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84 Five-Day Versus Ten-Day Schedules of Decitabine in Older Patients with Newly Diagnosed Acute Myeloid Leukemia: Results of a Randomized Phase II Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 615. Acute Myeloid Leukemia: Commercially Available Therapy, excluding Transplantation: Optimal Induction and Re-Induction Regimens For Acute Myeloid Leukemia
Hematology Disease Topics & Pathways:
Diseases, AML, Therapies, Non-Biological, Elderly, chemotherapy, Biological Processes, epigenetics, Study Population, Clinically relevant, Myeloid Malignancies
Saturday, December 1, 2018: 10:45 AM
Seaport Ballroom F (Manchester Grand Hyatt San Diego)

Nicholas J Short, MD1, Hagop M. Kantarjian, MD1, Sanam Loghavi, MD2, Xuelin Huang, PhD3*, Wei Qiao, PhD3*, Gautam Borthakur, MD1, Tapan M. Kadia, MD4, Naval G. Daver, MD1, Maro N. Ohanian, DO1, Courtney D. DiNardo, MD, MSc5, Zeev E. Estrov, MD6, Rashmi Kanagal-Shamanna, MD2, Abhishek Maiti, MBBS1, Christopher B. Benton, MD1, Prithviraj Bose, MD1, Yesid Alvarado, MD1, Elias J. Jabbour, MD1, Steven M. Kornblau, MD1, Naveen Pemmaraju, MD1, Nitin Jain, MD7, Yvonne Gasior, RN1*, Mary Ann Richie8*, Sherry A. Pierce, BSN, BA1*, Jorge E. Cortes, MD1, Marina Y. Konopleva, MD, PhD1, Guillermo Garcia-Manero, MD6 and Farhad Ravandi, MBBS9

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
3Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
4Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX
5Department of Leukemia, UT MD Anderson Cancer Center, Houston, TX
6Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX
7Department of Leukemia, MD Anderson Cancer Center, Houston, TX
8Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston
9Department of Leukemia, University of Texas- MD Anderson Cancer Center, Houston, TX

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. Kantarjian: Pfizer: Honoraria, Research Funding; Orsenix: Honoraria; Novartis: Research Funding; Immunogen: Honoraria; BMS: Honoraria, Research Funding; Astex: Research Funding; ARIAD: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria; AbbVie: Honoraria. 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: Sunesis: Consultancy; Otsuka: Consultancy; Novartis: Research Funding; Incyte: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Alexion: Consultancy; ImmunoGen: Consultancy, Research Funding; Kiromic: Research Funding; Novartis: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; ARIAD: Research Funding; Pfizer: Research Funding. DiNardo: Medimmune: Honoraria; Abbvie: Consultancy; Celgene: Consultancy; Agios: Consultancy; Bayer: Honoraria; Syros: Honoraria; Karyopharm: Honoraria; Jazz: 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: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, 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, Research Funding; Adaptive Biotechnologioes: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; BMS: Research Funding. Cortes: Arog: Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: 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.

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