Poster: AML-282: Prognostic Values of D816V KIT Mutation and Peri-Transplant CBFB-MYH11 MRD Monitoring on Acute Myeloid Leukemia with CBFB-MYH11

The prognostic significance of KIT mutations and optimal thresholds and time points of measurable residual disease (MRD) monitoring for acute myeloid leukemia (AML) with RUNX1-RUNX1T1 remain controversial in the setting of hematopoietic stem cell transplantation (HSCT). We retrospectively evaluated 166 high-risk patients who underwent allogeneic (Allo-HSCT, n = 112) or autologous HSCT (Auto-HSCT, n = 54). D816V KIT mutation, a subtype of exon 17 mutations, was significantly associated with post-transplant relapse and poor survival, while other types of mutations in exons 17 and 8 were not associated with post-transplant relapse. Pre- and post-transplant RUNX1–RUNX1T1 MRD assessments were useful for predicting post-transplant relapse and poor survival with a higher sensitivity at later time points. Survival analysis for each stratified group by D816V KIT mutation and pre-transplant RUNX1–RUNX1T1 MRD status demonstrated that Auto-HSCT was superior to Allo-HSCT in MRD-negative patients without D816V KIT mutation, while Allo-HSCT was superior to Auto-HSCT in MRD-negative patients with D816V KIT mutation. Very poor outcomes of pre-transplant MRD-positive patients with D816V KIT mutation suggested that this group should be treated in clinical trials. Risk stratification by both D816V KIT mutation and RUNX1–RUNX1T1 MRD status will provide a platform for decision-making or risk-adapted therapeutic approaches.

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A Predictor Combining Clinical and Genetic Factors for AML1-ETO Leukemia Patients

Frontiers in Oncology ◽

10.3389/fonc.2021.783114 ◽

2022 ◽

Vol 11 ◽

Author(s):

Min Yang ◽

Bide Zhao ◽

Jinghan Wang ◽

Yi Zhang ◽

Chao Hu ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Somatic Mutations ◽

Genetic Factors ◽

Risk Model ◽

Core Binding Factor ◽

Kit Mutation ◽

Binding Factor ◽

Prognostic Prediction ◽

Acute Myeloid

Core Binding Factor (CBF)-AML is one of the most common somatic mutations in acute myeloid leukemia (AML). t(8;21)/AML1-ETO-positive acute myeloid leukemia accounts for 5-10% of all AMLs. In this study, we consecutively included 254 AML1-ETO patients diagnosed and treated at our institute from December 2009 to March 2020, and evaluated molecular mutations by 185-gene NGS platform to explore genetic co-occurrences with clinical outcomes. Our results showed that high KIT VAF(≥15%) correlated with shortened overall survival compared to other cases with no KIT mutation (3-year OS rate 26.6% vs 59.0% vs 69.6%, HR 1.50, 95%CI 0.78-2.89, P=0.0005). However, no difference was found in patients’ OS whether they have KIT mutation in two or three sites. Additionally, we constructed a risk model by combining clinical and molecular factors; this model was validated in other independent cohorts. In summary, our study showed that c-kit other than any other mutations would influence the OS in AML1-ETO patients. A proposed predictor combining both clinical and genetic factors is applicable to prognostic prediction in AML1-ETO patients.

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AML-282: Prognostic Values of D816V KIT Mutation and Peri-Transplant CBFB-MYH11 MRD Monitoring on Acute Myeloid Leukemia with CBFB-MYH11

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/s2152-2650(21)01713-4 ◽

2021 ◽

Vol 21 ◽

pp. S299-S300

Author(s):

Daehun Kwag ◽

Byung-Sik Cho ◽

Gi-June Min ◽

Sung-Soo Park ◽

Silvia Park ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Kit Mutation ◽

Acute Myeloid

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C-KIT mutation cooperates with full-length AML1-ETO to induce acute myeloid leukemia in mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1019625108 ◽

2011 ◽

Vol 108 (6) ◽

pp. 2450-2455 ◽

Cited By ~ 83

Author(s):

Y.-Y. Wang ◽

L.-J. Zhao ◽

C.-F. Wu ◽

P. Liu ◽

L. Shi ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Full Length ◽

Kit Mutation ◽

Acute Myeloid

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Importance of c-kit mutation detection method sensitivity in prognostic analyses of t(8;21)(q22;q22) acute myeloid leukemia

Leukemia ◽

10.1038/leu.2011.104 ◽

2011 ◽

Vol 25 (9) ◽

pp. 1423-1432 ◽

Cited By ~ 41

Author(s):

S Wakita ◽

H Yamaguchi ◽

K Miyake ◽

Y Mitamura ◽

F Kosaka ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Mutation Detection ◽

Detection Method ◽

Kit Mutation ◽

Acute Myeloid

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The Role of C-KIT Mutations in the Leukemogenesis of Core-Binding Factor Acute Myeloid Leukemia: A Comparative Analysis on Paired Diagnosis and Relapse Samples.

Blood ◽

10.1182/blood.v108.11.2307.2307 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2307-2307

Author(s):

Der-Cherng Liang ◽

Lee-Yung Shih ◽

Chein-Fuang Huang ◽

Ya-Tzu Chang ◽

Huei-Ying Li ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Comparative Analysis ◽

Crucial Role ◽

Myeloid Leukemia ◽

Tandem Repeats ◽

Core Binding Factor ◽

Kit Mutation ◽

Binding Factor ◽

Acute Myeloid

Abstract C-KIT is a member of the type III receptor tyrosine kinase family and plays a crucial role in normal hematopoiesis and acute myeloid leukemia (AML). C-KIT mutations have been described in core-binding factor (CBF) AML at initial diagnosis. The role of C-KIT mutations in the relapse of CBF AML is not clear. In the present study, we analyzed C-KIT mutations on paired diagnosis and relapse samples in CBF AML. Among 1014 adults and 162 children with AML, CBF AML was detected in 11.4% of adults and 25.3% of children. Mutational analysis of C-KIT was performed by direct sequencing for all cDNA PCR products amplified with 5 overlapping primer pairs, which cover the whole coding sequences of C-KIT gene from exon 1 through exon 21. In AML with t(8;21)/AML1-ETO, 33.0 % (29/88) of adults and 44.4 % (12/27) of children had C-KIT mutations. In AML with inv(16)/CBFβ-MYH11, 22.2 % (6/27) of adults and 38.5 %(5/13) of children had C-KIT mutations. Taken together, C-KIT mutations were present in 30.4 % (35/115) of adults and 42.5 % (17/40) of children with CBF AML. Forty-two patients with CBF AML relapsed. Twenty-two(18 adults and 4 children) of the 23 patients with CBF AML and C-KIT(+) at diagnosis had relapse samples available for comparative analysis. All the 22 patients relapsed with C-KIT mutations, 21 of them showed the identical C-KIT mutation patterns as those at diagnosis. Of the 20 relapsed patients with t(8;21)/AML1-ETO and C-KIT(+), 3 had mutations in exon 8: T417_D419delinsY, Y418_D419delinsA, and [Y418N;Y418_D419insFF], respectively; one had mutation in exon 9: I478V; another one had mutation in exon 11: [D572_P573insL; E561_D572dup]; 14 had mutations in exon 17: 5 D816V, 3 N822K, 3 D816Y, and one each with D816H, D820G, and D820Y; the remaining one patient relapsed twice, the patterns of C-KIT mutations changed but remained in exon 17: D816A at diagnosis, D816V at the first relapse, and N822K at the second relapse. Genotyping analysis with 15 loci of short tandem repeats at 13 different chromosomes showed identity for the diagnosis and the two relapse samples. Of the 2 adults with inv(16)/CBFβ-MYH11 and C-KIT(+) who relapsed, both had mutations in exon 17: N822K and D816Y, respectively. C-KIT mutations were absent in all of the 35 complete remission samples examined. In those with CBF AML and C-KIT(−) at diagnosis, 19 patients including 16 adults and 3 children relapsed; C-KIT mutations were not present in all the relapse samples except one who acquired D816H mutation. The present study showed that all patients with de novo CBF AML harboring C-KIT mutations at diagnosis retained the mutations at relapse, indicating that C-KIT mutations play a crucial role in the leukemogenesis in a substantial proportion of patients with CBF AML.

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Highly Sensitive Quenching Probe (QProbe) Method Is Useful to Detect c-Kit Mutation and to Predict Relapse of t(8;21)(q22;q22) Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v114.22.2646.2646 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2646-2646

Author(s):

Satoshi Wakita ◽

Hiroki Yamaguchi ◽

Yoshio Mitamura ◽

Fumiko Kosaka ◽

Koiti Inokuchi ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Myeloid Leukemia ◽

Direct Sequence ◽

Wild Type ◽

Kit Mutation ◽

Highly Sensitive ◽

Quenching Probe ◽

Acute Myeloid

Abstract Abstract 2646 Poster Board II-622 Background: t(8;21)(q22;q22) acute myeloid leukemia (t(8;21) AML) show a high rate of complete remission (CR) and prolonged CR duration, especially following consolidation chemotherapy with high-dose cytarabine (HD-ARAC), and are thought to have a better prognosis than other AML patients. Nevertheless, only approximately 50% of patients were alive at 5 years. This suggests that some patients have more aggressive leukemic phenotypes and indicates the need for predictive molecular marker of relapse and treatment optimization with novel and/or more aggressive therapies such as stem cell transplantation.Recently, several groups reported that c-kit mutation (MutKIT) defined an unfavorable subgroup in t(8;21) AML. However MutKIT has been reported approximately 20% at diagnostic samples of core binding factor leukemia. It is possible that MutKIT are more high frequency at relapse sample of t(8;21) AML. In the present study, we analyzed samples collected at diagnosis and relapse to investigate the role of MutKIT s and Flt3 internal tandem duplication (ITD) in t(8;21) AML. Methods: We analyzed MutKIT and Flt3 ITD among 32 t(8;21) AML patients diagnosed between 1991 to 2009 at the Nippon Medical School. All of them were succeeded achieving CR, but 18 patients (56.3%) relapsed, became refractory chemotherapy, and poor prognosis. Exon 8 and 17 of MutKIT were analyzed by direct sequence and QProbe-system (ARKRAY, Inc. Kyoto, Japan). QProbe-system was high sensitivity mutation screening method, detected approximately 1% MutKIT using mutation specific guanine quenching probe (Leukemia Res 32 (2008) 1462–1467). FLT3 ITD was analyzed by PCR amplification. Results: Using direct sequence, MutKITs were found in 5 (18.5%) of the 27 patients at diagnosis (D816V: 3 patients AN822K: 2 patients), and 7 (46.6%) of 15 patients at relapse. Interestingly 3 patients were detected MutKIT at only relapse (D816V: 2 patients AN822K: 1 patient). All mutations found in exon 17 clustered within the A-loop. Next we analyzed to detected very slight amount of mutation by QProbe-system. N822K were newly found of the 3 patients at diagnosis in spite of negative by direct sequence Finally MutKIT were found 8 (29.6%) at diagnosis. Flt3 ITD were found in 2 (9.5%) of the 21 patents at diagnosis, and none of 15 patients at relapse. 2 patients with Flt3 ITD were not accompanied MutKIT. All of N822K newly found by QProbe-system and Flt3 ITD positive patients were relapsed but turn to mutation negative. To evaluate the importance of MutKIT as a predicted relapse, we analyzed the cumulative incidence of relapse (CIR) and relapse free survival (RFS) of these patients with Kaplan-Meier method. The CIR was higher for patients with MutKIT (p=0.040, Wild type c-kit (WtKIT): 45.8% vs MutKIT: 87.5%). In direct sequencing method, The RFS tend to be shorter for patient with MutKIT, but no significant differences (p=0.260; WtKIT: 30 months vs MutKIT: 11 months).On the other hand, in QProbe-system, the median RFS was shorter for patients with MutKIT (p=0.033; WtKIT: 64 months vs MutKIT: 11 months). In addition of FLT3-ITD analysis, median RFS was shorter for patients with MutKIT or FLT3 ITD (p=0.005; Wild type of both genes: 64 months vs MutKIT or FLT3 ITD: 10 months). Additionally, we compared overall survival (OS) of wild type of both genes with MutKIT or FLT3 ITD. The OS tend to be shorter for patient with MutKIT or FLT3 ITD, but no significant differences. Discussion: In this study, we confirmed the prognostic significance of MutKIT in patients with t(8;21) AML when we use the highly sensitive quenching probe method (QProbe-system). We showed that QProbe-system is quite useful in predicting the prognosis of patients with t(8;21) AML and in determining its therapeutic strategy including tyrosine kinase inhibitors and/or up-front stem cell transplantation. We also revealed the important role of MutKIT (46.7%) at relapse, but several questions were still remained. It is unknown for some patients how to gain MutKIT at only relapse and why mutations detected at diagnosis were disappeared at relapse. We need further study to clarify the function and commitment of MutKIT in relapse of t(8;21) AML. Disclosures: No relevant conflicts of interest to declare.

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Low WT1 Expression At Diagnosis Is a Strong Predictor On Poor Outcome In Patients With t(8;21) Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v122.21.1346.1346 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1346-1346

Author(s):

Ya-Zhen Qin ◽

Hong-Hu Zhu ◽

Qian Jiang ◽

Dai-Hong Liu ◽

Hao Jiang ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Clinical Outcome ◽

Myeloid Leukemia ◽

Strong Predictor ◽

Hematopoietic Stem ◽

Kit Mutation ◽

Transcript Levels ◽

Poor Outcome ◽

Upper Limit ◽

Acute Myeloid

Abstract Introduction Acute myeloid leukemia (AML) with t(8;21) is a heterogeneous disease. The dynamic patterns of AML1-ETO transcript levels during treatment and clinical outcome of patients vary greatly. Our AML05 trial revealed that minimal residual disease (MRD)status and treatment strategy were independent risk factors for outcome and that risk stratification treatment directed by MRD may improve the outcome of t(8;21) AML in CR1 (Blood 2013; 121:4056). As for pretreatment parameters, c-KIT mutation is a well-established adverse predictor on survival. However, a subset of t (8;21) AML patients without c-KIT mutation still showed poor clinical outcome. The prognostic value of WT1 transcript levels at diagnosis in AML has been investigated and the results were controversial. We wondered if WT1 expression associated with outcome in t (8;21) AML patients. Methods A total of 101 patients were included. They all were eligible cases who enrolled into AML05 trial from June 2005 to December 2012, and had available bone marrow samples at diagnosis. After 1 or 2 induction therapy and 2 cycles of intermediate-dose cytarabine-based consolidation therapy, fifty-seven patients continued cytarabine-based consolidation chemotherapy or received autologous-hematopoietic stem-cell transplantation (auto-SCT) and were defined as CT group, the remaining 44 patients received allogeneic SCT (allo-SCT) and defined as SCT group.WT1 and ABL transcript were tested by real time quantitative PCR, and WT1 transcript levels were calculated as WT1copies/ABL copies in percentage. The upper limit of normal bone marrows (NBMs) was 0.5%. c-KIT mutations in exon 8 and 17 were screened by direct sequencing. Results The median follow-up time was 25 (6-93) months for 73 alive patients. The cumulative incidence of relapse (CIR) at 3 years was 35.3%. The 3-year disease free survival (DFS) and overall survival (OS) rates were 57.2% and 62.8%, respectively. The median WT1 transcript levelsssof all patients were 9.1% (0.02%-99.3%). c-KIT mutation was detected in 31 patients. Receiver operating characteristics (ROC) curves revealed that WT1 transcript levels of 5.0% (1-log increase compared to the upper limit of NBM) were the best cutoff values to discriminate patients with different outcome. WT1 transcript levels of ≤5.0% were significantly associated with c-KIT mutation (23/42 vs 8/59, P<0.001), but didn't related to other pretreatment parameters (all P>0.05). In CT group, patients with WT1≤5% (n=19) had significantly higher CIR rate at 3-year, lower 3-year DFS and OS rate than those with WT1>5% (n=38), respectively (89.5% vs 27.9%, P<0.0001; 10.5% vs 66.1%, P<0.0001; 28.5% vs 66.5%, P=0.0062). Furthermore, patients with WT1≤5% and c-KIT mutation (-) had similar CIR, DFS and OS rate to both patients with WT1≤5% and c-KIT mutation (+) and patients with WT1>5% and c-KIT mutation (+) (all P >0.05, Figure 1). Therefore, they were merged into one group (n=24). Thus, patients with WT1≤5% and/or KIT mutation (+) had significantly higher CIR rate at 3-year, lower 3-year DFS and OS rate than those with WT1>5% and c-KIT mutation (-) (n=33) in CT group, respectively (89.4% vs 27.4%,P<0.0001; 10.6% vs 72.6%, P<0.0001; 26.1% vs 72.2%, P=0.0013). For patients ith WT1≤5%, allo-SCT significantly lowered CIR rate at 3-year, improved 3-year DFS rate and tended to improve OS rate compared to chemotherapy/auto-SCT by landmark analysis, respectively (11.5% vs 88.2%, P<0.0001; 65.4% vs 11.8%, P=0.0001; 60.6% vs 32.6%, P=0.10. Figure 2). Multivariate analysis revealed that WT1 transcript levels (≤5% vs >5%) and treatment (chemotherapy/auto SCT vs allo-SCT) instead of other pretreatment parameters were independent prognostic factors for relapse (hazard ratio (HR) 0.20, 95% CI 0.093¨C0.44; 0.096, 95% CI 0.033¨C0.28. all P<0.0001) , DFS (HR 0.22, 95% CI 0.11¨C0.44; 0.23, 95% CI 0.11¨C0.49. all P<0.0001) and OS (HR 0.30, 95% CI 0.14¨C0.66, P=0.003; 0.37, 95% CI0.16¨C0.82, P=0.014). Conclusion Less than 1-log increase of WT1 transcript levels at diagnosis is a strong predictor on poor outcome in patients with t (8;21) AML, and allo-SCT could significantly improve outcome of such patients. Grant Support Bejing Municipal Science & Technology Commission(Z111107067311070) and Nature Science Foundation of China (81170483). Disclosures: No relevant conflicts of interest to declare.

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