Project title: Translational Research for Improving Cancer Patient Survival in Taiwan-A Multiple Center Approach

Program title: Blood cancer: acute myeloid leukemia

Clinical Impact of Minimal Residual Disease Monitoring by real time Quantitative PCR in Acute Myeloid Leukemia

Hsiao-Wen Kao 1, Ming-Chung Kuo1, Hung Chang1, Po-Nan Wang1, Chin-Ho Wu1, Tung-Liang Lin1, Chung-Chi Tang1, Tsai-Yun Chen2, Ching-Yuan Kuo3, Ming-Chung Wang3, Sung-Nan Pei3, Ming-Chun Ma3, Wen-Li Hwang4, Chieh-lin Teng4, Chih-Cheng Chen5, Cih-En Huang5, Yi-Yang Chen5, Yen-Min Huang6, Yueh-Shih Chang6, Su-Peng Yeh7, Ching-Yun Hsieh7, Ming-Yu Lein7, Tran-Der Tan8, Hsin-Hsuan Chen8, Lun-Wei Chiou8, Ming-Chih Chang9, Huan-Chau Lin9, Yen-Ning Hsu9, Yin-Hsun Feng10, Hung-Chang Wu10, Sheng-Yen Hsiao11 and Lee-Yung Shih1

高小雯 ，郭明宗，張鴻，王博南，吳金和，林棟樑，湯崇志，陳彩雲，郭景元， 王銘崇，裴松南，馬銘君，黃文豊，滕傑林，陳志丞，黃慈恩，陳苡揚，黃彥閔， 張悅詩，葉士芃，謝清昀，連銘渝，譚傳德，劉韋新，邱倫瑋，張明志，林煥超， 許彥寧，馮盈勳，吳鴻昌，蕭聖諺，施麗雲

1Chang Gung Memorial Hospital at Linkou, 2National Cheng Kung University Hospital, 3Chang Gung Memorial Hospital at Kaohsiung, 4Taichung Veterans General Hospital, 5Chang Gung Memorial Hospital at Chaiyi, 6Chang Gung Memorial Hospital at Keelung, 7China Medical University Hospital, 8Koo Foundation Sun Yat-Sen Cancer Center, 9Mackay Memorial Hospital, 10Chi Mei Hospital, 11E-Da Hospital

Backgrounds: Despite complete remission (CR) in most acute myeloid leukemia (AML) patients after induction therapy, a substantial proportion of patients eventually relapse. Monitoring of minimal residual disease (MRD) in AML patients is useful in identifying patients with high risk of relapse. Large scale MRD monitoring program of AML patients in Taiwan have not been available in the past. With the support of MOHW, we detected MRD for AML patients in. The purpose of this study was to evaluate the impact of MRD on outcome in AML patients with PML-RARa, RUNX1-RUNX1T1, CBFB-MYH11, NPM1 mutations and KMT2A-PTD from Taiwan AML Consortium.
Materials and Methods: A total of 304 AML patients were enrolled, in whom 134 AML patients with PML-RARA (2002-2017), 72 AML patients with RUNX1-RUNX1T1 (1999-2016), 21 AML patients with CBFB-MYH11 (2006-2016), 48 AML patients with NPM1 (2012-2017), and 29 AML patients with KMT2A-PTD (2000-2015). Follow-up bone marrow samples at different time points were analyzed by RQ-RT-PCR TaqMan assays to measure fusion transcripts or mutations detected at AML diagnosis. The results were expressed as log reduction, except that MRD cutoff by upper normalized copy number (NCN) limit levels of normal marrow in KMT2A-PTD AML (e9e3 NCN normal limit < 0.00012; e11e3 NCN normal limit < 0.000012). Relapse-free survival (RFS) and overall survival (OS) were analyzed according to the MRD level.
Results: The two-year relapse-free survival (RFS) rates of AML patients with PML-RARa, RUNX1-RUNX1T1, CBFB-MYH11, NPM1 mutation and KMT2A-PTD were 94%, 63%, 71%, 53%, and 16%. The two-year overall survival (OS) rates of AML patients with PML-RARa, RUNX1-RUNX1T1, CBFB-MYH11, NPM1 mutation and KMT2A-PTD were 97%, 73%, 91%, 59%, and 26%. For AML patients with PML-RARa, those with post-induction therapy MRD > 3 log reduction (n=60) had a trend of improved OS compared to patients with post-induction therapy MRD < 3 log reduction (n=54) (5-year OS rate 97% vs 88%). During consolidation chemotherapy, PML-RARa AML patients with MRD > 5 log reduction (n=94) had significantly improved RFS (5-year RFS rates 96% vs 73%, P=0.034) and OS (5-year OS rates 97% vs 71%, P=0.019) compared to patients with MRD < 5 log reduction (n=9). PML-RARa AML patients with off therapy MRD > 5 log reduction (n=107) had significantly improved RFS (5-year RFS rates 95% vs 50%, P=0.001) and OS (5-year OS rates 93% vs 50%, P=0.007) compared to patients with MRD < 5 log reduction (n=9). For AML patients with RUNX1-RUNX1T1 patients with post-induction MRD > 1 log reduction was associated with significantly improved RFS and OS compared to patients with post-induction MRD < 1 log reduction. RUNX1-RUNX1T1 AML patients with post-3rd consolidation therapy MRD > 3 log reduction or with off therapy MRD > 4 log reduction were all associated with significantly improved RFS and OS compared to those with post-3rd consolidation therapy MRD < 3 log reduction or with off therapy MRD < 4 log reduction. CBFB-MYH11AML patients who had during consolidation MRD > 3 log reduction had significant better RFS compared to patients with during consolidation MRD < 3 log reduction. MLL-PTD AML patients who had during consolidation MRD < NCN upper normal limits had significant better RFS (2-year RFS rates 57% vs 18%, P=0.048) and OS (2-year OS rates 100% vs 44%, P=0.013) compared to patients with during consolidation MRD > NCN upper normal limits.
Conclusions: Our data from Taiwan AML Consortium defined the optimal molecular responses at different time points following therapy in t(8;21) and t(15;17) AML patients. MRD monitoring is informative to identify favorable genetic AML patients with higher risk of relapse. MRD-guided therapy is expected to further improve their treatment outcomes.