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. 2020 Jan 14;4(1):66-75.
doi: 10.1182/bloodadvances.2019000709.

Prospective evaluation of prognostic impact of KIT mutations on acute myeloid leukemia with RUNX1-RUNX1T1 and CBFB-MYH11

Yuichi Ishikawa  1 , Naomi Kawashima  1 , Yoshiko Atsuta  2 , Isamu Sugiura  3 , Masashi Sawa  4 , Nobuaki Dobashi  5 , Hisayuki Yokoyama  6 , Noriko Doki  7 , Akihiro Tomita  8 , Toru Kiguchi  9 , Shiro Koh  10 , Heiwa Kanamori  11 , Noriyoshi Iriyama  12 , Akio Kohno  13 , Yukiyoshi Moriuchi  14 , Noboru Asada  15 , Daiki Hirano  16 , Kazuto Togitani  17 , Toru Sakura  18 , Maki Hagihara  19 , Tatsuki Tomikawa  20 , Yasuhisa Yokoyama  21 , Norio Asou  22 , Shigeki Ohtake  23 , Itaru Matsumura  24 , Yasushi Miyazaki  25 , Tomoki Naoe  16 , Hitoshi Kiyoi  1
Affiliations

Prospective evaluation of prognostic impact of KIT mutations on acute myeloid leukemia with RUNX1-RUNX1T1 and CBFB-MYH11

Yuichi Ishikawa et al. Blood Adv. .

Abstract

The prognostic impact of KIT mutation on core-binding factor acute myeloid leukemia (CBF-AML) remains controversial. We registered 199 newly diagnosed de novo CBF-AML patients, aged 16 to 64 years, who achieved complete remission. They received 3 courses of high-dose cytarabine therapy and no further treatment until hematological relapse. Mutations in exons 8, 10-11, and 17 of the KIT gene were analyzed. Furthermore, we analyzed mutations in 56 genes that are frequently identified in myeloid malignancies and evaluated minimal residual disease (MRD). The primary end point was relapse-free survival (RFS) according to KIT mutations. The RFS in KIT-mutated patients was inferior to that in unmutated patients (hazard ratio, 1.92; 95% confidence interval, 1.23-3.00; P = .003). Based on subgroup analysis, KIT mutations had a prognostic impact in patients with RUNX1-RUNX1T1, but not in those with CBFB-MYH11, and only exon 17 mutation had a significant prognostic impact. Multivariate Cox regression analysis with stepwise selection revealed that the KIT exon 17 mutation and the presence of extramedullary tumors in patients with RUNX1-RUNX1T1, and loss of chromosome X or Y and NRAS mutation in patients with CBFB-MYH11 were poor prognostic factors for RFS. MRD was evaluated in 112 patients, and it was associated with a poorer RFS in the patients with CBFB-MYH11, but not in those with RUNX1-RUNX1T1. These results suggested that it is necessary to separately evaluate AML with RUNX1-RUNX1T1 or CBFB-MYH11 according to appropriate prognostic factors. This study was registered at www.umin.ac.jp/ctr/ as #UMIN000003434.

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Conflict of interest statement

Conflict-of interest disclosure: H. Kiyoi received research funding from Chugai Pharmaceutical Co. Ltd., Kyowa Hakko Kirin Co. Ltd., Zenyaku Kogyo Co. Ltd., FUJIFILM Corporation, Astellas Pharma Inc., Otsuka Pharmaceutical Co. Ltd., Nippon Shinyaku Co. Ltd., Eisai Co. Ltd., Pfizer Japan Inc., Takeda Pharmaceutical Co. Ltd., Novartis Pharma K.K., Sumitomo Dainippon Pharma Co. Ltd., Sanofi K.K., and Celgene Corporation; consulting fees from Astellas Pharma Inc., Amgen Astellas BioPharma K.K., and Daiichi Sankyo Co. Ltd.; honoraria from Bristol-Myers Squibb, Astellas Pharma Inc., and Novartis Pharma K.K. N. Dobashi received research funding from Pfizer Japan Inc., Chugai Pharmaceutical Co. Ltd., Astellas Pharma Inc., Kyowa Hakko Kirin Co. Ltd., Zenyaku Kogyo Co. Ltd., Eisai Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Celgene Co., and Sysmex Co. N. Asou received research funding from Chugai Pharmaceutical Co. Ltd. and Toyama Chemical Co., Ltd., and consulting fees from SRL Inc. The remaining authors declare to competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
CONSORT flow diagram. The primary end point, relapse-free survival, was evaluated in 199 eligible patients. Prognostic analysis of MRD was performed on 112 patients whose samples were collected.
Figure 2.
Figure 2.
Mutation landscape of AML with RUNX1-RUNX1T1 or CBFB-MYH11. (A) Identified mutations in analyzed patients are shown. Gray boxes indicate the patients whose samples were not analyzed. (B) The frequency of recurrently mutated genes by CBF-AML fusion type is shown. (C) Circos plots illustrate the association of mutated genes in AML with RUNX1-RUNX1T1 or CBFB-MYH11. (D-E) Circos plots illustrate the association of mutated genes in AML with RUNX1-RUNX1T1 and AML with CBFB-MYH11. The width of the arches indicates the percentage of mutations.
Figure 3.
Figure 3.
RFS according to KIT mutation. (A) Kaplan-Meier estimates of RFS according to KIT mutation in 199 CBF-AML patients. Kaplan-Meier estimates of RFS in patients with (C) RUNX1-RUNX1T1 or (E) CBFB-MYH11. (B,D,F) Kaplan-Meier estimates of RFS according to the KIT mutation type.
Figure 4.
Figure 4.
RFS according to the MRD level. (A) The RUNX1-RUNX1T1 or CBFB-MYH11 chimeric transcript level in each patient after the completion of 3 courses of HiDAC therapy is shown. (B) Kaplan-Meier estimates of RFS according to the MRD status in 112 CBF-AML patients. Kaplan-Meier estimates of RFS in patients with (C) RUNX1-RUNX1T1 or (D) CBFB-MYH11.
See this image and copyright information in PMC

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