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ASXL1 MUTATIONS PREDICT A POOR RESPONSE TO DARBEPOETIN ALFA IN ANEMIC PATIENTS WITH LOW-RISK MDS: A MULTICENTER, PHASE II STUDY
Author(s): ,
Motoshi Ichikawa
Affiliations:
Department of Hematology and Oncology,Dokkyo Medical University,Tochigi,Japan
,
Yasuyoshi Morita
Affiliations:
Department of Hematology and Rheumatology,Kindai University Faculty of Medicine,Osaka,Japan
,
Hitoshi Hanamoto
Affiliations:
Department of Hematology, Nara Hospital, Kindai University Faculty of Medicine,Nara,Japan
,
Yasuhito Nannya
Affiliations:
Department of Pathology and Tumor Biology,Graduate School of Medicine, Kyoto University,Kyoto,Japan
,
Hirohiko Shibayama
Affiliations:
Department of Hematology and Oncology,Osaka University Graduate School of Medicine,Osaka,Japan
,
Yoshinobu Maeda
Affiliations:
Department of Hematology and Oncology,Okayama University,Okayama,Japan
,
Tomoko Hata
Affiliations:
Department of Hematology, Atomic Bomb Disease Institute,Nagasaki University,Nagasaki,Japan
,
Toshihiro Miyamoto
Affiliations:
Department of Medicine and Biosystemic Science,Kyushu University Graduate School of Medical Sciences,Fukuoka,Japan
,
Hiroshi Kawabata
Affiliations:
Department of Hematology and Immunology,Kanazawa Medical University,Uchinada,Japan
,
Kazuto Takeuchi
Affiliations:
First Department of Internal Medicine,Ehime University Hospital,Toon,Japan
,
Hiroko Tanaka
Affiliations:
Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science,The University of Tokyo,Tokyo,Japan
,
Junji Kishimoto
Affiliations:
Center for Clinical and Translational Research,Kyushu University Hospital,Fukuoka,Japan
,
Satoru Miyano
Affiliations:
Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science,The University of Tokyo,Tokyo,Japan
,
Itaru Matsumura
Affiliations:
Department of Hematology and Rheumatology,Kindai University Faculty of Medicine,Osaka,Japan
,
Seishi Ogawa
Affiliations:
Department of Pathology and Tumor Biology,Graduate School of Medicine, Kyoto University,Kyoto,Japan
,
Koichi Akashi
Affiliations:
Department of Medicine and Biosystemic Science,Kyushu University Graduate School of Medical Sciences,Fukuoka,Japan
,
Yuzuru Kanakura
Affiliations:
Director,Sumitomo Hospital,Osaka,Japan
Kinuko Mitani
Affiliations:
Department of Hematology and Oncology,Dokkyo Medical University,Tochigi,Japan
EHA Library. Ichikawa M. 06/09/21; 325672; EP914
Motoshi Ichikawa
Motoshi Ichikawa
Contributions
Abstract
Presentation during EHA2021: All e-poster presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: EP914

Type: E-Poster Presentation

Session title: Myelodysplastic syndromes - Clinical

Background
Myelodysplastic syndromes (MDS) develop and progress as a result of accumulation of genetic mutations. 

Aims
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, SRSF2, 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. 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, 6 patients (4 were judged ineligible and 2 discontinued the study prior to the start of treatment) were excluded, and 79 subjects were included in the analysis. 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 (≥10%) 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). Twenty-three deaths (29.1%) were observed, and the median survival time (95% CI) from the start of treatment to confirmed AML or death was 41.3 months (30.6 months - Not reached). Fifty-eight patients completed the 16 weeks of treatment without progression to AML. For these 58 patients, median survival time (95% CI) from the completion of 16 weeks of treatment was not reached (30.9 months – not reached) and the rate of survival without progression to AML within one year was 83.5% (70.7 – 91.1 %).

Conclusion
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.

Keyword(s): Anemia, Darbepoetin alfa, MDS, Mutation analysis

Presentation during EHA2021: All e-poster presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: EP914

Type: E-Poster Presentation

Session title: Myelodysplastic syndromes - Clinical

Background
Myelodysplastic syndromes (MDS) develop and progress as a result of accumulation of genetic mutations. 

Aims
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, SRSF2, 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. 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, 6 patients (4 were judged ineligible and 2 discontinued the study prior to the start of treatment) were excluded, and 79 subjects were included in the analysis. 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 (≥10%) 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). Twenty-three deaths (29.1%) were observed, and the median survival time (95% CI) from the start of treatment to confirmed AML or death was 41.3 months (30.6 months - Not reached). Fifty-eight patients completed the 16 weeks of treatment without progression to AML. For these 58 patients, median survival time (95% CI) from the completion of 16 weeks of treatment was not reached (30.9 months – not reached) and the rate of survival without progression to AML within one year was 83.5% (70.7 – 91.1 %).

Conclusion
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.

Keyword(s): Anemia, Darbepoetin alfa, MDS, Mutation analysis

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