
Zurück zum Zitat Itzykson R, Fenaux P. Optimizing hypomethylating agents in myelodysplastic syndromes. Curr Opin Hematol. 2012;19:65–70.PubMed Itzykson R, Fenaux P. Optimizing hypomethylating agents in myelodysplastic syndromes. Curr Opin Hematol. 2012;19:65–70.PubMed
18.
Zurück zum Zitat Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003;349:2042–54.PubMed Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003;349:2042–54.PubMed
19.
Zurück zum Zitat Jiang Y, Dunbar A, Gondek LP, et al. Aberrant DNA methylation is a dominant mechanism in MDS progression to AML. Blood. 2009;113:1315–25.PubMedCentralPubMed Jiang Y, Dunbar A, Gondek LP, et al. Aberrant DNA methylation is a dominant mechanism in MDS progression to AML. Blood. 2009;113:1315–25.PubMedCentralPubMed
20.
Zurück zum Zitat Shen L, Kantarjian H, Guo Y, et al. DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes. J Clin Oncol. 2010;28:605–13.PubMedCentralPubMed Shen L, Kantarjian H, Guo Y, et al. DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes. J Clin Oncol. 2010;28:605–13.PubMedCentralPubMed
21.
Zurück zum Zitat Briggs SD, Xiao T, Sun ZW, et al. Gene silencing: trans-histone regulatory pathway in chromatin. Nature. 2002;418:498.PubMed Briggs SD, Xiao T, Sun ZW, et al. Gene silencing: trans-histone regulatory pathway in chromatin. Nature. 2002;418:498.PubMed
22.
Zurück zum Zitat Gore SD, Baylin S, Sugar E, et al. Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res. 2006;66:6361–9.PubMed Gore SD, Baylin S, Sugar E, et al. Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res. 2006;66:6361–9.PubMed
23.
Zurück zum Zitat Santini V, Kantarjian HM, Issa JP. Changes in DNA methylation in neoplasia: pathophysiology and therapeutic implications. Ann Intern Med. 2001;134:573–86.PubMed Santini V, Kantarjian HM, Issa JP. Changes in DNA methylation in neoplasia: pathophysiology and therapeutic implications. Ann Intern Med. 2001;134:573–86.PubMed
24.
Zurück zum Zitat Santini V. Azacitidine: activity and efficacy as an epigenetic treatment of myelodysplastic syndromes. Expert Rev Hematol. 2009;2:121–7.PubMed Santini V. Azacitidine: activity and efficacy as an epigenetic treatment of myelodysplastic syndromes. Expert Rev Hematol. 2009;2:121–7.PubMed
25.
Zurück zum Zitat Silverman LR, Demakos EP, Peterson BL, 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;20:2429–40.PubMed Silverman LR, Demakos EP, Peterson BL, 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;20:2429–40.PubMed
26.
Zurück zum Zitat Silverman LR, McKenzie DR, Peterson BL, 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;24:3895–903.PubMed Silverman LR, McKenzie DR, Peterson BL, 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;24:3895–903.PubMed
27.
Zurück zum Zitat Fenaux P, Mufti GJ, Hellstrom-Lindberg E, 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;28:562–9.PubMed Fenaux P, Mufti GJ, Hellstrom-Lindberg E, 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;28:562–9.PubMed
28.••
Zurück zum Zitat Fenaux P, Mufti GJ, Hellstrom-Lindberg E, 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;10:223–32. This paper showed azacitidine resulted in a survival benefit when compared to standard-of-care regimens in high-risk MDS.PubMedCentralPubMed Fenaux P, Mufti GJ, Hellstrom-Lindberg E, 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;10:223–32. This paper showed azacitidine resulted in a survival benefit when compared to standard-of-care regimens in high-risk MDS.PubMedCentralPubMed
29.
Zurück zum Zitat Harousseau JL, Martinelli G, Jedrzejczak WW, et al. A randomized phase 3 study of tipifarnib compared with best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia in patients 70 years or older. Blood. 2009;114:1166–73.PubMed Harousseau JL, Martinelli G, Jedrzejczak WW, et al. A randomized phase 3 study of tipifarnib compared with best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia in patients 70 years or older. Blood. 2009;114:1166–73.PubMed
30.
Zurück zum Zitat Silverman LR, Fenaux P, Mufti GJ, et al. Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes. Cancer. 2011;117:2697–702.PubMedCentralPubMed Silverman LR, Fenaux P, Mufti GJ, et al. Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes. Cancer. 2011;117:2697–702.PubMedCentralPubMed
31.
Zurück zum Zitat Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106:1794–803.PubMed Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106:1794–803.PubMed
32.
Zurück zum Zitat Lubbert M, Suciu S, Baila L, et al. Low-dose decitabine versus best supportive care in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J Clin Oncol. 2011;29:1987–96.PubMed Lubbert M, Suciu S, Baila L, et al. Low-dose decitabine versus best supportive care in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J Clin Oncol. 2011;29:1987–96.PubMed
33.
Zurück zum Zitat Kantarjian HM, O’Brien S, Shan J, et al. Update of the decitabine experience in higher risk myelodysplastic syndrome and analysis of prognostic factors associated with outcome. Cancer. 2007;109:265–73.PubMed Kantarjian HM, O’Brien S, Shan J, et al. Update of the decitabine experience in higher risk myelodysplastic syndrome and analysis of prognostic factors associated with outcome. Cancer. 2007;109:265–73.PubMed
34.
Zurück zum Zitat Kantarjian H, Oki Y, Garcia-Manero G, et al. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood. 2007;109:52–7.PubMed Kantarjian H, Oki Y, Garcia-Manero G, et al. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood. 2007;109:52–7.PubMed
35.
Zurück zum Zitat Gore SD. New ways to use DNA methyltransferase inhibitors for the treatment of myelodysplastic syndrome. Hematol Am Soc Hematol Educ Program. 2011;2011:550–5. Gore SD. New ways to use DNA methyltransferase inhibitors for the treatment of myelodysplastic syndrome. Hematol Am Soc Hematol Educ Program. 2011;2011:550–5.
36.
Zurück zum Zitat Kornblith AB, Herndon 2nd JE, Silverman LR, et al. Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a Cancer and Leukemia Group B study. J Clin Oncol. 2002;20:2441–52.PubMed Kornblith AB, Herndon 2nd JE, Silverman LR, et al. Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a Cancer and Leukemia Group B study. J Clin Oncol. 2002;20:2441–52.PubMed
37.
Zurück zum Zitat Flotho C, Claus R, Batz C, et al. The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009;23:1019–28.PubMed Flotho C, Claus R, Batz C, et al. The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009;23:1019–28.PubMed
38.
Zurück zum Zitat Keating GM. Azacitidine: a review of its use in higher-risk myelodysplastic syndromes/acute myeloid leukaemia. Drugs. 2009;69:2501–18.PubMed Keating GM. Azacitidine: a review of its use in higher-risk myelodysplastic syndromes/acute myeloid leukaemia. Drugs. 2009;69:2501–18.PubMed
39.
Zurück zum Zitat Kumar A, List AF, Hozo I, Komrokji R, Djulbegovic B. Decitabine versus 5-azacitidine for the treatment of myelodysplastic syndrome: adjusted indirect meta-analysis. Haematologica. 2010;95:340–2. Author reply 3–4.PubMedCentralPubMed Kumar A, List AF, Hozo I, Komrokji R, Djulbegovic B. Decitabine versus 5-azacitidine for the treatment of myelodysplastic syndrome: adjusted indirect meta-analysis. Haematologica. 2010;95:340–2. Author reply 3–4.PubMedCentralPubMed
40.
Zurück zum Zitat Gurion R, Vidal L, Gafter-Gvili A, et al. 5-azacitidine prolongs overall survival in patients with myelodysplastic syndrome—a systematic review and meta-analysis. Haematologica. 2010;95:303–10.PubMedCentralPubMed Gurion R, Vidal L, Gafter-Gvili A, et al. 5-azacitidine prolongs overall survival in patients with myelodysplastic syndrome—a systematic review and meta-analysis. Haematologica. 2010;95:303–10.PubMedCentralPubMed
41.
Zurück zum Zitat Borthakur G, Ahdab SE, Ravandi F, et al. Activity of decitabine in patients with myelodysplastic syndrome previously treated with azacitidine. Leuk Lymphoma. 2008;49:690–5.PubMedCentralPubMed Borthakur G, Ahdab SE, Ravandi F, et al. Activity of decitabine in patients with myelodysplastic syndrome previously treated with azacitidine. Leuk Lymphoma. 2008;49:690–5.PubMedCentralPubMed
42.
Zurück zum Zitat Prebet T, Gore SD, Esterni B, et al. Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. J Clin Oncol. 2011;29:3322–7.PubMed Prebet T, Gore SD, Esterni B, et al. Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. J Clin Oncol. 2011;29:3322–7.PubMed
43.
Zurück zum Zitat Itzykson R, Thepot S, Quesnel B, et al. Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine. Blood. 2011;117:403–11.PubMed Itzykson R, Thepot S, Quesnel B, et al. Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine. Blood. 2011;117:403–11.PubMed
44.
Zurück zum Zitat Breccia M, Loglisci G, Cannella L, et al. Application of French prognostic score to patients with International Prognostic Scoring System intermediate-2 or high risk myelodysplastic syndromes treated with 5-azacitidine is able to predict overall survival and rate of response. Leuk Lymphoma. 2012;53:985–6.PubMed Breccia M, Loglisci G, Cannella L, et al. Application of French prognostic score to patients with International Prognostic Scoring System intermediate-2 or high risk myelodysplastic syndromes treated with 5-azacitidine is able to predict overall survival and rate of response. Leuk Lymphoma. 2012;53:985–6.PubMed
45.
Zurück zum Zitat Prebet T, Sun Z, Figueroa ME, et al. Prolonged administration of azacitidine with or without entinostat for myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes: results of the US Leukemia Intergroup trial E1905. J Clin Oncol. 2014;32:1242–8.PubMed Prebet T, Sun Z, Figueroa ME, et al. Prolonged administration of azacitidine with or without entinostat for myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes: results of the US Leukemia Intergroup trial E1905. J Clin Oncol. 2014;32:1242–8.PubMed
46.
Zurück zum Zitat Jabbour E, Garcia-Manero G, Batty N, et al. Outcome of patients with myelodysplastic syndrome after failure of decitabine therapy. Cancer. 2010;116:3830–4.PubMed Jabbour E, Garcia-Manero G, Batty N, et al. Outcome of patients with myelodysplastic syndrome after failure of decitabine therapy. Cancer. 2010;116:3830–4.PubMed
47.
Zurück zum Zitat Miller KB, Kim K, Morrison FS, et al. The evaluation of low-dose cytarabine in the treatment of myelodysplastic syndromes: a phase-III intergroup study. Ann Hematol. 1992;65:162–8.PubMed Miller KB, Kim K, Morrison FS, et al. The evaluation of low-dose cytarabine in the treatment of myelodysplastic syndromes: a phase-III intergroup study. Ann Hematol. 1992;65:162–8.PubMed
48.
Zurück zum Zitat de Witte T, Suciu S, Peetermans M, et al. Intensive chemotherapy for poor prognosis myelodysplasia (MDS) and secondary acute myeloid leukemia (sAML) following MDS of more than 6 months duration. A pilot study by the Leukemia Cooperative Group of the European Organisation for Research and Treatment in Cancer (EORTC-LCG). Leukemia. 1995;9:1805–11.PubMed de Witte T, Suciu S, Peetermans M, et al. Intensive chemotherapy for poor prognosis myelodysplasia (MDS) and secondary acute myeloid leukemia (sAML) following MDS of more than 6 months duration. A pilot study by the Leukemia Cooperative Group of the European Organisation for Research and Treatment in Cancer (EORTC-LCG). Leukemia. 1995;9:1805–11.PubMed
49.
Zurück zum Zitat Ruutu T, Hanninen A, Jarventie G, et al. Intensive chemotherapy of poor prognosis myelodysplastic syndromes (MDS) and acute myeloid leukemia following MDS with idarubicin and cytarabine. Leuk Res. 1997;21:133–8.PubMed Ruutu T, Hanninen A, Jarventie G, et al. Intensive chemotherapy of poor prognosis myelodysplastic syndromes (MDS) and acute myeloid leukemia following MDS with idarubicin and cytarabine. Leuk Res. 1997;21:133–8.PubMed
50.
Zurück zum Zitat Ossenkoppele GJ, Graveland WJ, Sonneveld P, et al. The value of fludarabine in addition to ARA-C and G-CSF in the treatment of patients with high-risk myelodysplastic syndromes and AML in elderly patients. Blood. 2004;103:2908–13.PubMed Ossenkoppele GJ, Graveland WJ, Sonneveld P, et al. The value of fludarabine in addition to ARA-C and G-CSF in the treatment of patients with high-risk myelodysplastic syndromes and AML in elderly patients. Blood. 2004;103:2908–13.PubMed
51.
Zurück zum Zitat Knipp S, Hildebrand B, Kundgen A, et al. Intensive chemotherapy is not recommended for patients aged >60 years who have myelodysplastic syndromes or acute myeloid leukemia with high-risk karyotypes. Cancer. 2007;110:345–52.PubMed Knipp S, Hildebrand B, Kundgen A, et al. Intensive chemotherapy is not recommended for patients aged >60 years who have myelodysplastic syndromes or acute myeloid leukemia with high-risk karyotypes. Cancer. 2007;110:345–52.PubMed
52.
Zurück zum Zitat Beran M, Shen Y, Kantarjian H, et al. High-dose chemotherapy in high-risk myelodysplastic syndrome: covariate-adjusted comparison of five regimens. Cancer. 2001;92:1999–2015.PubMed Beran M, Shen Y, Kantarjian H, et al. High-dose chemotherapy in high-risk myelodysplastic syndrome: covariate-adjusted comparison of five regimens. Cancer. 2001;92:1999–2015.PubMed
53.
Zurück zum Zitat Fukumoto JS, Greenberg PL. Management of patients with higher risk myelodysplastic syndromes. Crit Rev Oncol Hematol. 2005;56:179–92.PubMed Fukumoto JS, Greenberg PL. Management of patients with higher risk myelodysplastic syndromes. Crit Rev Oncol Hematol. 2005;56:179–92.PubMed
54.
Zurück zum Zitat Kantarjian H, Beran M, Cortes J, et al. Long-term follow-up results of the combination of topotecan and cytarabine and other intensive chemotherapy regimens in myelodysplastic syndrome. Cancer. 2006;106:1099–109.PubMed Kantarjian H, Beran M, Cortes J, et al. Long-term follow-up results of the combination of topotecan and cytarabine and other intensive chemotherapy regimens in myelodysplastic syndrome. Cancer. 2006;106:1099–109.PubMed
55.
Zurück zum Zitat Oosterveld M, Muus P, Suciu S, et al. Chemotherapy only compared to chemotherapy followed by transplantation in high risk myelodysplastic syndrome and secondary acute myeloid leukemia; two parallel studies adjusted for various prognostic factors. Leukemia. 2002;16:1615–21.PubMed Oosterveld M, Muus P, Suciu S, et al. Chemotherapy only compared to chemotherapy followed by transplantation in high risk myelodysplastic syndrome and secondary acute myeloid leukemia; two parallel studies adjusted for various prognostic factors. Leukemia. 2002;16:1615–21.PubMed
56.
Zurück zum Zitat Wattel E, De Botton S, Luc Lai J, et al. Long-term follow-up of de novo myelodysplastic syndromes treated with intensive chemotherapy: incidence of long-term survivors and outcome of partial responders. Br J Haematol. 1997;98:983–91.PubMed Wattel E, De Botton S, Luc Lai J, et al. Long-term follow-up of de novo myelodysplastic syndromes treated with intensive chemotherapy: incidence of long-term survivors and outcome of partial responders. Br J Haematol. 1997;98:983–91.PubMed
57.
Zurück zum Zitat Vaughn JE, Scott BL, Deeg HJ. Transplantation for myelodysplastic syndromes 2013. Curr Opin Hematol. 2013;20:494–500.PubMedCentralPubMed Vaughn JE, Scott BL, Deeg HJ. Transplantation for myelodysplastic syndromes 2013. Curr Opin Hematol. 2013;20:494–500.PubMedCentralPubMed
58.
Zurück zum Zitat Cutler CS, Lee SJ, Greenberg P, et al. A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood. 2004;104:579–85.PubMed Cutler CS, Lee SJ, Greenberg P, et al. A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood. 2004;104:579–85.PubMed
59.
Zurück zum Zitat Koreth J, Pidala J, Perez WS, et al. Role of reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation in older patients with de novo myelodysplastic syndromes: an international collaborative decision analysis. J Clin Oncol. 2013;31:2662–70.PubMedCentralPubMed Koreth J, Pidala J, Perez WS, et al. Role of reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation in older patients with de novo myelodysplastic syndromes: an international collaborative decision analysis. J Clin Oncol. 2013;31:2662–70.PubMedCentralPubMed
60.
Zurück zum Zitat Deeg HJ, Scott BL, Fang M, et al. Five-group cytogenetic risk classification, monosomal karyotype, and outcome after hematopoietic cell transplantation for MDS or acute leukemia evolving from MDS. Blood. 2012;120:1398–408.PubMedCentralPubMed Deeg HJ, Scott BL, Fang M, et al. Five-group cytogenetic risk classification, monosomal karyotype, and outcome after hematopoietic cell transplantation for MDS or acute leukemia evolving from MDS. Blood. 2012;120:1398–408.PubMedCentralPubMed
61.
Zurück zum Zitat Scott BL, Wells DA, Loken MR, Myerson D, Leisenring WM, Deeg HJ. Validation of a flow cytometric scoring system as a prognostic indicator for posttransplantation outcome in patients with myelodysplastic syndrome. Blood. 2008;112:2681–6.PubMedCentralPubMed Scott BL, Wells DA, Loken MR, Myerson D, Leisenring WM, Deeg HJ. Validation of a flow cytometric scoring system as a prognostic indicator for posttransplantation outcome in patients with myelodysplastic syndrome. Blood. 2008;112:2681–6.PubMedCentralPubMed
62.
Zurück zum Zitat Della Porta MG, Alessandrino EP, Bacigalupo A, et al. Predictive factors for the outcome of allogeneic transplantation in patients with MDS stratified according to the revised IPSS-R. Blood. 2014;123:2333–42.PubMed Della Porta MG, Alessandrino EP, Bacigalupo A, et al. Predictive factors for the outcome of allogeneic transplantation in patients with MDS stratified according to the revised IPSS-R. Blood. 2014;123:2333–42.PubMed
63.••
Zurück zum Zitat Bejar R, Stevenson K, Abdel-Wahab O, et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med. 2011;364:2496–506. Detailed characterization of the incidence and prognosis of several dozen mutations in MDS.PubMedCentralPubMed Bejar R, Stevenson K, Abdel-Wahab O, et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med. 2011;364:2496–506. Detailed characterization of the incidence and prognosis of several dozen mutations in MDS.PubMedCentralPubMed
64.
Zurück zum Zitat Damaj G, Mohty M, Robin M, et al. Upfront allogeneic stem cell transplantation after reduced-intensity/nonmyeloablative conditioning for patients with myelodysplastic syndrome: a study by the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire. Biol Blood Marrow Transplant. 2014;20:1349–55.PubMed Damaj G, Mohty M, Robin M, et al. Upfront allogeneic stem cell transplantation after reduced-intensity/nonmyeloablative conditioning for patients with myelodysplastic syndrome: a study by the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire. Biol Blood Marrow Transplant. 2014;20:1349–55.PubMed
65.
Zurück zum Zitat Damaj G, Duhamel A, Robin M, et al. Impact of azacitidine before allogeneic stem-cell transplantation for myelodysplastic syndromes: a study by the Societe Francaise de Greffe de Moelle et de Therapie-Cellulaire and the Groupe-Francophone des Myelodysplasies. J Clin Oncol. 2012;30:4533–40.PubMed Damaj G, Duhamel A, Robin M, et al. Impact of azacitidine before allogeneic stem-cell transplantation for myelodysplastic syndromes: a study by the Societe Francaise de Greffe de Moelle et de Therapie-Cellulaire and the Groupe-Francophone des Myelodysplasies. J Clin Oncol. 2012;30:4533–40.PubMed
66.
Zurück zum Zitat Gerds AT, Gooley TA, Estey EH, Appelbaum FR, Deeg HJ, Scott BL. Pretransplantation therapy with azacitidine vs induction chemotherapy and posttransplantation outcome in patients with MDS. Biol Blood Marrow Transplant. 2012;18:1211–8.PubMedCentralPubMed Gerds AT, Gooley TA, Estey EH, Appelbaum FR, Deeg HJ, Scott BL. Pretransplantation therapy with azacitidine vs induction chemotherapy and posttransplantation outcome in patients with MDS. Biol Blood Marrow Transplant. 2012;18:1211–8.PubMedCentralPubMed
67.
Zurück zum Zitat Warlick ED, Cioc A, Defor T, Dolan M, Weisdorf D. Allogeneic stem cell transplantation for adults with myelodysplastic syndromes: importance of pretransplant disease burden. Biol Blood Marrow Transplant. 2009;15:30–8.PubMed Warlick ED, Cioc A, Defor T, Dolan M, Weisdorf D. Allogeneic stem cell transplantation for adults with myelodysplastic syndromes: importance of pretransplant disease burden. Biol Blood Marrow Transplant. 2009;15:30–8.PubMed
68.
Zurück zum Zitat Brunner AM, Kim HT, Coughlin E, et al. Outcomes in patients age 70 or older undergoing allogeneic hematopoietic stem cell transplantation for hematologic malignancies. Biol Blood Marrow Transplant. 2013;19:1374–80.PubMed Brunner AM, Kim HT, Coughlin E, et al. Outcomes in patients age 70 or older undergoing allogeneic hematopoietic stem cell transplantation for hematologic malignancies. Biol Blood Marrow Transplant. 2013;19:1374–80.PubMed
69.
Zurück zum Zitat Sorror ML, Sandmaier BM, Storer BE, et al. Long-term outcomes among older patients following nonmyeloablative conditioning and allogeneic hematopoietic cell transplantation for advanced hematologic malignancies. JAMA. 2011;306:1874–83.PubMedCentralPubMed Sorror ML, Sandmaier BM, Storer BE, et al. Long-term outcomes among older patients following nonmyeloablative conditioning and allogeneic hematopoietic cell transplantation for advanced hematologic malignancies. JAMA. 2011;306:1874–83.PubMedCentralPubMed
70.
Zurück zum Zitat McClune BL, Weisdorf DJ, Pedersen TL, et al. Effect of age on outcome of reduced-intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome. J Clin Oncol. 2010;28:1878–87.PubMedCentralPubMed McClune BL, Weisdorf DJ, Pedersen TL, et al. Effect of age on outcome of reduced-intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome. J Clin Oncol. 2010;28:1878–87.PubMedCentralPubMed
71.
Zurück zum Zitat Lim Z, Brand R, Martino R, et al. Allogeneic hematopoietic stem-cell transplantation for patients 50 years or older with myelodysplastic syndromes or secondary acute myeloid leukemia. J Clin Oncol. 2010;28:405–11.PubMed Lim Z, Brand R, Martino R, et al. Allogeneic hematopoietic stem-cell transplantation for patients 50 years or older with myelodysplastic syndromes or secondary acute myeloid leukemia. J Clin Oncol. 2010;28:405–11.PubMed
72.
Zurück zum Zitat Hahn T, McCarthy Jr PL, Hassebroek A, et al. Significant improvement in survival after allogeneic hematopoietic cell transplantation during a period of significantly increased use, older recipient age, and use of unrelated donors. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31:2437–49. Hahn T, McCarthy Jr PL, Hassebroek A, et al. Significant improvement in survival after allogeneic hematopoietic cell transplantation during a period of significantly increased use, older recipient age, and use of unrelated donors. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31:2437–49.
73.
Zurück zum Zitat Valcarcel D, Sierra J, Wang T, et al. One-antigen mismatched related versus HLA-matched unrelated donor hematopoietic stem cell transplantation in adults with acute leukemia: Center for International Blood and Marrow Transplant Research results in the era of molecular HLA typing. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2011;17:640–8. Valcarcel D, Sierra J, Wang T, et al. One-antigen mismatched related versus HLA-matched unrelated donor hematopoietic stem cell transplantation in adults with acute leukemia: Center for International Blood and Marrow Transplant Research results in the era of molecular HLA typing. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2011;17:640–8.
74.
Zurück zum Zitat Woolfrey A, Lee SJ, Gooley TA, et al. HLA-allele matched unrelated donors compared to HLA-matched sibling donors: role of cell source and disease risk category. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2010;16:1382–7. Woolfrey A, Lee SJ, Gooley TA, et al. HLA-allele matched unrelated donors compared to HLA-matched sibling donors: role of cell source and disease risk category. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2010;16:1382–7.
75.
Zurück zum Zitat Brunstein CG, Gutman JA, Weisdorf DJ, et al. Allogeneic hematopoietic cell transplantation for hematologic malignancy: relative risks and benefits of double umbilical cord blood. Blood. 2010;116:4693–9.PubMedCentralPubMed Brunstein CG, Gutman JA, Weisdorf DJ, et al. Allogeneic hematopoietic cell transplantation for hematologic malignancy: relative risks and benefits of double umbilical cord blood. Blood. 2010;116:4693–9.PubMedCentralPubMed
76.
Zurück zum Zitat Eapen M, Rocha V, Sanz G, et al. Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukaemia: a retrospective analysis. Lancet Oncol. 2010;11:653–60.PubMedCentralPubMed Eapen M, Rocha V, Sanz G, et al. Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukaemia: a retrospective analysis. Lancet Oncol. 2010;11:653–60.PubMedCentralPubMed
77.
Zurück zum Zitat PeffaultdeLatour R, Brunstein CG, Porcher R, et al. Similar overall survival using sibling, unrelated donor, and cord blood grafts after reduced-intensity conditioning for older patients with acute myelogenous leukemia. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2013;19:1355–60. PeffaultdeLatour R, Brunstein CG, Porcher R, et al. Similar overall survival using sibling, unrelated donor, and cord blood grafts after reduced-intensity conditioning for older patients with acute myelogenous leukemia. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2013;19:1355–60.
78.
Zurück zum Zitat Brunstein CG, Fuchs EJ, Carter SL, et al. Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood. 2011;118:282–8.PubMedCentralPubMed Brunstein CG, Fuchs EJ, Carter SL, et al. Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood. 2011;118:282–8.PubMedCentralPubMed
79.
Zurück zum Zitat Medyouf H, Mossner M, Jann JC, et al. Myelodysplastic cells in patients reprogram mesenchymal stromal cells to establish a transplantable stem cell niche disease unit. Cell Stem Cell. 2014;14:824–37.PubMed Medyouf H, Mossner M, Jann JC, et al. Myelodysplastic cells in patients reprogram mesenchymal stromal cells to establish a transplantable stem cell niche disease unit. Cell Stem Cell. 2014;14:824–37.PubMed
80.
Zurück zum Zitat Tzu, Sun, translated by Samuel B. Griffith. The Art of War. Oxford University Press, 1963. Tzu, Sun, translated by Samuel B. Griffith. The Art of War. Oxford University Press, 1963.
81.
Zurück zum Zitat Goldberg SL, Chen E, Sasane M, Paley C, Guo A, Laouri M. Economic impact on US Medicare of a new diagnosis of myelodysplastic syndromes and the incremental costs associated with blood transfusion need. Transfusion. 2012;52:2131–8.PubMed Goldberg SL, Chen E, Sasane M, Paley C, Guo A, Laouri M. Economic impact on US Medicare of a new diagnosis of myelodysplastic syndromes and the incremental costs associated with blood transfusion need. Transfusion. 2012;52:2131–8.PubMed
82.
Zurück zum Zitat Sekeres MA, Cutler C. How we treat higher-risk myelodysplastic syndromes. Blood. 2014;123:829–36.PubMed Sekeres MA, Cutler C. How we treat higher-risk myelodysplastic syndromes. Blood. 2014;123:829–36.PubMed
83.
Zurück zum Zitat Papaemmanuil E, Gerstung M, Malcovati L, et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013;122:3616–27. Quiz 99.PubMedCentralPubMed Papaemmanuil E, Gerstung M, Malcovati L, et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013;122:3616–27. Quiz 99.PubMedCentralPubMed
84.•
Zurück zum Zitat Haferlach T, Nagata Y, Grossmann V, et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia. 2014;28:241–7. Large series of patients with detailed characterization of the incidence and prognosis of the relevant recurrent mutations in MDS.PubMedCentralPubMed Haferlach T, Nagata Y, Grossmann V, et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia. 2014;28:241–7. Large series of patients with detailed characterization of the incidence and prognosis of the relevant recurrent mutations in MDS.PubMedCentralPubMed
85.
Zurück zum Zitat Kita-Sasai Y, Horiike S, Misawa S, et al. International prognostic scoring system and TP53 mutations are independent prognostic indicators for patients with myelodysplastic syndrome. Br J Haematol. 2001;115:309–12.PubMed Kita-Sasai Y, Horiike S, Misawa S, et al. International prognostic scoring system and TP53 mutations are independent prognostic indicators for patients with myelodysplastic syndrome. Br J Haematol. 2001;115:309–12.PubMed
86.
Zurück zum Zitat Jadersten M, Saft L, Smith A, et al. TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. J Clin Oncol. 2011;29:1971–9.PubMed Jadersten M, Saft L, Smith A, et al. TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. J Clin Oncol. 2011;29:1971–9.PubMed
87.
Zurück zum Zitat Sebaa A, Ades L, Baran-Marzack F, et al. Incidence of 17p deletions and TP53 mutation in myelodysplastic syndrome and acute myeloid leukemia with 5q deletion. Genes Chromosome Cancer. 2012;51:1086–92. Sebaa A, Ades L, Baran-Marzack F, et al. Incidence of 17p deletions and TP53 mutation in myelodysplastic syndrome and acute myeloid leukemia with 5q deletion. Genes Chromosome Cancer. 2012;51:1086–92.
88.
Zurück zum Zitat Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet. 1999;21:103–7.PubMed Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet. 1999;21:103–7.PubMed
89.
Zurück zum Zitat Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, et al. Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia. Blood. 2006;108:3271–9.PubMedCentralPubMed Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, et al. Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia. Blood. 2006;108:3271–9.PubMedCentralPubMed
90.
Zurück zum Zitat Soriano AO, Yang H, Faderl S, et al. Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood. 2007;110:2302–8.PubMed Soriano AO, Yang H, Faderl S, et al. Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood. 2007;110:2302–8.PubMed
91.
Zurück zum Zitat Blum W, Klisovic RB, Hackanson B, et al. Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. J Clin Oncol. 2007;25:3884–91.PubMed Blum W, Klisovic RB, Hackanson B, et al. Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. J Clin Oncol. 2007;25:3884–91.PubMed
92.
Zurück zum Zitat Prebet T, Braun T, Beyne-Rauzy O, et al. Combination of vorinostat and low dose cytarabine for patients with azacitidine-refractory/relapsed high risk myelodysplastic syndromes. Leuk Res. 2014;38:29–33.PubMed Prebet T, Braun T, Beyne-Rauzy O, et al. Combination of vorinostat and low dose cytarabine for patients with azacitidine-refractory/relapsed high risk myelodysplastic syndromes. Leuk Res. 2014;38:29–33.PubMed
93.
Zurück zum Zitat Blum W, Garzon R, Klisovic RB, 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 U S A. 2010;107:7473–8.PubMedCentralPubMed Blum W, Garzon R, Klisovic RB, 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 U S A. 2010;107:7473–8.PubMedCentralPubMed
94.
Zurück zum Zitat Grovdal M, Karimi M, Khan R, et al. Maintenance treatment with azacytidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy. Br J Haematol. 2010;150:293–302.PubMed Grovdal M, Karimi M, Khan R, et al. Maintenance treatment with azacytidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy. Br J Haematol. 2010;150:293–302.PubMed
95.
Zurück zum Zitat Oganesian A, Redkar S, Taverna P, Joshi-Hangal R, Azab M. Preclinical data in cynomolgus (cyn) monkeys of ASTX727, a novel oral hypomethylating agent (HMA) composed of low-dose oral decitabine combined with a novel cytidine deaminase inhibitor (CDAi) E7727. Blood. 2013;122. Oganesian A, Redkar S, Taverna P, Joshi-Hangal R, Azab M. Preclinical data in cynomolgus (cyn) monkeys of ASTX727, a novel oral hypomethylating agent (HMA) composed of low-dose oral decitabine combined with a novel cytidine deaminase inhibitor (CDAi) E7727. Blood. 2013;122.
96.
Zurück zum Zitat Chuang JC, Warner SL, Vollmer D, et al. S110, a 5-Aza-2′-deoxycytidine-containing dinucleotide, is an effective DNA methylation inhibitor in vivo and can reduce tumor growth. Mol Cancer Ther. 2010;9:1443–50.PubMedCentralPubMed Chuang JC, Warner SL, Vollmer D, et al. S110, a 5-Aza-2′-deoxycytidine-containing dinucleotide, is an effective DNA methylation inhibitor in vivo and can reduce tumor growth. Mol Cancer Ther. 2010;9:1443–50.PubMedCentralPubMed
97.
Zurück zum Zitat Laille E, Savona MR, Scott BL, Boyd TE, Dong Q, Skikne B. Pharmacokinetics of different formulations of oral azacitidine (CC-486) and the effect of food and modified gastric pH on pharmacokinetics in subjects with hematologic malignancies. J Clin Pharmacol. 2014;54:630–9.PubMed Laille E, Savona MR, Scott BL, Boyd TE, Dong Q, Skikne B. Pharmacokinetics of different formulations of oral azacitidine (CC-486) and the effect of food and modified gastric pH on pharmacokinetics in subjects with hematologic malignancies. J Clin Pharmacol. 2014;54:630–9.PubMed
98.
Zurück zum Zitat Goodyear O, Agathanggelou A, Novitzky-Basso I, et al. Induction of a CD8+ T-cell response to the MAGE cancer testis antigen by combined treatment with azacitidine and sodium valproate in patients with acute myeloid leukemia and myelodysplasia. Blood. 2010;116:1908–18.PubMed Goodyear O, Agathanggelou A, Novitzky-Basso I, et al. Induction of a CD8+ T-cell response to the MAGE cancer testis antigen by combined treatment with azacitidine and sodium valproate in patients with acute myeloid leukemia and myelodysplasia. Blood. 2010;116:1908–18.PubMed
99.
Zurück zum Zitat Sanchez-Abarca LI, Gutierrez-Cosio S, Santamaria C, et al. Immunomodulatory effect of 5-azacytidine (5-azaC): potential role in the transplantation setting. Blood. 2010;115:107–21.PubMed Sanchez-Abarca LI, Gutierrez-Cosio S, Santamaria C, et al. Immunomodulatory effect of 5-azacytidine (5-azaC): potential role in the transplantation setting. Blood. 2010;115:107–21.PubMed
100.
Zurück zum Zitat Scott BL, Ramakrishnan A, Storer B, et al. Prolonged responses in patients with MDS and CMML treated with azacitidine and etanercept. Br J Haematol. 2010;148:944–7.PubMedCentralPubMed Scott BL, Ramakrishnan A, Storer B, et al. Prolonged responses in patients with MDS and CMML treated with azacitidine and etanercept. Br J Haematol. 2010;148:944–7.PubMedCentralPubMed
101.
Zurück zum Zitat Sekeres MA, List AF, Cuthbertson D, et al. Phase I combination trial of lenalidomide and azacitidine in patients with higher-risk myelodysplastic syndromes. J Clin Oncol. 2010;28:2253–8.PubMedCentralPubMed Sekeres MA, List AF, Cuthbertson D, et al. Phase I combination trial of lenalidomide and azacitidine in patients with higher-risk myelodysplastic syndromes. J Clin Oncol. 2010;28:2253–8.PubMedCentralPubMed
102.
Zurück zum Zitat Sekeres MA, O’Keefe C, List AF, et al. Demonstration of additional benefit in adding lenalidomide to azacitidine in patients with higher-risk myelodysplastic syndromes. Am J Hematol. 2011;86:102–3.PubMed Sekeres MA, O’Keefe C, List AF, et al. Demonstration of additional benefit in adding lenalidomide to azacitidine in patients with higher-risk myelodysplastic syndromes. Am J Hematol. 2011;86:102–3.PubMed
103.
Zurück zum Zitat Silverman LR, Greenberg P, Raza A, et al. Clinical activity and safety of the dual pathway inhibitor rigosertib for higher risk myelodysplastic syndromes following DNA methyltransferase inhibitor therapy. Hematol Oncol. 2014. Silverman LR, Greenberg P, Raza A, et al. Clinical activity and safety of the dual pathway inhibitor rigosertib for higher risk myelodysplastic syndromes following DNA methyltransferase inhibitor therapy. Hematol Oncol. 2014.
104.
Zurück zum Zitat Kantarjian H, Garcia-Manero G, O’Brien S, et al. Phase I clinical and pharmacokinetic study of oral sapacitabine in patients with acute leukemia and myelodysplastic syndrome. J Clin Oncol. 2010;28:285–91.PubMedCentralPubMed Kantarjian H, Garcia-Manero G, O’Brien S, et al. Phase I clinical and pharmacokinetic study of oral sapacitabine in patients with acute leukemia and myelodysplastic syndrome. J Clin Oncol. 2010;28:285–91.PubMedCentralPubMed
105.
Zurück zum Zitat Ferrero D, Crisa E, Marmont F, et al. Survival improvement of poor-prognosis AML/MDS patients by maintenance treatment with low-dose chemotherapy and differentiating agents. Ann Hematol. 2014. Ferrero D, Crisa E, Marmont F, et al. Survival improvement of poor-prognosis AML/MDS patients by maintenance treatment with low-dose chemotherapy and differentiating agents. Ann Hematol. 2014.
106.
Zurück zum Zitat Tahiliani M, Koh KP, Shen Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009;324:930–5.PubMedCentralPubMed Tahiliani M, Koh KP, Shen Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009;324:930–5.PubMedCentralPubMed
107.
Zurück zum Zitat Ko M, Huang Y, Jankowska AM, et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature. 2010;468:839–43.PubMedCentralPubMed Ko M, Huang Y, Jankowska AM, et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature. 2010;468:839–43.PubMedCentralPubMed
108.•
Zurück zum Zitat Langemeijer SM, Kuiper RP, Berends M, et al. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet. 2009;41:838–42. Report of the important finding that mutations in TET2 are recurrent in MDS.PubMed Langemeijer SM, Kuiper RP, Berends M, et al. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet. 2009;41:838–42. Report of the important finding that mutations in TET2 are recurrent in MDS.PubMed
109.
Zurück zum Zitat Tefferi A, Lim KH, Abdel-Wahab O, et al. Detection of mutant TET2 in myeloid malignancies other than myeloproliferative neoplasms: CMML, MDS, MDS/MPN and AML. Leukemia. 2009;23:1343–5.PubMed Tefferi A, Lim KH, Abdel-Wahab O, et al. Detection of mutant TET2 in myeloid malignancies other than myeloproliferative neoplasms: CMML, MDS, MDS/MPN and AML. Leukemia. 2009;23:1343–5.PubMed
110.
Zurück zum Zitat Jankowska AM, Szpurka H, Tiu RV, et al. Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms. Blood. 2009;113:6403–10.PubMedCentralPubMed Jankowska AM, Szpurka H, Tiu RV, et al. Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms. Blood. 2009;113:6403–10.PubMedCentralPubMed
111.
Zurück zum Zitat 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. 2011;25:1147–52.PubMed 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. 2011;25:1147–52.PubMed
112.•
Zurück zum Zitat Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18:553–67. Described mechanism of interaction between IDH and TET2 to contribute to MDS pathogenesis.PubMedCentralPubMed Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18:553–67. Described mechanism of interaction between IDH and TET2 to contribute to MDS pathogenesis.PubMedCentralPubMed
113.
Zurück zum Zitat Jin J, Hu C, Yu M, et al. Prognostic value of isocitrate dehydrogenase mutations in myelodysplastic syndromes: a retrospective cohort study and meta-analysis. PLoS One. 2014;9:e100206.PubMedCentralPubMed Jin J, Hu C, Yu M, et al. Prognostic value of isocitrate dehydrogenase mutations in myelodysplastic syndromes: a retrospective cohort study and meta-analysis. PLoS One. 2014;9:e100206.PubMedCentralPubMed
114.
Zurück zum Zitat Yen K, Wang F, Travins J, et al. AG-221 offers a survival advantage in a primary human IDH2 mutant AML xenograft model. Blood. 2013;122. Yen K, Wang F, Travins J, et al. AG-221 offers a survival advantage in a primary human IDH2 mutant AML xenograft model. Blood. 2013;122.
115.
Zurück zum Zitat Schumacher T, Bunse L, Pusch S, et al. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature. 2014. Schumacher T, Bunse L, Pusch S, et al. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature. 2014.
116.
Zurück zum Zitat Ogasawara S, Kaneko MK, Tsujimoto Y, Liu X, Kato Y. Multi-specific monoclonal antibody MsMab-2 recognizes IDH1-R132L and IDH2-R172M mutations. Monoclon Antibodies Immunodiagnosis Immunother. 2013;32:377–81. Ogasawara S, Kaneko MK, Tsujimoto Y, Liu X, Kato Y. Multi-specific monoclonal antibody MsMab-2 recognizes IDH1-R132L and IDH2-R172M mutations. Monoclon Antibodies Immunodiagnosis Immunother. 2013;32:377–81.
117.
Zurück zum Zitat Nikoloski G, Langemeijer SM, Kuiper RP, et al. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat Genet. 2010;42:665–7.PubMed Nikoloski G, Langemeijer SM, Kuiper RP, et al. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat Genet. 2010;42:665–7.PubMed
118.
Zurück zum Zitat Gelsi-Boyer V, Trouplin V, Adelaide J, et al. Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. Br J Haematol. 2009;145:788–800.PubMed Gelsi-Boyer V, Trouplin V, Adelaide J, et al. Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. Br J Haematol. 2009;145:788–800.PubMed
119.
Zurück zum Zitat Walter MJ, Ding L, Shen D, et al. Recurrent DNMT3A mutations in patients with myelodysplastic syndromes. Leukemia. 2011;25:1153–8.PubMedCentralPubMed Walter MJ, Ding L, Shen D, et al. Recurrent DNMT3A mutations in patients with myelodysplastic syndromes. Leukemia. 2011;25:1153–8.PubMedCentralPubMed
120.
Zurück zum Zitat Traina F, Visconte V, Elson P, et al. Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms. Leukemia. 2014;28:78–87.PubMed Traina F, Visconte V, Elson P, et al. Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms. Leukemia. 2014;28:78–87.PubMed
121.•
Zurück zum Zitat Yoshida K, Sanada M, Shiraishi Y, et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature. 2011;478:64–9. Detailed the high prevalence of splicing gene mutations in MDS.PubMed Yoshida K, Sanada M, Shiraishi Y, et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature. 2011;478:64–9. Detailed the high prevalence of splicing gene mutations in MDS.PubMed
122.
Zurück zum Zitat Abdel-Wahab O, Levine R. The spliceosome as an indicted conspirator in myeloid malignancies. Cancer Cell. 2011;20:420–3.PubMedCentralPubMed Abdel-Wahab O, Levine R. The spliceosome as an indicted conspirator in myeloid malignancies. Cancer Cell. 2011;20:420–3.PubMedCentralPubMed
123.
Zurück zum Zitat Damm F, Thol F, Kosmider O, et al. SF3B1 mutations in myelodysplastic syndromes: clinical associations and prognostic implications. Leukemia. 2012;26:1137–40.PubMed Damm F, Thol F, Kosmider O, et al. SF3B1 mutations in myelodysplastic syndromes: clinical associations and prognostic implications. Leukemia. 2012;26:1137–40.PubMed
124.••
Zurück zum Zitat Papaemmanuil E, Cazzola M, Boultwood J, et al. Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N Engl J Med. 2011;365:1384–95. Reported the association between mutations in SF3B1 and the morphologic finding of ring sideroblasts.PubMedCentralPubMed Papaemmanuil E, Cazzola M, Boultwood J, et al. Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N Engl J Med. 2011;365:1384–95. Reported the association between mutations in SF3B1 and the morphologic finding of ring sideroblasts.PubMedCentralPubMed
125.
Zurück zum Zitat Kaida D, Motoyoshi H, Tashiro E, et al. Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA. Nat Chem Biol. 2007;3:576–83.PubMed Kaida D, Motoyoshi H, Tashiro E, et al. Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA. Nat Chem Biol. 2007;3:576–83.PubMed
126.
Zurück zum Zitat Schlenk RF, Dohner K, Kneba M, et al. Gene mutations and response to treatment with all-trans retinoic acid in elderly patients with acute myeloid leukemia. Results from the AMLSG Trial AML HD98B. Haematologica. 2009;94:54–60.PubMedCentralPubMed Schlenk RF, Dohner K, Kneba M, et al. Gene mutations and response to treatment with all-trans retinoic acid in elderly patients with acute myeloid leukemia. Results from the AMLSG Trial AML HD98B. Haematologica. 2009;94:54–60.PubMedCentralPubMed
127.
Zurück zum Zitat Renneville A, Quesnel B, Charpentier A, et al. High occurrence of JAK2 V617 mutation in refractory anemia with ringed sideroblasts associated with marked thrombocytosis. Leukemia. 2006;20:2067–70.PubMed Renneville A, Quesnel B, Charpentier A, et al. High occurrence of JAK2 V617 mutation in refractory anemia with ringed sideroblasts associated with marked thrombocytosis. Leukemia. 2006;20:2067–70.PubMed
128.
Zurück zum Zitat Constantinidou M, Chalevelakis G, Economopoulos T, et al. Codon 12 ras mutations in patients with myelodysplastic syndrome: incidence and prognostic value. Ann Hematol. 1997;74:11–4.PubMed Constantinidou M, Chalevelakis G, Economopoulos T, et al. Codon 12 ras mutations in patients with myelodysplastic syndrome: incidence and prognostic value. Ann Hematol. 1997;74:11–4.PubMed
129.
Zurück zum Zitat Santamaria C, Ramos F, Puig N, et al. Simultaneous analysis of the expression of 14 genes with individual prognostic value in myelodysplastic syndrome patients at diagnosis: WT1 detection in peripheral blood adversely affects survival. Ann Hematol. 2012;91:1887–95.PubMed Santamaria C, Ramos F, Puig N, et al. Simultaneous analysis of the expression of 14 genes with individual prognostic value in myelodysplastic syndrome patients at diagnosis: WT1 detection in peripheral blood adversely affects survival. Ann Hematol. 2012;91:1887–95.PubMed
130.
Zurück zum Zitat Wanquet A, Berthon C, Sebert M, et al. Azacitidine treatment for patients with myelodysplastic syndromes and acute myeloid leukemia harboring chromosome 3q abnormalities. Blood. 2013;122. Wanquet A, Berthon C, Sebert M, et al. Azacitidine treatment for patients with myelodysplastic syndromes and acute myeloid leukemia harboring chromosome 3q abnormalities. Blood. 2013;122.
131.
Zurück zum Zitat Sekeres MA, Maciejewski JP, List AF, et al. Perceptions of disease state, treatment outcomes, and prognosis among patients with myelodysplastic syndromes: results from an internet-based survey. Oncologist. 2011;16:904–11.PubMedCentralPubMed Sekeres MA, Maciejewski JP, List AF, et al. Perceptions of disease state, treatment outcomes, and prognosis among patients with myelodysplastic syndromes: results from an internet-based survey. Oncologist. 2011;16:904–11.PubMedCentralPubMed
132.
Zurück zum Zitat Steensma DP, Heptinstall KV, Johnson VM, et al. Common troublesome symptoms and their impact on quality of life in patients with myelodysplastic syndromes (MDS): results of a large internet-based survey. Leuk Res. 2008;32:691–8.PubMed Steensma DP, Heptinstall KV, Johnson VM, et al. Common troublesome symptoms and their impact on quality of life in patients with myelodysplastic syndromes (MDS): results of a large internet-based survey. Leuk Res. 2008;32:691–8.PubMed
Metadaten
Titel
Stopping Higher-Risk Myelodysplastic Syndrome in Its Tracks
verfasst von
Daniel A. Pollyea
Jonathan A. Gutman
Publikationsdatum
01.12.2014
Verlag
Springer US
Erschienen in
Current Hematologic Malignancy Reports / Ausgabe 4/2014
Print ISSN: 1558-8211
Elektronische ISSN: 1558-822X
DOI
https://doi.org/10.1007/s11899-014-0234-1

Weitere Artikel der Ausgabe 4/2014

Antiplatelet Therapy in the Management of Myeloproliferative Neoplasms

  • Myeloproliferative Disorders (C Harrison, Section Editor)

Quality of Life in MPN Comes of Age as a Therapeutic Target

  • Myeloproliferative Disorders (C Harrison, Section Editor)

Epidemiology of MPN: What Do We Know?

  • Myeloproliferative Disorders (C Harrison, Section Editor)

Lessons from the Atomic Bomb About Secondary MDS

  • Myelodysplastic Syndromes (M Sekeres, Section Editor)

I Walk the Line: How to Tell MDS From Other Bone Marrow Failure Conditions

  • Myelodysplastic Syndromes (M Sekeres, Section Editor)

Neu im Fachgebiet Onkologie

Frühe CLL-Therapie: BTK-Hemmer verlängert EFS und PFS, aber nicht OS

Auch nach sechs Jahren ergibt sich kein Überlebensvorteil einer Therapie mit dem BTK-Hemmer Ibrutinib für Menschen mit frühem CLL-Stadium und erhöhtem Progressionsrisiko. Die Progressionsrate wird mit der Behandlung jedoch um über 80% gesenkt.

Adjuvantes Atezolizumab ohne Nutzen bei frühem TNBC

Patientinnen mit frühem triple-negativem Brustkrebs profitieren nach der Operation offenbar nicht von einer Zugabe des PD-L1-Hemmers Atezolizumab zur adjuvanten Standardchemotherapie. Die Studie, die das untersucht hat, wurde vorzeitig abgebrochen. Was könnte die schlechte Wirksamkeit erklären?

Brustkrebstherapie: zu wenig Aufklärung über Nebenwirkungen?

Ergebnisse eines internationalen Surveys legen nahe, dass die Aufklärung über Nebenwirkungen einer Brustkrebstherapie häufig unzureichend ausfällt bzw. zu spät erfolgt.

Neue chemotherapiefreie Kombinationstherapie punktet bei CLL

Zwischenergebnisse der Phase-III-Studie AMPLIFY sprechen dafür, dass die zeitlich begrenzte Behandlung mit Acalabrutinib und Venetoclax fitte Personen mit chronischer lymphatischer Leukämie länger leben lässt als eine Chemoimmuntherapie.

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.