Background

Acute myeloid leukemia (AML) is known to have a relatively small number of genomic mutations compared to solid tumors. With the development and clinical application of drugs targeting genetic mutations involved in the pathogenesis of AML, the Japanese Society of Hematology has defined “fast-track mutations” as those that should be reported promptly due to clinical necessity. A multicenter genomic profiling study (HM-SCREEN-JAPAN01: HM01 study) was conducted to comprehensively sequence 406 DNA mutations and 265 RNA aberrations in 177 AML patients, suggesting its usefulness in clinical practice, but the turnaround time (TAT) until results are reported remains an issue (Hosono, et al. Cancer Sci, 2023).

Aims

We have launched the HM-SCREEN-JAPAN02 (HM02) study, a practice-oriented genome profiling study that improves on the previous HM01 study and uses a newly developed targeted sequencing method. The HM02 study adopted the novel Amoy Myeloid Panel® method, which uses the HANDLE (Halo-shape ANnealing and Defer-Ligation Enrichment) system to significantly shorten TAT and facilitate specimen submission, and was designed to be completed in 7 days from sequencing to reporting. The HM02 study allows mutation analysis at any treatment timing, such as at initial presentation, during treatment, or at relapse, as well as the capability to track clonal changes through repeat analysis; the HM02 study was designed to determine whether such flexible analysis is useful in determining treatment strategy.

Results

The study was conducted at 23 centers in Japan, enrolling a total of 154 cases from 2020 to 2022, with 191 samples analyzed to assess the usefulness of the study. Repetitive mutation analysis was performed in 21 cases, and clonal changes could be tracked. Among the mutations detected, we selected those that were determined to be pathogenic or likely pathogenic by ClinVar. Of the 154 cases analyzed, none of the pathogenic mutations were detected in 9 cases, and 6 were of the normal karyotype. The most frequently observed mutations were TET2 (51%), FLT3 (30%), TP53 (18%), and NPM1 (17%) (Figure 1). In multivariate analysis adjusted for age, gender, and stem cell transplantation status, TP53 and NRAS mutations were associated with higher risk for death (HR=6.82 and 14.98, respectively).

Of the 19 cases in which pathological mutations were repeatedly investigated, 8 were useful in determining minimal/measurable residual disease (MRD) (2 cases of MRD loss and 6 cases of MRD retained), 6 cases showed the development of new clones and 5 cases showed clonal evolution, indicating that repeated mutation analysis can be used to evaluate detailed disease status. In terms of clinical utility, HM02 mutation analysis was useful in 62% of cases (98 of 158), particularly for risk assessment and determining the indication for stem cell transplantation (Figure 2).

Conclusion

Flexible analysis using the novel Amoy Myeloid Panel® method suggests that it can be used to assess the risk of relapse, evaluate the need for transplantation, and select optimal therapeutic agents. NGS-based mutation analysis provides useful information at any point in AML treatment and is expected to improve outcomes.

Hosono:Abbvie: Honoraria. Yamauchi:Chugai: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Nihon Shinyaku: Honoraria, Research Funding; Sumitomo Pharma: Honoraria, Research Funding; Janssen Pharma: Honoraria, Research Funding; Nihon Kayaku: Honoraria, Research Funding. Fukushima:Janssen: Honoraria. 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. Gotoh:Nihon Pharmaceutical: Honoraria; Bristol Myers Squibb: Honoraria; Taiho Pharmaceutical: Honoraria, Research Funding; Sumitomo Pharma: Honoraria, Research Funding; Janssen Pharmaceutical: Honoraria; Chugai Pharmaceuticals: Consultancy, Honoraria, Research Funding; Asahi Kasei Pharma: Research Funding; Kyowa Kirin: Honoraria; Takeda Pharmaceutical: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; AstraZeneca: Honoraria; Abbvie: Honoraria; Alexion Pharmaceuticals: Consultancy, Honoraria; Novartis: Honoraria; Pfizer Japan: Honoraria; Otsuka Pharmaceutical: Honoraria, Research Funding; Nippon Shinyaku: Honoraria; Sanofi: Honoraria; PharmaEssentia Japan: Consultancy, Honoraria. Ikezoe:AsahiKasei Pharma, Nippon Shinyaku Co., Ltd: Research Funding; Bristol-Myers Squibb Company, Novartis Pharma KK, Pfizer Japan Inc., Takeda: Honoraria. Yoshida:Novartis Pharmaceuticals: Honoraria; Bristol Myers Squibb: Research Funding. Yoshimoto:AbbVie: Honoraria; astellas: Honoraria; Daiichi Sankyo Company, Limited: Honoraria; Amgen inc.: Honoraria. Kanda:Amgen: Ended employment in the past 24 months, Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Novartis Pharma K.K.: Honoraria; Sanofi K.K.: Honoraria; AbbVie Pharma: Honoraria; Megakaryon Co.: Honoraria; Eisai Co.: Research Funding. Takahashi:Astellas pharma: Other: Commissioned research and joint research , Research Funding; Asahi-Kasei: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Otsuka Pharmacuetical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Mochida Pharma: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Sakaida:Takeda: Speakers Bureau; Kyowa-Kirin: Research Funding; Chugai: Research Funding; Human Life Cord Japan: Consultancy; Ohara: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Janssen: Speakers Bureau. Usuki:Takeda: Research Funding; Nippon Shinyaku: Research Funding; SymBio: Research Funding; Alexion: Research Funding; Amgen: Research Funding; Sanofi: Research Funding; Alnylam Japan: Research Funding; Sando: Research Funding; Astellas: Research Funding; Otsuka: Research Funding; Eisai: Research Funding; Ohara: Research Funding; Chugai: Research Funding; Kyowa-Kirin: Research Funding. Minami:Daiichi Sankyo: Honoraria, Research Funding; Taiho Pharmaceutical: Research Funding; Tejin Pharma: Research Funding; Takeda: Research Funding; Sumitomo Pharma Oncology: Research Funding; Shionogi: Research Funding; Sanofi: Research Funding; Otsuka: Research Funding; Nippon Shinyaku: Research Funding; Nihonkayaku: Research Funding; Kyowa Hakko Kirin: Research Funding; Dainippon Sumitomo Pharma: Research Funding; Asahi Kasei: Research Funding; Taiho Pharmaceutical: Honoraria; Shinogi: Honoraria; Sanofi: Honoraria; Otsuka: Honoraria; Ono Pharmaceutical: Honoraria; Merck: Honoraria; Meiji Seika Kaisha: Honoraria; Lilly: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria; Eisai: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Abbvie: Honoraria; Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb Company: Honoraria; Takeda: Honoraria; Novartis Pharma KK: Honoraria.

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2023
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