Prospective Evaluation of Prognostic Relevance of Gene Mutations and Minimal Residual Disease in Acute Myeloid Leukaemia with RUNX1-RUNX1T1 or CBFB-MYH11

Abstract

Background: Although acute myeloid leukaemia (AML) with RUNX1-RUNX1T1 and CBFB-MYH11 is categorized into a favorable cytogenetic risk group, several prognostic factors are suggested. However, those clinical significance remains controversial. We aimed to evaluate the prognostic relevance of gene mutations and minimal residual disease (MRD) in AML with RUNX1-RUNX1T1 and CBFB-MYH11. Methods: In this phase 4 trial, we enrolled AML with RUNX1-RUNX1T1 or CBFB-MYH11 patients aged 16 to 64 years old who achieved complete remission. Patients received three courses of high-dose cytarabine therapy, but no further treatment until haematological relapse. We analyzed mutations in exons 8, 10-11, and 17 of the KIT gene, and 55 genes that are frequently identified in myeloid malignancies, and also evaluated MRD. The primary endpoint was relapse-free survival (RFS) according to KIT mutation. This study is registered with UMIN Clinical Trials Registry, number UMI03434. Findings: Between May 25, 2010, and September 10, 2014, 203 patients were enrolled, and 199 patients were eligible. Median follow-up was 52·2 months (IQR 39·2-62·2). The primary endpoint RFS in KIT-mutated patients was inferior to that in unmutated patients (hazard ratio [HR] 1·92; 95% CI 1·23-3·00; p=0·003). Subgroup analysis showed a prognostic impact of KIT mutation in patients with RUNX1-RUNX1T1 (HR 3·27; 95% CI 1·90-5·64; p<0·001), but not in those with CBFB-MYH11, and only exon 17 mutation had such a notable impact. MRD was evaluated in 112 patients, and its presence was associated with a lower RFS in patients with CBFB-MYH11 (HR 4·55; 95% CI 1·20-17·2; p=0·03), but not in those with RUNX1-RUNX1T1. Interpretation: KIT exon 17 mutation was an unfavorable prognostic factor for RFS in AML patients with RUNX1-RUNX1T1. In contrast, the positivity of MRD was an unfavorable prognostic factor for RFS in AML patients with CBFB-MYH11. Trial Registration Number: This study is registered with UMIN Clinical Trials Registry, number UMI03434. Funding: Japan Agency for Medical Research and Development (AMED). Conflict of Interest: HKi 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., and honoraria from Bristol-Myers Squibb. NDob 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. NA received research funding from Chugai Pharmaceutical Co., Ltd., and Toyama Chemical Co., Ltd., and consulting fee from SRL Inc. No other potential conflict of interest relevant to this article was reported. Ethical Approval: The protocol was approved by the Ethics Committees of all participating institutions.