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1470 Genetic Mutation and Outcome of Venetoclax-Based Therapy in Newly Diagnosed AML in the Real World: Hokkaido Leukemia Net Study

Program: Oral and Poster Abstracts
Session: 613. Acute Myeloid Leukemias: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Research, Acute Myeloid Malignancies, AML, Clinical Research, Diseases, real-world evidence, Myeloid Malignancies
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Naoki Miyashita, MD1*, Masahiro Onozawa, M.D., Ph.D.1, Jun Nagai, M.D.1*, Shota Yoshida, M.D.1*, Hiroyuki Kimura, MD1*, Toshihiro Matsukawa, M.D., Ph.D.1*, Shinsuke Hirabayashi, M.D., Ph.D.2*, Akio Mori, M.D., Ph.D.3, Takeshi Kondo, MD, PhD3, Daisuke Hidaka, M.D., Ph.D.4*, Koichiro Minauchi, M.D., Ph.D.5*, Akio Shigematsu, M.D., Ph.D.6, Junichi Hashiguchi, M.D.7*, Tetsuyuki Igarashi, M.D.8*, Yasutaka Kakinoki, M.D., Ph.D.9*, Yutaka Tsutsumi, M.D., Ph.D.10*, Hiroshi Iwasaki, M.D.11*, Shota Yokoyama12*, Kentaro Wakasa, M.D., Ph.D.12*, Katsuya Fujimoto, M.D., Ph.D.13*, Toshimichi Ishihara, M.D.14*, Hajime Sakai, M.D., Ph.D.15, Satoshi Iyama, M.D., Ph.D.16*, Tatsuo Oyake, M.D., Ph.D.17* and Takanori Teshima, M.D., Ph.D.1

1Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan
2Department of Pediatrics, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
3Blood Disorders Center, Aiiku Hospital, Sapporo, Japan
4Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan
5Department of Hematology, Sapporo City General Hospital, Sapporo, Japan
6Department of Hematology, Kushiro Rosai Hospital, Kushiro, Japan
7Department of Internal Medicine, Kitami Red Cross Hospital, Kitami, Japan
8Department of Hematology, Tenshi Hospital, Sapporo, Japan
9Department of Hematology, Asahikawa City Hospital, Asahikawa, Japan
10Hakodate Municipal Hospital, Hakodate, Japan
11Sapporokousei General Hospital, Sapporo, Japan
12Department of Hematology, Obihiro Kosei Hospital, Obihiro, Japan
13Department of Hematology, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan
14Department of Hematology, Kin-ikyo Chuo Hospital, Sapporo, Japan
15Teine Keijinkai Hospital, Sapporo, Japan
16Department of Hematology, Sapporo Medical University School of Medicine, Sapporo, Japan
17Department of Hematology, Internal Medicine Iwate Medical University, Yahaba, Japan

Introduction

Venetoclax (VEN) had been approved in Japan since March 2021 for acute myeloid leukemia (AML), and VEN-based regimens were widely used as initial therapy predominantly for elderly or unfit patients. Genetic mutations affect therapeutic outcomes of VEN-based therapy (CD DiNardo, et al. Blood. 2020). We performed gene panel sequencing using a next-generation sequencer for the newly diagnosed AML patients who were initially treated by VEN-based regimen and analyzed the relationship between gene mutations and outcomes in our regional cohort.

Patients and Methods

Hokkaido Leukemia Net (HLN) is prospective cohort study collecting acute leukemia samples from affiliated hospitals of the North Japan Hematology Study Group (NJHSG) covering Hokkaido and Iwate, Japan. We developed a compact AML panel covering mutation hot spots of 14 genes including TP53, CEBPA, NPM1, FLT3, KIT, NRAS, KRAS, CBL, PTPN11, DNMT3A, IDH1, IDH2, RUNX1 and ASXL1. Treatment efficacy was determined based on European LeukemiaNet 2017 response criteria in AML. This study was conducted in accordance with the Helsinki Declaration and was approved by the institutional review boards.

Results

A total of 89 AML cases registered in HLN from May 2021 to April 2023 were initially treated by VEN-based therapy (age range, 57-90 years; median age, 75 years; 49 males and 40 females, VEN+AZA 85, VEN+AraC 4). The median overall survival (OS) for all patients was 367 days (range 12-636).

Patients who achieved complete remission (CR), CR with incomplete hematologic recovery (CRi), morphologic leukemia-free state (MLFS), or partial remission (PR) during the observation period and had no relapse were designated as Group 1, those who relapsed as Group 2, and those who became Stable disease (SD) or Progressive disease (PD) as Group 3. IDH2 mutations were significantly more frequent in Group 1 (P=0.010), and NPM1 mutations also tended to be more frequent in Group 1 and 2 (P=0.064). Furthermore, the ratio of CR or CRi was more than 80% in the patients with mutation of CEBPA-bZIP, DNMT3A, IDH1, IDH2, and NPM1 mutation-positive groups, respectively. These response groups clearly stratified prognosis. On the other hand, prognostic stratification according to biological disease factors depending on National Comprehensive Cancer Network (NCCN) 2017 stratification could not stratify the VEN-treated cohort (P=0.26) (Figure 1).

Next, the mutations with high CR+CRi rate (CEBPA-bZIP, DNMT3A, IDH1, IDH2, and NPM1) were classified as “high-sensitivity mutations”. Patients with high-sensitivity mutations were significantly less likely to have complex karyotypes (P=0.026), but other patient characteristics such as age, sex, performance status, WBC count, other genetic mutations were not statistically different. Patients with high-sensitivity mutations had a significantly favorable OS than those without (median OS not reached; 95% CI, 367 - NA vs 331 days; 95% CI, 259-430, p=0.0022).

Univariate analysis was carried out for age, sex, karyotype, each gene mutation and “high-sensitivity mutations”. IDH2 mutation and high-sensitivity mutations were associated with favorable OS (P=0.016, 0.0022, log-rank test). As previously reported, complex karyotypes and TP53 mutations were associated with poor OS (p<0.001, <0.001, log-rank test).

Multivariate analysis including age, sex, “complex karyotype and/or TP53 mutation” and “high-sensitivity mutations” showed that the high-sensitivity mutations were independently associated with favorable OS (HR, 0.16; 95% CI, 0.053 to 0.62, p=0.0067; cox regression). Complex karyotype and/or TP53 mutation was independently associated with poor OS (HR, 2.39; 95% CI, 1.12 to 5.09, p=0.024; cox regression).

Based on these results, we were able to stratify the prognosis by dividing the patients into three groups according to the presence of high-sensitivity mutations, complex karyotype and/or TP53 mutations (Figure 2).

Conclusion

VEN-based therapy abrogates the efficacy of NCCN2017 stratification, however, the genetic mutation profile of the initial disease successfully stratified prognosis.

Disclosures: Kondo: Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Otsuka Pharmaceuticals: Honoraria, Speakers Bureau. Iyama: Alexion Pharmaceuticals: Honoraria, Research Funding; MSD: Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; SymBio Pharmaceuticals: Honoraria, Research Funding; Astellas: Honoraria; CSL Behring: Honoraria; Daiichi Sankyo: Honoraria; Meiji Pharma: Honoraria; Nippon Shinyaku: Honoraria; Novartis: Honoraria. Teshima: Meiji Seika Pharma: Membership on an entity's Board of Directors or advisory committees; DAIICHI SANKYO: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; Sumitomo Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: 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; AbbVie: Honoraria; Roche Diagnostics: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria; Merck Sharp & Dohme: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; ONO: Research Funding; Asahi Kasei Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Fuji Pharma: Research Funding; NIPPON SHINYAKU: Honoraria, Research Funding; Otsuka: Research Funding; LUCA Science: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Priothera SAS: Research Funding; SHIONOGI: Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

*signifies non-member of ASH