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      Heterogeneous prognosis among KIT mutation types in adult acute myeloid leukemia patients with t(8;21)

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          Abstract

          Acute myeloid leukemia (AML) with t(8;21) is a heterogeneous disease 1 . Therefore, additional prognostic factors are needed in order to make risk-adapted treatment approaches. KIT mutations are the most common mutations of t(8;21) AML patients, and a spectrum of mutations has been detected to date 2–6 . Limited by sample size or the screening method, previous studies have usually analyzed all types of mutations as a whole or just analyzed the most prevalent D816 mutation 2–7 . Thus, whether each type of mutation has similar adverse impacts remains unclear to date. A reflection is that the existence of the KIT mutation brings t(8;21) AML from low to intermediate risk regardless of mutation type in the National Comprehensive Cancer Network guidelines 8 , whereas European LeukemiaNet has provided no further recommendation for those with a KIT mutation 9 . Recently, Yui et al. 10 showed that the D816 mutation had a poorer prognosis than other mutations. Thus, it is urgent to perform large-scale studies under modern treatment modes to comprehensively evaluate the prognoses of the individual KIT mutation types. A total of 275 consecutive adult patients with t(8;21) AML who were diagnosed and received treatment in our institute from June 2005 to December 2017 were, retrospectively, evaluated. Totally, 150 patients (54.5%) were male. The median age of the patients at diagnosis was 36 (range: 16–69) years. As we previously reported, induction chemotherapy comprised 1–2 cycles of induction with the “3 + 7” regimen or the homoharringtonine, aclarubicin, and cytarabine regimen (homoharringtonine 2 mg/m2 per day, cytarabine 100 mg/m2, and aclarubicin 20 mg/day on days 1–7) 11,12 . Among the 263 patients achieving complete remission (CR), 142 received the intermediate-dose cytarabine-based chemotherapy, 13 received chemotherapy followed by autologous-hematopoietic stem cell transplantation (auto-HSCT), 108 received chemotherapy followed by allogeneic-HSCT (allo-HSCT, human leukocyte antigen-identical sibling donor, n = 43; matched unrelated donor, n = 7; haploidentical related donor, n = 58) as postremission therapy 13 . Dasatinib were used in some patients with KIT mutation if RUNX1–RUNX1T1 reduction is less than 3-log after cycle 2 consolidation since 2015. Nine and one patients who relapsed after chemotherapy and auto-HSCT received allo-HSCT as salvage therapy. The study was approved by the Ethics Committee of the Peking University People’s Hospital. Informed consent was obtained from all subjects in accordance with the Declaration of Helsinki. The cutoff date for the follow-up was April 15, 2018. As we previously reported, the complementary DNA was used to amplify KIT exons 17 and 8 and sequencing 4 , and TaqMan-based real-time quantitative polymerase chain reaction technology was used to detect RUNX1–RUNX1T1 transcript levels 11 . The survival functions were estimated using the Kaplan–Meier method and were compared using the log-rank test. The parameters with P < 0.20 by the univariate analysis were entered into a multivariate model using a Cox proportional hazards model to identify the most statistically significant parameters associated with relapse free survival (RFS) and overall survival (OS). The SPSS 16.0 software package (SPSS Inc., Chicago, IL) and GraphPad Prism 5 (GraphPad Software Inc., La Jolla, CA) were used for the data analysis. The median follow-up time was 20 (2–93) months. The 3-year RFS and OS rates were 61.5% (95% confidence interval (CI), 53.9–68.2%) and 73.2% (95% CI, 67.3–80.4%), respectively. Overall, 114 patients (41.5%) had KIT mutations, and a total of 22 types of mutations were detected (Table 1). In all, 103 and 11 patients, respectively, had sole and compound mutations (combination of 2 types), and 104 (37.8%) and 14 (5.1%) patients had a KIT mutation in exon 17 and exon 8 (sole or compound), respectively. The most prevalent mutation was exon 17 D816 (57.0% of the patients with KIT mutations), followed by the exon 17 N822, exon 8 deletion–insertion and exon 17 D820 mutations (27.2, 12.3 and 4.4%). The one-course and two-course CR rates were similar between the patients with KIT mutations and no mutation (P = 1.0 and 0.45). Patients with a KIT mutation had significantly lower 3-year RFS and OS rates than those with no mutation (RFS: P = 0.0002, 49.3% [95% CI: 37.0–60.5%] vs. 69.7% [95% CI 59.9–77.6%]; OS: P = 0.0055, 67.1% [95% CI: 55.0–76.6%] vs. 77.6% [95% CI: 68.3–84.5%]). Patients with sole D816V, D816Y, and D816H mutation had similar 3-year RFS and OS rates (P = 0.57 and 0.087). Patients with a sole D816 mutation had significantly lower 3-year RFS and OS rates than those with no mutation (RFS, P < 0.0001, 33.7% [95% CI: 17.3–50.9%] vs. 69.7% [95% CI: 59.9–77.6%], Fig. 1a; OS, P < 0.0001, 54.9% [95% CI: 37.9–69.1%] vs. 77.6% [95% CI: 68.3–84.5%], Fig. 1b); Similar results existed if the patients who underwent allo-HSCT were censored at the time of transplantation (RFS: P < 0.0001, 19.4% [95% CI: 1.6–52.3%] vs. 57.7% [95% CI: 43.8–69.3%], Fig. 1c; OS: P = 0.0003, 53.7% [95% CI: 23.9–76.3%] vs. 77.0% [95% CI: 63.2–86.2%], Fig. 1d). In addition, the 3-year RFS and OS rates were similar among the patients with the sole N822 mutation, the exon 8 mutation and no mutation (RFS: P = 0.47, 69.6% [95% CI: 46.1–84.4%] vs. 88.9% [95% CI: 43.3–98.4%] vs. 69.7% [95% CI: 59.9–77.6%], Fig. 1a; OS: P = 0.70, 71.9% [95% CI: 42.7–88.0%] vs. 83.3% [95% CI: 27.3–97.4%] vs. 77.6% [95% CI: 68.3–84.5%], Fig. 1b). Likewise, the 3-year RFS and OS rates were similar if censoring at the time of transplantation (RFS: P = 0.36, 52.6% [95% CI: 18.5–78.3%] vs. 80.0% [95% CI: 20.4–96.9%] vs. 57.7% [95% CI: 43.8–69.3%], Fig. 1c; OS: P = 0.32, 0 [95% CI: 0–0] vs. 75.0% [95% CI: 12.8–96.1%] vs. 77.0% [95% CI: 63.2–86.2%], Fig. 1d). Because of the similar prognoses for the N822 and exon 8 mutations compared to no mutation, five patients with sole or compound D820 mutation (Table 1) were analyzed together. Patients with the D820 mutation had significantly lower 3-year RFS rates than those with no mutation despite of no censoring or censoring (no censoring: P = 0.0050, 20.0% [95% CI: 0.8–58.2%] vs. 69.7% [95% CI: 59.9–77.6%], Fig. 1a; censoring: P < 0.0001, 0% [95% CI: 0–0%] vs. 57.7% [95% CI: 43.8–69.3%], Fig. 1c). However, the D820 mutation had no impact on OS (P = 0.73 and 0.72, Fig. 1b and d). Table 1 KIT mutation patterns Type of mutation Number of patients (%) Sole mutation 103 (90.4%) Exon 17 92 (80.7%) R815_D816delinsK 1 (0.9%) R815_D816insT 1 (0.9%) R815_D816insIR 1 (0.9%) D816A 1 (0.9%) D816H 8 (7.0%) D816V 37 (32.5%) D816Y 10 (8.8%) D820G 3 (2.6%) N822K 28 (24.6%) N822Y 1 (0.9%) A829P 1 (0.9%) Exon 8 11 (9.6%) T417_D419DelinsI 1 (0.9%) T417_D419delinsY 1 (0.9%) T417_R420DelinsG 1 (0.9%) Y418delinsFFW 1 (0.9%) Y418_D419delinsP 1 (0.9%) Y418_R420delinsSW 1 (0.9%) Y418_L421delinsTRVY 1 (0.9%) D419del 1 (0.9%) D419_R420delinsK 2 (1.8%) D419_L421DelinsVEV 1 (0.9%) Compound mutations 11 (9.6%) D816V + D816H 2 (1.8%) D816V + D816Y 3 (2.6%) D816V + D820G 1 (0.9%) D816V + D419del 1 (0.9%) D816V + T417_L421delinsLPRF 1 (0.9%) D816Y + N822K 1 (0.9%) D820G + N822K 1 (0.9%) D820G + D419del 1 (0.9%) Total 114 (100%) Fig. 1 RFS and OS of patients grouped by KIT mutation status and type. a RFS, no censoring. b OS, no censoring. c RFS, censoring at the time of allo-HSCT. d OS, censoring at the time of allo-HSCT Next, patients with KIT D816 and D820 mutations were defined as the D816/D820 mutation group (n = 70, 25.5%), whereas the N822 and exon 8 mutation and no mutation were defined as the N822/exon 8/no mutation group (n = 201, 73.1%). Patients with the D816/D820 mutation had significantly lower 3-year RFS and OS rates than those with the N822/exon 8/no mutation (RFS: P < 0.0001, 33.1% [95% CI: 18.7–48.2%] vs. 70.5% [95% CI: 61.9–77.5%]; OS: P < 0.0001, 60.5% [95% CI: 45.3–72.7%] vs. 77.2% [95% CI: 68.8–83.6%]). Similar results existed when censoring (RFS: P < 0.0001, 0% [95% CI: 0–0%] vs. 57.9% [95% CI: 45.2–68.7%]; OS: P = 0.0002, 58.5% [95% CI: 31.9–77.7%] vs. 73.6% [95% CI: 60.3–83.1%]). Multivariate analyses showed that the KIT D816/D820 mutation, a <3-log reduction in the RUNX1–RUNX1T1 transcript levels at cycle 2 consolidation and treatment with chemotherapy only/auto-HSCT were independent adverse prognostic factors for both RFS and OS (Table S1). In accordance with the majority of previous studies 2–7 , we confirmed that both the KIT mutation and the KIT D816 mutation were significantly associated with lower RFS and OS rates in adult t(8;21) AML. We also showed that the three common D816 mutations had similar clinical impacts. Furthermore, we demonstrated that the N822 and exon 8 mutations had similar RFS and OS rates compared to no mutation, whereas the D820 mutation had a significantly higher relapse probability than no mutation. The results implied that we should stratify the patients not only according to the existence of the KIT mutation but also according to the type of mutation. After regrouping, the KIT D816/D820 mutation was shown to be an independent adverse prognostic factor for both RFS and OS. The multivariate analyses result reflected that the pretreatment factor, treatment response and treatment modality were all relevant to the outcome of t(8;21) AML. Consistent with the current clinical results, animal and in vitro studies show a functional difference between KIT mutations. Nick et al. 14 used a murine model to illustrate that KIT D814V promoted a more varied and aggressive leukemic phenotype than KIT T417IΔ418–419 when coexpressed with RUNX1–RUNX1T1. Omori et al. demonstrated that in addition to the common JAK/STAT signaling pathway, the D816V mutation activated SRC family kinases, whereas N822K activated the MAPK pathway. The consequence was that D816V had a greater cell-proliferative and antiapoptotic ability than the N822K mutation 15 . The limitation was that this was a retrospective study. The treatment regimens were not uniform. Furthermore, we could not analyze the synergistic impact of the individual KIT mutations with other gene mutations due to lack of data. In conclusion, the individual KIT mutations had distinct prognoses in adult t(8;21) AML. Exon 17 D816 and D820 mutation had an adverse prognosis, whereas the exon 17 N822 and exon 8 mutation had a similar prognosis to no mutation. This result is helpful for a more precise stratification and for directing the appropriate treatment in t(8;21) AML. Multicenter prospective studies with a large sample size are warranted. Electronic supplementary material Table S1

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          Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B Study.

          To analyze the prognostic impact of mutated KIT (mutKIT) in core-binding factor acute myeloid leukemia (AML) with inv(16)(p13q22) and t(8;21)(q22;q22). Sixty-one adults with inv(16) and 49 adults with t(8;21), assigned to postremission therapy with repetitive cycles of higher dose cytarabine were analyzed for mutKIT in exon 17 (mutKIT17) and 8 (mutKIT8) by denaturing high-performance liquid chromatography and direct sequencing at diagnosis. The median follow-up was 5.3 years. Among patients with inv(16), 29.5% had mutKIT (16% with mutKIT17 and 13% with sole mutKIT8). Among patients with t(8;21), 22% had mutKIT (18% with mutKIT17 and 4% with sole mutKIT8). Complete remission rates of patients with mutKIT and wild-type KIT (wtKIT) were similar in both cytogenetic groups. In inv(16), the cumulative incidence of relapse (CIR) was higher for patients with mutKIT (P = .05; 5-year CIR, 56% v 29%) and those with mutKIT17 (P = .002; 5-year CIR, 80% v 29%) compared with wtKIT patients. Once data were adjusted for sex, mutKIT predicted worse overall survival (OS). In t(8;21), mutKIT predicted higher CIR (P = .017; 5-year CIR, 70% v 36%), but did not influence OS. We report for the first time that mutKIT, and particularly mutKIT17, confer higher relapse risk, and both mutKIT17 and mutKIT8 appear to adversely affect OS in AML with inv(16). We also confirm the adverse impact of mutKIT on relapse risk in t(8;21) AML. We suggest that patients with core-binding factor AML should be screened for mutKIT at diagnosis for both prognostic and therapeutic purposes, given that activated KIT potentially can be targeted with novel tyrosine kinase inhibitors.
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            MRD-directed risk stratification treatment may improve outcomes of t(8;21) AML in the first complete remission: results from the AML05 multicenter trial.

            We aimed to improve the outcome of t(8;21) acute myeloid leukemia (AML) in the first complete remission (CR1) by applying risk-directed therapy based on minimal residual disease (MRD) determined by RUNX1/RUNX1T1 transcript levels. Risk-directed therapy included recommending allogeneic hematopoietic stem cell transplantation (allo-HSCT) for high-risk patients and chemotherapy/autologous-HSCT (auto-HSCT) for low-risk patients. Among 116 eligible patients, MRD status after the second consolidation rather than induction or first consolidation could discriminate high-risk relapse patients (P = .001). Allo-HSCT could reduce relapse and improve survival compared with chemotherapy for high-risk patients (cumulative incidence of relapse [CIR]: 22.1% vs 78.9%, P < .0001; disease-free survival [DFS]: 61.7% vs 19.6%, P = .001), whereas chemotherapy/auto-HSCT achieved a low relapse rate (5.3%) and high DFS (94.7%) for low-risk patients. Multivariate analysis revealed that MRD status and treatment choice were independent prognostic factors for relapse, DFS, and OS. We concluded that MRD status after the second consolidation may be the best timing for treatment choice. MRD-directed risk stratification treatment may improve the outcome of t(8;21) AML in CR1. This trial was registered at http://www.chictr.org as #ChiCTR-OCH-12002406.
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              Prognostic factors and outcome of core binding factor acute myeloid leukemia patients with t(8;21) differ from those of patients with inv(16): a Cancer and Leukemia Group B study.

              Because both t(8;21) and inv(16) disrupt core binding factor (CBF) in acute myeloid leukemia (AML) and confer relatively favorable prognoses, these cytogenetic groups are often treated similarly. Recent studies, however, have shown different gene profiling for the two groups, underscoring potential biologic differences. Therefore, we sought to determine whether these two cytogenetic groups should also be considered separate entities from a clinical standpoint. We analyzed 144 consecutive adults with t(8;21) and 168 with inv(16) treated on Cancer and Leukemia Group B front-line studies. We compared pretreatment features, probability of achieving complete remission (CR), overall survival (OS) and cumulative incidence of relapse (CIR) between the two groups. With a median follow-up of 6.4 years, for CBF AML as a whole, the CR rate was 88%, 5-year OS was 50% and CIR was 53%. After adjusting for covariates, patients with t(8;21) had shorter OS (hazard ratio [HR] = 1.5; P = .045) and survival after first relapse (HR = 1.7; P = .009) than patients with inv(16). Unexpectedly, race was an important predictor for t(8;21) AML, in that nonwhites failed induction more often (odds ratio = 5.7; P = .006) and had shorter OS than whites when certain secondary cytogenetic abnormalities were present. In patients with t(8;21) younger than 60 years, type of induction also correlated with relapse risk. For inv(16) AML, secondary cytogenetic abnormalities (especially +22) and male sex predicted better outcome. When the prognostic impact of race, secondary cytogenetic abnormalities, sex, and response to salvage treatment is considered, t(8;21) and inv(16) AMLs seem to be distinct clinical entities and should be stratified and reported separately.
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                Author and article information

                Contributors
                +8610-88326006 , huangxiaojun@bjmu.edu.cn
                Journal
                Blood Cancer J
                Blood Cancer J
                Blood Cancer Journal
                Nature Publishing Group UK (London )
                2044-5385
                7 August 2018
                7 August 2018
                August 2018
                : 8
                : 8
                : 76
                Affiliations
                [1 ]Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044 China
                [2 ]GRID grid.452723.5, Peking-Tsinghua Center for Life Sciences, ; Beijing, 100871 China
                Author information
                http://orcid.org/0000-0003-2343-0436
                http://orcid.org/0000-0002-2145-6643
                Article
                116
                10.1038/s41408-018-0116-1
                6081455
                30087318
                a39f0a71-2037-4aaf-9ce4-e3035c609dfc
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 21 May 2018
                : 1 July 2018
                : 6 July 2018
                Funding
                Funded by: the Natural Science Foundation of China
                Funded by: the Foundation for Innovative Research Groups of the National Natural Science Foundation of China
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                Correspondence
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                © The Author(s) 2018

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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