Decitabine versus best supportive care in older patients with refractory anemia with excess blasts in transformation (RAEBt) - results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group (GMDSSG)
BECKER, Heiko; SUCIU, Stefan; RUTER, Björn Hanset al.
[en] In the European Organisation for Research and Treatment of Cancer (EORTC)/GMDSSG phase III trial06011, we compared decitabine (15 mg/m² every 8 h for 3 days) with best supportive care (BSC) in patients >/= 60 years with myelodysplastic syndromes (MDS) by French-Amercian-British (FAB) criteria. Here, we reinvestigate trial 06011 for the activity and efficacy specifically in patients with refractory anemia with excess blasts in transformation (RAEBt). Response rates in the decitabine arm (N=40) were as follow: complete or partial remission, 15 %; hematologic improvement, 15 %; resistant disease, 30 %. RAEBt patients in the decitabine arm had longer progression-free survival (PFS; hazard ratio (HR) 0.30, 95 % confidence interval (CI) 0.18-0.51; median, 6.2 vs 2.8 months) and overall survival (OS; HR 0.68, 95 % CI 0.42-1.11; median, 8.0 vs 6.0 months) than in the BSC arm (N=35). Censoring at allogeneic hematopoietic stem cell transplantation, the OS difference between the treatment groups increased, particularly among patients.
Disciplines :
Hematology
Author, co-author :
BECKER, Heiko
SUCIU, Stefan
RUTER, Björn Hans
PLATZBECKER, Uwe
GIAGOUNIDIS, Aristoteles
SELLESLAG, Dominik
LABAR, Boris
GERMING, Ulrich
SALIH, Helmut R.
MUUS, Petra
PFLUGER, Karl-Heinz
HAGEMEIJER, Anne
SCHAEFER, Hans-Eckart
FIACCADORI, Valeria
BARON, Frédéric ; Centre Hospitalier Universitaire de Liège - CHU > Hématologie clinique
Decitabine versus best supportive care in older patients with refractory anemia with excess blasts in transformation (RAEBt) - results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group (GMDSSG)
Greenberg P, Cox C, LeBeau MM et al (1997) International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079–2088
Germing U, Gattermann N, Strupp C, Aivado M, Aul C (2000) Validation of the WHO proposals for a new classification of primary myelodysplastic syndromes: a retrospective analysis of 1600 patients. Leuk Res 24:983–992
Kantarjian H, Beran M, Cortes J et al (2006) Long-term follow-up results of the combination of topotecan and cytarabine and other intensive chemotherapy regimens in myelodysplastic syndrome. Cancer 106:1099–1109
Deschler B, de Witte T, Mertelsmann R, Lübbert M (2006) Treatment decision-making for older patients with high-risk myelodysplastic syndrome or acute myeloid leukemia: problems and approaches. Haematologica 91:1513–1522
Estey EH (2013) Epigenetics in clinical practice: the examples of azacitidine and decitabine in myelodysplasia and acute myeloid leukemia. Leukemia 27:1803–1812
Fenaux P, Mufti GJ, Hellström-Lindberg E et al (2010) Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low BM blast count acute myeloid leukemia. J Clin Oncol 28:562–569
Kantarjian HM, Thomas XG, Dmoszynska A et al (2012) Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol 30:2670–2677
Lübbert M, Suciu S, Baila L et al (2011) 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 29:1987–1996
Bennett JM, Catovsky D, Daniel MT et al (1982) Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51:189–199
Cheson BD, Bennett JM, Kantarjian H et al (2000) World Health Organization (WHO) international working group. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood 96:3671–3674
Kalbfleisch JD, Prentice RL (2002) The survival analysis of failure time data, 3rd edn. Wiley Inter-Science, Hoboken
Early Breast Cancer Trialists’ Collaborative Group (1992) Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 339:71–85
Vardiman JW, Brunning RD, Arber DA et al (2008) Introduction and overview of the classification of the myeloid neoplasms. In: Swerdlow SH, Campo E, Harris NL et al (eds) WHO classification of tumours of haematopoietic and lymphoid tissues, 4th edn. IARC, Lyon, pp 18–30
Silverman LR, McKenzie DR, Peterson BL et al (2006) 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 24:3895–3903
Kantarjian H, Issa JP, Rosenfeld CS et al (2006) Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 106:1794–1803
Steensma DP, Baer MR, Slack JL et al (2009) Multicenter study of decitabine administered daily for 5 days every 4 weeks to adults with myelodysplastic syndromes: the alternative dosing for outpatient treatment (ADOPT) trial. J Clin Oncol 27:3842–3848
Jabbour E, Kantarjian H, O’Brien S et al (2013) Retrospective analysis of prognostic factors associated with response and overall survival by baseline marrow blast percentage in patients with myelodysplastic syndromes treated with decitabine. Clin Lymphoma Myeloma Leuk 13:592–596
Quintás-Cardama A, Ravandi F, Liu-Dumlao T et al (2012) Epigenetic therapy is associated with similar survival compared with intensive chemotherapy in older patients with newly diagnosed acute myeloid leukemia. Blood 120:4840–4845
Lee YG, Kim I, Yoon SS et al (2013) Comparative analysis between azacitidine and decitabine for the treatment of myelodysplastic syndromes. Br J Haematol 161:339–347
Lee JH, Choi Y, Kim SD et al (2013) Comparison of 7-day azacitidine and 5-day decitabine for treating myelodysplastic syndrome. Ann Hematol 92:889–897
Smith BD, Beach CL, Mahmoud D, Weber L, Henk HJ (2014) Survival and hospitalization among patients with acute myeloid leukemia treated with azacitidine or decitabine in a large managed care population: a real-world, retrospective, claims-based, comparative analysis. Exp Hematol Oncol 3:10
Xie M, Jiang Q, Xie Y (2015) Comparison between decitabine and azacitidine for the treatment of myelodysplastic syndrome: a meta-analysis with 1,392 participants. Clin Lymphoma Myeloma Leuk 15:22–28
Arber DA, Brunning RD, Orazi A et al (2008) Acute myeloid leukaemia with myelodysplasia-related changes. In: Swerdlow SH, Campo E, Harris NL et al (eds) WHO classification of tumours of haematopoietic and lymphoid tissues, 4th edn. IARC, Lyon, pp 124–126
Dombret H, Seymour JF, Butrym A et al (2015) International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 126:291–299
Shen L, Kantarjian H, Guo Y et al (2010) DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes. J Clin Oncol 28:605–613
Blum W, Garzon R, Klisovic RB et al (2010) 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 107:7473–7478
Metzeler KH, Walker A, Geyer S et al (2012) DNMT3A mutations and response to the hypomethylating agent decitabine in acute myeloid leukemia. Leukemia 26:1106–1107
Lübbert M, Rüter BH, Claus R et al (2012) A multicenter phase II trial of decitabine as first-line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy. Haematologica 97:393–401
Wang H, Fan R, Wang XQ et al (2013) Methylation of Wnt antagonist genes: a useful prognostic marker for myelodysplastic syndrome. Ann Hematol 92:199–209
Yi JH, Huh J, Kim HJ et al (2013) Genome-wide single-nucleotide polymorphism array-based karyotyping in myelodysplastic syndrome and chronic myelomonocytic leukemia and its impact on treatment outcomes following decitabine treatment. Ann Hematol 92:459–469
Yun H, Damm F, Yap D et al (2014) Impact of MLL5 expression on decitabine efficacy and DNA methylation in acute myeloid leukemia. Haematologica 99:1456–1464
Bejar R, Lord A, Stevenson K et al (2014) TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood 124:2705–2712
Momparler RL, Côté S, Eliopoulos N (1997) Pharmacological approach for optimization of the dose schedule of 5-aza-2’-deoxycytidine (decitabine) for the therapy of leukemia. Leukemia 11:175–180
Cabrero M, Jabbour E, Ravandi F et al (2015) Discontinuation of hypomethylating agent therapy in patients with myelodysplastic syndromes or acute myelogenous leukemia in complete remission or partial response: retrospective analysis of survival after long-term follow-up. Leuk Res 39:520–524
de Lima M, Giralt S, Thall PF et al (2010) Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute myelogenous leukemia or myelodysplastic syndrome: a dose and schedule finding study. Cancer 116:5420–5431
Pusic I, Choi J, Fiala MA et al (2015) Maintenance therapy with decitabine after allogeneic stem cell transplantation for acute myelogenous leukemia and myelodysplastic syndrome. Biol Blood Transplant 21:1761–1769