Abstract
Acute myeloid leukemia (AML) is recognized to rely on relatively small number of genomic alterations compared with solid tumors. However, a variety of genomic backgrounds considerably affect to pathological characteristics and clinical outcomes of patients with AML. Upon clinical needs, the Japan Hematology Society (JSH) recently defined "fast-track” mutations for which rapid reporting would be hopeful in practice.
In the multicenter genome profiling study conducted in Japan (HM-SCREEN-JAPAN01 : HM01 study), comprehensive genomic sequencings were performed which examined 406 DNA and 265 RNA abnormalities for the 177 patients with AML. A variety of variants were detected which suggested some mutations could contribute to the diagnosis and the prognosis of the patients. Our data established the strategic foundation for mutation-based personalized treatment in AML.
We have launched a practice-oriented genome profiling study, HM-SCREEN-JAPAN02 (HM02 study) with a newly developed targeted sequencing method. The median turn-around time (TAT) in HM01 study was thirteen days and only paraffin-embedded specimens were allowed to submit. In HM02 study, we employed a new method named Amoy Myeloid Panel® which enabled to shorten the TAT significantly and made it easy to submit specimens. It used Halo-shape ANnealing and Defer-Ligation Enrichment (HANDLE) System which was designed to complete the process from sequencing to return the reports within seven days. The fresh bone marrow and the peripheral blood samples were able to be submitted.
Based on the findings obtained in HM01 study, Amoy Myeloid Panel® targeted in total 57 DNA and RNA abnormalities including 12 fusions which were frequently detected and considered clinically significant in AML. All the fast-track mutations of JSH Genome-Guideline for AML were included. The sequencing results of Amoy Myeloid Panel® were consistent enough with those of HM01 study. HM02 study allowed to submit the specimens of the same patients repeatedly to the genome profiling, for example, in order to follow the clonal changes. In summary, HM02 study used the selective gene profiling panel to specialize in treatment decision, taking advantage of the short TAT, easy submit and follow up.
HM02 study is now on-going in 23 faculties in Japan and 200 cases in total will be assayed by the end of this autumn and will be evaluated if Amoy Myeloid Panel® is feasible for cytogenetically proper diagnosis. In 44 out of 67 cases analyzed so far, various kinds of mutation were detected which were determined as pathogenic or likely pathogenic by Clinvar. 25 cases had several co-mutations with potential pathogenesis. A majority of the variants were non-synonymous substitutions. Some fusions, frameshifts, splicing and nonsense mutations were also detected. The mutations ovserved in more than 5% of 44 cases were NPM1 (27%), RUNX1 (16%), KRAS (16%), TP53 (16%), IDH2 (14%), NRAS (14%), NF1 (14%), PTPN11 (11%), FLT3 (11%), CBL (9%), IDH1 (9%), SETBP1 (7%), EZH2 (5%) and IKZF1 (5%) (Figure 1). The circos plot shows how likely these mutations were to coexist (Figure 2). Although these mutations are considered as pathogenic or likely pathogenic, it is not certain whether they were actually involved in the development of AMLs.
When the assays of 200 cases are finished as planned, we may be able to get some clues as to the relationship between these mutaitons. On the other hand, some gene mutations such as KRAS and NF1, for which therapeutic agents have been developed for other kinds of cancer, were also observed. Accumulation of future cases is expected to contribute the elucidation of AML with pathogenic mutations and to develop new treatment strategies.
Disclosures
Yamauchi:Janssen Pharmaceutical K.K.: Consultancy; Solasia: Research Funding; Pfizer: Research Funding; Nippon Shinyaku: Research Funding; Janssen Pharmaceutical K.K.: Research Funding; Chugai: Research Funding; Boehringer Ingelheim Japan: Research Funding; Abbvie: Research Funding; Takeda Pharmaceutical: Research Funding. Horiguchi:AstraZeneca KK: Honoraria; AbbVie GK: Honoraria; Janssen Pharmaceutical KK: Honoraria. Iyama:Nippon Shinyaku: Honoraria; Meiji Pharma: Research Funding; Otsuka Pharmaceuticals Factory: Honoraria; Daiichi Sankyo: Honoraria; CSL Behring: Honoraria; Astellas: Honoraria; SymBio Pharmaceuticals: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; MSD: Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Novartis: Honoraria. Kanda:AbbVie Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Ono Pharma Inc.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Megakaryon Co: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin Co., Ltd.: Honoraria; Sanofi K.K.: Honoraria; SymBio Pharmaceuticals, Ltd.: Membership on an entity's Board of Directors or advisory committees; DAIICHI SANKYO Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; CHUGAI PHARMACEUTICAL Co., Ltd.: Honoraria; TEIJIN PHARMA LIMITED.: Honoraria; Novartis Pharma K.K.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb Co: Honoraria; Janssen Pharmaceutical K.K.: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASAHI KASEI PHARMA CORPORATION: Honoraria; asclepia: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; NIPPON KAYAKU CO．，LTD．: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria; Eisai: Research Funding; CSL Behring K.K.: Honoraria; MSD K.K.: Honoraria; Astellas Pharma Inc.: Consultancy, Honoraria. Gotoh:MSD: Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding; Sumitomo Pharma: Honoraria, Research Funding; Bayer: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Nihon Pharmaceutical: Research Funding; Asahi Kasei Pharma: Research Funding; AbbVie GK: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Novartis Pharma: Honoraria; Alexion Pharma: Honoraria; Janssen Pharmaceutical: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; BMS: Honoraria; AstraZeneca: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Taiho Pharmaceutical: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding. Ikezoe:AbbVie GK: Research Funding; GlaxoSmithKline K.K.: Research Funding; Novartis Pharma: Honoraria, Research Funding; Janssen Pharmaceutical: Honoraria, Research Funding; Alexion Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai Pharmaceutical: Honoraria; Otsuka Pharmaceutical: Honoraria; Sumitomo Pharma: Honoraria; Daiichi-Sankyo: Honoraria; Kyowa Kirin: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; BMS: Honoraria; Takeda Pharmaceutical: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Nippon Shinyaku Co., Ltd: Honoraria; Asahi Kasei Pharma: Research Funding. Kondo:Alexion Pharma: Honoraria; PharmaEssentia Japan: Honoraria; Chugai Pharmaceutical: Honoraria. Izutsu:Ono Pharmaceutical: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Beigene: Consultancy, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Eli Lilly and Company: Consultancy, Honoraria; Merck Sharp & Dohme: Honoraria, Research Funding; Eizai: Honoraria, Research Funding; Incyte: Research Funding; Yakult: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Genmab: Research Funding; Loxo Oncology: Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Symbio: Honoraria; Takeda: Honoraria; Janssen: Research Funding. Yamauchi:Daiichi-Sankyo: Research Funding; Genmab: Research Funding; Incyte Biosciences: Research Funding; Takeda: Research Funding; Bristol Myers Squibb: Research Funding. Minami:Pfizer Japan Inc.: Honoraria; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria; Takeda: Honoraria.
