Concomitant WT1 mutations predicted poor prognosis in CEBPA double-mutated acute myeloid leukemia

Transcription

1 Concomitant WT1 mutations predicted poor prognosis in CEBPA double-mutated acute myeloid leukemia Feng-Ming Tien, Hsin-An Hou, Jih-Luh Tang, Yuan-Yeh Kuo, Chien-Yuan Chen, Cheng-Hong Tsai, Ming Yao, Chi-Cheng Li, Chien-Ting Lin, Shang-Yi Huang, Bor- Sheng Ko, Szu-Chun Hsu, Shang-Ju Wu, Woei Tsay, Liang-In Lin, Wen-Chien Chou, Hwei-Fang Tien Division of Hematology, Department of Medicine, National Taiwan University Hospital & Tai-cheng Stem Cell Therapy Center Taipei, Taiwan 1

2 Blood. 2016; 127(20): Blood : Introduction Acute myeloid leukemia (AML) with CEBPA double mutations (CEBPA dm ) A new entity in the 2016 WHO Classification Favorable risk group in the 2017 ELN recommendation

3 Unmet needs for CEBPA dm patients However, a subset of CEBPA dm patients still relapses and dies of disease progression. Relapse rate after complete remission: 41~44% Blood. 2009;113: J Clin Oncol 28: There is limited information concerning risk stratification in the CEBPA dm patients. 3

4 Treatment algorithm for AML AML Diagnosis 3+7 Regimen (fit patients) CR Younger Pts (<60 years) with unfavorable cytogenetics RUNX1, FLT3-ITD, others CBF Leukemia CEBPA dm NPM1(+)/FLT3-ITD(-) Blood 2007, 109, JAMA 2009, 301, NEJM, 2008, 358, Allo-HSCT? HDAC (IV) NEJM 1994, 331: ASH Abstracts 2009; 114:484 Blood 2011, 117: Blood 2011, 118: JCO 2011, 29: Blood. 2016; 127(20): Blood : For those CEBPA dm patients who have high-risk for relapse, is it mandatory to perform upfront all-hsct? 4

5 Aims of this study Investigate the prognostic impact of other concomitant molecular mutations in CEBPA dm patients. Investigate the necessity of upfront allogenic transplantation in high-risk CEBPA dm patients. 5

6 Patients & Methods Patients 759 de novo AML patients, diagnosed from 1994 to 2011 at the National Taiwan University Hospital --69 CEBPA dm patients (9.1%) Methods Chromosome analysis Mutation analyses of 19 other relevant genes (FLT3-ITD, FLT3- TKD, NRAS, KRAS, KIT, PTPN11, RUNX1, GATA2, MLL/PTD, ASXL1, IDH1, IDH2, TET2, DNMT3A, SF3B1, SRSF2, U2AF1, NPM1, WT1, and TP53) by Sanger direct sequencing or next generation sequencing (NGS) (Ion Torrent, MA, USA) 6

7 Baseline characteristics (1) Variables CEBPAwt N=657 CEBPA sm N=33 CEBPA dm N=69 P value* P value Sex Male Female Age, years 49 (23-82) 52 (18-85) 40 (17-90) < Lab WBC (/μl) 6390 ( ) ( ) ( ) < Hb (g/dl) Platelet (k/μl) Blast (/μl) 8.1 ( ) 28 (5-122) 770 ( ) 8.2 ( ) 28 (10-712) ( ) 8.8 (3-13.6) 41 (5-204) ( ) *comparison of CEBPAwt and CEBPA dm comparison of CEBPA sm and CEBPA dm 7

8 Baseline characteristics (2) FAB M0 M1 M2 M3 M4 M5 M6 NA Total CEBPAwt N=654 (%) 18 (2.8) 115 (17.6) 212 (32.4) 63 (9.6) 180 (27.5) 30 (4.6) 26 (4.0) 10 (1.5) CEBPA sm N=33 (%) 0 (0) 11 (33.3) 17 (51.5) 0 (0) 3 (9.1) 1 (3.0) 1 (3.0) 0 (0) CEBPA dm N=69 (%) 0 (0) 39 (56.5) 27 (39.1) 0 (0) 3 (4.3) 0 (0) 0 (0) 0 (0) P value* P value < < Karyotype Total CEBPAwt CEBPA sm CEBPA dm N=633 (%) N=31 (%) N=68 (%) P value* P value Favorable (23.1) 0 (0) 0 (0) < Intermediate (61.9) 30 (96.8) 67 (98.5) < Unfavorable (15.0) 1 (3.2) 1 (1.5)

9 Tumor suppressor Activated signaling Chromatin modifier Transcription DNA methylation Miscellaneous RNA splicing Cytogenetics Concurrent mutations in CEBPA dm patients WT1 TP53 FLT3 /ITD FLT3 /TKD NRAS PTPN11 KRAS KIT ASXL1 MLL /PTD CEBPA RUNX1 GATA2 DNMT3A TET2 IDH1 IDH2 NPM1 SRSF2 U2AF1 SF3B1 Fifty CEBPA dm patients (72.5%) had concomitant genetic alterations. GATA2 was the most frequently concurrent mutated gene, followed by FLT3-ITD, NRAS, TET2, WT1 and FLT3-TKD. SF: splicing factors, including SF3B1, SRSF2, and U2AF1 Frameshift Missense Inframe indel Mutated Wild type No data/unknown significance Intermediate-risk Unfavorable-risk 9

10 Clinical outcome of CEBPA dm patients 60 CEBPA dm patients received standard induction chemotherapy. Complete remission (CR) rate: 90.2% Relapse after CR: 38.2% CR rate (%) Induction death (%) Relapse rate (%) P= P= P= others* CEBPAdm dm others CEBPAdm *others denote intermediate-risk cytogenetics patients without CEBPA dm others* CEBPA dm others* CEBPA dm 20 0 others CEBPAdm 10

11 WT1 mutations predicted poor prognosis in CEBPA dm patients Patients harboring concomitant WT1 mutations (n=7) CR rate: 71.4% Relapse rate: 80% CR rate (%) Relapse rate (%) P= P= WT1 wt WT1 mut. CEBPA dm patients 0 WT1 WT1 wt WT1 mut. CEBPA dm patients 11

12 WT1 mutations predicted poor prognosis in CEBPA dm patients median follow-up of 68.5 months WT1 mutated vs. wide-type Median OS: 14 months vs. not reached; P=0.005 Median DFS: 7.8 vs months, P=0.002 Wild-type WT1, n=53 Wild type WT1, n=53 WT1 mutation, n=7 WT1 mutation, n=7 P=0.005 P=

13 Detailed survival outcome of WT1-mutated patients in CEBPA dm group Pt No. Karyotype Induction Remission response Relapse duration (months) Note Long-term survival sp:+21, -x CR death CN Refractory death CN CR1 + 7 CR2 HSCT yes Complex CR1 CR1 HSCT yes CN CR1 + 9 CR2 HSCT yes CN Refractory death CN CR1 + 7 death 13

14 Implications of other concomitant mutations on prognosis GATA2 mutation, n=21 Wild-type, n=36 NRAS mutation, n=21 Wild-type, n=36 GATA2 P=0.07 NRAS P=0.07 Wild-type, n=53 Wild-type, n=53 FLT3-ITD mutation, n=8 TET2 mutation, n=7 FLT3-ITD P=0.552 TET2 P=

15 Discussion The Wilms Tumor 1 (WT1) gene, encoding a zinc-finger transcription factor, is physiologically expressed in hematopoietic stem cells. WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation. WT1-WT WT1 mutated NTUH: Blood. 2010;115(25): Mol Cell. 2015;57(4):

16 Concomitant mutations in CEBPA dm patients GATA2 mutations: mostly better survival Blood. 2012;120(2): ; Leukemia. 2013;27(2): Ann Hematol. 2015;94(2): ; Leukemia. 2016;30(11): TET2 mutations: worse survival Br J Haematol. 2013;161(5):

17 Conclusion CEBPA dm AML patients GATA2 mutation (33.8%), FLT3-ITD, NRAS, TET2, and WT1 mutations are the most frequently concurrent genetic alterations. A non-neglectable relapse rate (38.2%) after CR1. Risk stratification is important Concurrent WT1 mutations predict poor prognosis. All encountered relapse if no HSCT at CR1 HSCT prolongs survival 17

18 Acknowledgments Lab colleagues Hwei-Fang Tien, MD, PhD Wen-Chien Chou, MD, PhD Hsin-An Hou, MD, PhD Chien-Chin Lin, MD Mei-Hsuan Tseng Chi-Fei Huang Chromosomal analysis Ming-Chih Liu All patients that participated this study Hematologists Woei Tsai, MD, PhD Jih-Luh Tang, MD, PhD Ming Yao, MD Chi-Cheng Li, MD Shang-Yi Huang, MD, PhD Bor-Sheng Ko, MD, PhD Szu-Chun Hsu, MD Chien-Yuan Chen, MD, PhD Shang-Ju Wu, MD, PhD Chien-Ting Lin, MD National Taiwan University Hospital National Taiwan University Cancer Center 18