Decitabine Improves Response Rate and Prolongs Progression Free Survival in Older Patients with Newly Diagnosed Acute Myeloid Leukemia with Monosomal Karyotype: A Subgroup Analysis of the Daco-16 Trial
Authors: Wierzbowska Agnieszka , Wawrzyniak Ewa , Pluta Agnieszka , Robak Tadeusz , Mazur Grzegorz J. , Dmoszynska Anna , Cermak Jaroslav , Oriol Albert , Ravandi Farhad , Kantarjian Hagop M. 
Published: October 2019

Abstract
Background: Cytogenetics is one of the most important prognostic factors in acute myeloid leukemia (AML). Monosomal karyotype (MK), defined as two or more distinct autosomal monosomies or one single autosomal monosomy in the presence of at least one structural abnormality, has been identified as a new cytogenetic category associated with particularly poor prognosis (Breems, JCO, 2008). AML patients (pts) with MK+ have shorter overall survival (OS) compared to other unfavorable karyotypes, irrespective of treatment intensity. However, preliminary results from a phase II trial of decitabine (DEC) as first-line treatment for elderly AML pts demonstrated that an objective response rate (CR+PR) in MK+ pts was higher than in the MK- cases with abnormal cytogenetics. Moreover, the OS of MK+ pts was comparable to that of MK- pts (LÃ¼bbert, Haematologica, 2012). This observation might suggest a positive effect of DEC in patients with MK+ AML.
Objective: To determine the effects of treatment with DEC vs low-dose cytarabine or best supportive care (BSC) as a treatment of choice (TC) on OS, progression free survival (PFS) and response rate (CR/CRp) in the subset of pts with AML MK+, who were treated in the randomized phase III DACO-16 study. A second objective is to compare the OS, PFS and CR/CRp of MK+ vs other unfavorable karyotype cases.
Methods: Eligible pts were ≥65 years old with newly diagnosed, de novo or secondary AML with ≥20% bone marrow blasts, ECOG performance status 0-2, WBC count ≤40x109/L. According to study protocol pts were randomly assigned 1:1 to receive DEC 20 mg/m2 per day as a 1-hour i.v. infusion for five days every 4 weeks or TC (BSC or cytarabine 20 mg/m2 s.c. for 10 days every 4 weeks). This analysis included pts identified from the clinical database whose locally obtained cytogenetics data indicated they had MK+. Pts with poor-risk cytogenetics (Southwest Oncology Group classification) but MK- (poor-risk MK-) were used as the comparison group. Median OS (Kaplan-Meier method) and PFS were compared between decitabine vs TC treatment arms for pts MK+ and poor-risk MK-. Remission was assessed using modified IWG AML criteria (Cheson, Blood, 2003).
Results: Of 480 pts in DACO-16 study, 64 (13.3%) fulfilled the criteria for MK+ and additional 99 (20.6%) had poor-risk MK- cytogenetics. In MK+ group 33 pts received DEC and 31 pts were assigned to TC. In poor-risk MK- group DEC and TC was administered to 49 and 50 pts respectively. Baseline characteristics of treatment subgroups were comparable.
Outcome of MK+ and poor-risk MK- pts according to treatment arm
The CR/CRp rate in MK+ pts was higher in the DEC arm compared to TC (21% vs 3%; OR=8.1; 95% CI, 0.93 to 70.04; P = 0.054). The median PFS was also improved in the DEC arm vs TC (2.6 vs 1.3 mos, HR=0.53; 95% CI, 0.31 to 0.9; P = 0.018) Fig.1. There was a trend towards longer OS by ~4 mos in the DEC arm vs TC (2.6 vs 6.3 mos; HR=0.67; 95% CI, 0.39 to 1.15; p=0.14) Fig.2. In contrast, no difference in CR/CRp rate between DEC vs TC was observed in poor-risk MK- pts (respectively 8% vs 10%; OR=0.8; 95% CI, 0.2 to 3.17; P = 1.0). Similarly, no improvement in PFS as well as OS was observed in poor-risk MK- cases treated with DEC compared to TC.
Overall survival in decitabine and TC treatment arms according to cytogenetics
In AML patients receiving low-dose cytarabine or BSC, patients with MK+ appeared to have a poorer outcome than pts with poor-risk MK-. The median OS was 2.6 vs 4.7 mos (HR=1.52; 95% CI, 0.91 to 2.54; p=0.11) in MK+ and poor-risk MK- pts, respectively. In contrast, in the DEC arm MK+ pts did not do worse than MK- cases with poor-risk cytogenetics. The median OS was similar: 6.3 vs 5.0 mos for MK+ and poor-risk MK- (HR=0.98; 95% CI, 0.6 to 1.58; p=0.92), respectively.
Conclusions: In older patients with AML-MK+, decitabine improved CR/CRp rate and PFS compared with standard therapies. A survival analysis suggesting a benefit of about 4 months in median OS for decitabine in MK+ AML needs confirmation in further studies with larger sample size. These data might suggest decitabine overcomes the extremely poor prognosis associated with MK and may be a beneficial initial treatment as an alternative to low-dose cytarabine or best supportive care.
Figure 1. PFS of patients with AML MK+ according to treatment Figure 1. PFS of patients with AML MK+ according to treatment Figure 2. OS of patients with AML MK+ according to treatment Figure 2. OS of patients with AML MK+ according to treatment

Disclosures
Wierzbowska: Janssen, Celgene: Consultancy. Off Label Use: Decitabine in elderly AML patients. Robak:Eisai Inc: Research Funding. Oriol:Celgene, Janssen, Amgen: Consultancy, Speakers Bureau.