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3125 ASXL1 Mutations Predict a Poor Response to Darbepoetin Alfa in Anemic Patients with Low-Risk MDS: A Multicenter, Phase II Study

Program: Oral and Poster Abstracts
Session: 637. Myelodysplastic Syndromes—Clinical Studies: Poster III
Hematology Disease Topics & Pathways:
Diseases, Non-Biological, MDS, Myeloid Malignancies
Monday, December 7, 2020, 7:00 AM-3:30 PM

Hitoshi Hanamoto1*, Yasuyoshi Morita2*, Motoshi Ichikawa3*, Yasuhito Nannya, MD, PhD4, Hirohiko Shibayama, MD, PhD5, Yoshinobu Maeda, MD6, Tomoko Hata7*, Toshihiro Miyamoto, MD, PhD8, Hiroshi Kawabata, MD, PhD9, Kazuto Takeuchi10*, Hiroko Tanaka11*, Junji Kishimoto12*, Satoru Miyano, PhD11*, Itaru Matsumura, MD, PhD13, Seishi Ogawa, MD, PhD14, Koichi Akashi, MD, PhD15, Yuzuru Kanakura, MD, PhD16 and Kinuko Mitani17

1Department of Hematology, Nara Hospital, Kindai University, Ikoma City, Nara, Japan
2Department of Hematology and Rheumatology, Kindai University Hospital, Sakai, OSA, JPN
3Department of Hematology and Oncology, Dokkyo Medical University School of Medicine, Tochigi, Japan
4Department of Pathology and Tumor Biology, Kyoto University, Kyoto City, Japan
5Osaka University Hospital, Suita, Japan
6Department of Hematology and Oncology, Okayama University, Okayama, Japan
7Atomic Bomb Disease Institute Nagasaki, Nagasaki, JPN
8Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
9Dept. Hem/Immun, Kanazawa Medical University, Ishikawa, Japan
10First Department of Internal Medicine, Ehime University Hospital, Ehime, Japan
11Department of Integrated Data Science, M&D Data Science Center, Tokyo Medical and Dental University, Tokyo, Japan
12Kyushu University Hospital, Fukuoka, JPN
13Faculty of Medicine Kinki University, Osaka-Sayama, Japan
14Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
15Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
16Sumitomo Hospital, Osaka, Japan
17Department of Hematology and Oncology, Dokkyo Medical University, Tochigi, Japan

Introduction: Myelodysplastic syndromes (MDS) is thought to develop and progress as a result of accumulation of genetic mutations. This multicenter, open-label, phase II study examined impact of gene mutations on the effect of darbepoetin alfa (DA) for anemia. Death within 1 year and progression to acute myeloid leukemia (AML) were also examined.

Methods: DA ≤240 μg was administered once weekly for 16 weeks to DA-naive, low-risk MDS (low or Intermediate-1 [Int-1] risk defined by the International Prognostic Scoring System [IPSS] risk classification) patients with anemia. DNA was extracted from the peripheral blood of patients, and presence of previously reported high-frequency gene mutations in MDS (SF3B1, TET2, SFRS2, ASXL1, DNMT3A, etc.) was analyzed by next-generation sequencing. Primary endpoint was association between frequently observed mutated genes and therapeutic effect of DA (IWG criteria 2006 (HIE)) at 16 weeks. A secondary endpoint was survival analysis results for death and progression to AML within one year after 16 weeks of treatment, with the date of first treatment as the starting date. For AML, progression to AML and subsequent death were stated as events, and the patients without confirmed progression to AML were censored at the date of last known survival. For overall survival, death from any cause was considered an event, and for the survival cases, the study was terminated at the date of last known survival.

For the primary endpoint, relative risk and 95% confidence intervals (CI) were calculated using Wilson’s score method; statistical significance was assessed using Pearson's chi-square test. Multivariate analysis was performed by adding baseline erythropoietin (EPO) levels (low: <91.8, high: 91.8+ [mIU/mL]) to the explanatory variables, and odds ratio was calculated using logistic regression model. Survival curve was estimated using Kaplan-Meier method and median survival time (MST) was calculated using Brookmeyer and Crowley method.

Results: Of the 85 patients enrolled between August 2016 and May 2019, 4 patients who were judged ineligible and 2 patients who discontinued the study prior to the start of treatment were excluded, and 79 subjects were included in the analysis (full analysis set). Of 79 subjects, 52 (65.8%) were male (median age 77.0 [29-90] years). IPSS risk was low in 27 (36.7%) and Int-1 in 50 (63.3%) subjects. The frequently mutated genes (³10%) were SF3B1 (24, 30.4%), TET2 (20, 25.3%), SRSF2 (10 cases, 12.7%), ASXL1 (9, 11.4%), and DNMT3A (8, 10.1%). Overall response rate was 70.9%. Univariate logistic regression analaysis did not show any significant association between these mutations and therapeutic efficacy of DA. The same results were obtained when the analysis was limited to red blood cell transfusion-dependent subjects (n=15). After adjusting against baseline EPO values, mutations of ASXL1 gene were associated with significantly worse response (odds ratio 0.180 [0.035-0.928], p = 0.040).

Six (7.6%) confirmed cases of AML and 17 (21.5%) deaths (death before confirmed AML) were observed. Overall, 21 deaths were observed including 4 deaths after progression to AML. The median survival time (95% confidence interval) from the start of treatment to confirmed AML or death was 41.3 months (30.6 months - Not reached).

Conclusions: The results of this exploratory study suggest that the presence of ASXL1 gene mutations may result in poor response to the anemic treatment with DA in low-risk MDS. The current analysis of progression to AML and death included subjects whose observation period did not reach the prespecified number of days. For such cases, the outcome research will be conducted around October 2020 and updated results will be presented at the ASH 2020 conference.

Disclosures: Ichikawa: Novartis, Takeda: Honoraria. Shibayama: Taiho: Research Funding; Shionogi: Research Funding; Ono: Honoraria, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Takeda: Honoraria, Research Funding; Merck Sharp & Dohme: Research Funding; Sumitomo Dainippon: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Kirin: Honoraria; Otsuka: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Fujimoto: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Teijin: Research Funding; Mundi Pharma: Honoraria. Maeda: Kyowa Kirin Co.Ltd.: Honoraria, Research Funding. Kawabata: Celgene Corporation: Consultancy; Celgene Corporation: Honoraria; Sanofi K. K: Honoraria; Novartis Pharma K. K.: Honoraria; Chugai Pharmaceutical Co., Ltd: Honoraria. Matsumura: Shionogi & Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Kyowa Kirin Co., Ltd.: Research Funding; ONO PHARMACEUTICAL CO., LTD.: Research Funding; Eisai Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Janssen Pharmaceutical K.K: Speakers Bureau; Amgen K.K.: Speakers Bureau; Otsuka Pharmaceutical Co., Ltd.: Speakers Bureau; Astellas Pharma Inc.: Speakers Bureau; DAIICHI SANKYO COMPANY, LIMITED.: Speakers Bureau; Pfizer Japan Inc.: Speakers Bureau; Novartis Pharma KK: Speakers Bureau; Bristol-Myers Squibb Company: Speakers Bureau. Ogawa: Eisai Co., Ltd.: Research Funding; KAN Research Institute, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chordia Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Asahi Genomics Co., Ltd.: Current equity holder in private company; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding. Mitani: CHUGAI: Research Funding; Takeda: Research Funding; KYOWA KIRIN: Consultancy, Research Funding.

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