COMPARATIVE RESULTS OF AZACITIDINE AND DECITABINE FROM A LARGE PROSPECTIVE PHASE 3 STUDY IN TREATMENT NAÏVE ACUTE MYELOID LEUKEMIA (TN-AML) NOT ELIGIBLE FOR INTENSIVE CHEMOTHERAPY
Author(s): ,
Amer M. Zeidan
Affiliations:
Yale University and Yale Cancer Center,New Haven,United States
,
Pierre Fenaux
Affiliations:
Hôpital Saint Louis,Paris,France
,
Marco Gobbi
Affiliations:
Ospedale Policlinico San Martino,Genova,Italy
,
Jiří Mayer
Affiliations:
Fakultní Nemocnice,Brno,Czech Republic
,
Gail J. Roboz
Affiliations:
Weill Cornell Medical College,New York,United States
,
Jürgen Krauter
Affiliations:
Städtisches Klinikum Braunschweig,Braunschweig,Germany
,
Tadeusz Robak
Affiliations:
Wojewódzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w Lodzi,Łódź,Poland
,
Hagop M. Kantarjian
Affiliations:
The University of Texas MD Anderson Cancer Center,Houston,United States
,
Jan Novák
Affiliations:
Fakultní Nemocnice Královské Vinohrady,Praha,Czech Republic
,
W.W. Jedrzejczak
Affiliations:
Samodzielny Publiczny Centralny Szpital Kliniczny,Warsaw,Poland
,
Xavier Thomas
Affiliations:
Centre Hospitalier Lyon Sud,Pierre Bénite,France
,
Mario Ojeda-Uribe
Affiliations:
GHR Mulhouse Sud-Alsace,Mulhouse,France
,
Yasushi Miyazaki
Affiliations:
Nagasaki University Hospital,Nagasaki,Japan
,
Yoo Hong Min
Affiliations:
Severance Hospital, Yonsei University Health System,Seoul,Korea, Republic Of
,
Su-Peng Yeh
Affiliations:
China Medical University Hospital,Taichung,Taiwan, Province of China
,
Joseph Brandwein
Affiliations:
University of Alberta Hospital,Edmonton,Canada
,
Liana Gercheva
Affiliations:
Multiprofile Hospital for Active Treatment Sveta Marina EAD,Varna,Bulgaria
,
Judit Demeter
Affiliations:
Semmelweis Egyetem,Budapest,Hungary
,
Elizabeth A. Griffiths
Affiliations:
Roswell Park Cancer Institute,Buffalo,United States
,
Karen W.L. Yee
Affiliations:
Princess Margaret Hospital,Toronto,Canada
,
Jean-Pierre Issa
Affiliations:
Fels Institute, Temple University,Philadelphia,United States
,
Yong Hao
Affiliations:
Astex Pharmaceuticals, Inc.,Pleasanton,United States
,
Mohammad Azab
Affiliations:
Astex Pharmaceuticals, Inc.,Pleasanton,United States
Hartmut Döhner
Affiliations:
Universität Ulm,Ulm,Germany
EHA Library. M. Zeidan A. 06/12/20; 294962; S142
Amer M. Zeidan
Amer M. Zeidan
Contributions
Abstract

Abstract: S142

Type: Oral Presentation

Presentation during EHA25: All oral abstract presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Session title: AML therapy

Background
Older patients with TN-AML who are ineligible for intensive chemotherapy have limited therapeutic options and poor outcomes. Hypomethylating agents (HMAs) azacitidine (AZA) and decitabine (DEC) have been the standard of care in this population for more than a decade and were approved in Europe for patients not candidates for intensive chemotherapy or patients not candidates for hematopoietic cell transplant. However, there is no direct efficacy and safety comparative data of AZA and DEC from a prospective large randomzied study.  We took advantage of the largest randomized trial for patients with TN-AML who were not eligible for intensive chemotherapy, ASTRAL-1, to compare efficacy and safety of AZA vs DEC in patients randomized to these 2 treatments.

Aims
To compare clinical outcomes between AZA and DEC in TN-AML patients not eligible for intensive chemotherapy

Methods
ASTRAL-1 is a global randomized Phase 3 trial which enrolled 815 patients with TN AML who were not eligible for intensive chemotherapy using stringent criteria including age ≥ 75 year or comorbidities including ECOG PS 3. Patients were randomized 1:1 to either Guadecitabine (G), a next generation HMA (60 mg/m2/d SC days 1-5) or a preselected Treatment Choice (TC) of AZA (75 mg/m2/d IV or SC days 1-7), DEC (20 mg/m2/d IV days 1-5), or low dose Ara-C (LDAC) (20 mg SC BID days 1-10). AML diagnosis and responses were assessed by an independent central pathologist blinded to randomization assignment. Responses were recorded using IWG 2003 criteria. Rates of Complete Response (CR) and Overall Survival (OS) were co-primary endpoints.

Results
815 patients were randomized to G (408) or TC (407). Preselected TCs were DEC (43%), AZA (42%), or LDAC (15%). Of 407 patients randomized to TC, 338 (83%) were treated with either AZA (171 patients) or DEC (167 patients). Baseline variables were well balanced between AZA and DEC patients with no statistically significant differences in baseline characteristics: median age 76 y for both treatments, with poor PS 2-3 in 47.4% vs 53.9%, poor risk cytogenetics 38% vs 33.5%, secondary AML 38% vs 36.5%, BM blasts > 30% in 63.7% vs 71.3%, and TP53 mutations in 12.9% vs 11.3% for AZA vs DEC respectively. Median follow up was 25.5 months and median number of treatment cycles was 6 for AZA (range 1,31), and 5 for DEC (range 1,34). The ITT analyses showed a CR rate of 17.5% vs 19.2% (p= 0.70); and overall CR (CR+CRp+CRi) of 22.2% vs 25.1% (p= 0.53) for AZA vs DEC respectively. Median OS was 8.7 vs 8.2 months for AZA vs DEC respectively with Hazard Ratio of 0.97 (95% CI 0.77, 1.23; log rank p= 0.8). Additional subgroup analyses by baseline characteristics and molecular genetic mutations will be presented at the meeting. There was no statistically significant difference in the incidence of Grade ≥ 3 AEs (88.9% vs 87.4%), serious AEs (81.9% vs 76.0%), or 30-day all-cause mortality (11.7% vs 7.8%) for AZA vs DEC respectively. There was a trend of higher 60-day all-cause mortality on AZA (20.5%) vs DEC (13.2%) (p= 0.07).   

Conclusion
This is the largest comparison of clinical outcomes associated with AZA and DEC for patients with TN AML not eligible for intensive chemotherapy who were treated in the same prospective study. While patients were randomized between G and each of AZA and DEC separately with no direct randomization of AZA vs DEC, the patients’ characteristics were well balanced in patients randomized to the two HMA treatments. There were no significant differences in CR, overall CR, OS, or safety between AZA and DEC.

Session topic: 04. Acute myeloid leukemia - Clinical

Keyword(s): AML, Azacitidine, Decitabine, Hypomethylation

Abstract: S142

Type: Oral Presentation

Presentation during EHA25: All oral abstract presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Session title: AML therapy

Background
Older patients with TN-AML who are ineligible for intensive chemotherapy have limited therapeutic options and poor outcomes. Hypomethylating agents (HMAs) azacitidine (AZA) and decitabine (DEC) have been the standard of care in this population for more than a decade and were approved in Europe for patients not candidates for intensive chemotherapy or patients not candidates for hematopoietic cell transplant. However, there is no direct efficacy and safety comparative data of AZA and DEC from a prospective large randomzied study.  We took advantage of the largest randomized trial for patients with TN-AML who were not eligible for intensive chemotherapy, ASTRAL-1, to compare efficacy and safety of AZA vs DEC in patients randomized to these 2 treatments.

Aims
To compare clinical outcomes between AZA and DEC in TN-AML patients not eligible for intensive chemotherapy

Methods
ASTRAL-1 is a global randomized Phase 3 trial which enrolled 815 patients with TN AML who were not eligible for intensive chemotherapy using stringent criteria including age ≥ 75 year or comorbidities including ECOG PS 3. Patients were randomized 1:1 to either Guadecitabine (G), a next generation HMA (60 mg/m2/d SC days 1-5) or a preselected Treatment Choice (TC) of AZA (75 mg/m2/d IV or SC days 1-7), DEC (20 mg/m2/d IV days 1-5), or low dose Ara-C (LDAC) (20 mg SC BID days 1-10). AML diagnosis and responses were assessed by an independent central pathologist blinded to randomization assignment. Responses were recorded using IWG 2003 criteria. Rates of Complete Response (CR) and Overall Survival (OS) were co-primary endpoints.

Results
815 patients were randomized to G (408) or TC (407). Preselected TCs were DEC (43%), AZA (42%), or LDAC (15%). Of 407 patients randomized to TC, 338 (83%) were treated with either AZA (171 patients) or DEC (167 patients). Baseline variables were well balanced between AZA and DEC patients with no statistically significant differences in baseline characteristics: median age 76 y for both treatments, with poor PS 2-3 in 47.4% vs 53.9%, poor risk cytogenetics 38% vs 33.5%, secondary AML 38% vs 36.5%, BM blasts > 30% in 63.7% vs 71.3%, and TP53 mutations in 12.9% vs 11.3% for AZA vs DEC respectively. Median follow up was 25.5 months and median number of treatment cycles was 6 for AZA (range 1,31), and 5 for DEC (range 1,34). The ITT analyses showed a CR rate of 17.5% vs 19.2% (p= 0.70); and overall CR (CR+CRp+CRi) of 22.2% vs 25.1% (p= 0.53) for AZA vs DEC respectively. Median OS was 8.7 vs 8.2 months for AZA vs DEC respectively with Hazard Ratio of 0.97 (95% CI 0.77, 1.23; log rank p= 0.8). Additional subgroup analyses by baseline characteristics and molecular genetic mutations will be presented at the meeting. There was no statistically significant difference in the incidence of Grade ≥ 3 AEs (88.9% vs 87.4%), serious AEs (81.9% vs 76.0%), or 30-day all-cause mortality (11.7% vs 7.8%) for AZA vs DEC respectively. There was a trend of higher 60-day all-cause mortality on AZA (20.5%) vs DEC (13.2%) (p= 0.07).   

Conclusion
This is the largest comparison of clinical outcomes associated with AZA and DEC for patients with TN AML not eligible for intensive chemotherapy who were treated in the same prospective study. While patients were randomized between G and each of AZA and DEC separately with no direct randomization of AZA vs DEC, the patients’ characteristics were well balanced in patients randomized to the two HMA treatments. There were no significant differences in CR, overall CR, OS, or safety between AZA and DEC.

Session topic: 04. Acute myeloid leukemia - Clinical

Keyword(s): AML, Azacitidine, Decitabine, Hypomethylation

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