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Multicenter Study
. 2023 May;114(5):2098-2108.
doi: 10.1111/cas.15746. Epub 2023 Mar 1.

Clinical utility of genomic profiling of AML using paraffin-embedded bone marrow clots: HM-SCREEN-Japan 01

Naoko Hosono  1 , SungGi Chi  2 , Takahiro Yamauchi  1 , Kentaro Fukushima  3 , Hirohiko Shibayama  3 , Seiichiro Katagiri  4 , Akihiko Gotoh  4 , Motoki Eguchi  5 , Takanobu Morishita  5 , Reiki Ogasawara  6 , Takeshi Kondo  6 , Masamitsu Yanada  7 , Kazuhito Yamamoto  7 , Tsutomu Kobayashi  8 , Junya Kuroda  8 , Kensuke Usuki  9 , Yoshikazu Utsu  10 , Makoto Yoshimitsu  11 , Kenji Ishitsuka  11 , Takaaki Ono  12 , Naoto Takahashi  13 , Satoshi Iyama  14 , Kensuke Kojima  15 , Yukinori Nakamura  16 , Suguru Fukuhara  17 , Koji Izutsu  17 , Hikaru Abutani  18 , Nobuhiko Yamauchi  2 , Junichiro Yuda  2 , Yosuke Minami  2 ; All HM-SCREEN-Japan 01 Investigators
Affiliations
Multicenter Study

Clinical utility of genomic profiling of AML using paraffin-embedded bone marrow clots: HM-SCREEN-Japan 01

Naoko Hosono et al. Cancer Sci. 2023 May.

Abstract

Next-generation sequencing of AML has identified specific genetic mutations in AML patients. Hematologic Malignancies (HM)-SCREEN-Japan 01 is a multicenter study to detect actionable mutations using paraffin-embedded bone marrow (BM) clot specimens rather than BM fluid in AML patients for whom standard treatment has not been established. The purpose of this study is to evaluate the presence of potentially therapeutic target gene mutations in patients with newly diagnosed unfit AML and relapsed/refractory AML (R/R-AML) using BM clot specimens. In this study, 188 patients were enrolled and targeted sequencing was undertaken on DNA from 437 genes and RNA from 265 genes. High-quality DNA and RNA were obtained using BM clot specimens, with genetic alterations successfully detected in 177 patients (97.3%), and fusion transcripts in 41 patients (23.2%). The median turnaround time was 13 days. In the detection of fusion genes, not only common fusion products such as RUNX1-RUX1T1 and KMT2A rearrangements, but also NUP98 rearrangements and rare fusion genes were observed. Among 177 patients (72 with unfit AML, 105 with R/R-AML), mutations in KIT and WT1 were independent factors for overall survival (hazard ratio = 12.6 and 8.88, respectively), and patients with high variant allele frequency (≥40%) of TP53 mutations had a poor prognosis. As for the detection of actionable mutations, 38% (n = 69) of patients had useful genetic mutation (FLT3-ITD/TKD, IDH1/2, and DNMT3AR822 ) for treatment selection. Comprehensive genomic profiling using paraffin-embedded BM clot specimens successfully identified leukemic-associated genes that can be used as therapeutic targets.

Keywords: AML; FoundationOne Heme; actionable mutation; ineligible for standard chemotherapy; paraffin-embedded bone marrow clot.

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Conflict of interest statement

T.Y.: Otsuka, Pfizer, Abbie, Astellas, Daiichi Sankyo, Solasia Pharma (research funding); Ono Pharmaceutical, Pfizer, Chugai (honoraria). Y.M.: Bristol‐Myers Squibb, Novartis Pharma KK, Pfizer Japan, Inc., Takeda (honoraria). H.S.: Astellas, Teijin, Shionogi, Taiho, Eisai, Celgene, Ono, Takeda, Merck Sharp & Dohme, Sumitomo Dainippon, Nippon Shinyaku, Novartis, Janssen, Chugai, AbbVie (research funding); Eisai, Ono, Takeda, Sumitomo Dainippon, Nippon Shinyaku, Daiichi Sankyo, Novartis, Janssen, Chugai, Kyowa Kirin, Otsuka, Bristol‐Myers Squibb, Pfizer, Fujimoto, AbbVie, AstraZeneca, Sanofi, Mundi Pharma (honoraria); Eisai, Celgene, Chugai, AbbVie, AstraZeneca (membership on an entity's Board of Directors or advisory committees). K.Y.: AbbVie, Astra‐Zeneca, Bayer, Celgene, Chugai, Eisai, IQIVA/Incyte, Gilead Sciences, MSD, Mundipharma, Nippon Shinyaku, Novartis, Ono, Otsuka, Solasia Pharma, SymBio, Takeda, Yakult, Zenyaku (research funding); AbbVie, Bristol‐Myers Squibb, Celgene, Chugai, Eisai, IQIVA/HUYA, Janssen, Kyowa Kirin, Meiji Seika Pharma, Mochida, MSD, Mundipharma, Nippon Shinyaku, Novartis, Ono, Otsuka, Pfizer, Sanofi, Sumitomo Dainippon, Takeda (honoraria); AbbVie, Astra‐Zeneca, Celgene, Chugai, Eisai, Daiichi Sankyo, HUYA, Meiji Seika Pharma, MSD, Mundipharma, Ono, Otsuka, Stemline Therapeutics, Takeda (consultancy). J.K.: Bristol‐Myers Squibb, Chugai Pharmaceutical, Dainippon Sumitomo Pharma, Daiichi Sankyo, Sanofi, Kyowa Kirin, Otsuka Pharmaceutical, Astellas Pharma, Takeda, Celgene, MSD, Ono Pharmaceutical, Eisai, Sysmex, Pfizer, Nippon Shinyaku, Shionogi, Asahi Kasei, Taiho Pharmaceutical, Fujimoto Pharmaceutical (research funding); Bristol‐Myers Squibb, Chugai Pharmaceutical, Dainippon Sumitomo Pharma, Daiichi Sankyo, Sanofi, Kyowa Kirin, Otsuka Pharmaceutical, Astellas Pharma, Takeda, Celgene, Abbvie, Ono Pharmaceutical, Eisai, Pfizer, Nippon Shinyaku, Fujimoto Pharmaceutical (honoraria); Janssen Pharmaceutical KK, Bristol‐Myers Squibb, Sanofi, Celgene, Abbvie (consultancy). K.U.: Astellas, Abbvie, Gilead, Symbio, Daiichi Sankyo, Sumitomo Dainippon, Otsuka, Novartis, Bristol‐Myers Squibb, Ono, Janssen, Celgene, Takeda, Nippon Boehringer Ingelheim, Mundipharma, Astellas‐Amgen‐Biopharma, Nippon Shinyaku, Kyowa Kirin, Pfizer (research funding); Astellas, Symbio, Daiichi Sankyo, Otsuka, Novartis, Bristol‐Myers Squibb, Ono, Celgene, Nippon Shinyaku, Kyowa Kirin, Alexion, Eisai, MSD, Takeda, PharmaEssentia, Yakult (speakers bureau). A.G.: Eisai Co., Ltd., Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Nippon Shinyaku Co., Ltd., Chugai Pharmaceutical Co., Ltd., MSD KK, Otsuka Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Bayer Yakuhin, Ltd., Daiichi‐Sankyo Co., Ltd., and Nihon Pharmaceutical Co., Ltd. (research funding); Novartis Pharma KK, Alexion Pharmaceuticals, Inc., Eisai Co., Ltd., Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Nippon Shinyaku Co., Ltd., Chugai Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Daiichi‐Sankyo Co., Ltd., Nihon Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Janssen Pharmaceutical KK, Pfizer Japan Inc., Sanofi KK (honoraria); PharmaEssentia Japan KK, Chugai Pharmaceutical Co. (consultancy).

Figures

FIGURE 1
FIGURE 1
Extraction of DNA and RNA from bone marrow (BM) clot specimens from AML patients and mutation analysis. (A) Consort diagram and success rate of DNA and RNA yielded from BM clot samples. (B) Distribution of tumor mutation burden according to the WHO 2017 classification in relapsed refractory (R/R)‐AML and newly diagnosed unfit AML. HSCT, hematopoietic stem cell transplantation; MRC, myelodysplasia‐related changes; RGA, recurrent genetic abnormality; t‐AML, therapy‐related AML
FIGURE 2
FIGURE 2
Landscape of mutations and mutational spectrum of the cohort of AML patients. (A) Gene mutation profile in newly diagnosed unfit AML. (B) Gene mutation profile in relapsed or refractory AML (R/R‐AML). (C) Differences in the prevalence of gene mutations. Comparison of mutation analysis using FoundationOne Heme between the 177 patient Japanese cohort and the 2247 patients in the cohort from the United States and Europe. The symbol size represents the number of cases. SNV, single nucleotide variation
FIGURE 3
FIGURE 3
Overall survival (OS) and impact for death of the analysis cohort of AML patients. (A) Survival curves for newly diagnosed unfit AML and relapsed or refractory (R/R) AML. (B) Survival analysis with or without stem cell transplantation (SCT) in relapsed or refractory AML. Log–rank test was used in survival time analysis. (C) OS, hazard ratio (HR) of death by each mutation. Multivariable Cox proportional hazards regression model was used to estimate the effect of various predictor variables. *p < 0.05; **p < 0.01; ***p < 0.001. (D) Survival analysis according to TP53 valiant allele frequency (VAF). Log–rank test was used in survival time analysis. CI, confidence interval; mo, months; mOS, median overall survival; NR, not reached.
FIGURE 4
FIGURE 4
Number of detected genetic mutations in AML patients. (A) Detection of genetic mutations that affect treatment decisions. Actionable mutations include FLT3‐ITD/TKD, IDH2 R140Q/W,R172K, IDH1 R132, and DNMT3A R882C/H mutation. Overall, 38% (n = 69) of the cases possessed usable genetic alteration for selecting treatment options. (B) Distribution of therapeutic target genes in the analyzed cohort. Gene mutations that can be used to determine treatment include FLT3‐ITD/TKD, IDH2 R140Q/W,R172K, IDH1 R132, and DNMT3A R882C/H mutation. Candidate gene mutations for clinical trials include mutation of TP53, KIT D816 , KRAS G12C , NPM1, and KMT2A rearrangements
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