Five-Day Versus Ten-Day Schedules of Decitabine in Older Patients with Newly Diagnosed Acute Myeloid Leukemia: Results of a Randomized Phase II Study
Authors: Short Nicholas J , Kantarjian Hagop M. , Loghavi Sanam , Huang Xuelin , Qiao Wei , Borthakur Gautam , Kadia Tapan M. , Daver Naval G. , Ohanian Maro N. , DiNardo Courtney D. , Estrov Zeev E. , Kanagal-Shamanna Rashmi , Maiti Abhishek , Benton Christopher B. , Bose Prithviraj , Alvarado Yesid , Jabbour Elias J. , Kornblau Steven M. , Pemmaraju Naveen , Jain Nitin , Gasior Yvonne , Richie Mary Ann , Pierce Sherry A. , Cortes Jorge E. , Konopleva Marina Y. , Garcia-Manero Guillermo , Ravandi Farhad 
Published: October 2019

Abstract
Background: Single-arm studies have suggested that a 10-day schedule of decitabine (DAC) may result in better outcomes than the standard 5-day schedule in older patients (pts) with acute myeloid leukemia (AML), particularly in pts with TP53 mutations. We therefore designed a randomized phase II study to evaluate the relative safety and efficacy of these two different schedules of DAC in this older population.
Methods: Adults ≥60 years of age with newly diagnosed AML were randomized using a Bayesian adaptive design to receive DAC at a dose of 20 mg/m2 IV daily for either 5 or 10 consecutive days as induction. Pts <60 years of age were also eligible if not suitable candidates for intensive chemotherapy. Pts were required to have an ECOG performance status of 0-3 and adequate renal and hepatic function. Pts who had received prior hypomethylating agents were ineligible. Pts could receive up to 3 courses of DAC at the randomly assigned dose; once in remission, pts received the 5-day schedule of DAC for consolidation (up to 24 total cycles). The primary endpoint was the response rates of the 2 DAC schedules. Secondary endpoints included the response duration, overall survival (OS) and the safety of the 2 schedules. As an exploratory analysis, pts with baseline TP53 mutation underwent single-gene TP53 sequencing in serial samples to track TP53 clones with DAC treatment.
Results: Between 2/2013 and 4/2018, 71 pts were randomized to receive DAC for either 5 days (n=28) or 10 days (n=43). Baseline characteristics of the 2 arms were well-balanced and are shown in Table 1. The median age of the entire cohort was 78 years (range, 57-94 years). TP53 mutations were detected in 7/24 pts (29%) in the 5-day arm and in 17/41 pts (41%) in the 10-day arm.
The composite CR + CRp + CRi rate was similar in both arms (12/28 [43%] in 5-day arm vs 17/43 [40%] in the 10-day arm; P=0.78). CR rates were 29% and 30%, respectively. Given the similar response rates, this trial terminated early for futility. There was a trend towards earlier responses with the 10-day schedule (P=0.09). No significant differences in response rates were observed by disease subgroups (cytogenetics, de novo vs. secondary AML, or TP53 mutation). The 30-day mortality rates for the 5-day and 10-day arms were 4% and 9%, and the 60-day mortality rates were 21% and 25%, respectively.
The median duration of follow-up was 38.2 months. The median remission duration for the 5-day and 10-day schedules was 9.4 and 6.4 months, and 1-year continuous remission rates were 26% and 33%, respectively (P=0.98; Figure 1A). The median OS was 5.5 and 6.0 months, respectively, and 1-year OS rates were 25% in both arms (P=0.47; Figure 1B). No significant difference in OS was observed between schedules when stratified by disease subgroups. Median OS for pts with TP53-mutated AML was 5.5 months for the 5-day arm and 4.9 months for the 10-day arm (P=0.55).
There were no differences in baseline TP53 variant allelic frequency (VAF) in pts who responded to DAC compared to those who did not (P=0.70). Responding pts had a significant decline in TP53 VAF at the end of cycle 1 (mean ± SD baseline VAF 53.2% ± 19.7% vs end-of-cycle 1 VAF 27.5% ± 23.9%, P<0.001; Figure 2). In contrast, non-responding pts did not have a significant change in the TP53 VAF. Two pts had no TP53 mutation detected in a post-treatment sample (both 10-day arm). These two pts were the longest survivors in the mutant TP53 cohort (OS of 12.4 and 19.9 months)
Conclusions: In older adults with newly diagnosed AML, DAC given for either 5 or 10 consecutive days resulted in similar response rates, early mortality and survival. No differences in response or survival were observed in any subgroup, including TP53-mutated AML.

Disclosures
Short: Takeda Oncology: Consultancy. Kadia:Pfizer: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy; Celgene: Research Funding; Celgene: Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Novartis: Consultancy; BMS: Research Funding; Novartis: Consultancy; Abbvie: Consultancy; BMS: Research Funding; Abbvie: Consultancy; Pfizer: Consultancy, Research Funding. Daver:Incyte: Research Funding; Pfizer: Consultancy; Kiromic: Research Funding; Otsuka: Consultancy; Karyopharm: Consultancy; BMS: Research Funding; Karyopharm: Research Funding; Incyte: Consultancy; ARIAD: Research Funding; Daiichi-Sankyo: Research Funding; ImmunoGen: Consultancy; Alexion: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; Sunesis: Consultancy; Novartis: Consultancy; Sunesis: Research Funding. DiNardo:Celgene: Honoraria; Agios: Consultancy; Medimmune: Honoraria; Abbvie: Honoraria; Karyopharm: Honoraria; Bayer: Honoraria. Maiti:Celgene Corporation: Other: Research funding to the institution. Bose:Blueprint Medicines Corporation: Research Funding; Celgene Corporation: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Constellation Pharmaceuticals: Research Funding; Incyte Corporation: Honoraria, Research Funding; Pfizer, Inc.: Research Funding; CTI BioPharma: Research Funding. Jabbour:Bristol-Myers Squibb: Consultancy, Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Pemmaraju:Affymetrix: Research Funding; SagerStrong Foundation: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Research Funding; cellectis: Research Funding; stemline: Consultancy, Honoraria, Research Funding; novartis: Research Funding. Jain:Abbvie: Research Funding; Celgene: Research Funding; Astra Zeneca: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Verastem: Research Funding; ADC Therapeutics: Research Funding; Cellectis: Research Funding; Celgene: Research Funding; Incyte: Research Funding; Pfizer: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Genentech: Research Funding; Incyte: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Pharmacyclics: Research Funding; Servier: Research Funding; Seattle Genetics: Research Funding; Astra Zeneca: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; ADC Therapeutics: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Infinity: Research Funding; BMS: Research Funding; Infinity: Research Funding; Genentech: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cortes:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding; Daiichi Sankyo: Consultancy, Research Funding. Konopleva:Stemline Therapeutics: Research Funding. Ravandi:Xencor: Research Funding; Macrogenix: Honoraria, Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Orsenix: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Abbvie: Research Funding; Xencor: Research Funding; Seattle Genetics: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Orsenix: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Research Funding; Sunesis: Honoraria; Sunesis: Honoraria; Abbvie: Research Funding; Jazz: Honoraria; Jazz: Honoraria.