A multicenter phase II trial of decitabine as first-line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy

Abstract

The online version of this article has a Supplementary Appendix. BackgroundThe treatment of acute myeloid leukemia of older, medically non-fit patients still poses a highly unmet clinical need, and only few large, prospective studies have been performed in this setting. Given the established activity of hypomethylating agents such as 5-aza-2'-deoxycytidine (decitabine) in myelodysplastic syndromes and acute myeloid leukemia with 20-30% bone marrow blasts, we investigated whether this drug is also active in patients with more than 30% blasts. Design and MethodsTo evaluate the efficacy and toxicity of decitabine in patients over 60 years old with untreated acute myeloid leukemia ineligible for induction chemotherapy, 227 patients (median age, 72 years), many with comorbidities, adverse cytogenetics and/or preceding myelodysplastic syndrome were treated with this hypomethylating agent. During the initial decitabine treatment (135 mg/m 2 total dose infused intravenously over 72 hours every 6 weeks), a median of two cycles was administered (range, 1-4). All-trans retinoic acid was administered to 100 patients during course 2. Fifty-two patients who completed four cycles of treatment subsequently received a median of five maintenance courses (range, 1-19) with a lower dose of decitabine (20 mg/m 2 ) infused over 1 hour on 3 consecutive days every 4-6 weeks. ResultsThe complete and partial remission rate was 26%, 95% CI (20%, 32%), and an antileukemic effect was noted in 26% of patients. Response rates did not differ between patients with or without adverse cytogenetics; patients with monosomal karyotypes also responded. The median overall survival from the start of decitabine treatment was 5.5 months (range, 0-57.5+) and the 1-year survival rate was 28%, 95%CI (22%,34%). Toxicities were predominantly hematologic. ConclusionsDecitabine is well tolerated by older, medically non-fit patients with acute myeloid leukemia; myelosuppression is the major toxicity. The response rate and overall survival were not adversely influenced by poor-risk cytogenetics or myelodysplastic syndrome. Because of these encouraging results, randomized studies evaluating single-agent decitabine versus conventional treatment are warranted. The study is registered with the German Clinical Trials Registry, number DRKS00000069. chemotherapy. Haematologica 2012;97(3):393-401. doi:10.3324/haematol.2011 This is an open-access paper.A multicenter phase II trial of decitabine as first-line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy

Decitabine improves progression-free survival in older high-risk MDS patients with multiple autosomal monosomies: results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group

“…Not surprisingly, a complex karyotype thus scores in the very highrisk cytogenetic groups of AML and MDS [2][3][4][5]. Notably, it recently became apparent that clofarabine and the DNA hypomethylating agents azacytidine and decitabine (DAC) have marked activity in complex-karyotype AML [6][7][8][9] and MDS [10][11][12][13][14][15][16]. However, it is unclear why these drugs differ from cytarabine and other cytotoxic agents in that regard.…”

“…Since the large phase II DAC trial 00331 had recruited 54 CK+ patients, their outcome was compared with regard to the presence (MK+/ CK+, n = 37) or absence (MK−/CK+, n = 17) of the monosomal karyotype [8]. Intriguingly, the response rate was superior in the MK+/CK+ AML patients compared to MK−/CK+ patients (complete plus partial remissions 37 vs. 12 %).…”

Comparison of epigenetic versus standard induction chemotherapy for newly diagnosed acute myeloid leukemia patients ≥60 years old

“…HMA inhibit epigenetic silencing of cell-cycle regulatory elements and tumor suppressor genes, thus suppressing the reversible epigenetic changes that play a major role in pathogenesis of leukemogenesis [13][14][15][16]. Two agents, decitabine (Dec) and azacitidine (Aza), have been approved for the treatment of patients with myelodysplastic syndrome (MDS) and have been well tolerated in elderly individuals, leading to multiple clinical trials evaluating their use in older AML patients [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32]. The earliest clinical data of HMAs in AML patients were noncomparative trials mostly involving individuals unfit for IC [17][18][19][20]25].…”

“…Two agents, decitabine (Dec) and azacitidine (Aza), have been approved for the treatment of patients with myelodysplastic syndrome (MDS) and have been well tolerated in elderly individuals, leading to multiple clinical trials evaluating their use in older AML patients [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32]. The earliest clinical data of HMAs in AML patients were noncomparative trials mostly involving individuals unfit for IC [17][18][19][20]25]. Next, subgroup analyses of large prospective phase III trials of Aza or Dec demonstrated superior outcomes for HMA over best supportive care in AML patients with marrow blast counts of 20-30% [21,30,33].…”

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)

“…Studies have suggested associations between the response to decitabine and genetic aberrations (e.g., monosomal karyotype, TET2 mutations), mRNA or microRNA expression, or DNA methylation [25][26][27][28][29][30][31][32]. Unfortunately, we did not have sufficient material to investigate molecular markers in our cohort.…”