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

2006 ◽  
Vol 24 (24) ◽  
pp. 3904-3911 ◽  
Author(s):  
Peter Paschka ◽  
Guido Marcucci ◽  
Amy S. Ruppert ◽  
Krzysztof Mrózek ◽  
Hankui Chen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Direct Sequencing ◽  
Prognostic Significance ◽  
Prognostic Impact ◽  
Core Binding Factor ◽  
Relapse Risk ◽  
Binding Factor ◽  
Acute Myeloid

Purpose 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). Patients and Methods 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. Results 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. Conclusion 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.

scholarly journals Characteristics and outcome of patients with core binding factor acute myeloid leukemia and FLT3-ITD: results from an international collaborative study

Haematologica ◽  
2021 ◽  
Author(s):  
Sabine Kayser ◽  
Michael Kramer ◽  
David Martínez-Cuadrón ◽  
Justin Grenet ◽  
Klaus H. Metzeler ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Median Survival ◽  
Myeloid Leukemia ◽  
Collaborative Study ◽  
Published Data ◽  
Prognostic Impact ◽  
Core Binding Factor ◽  
Binding Factor ◽  
Multicenter Survey ◽  
Acute Myeloid

To evaluate the prognostic impact of FLT3-ITD in core-binding factor acute myeloid leukemia in an international, multicenter survey on 97 patients (52%, t(8;21)(q22;q22); 48% inv(16)(p13q22)/t(16;16)(p13;q22)). Median age was 53 (range, 19-81) years. Complete remission (CR) after anthracycline-based induction (n=86) and non-intensive therapy (n=11) was achieved in 97% and 36% of the patients. Median follow-up was 4.43 years (95%-CI, 3.35-7.39 years). Median survival after intensive and non-intensive treatment was not reached and 0.96 years, respectively. In intensively treated patients, inv(16) with trisomy 22 (n=11) was associated with a favorable 4-year relapse-free survival rate of 80% (95%-CI, 59-100%) as compared to 38% (95%-CI, 27-54%; P=0.02) in all other CBF-AML/FLT3- ITD positive patients (n=75). Overall, 24 patients underwent allogeneic hematopoietic cell transplantation (allo-HCT), 12 in first CR and 12 after relapse. Allo-HCT in first CR was not beneficial (P=0.60); however, allo-HCT seems to improve median survival in relapsed patients compared to chemotherapy (not reached versus 0.6 years; P=0.002). Excluding inv(16) with trisomy 22, our data indicate that the outcome of CBF-AML patients with FLT3-ITD seems to be inferior compared to published data on those without FLT3-ITD, suggesting that prognostically these patients should not be classified as favorable-risk. FLT3-inhibitors may improve outcome in those patients.

scholarly journals Genomic heterogeneity in core-binding factor acute myeloid leukemia and its clinical implication

2020 ◽  
Vol 4 (24) ◽  
pp. 6342-6352
Author(s):  
Nikolaus Jahn ◽  
Tobias Terzer ◽  
Eric Sträng ◽  
Anna Dolnik ◽  
Sibylle Cocciardi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Impact ◽  
Trisomy 8 ◽  
Core Binding Factor ◽  
Molecular Events ◽  
Binding Factor ◽  
Recurrent Mutations ◽  
Transcriptional Complex ◽  
Acute Myeloid

Abstract Core-binding factor (CBF) acute myeloid leukemia (AML) encompasses AML with inv(16)(p13.1q22) and AML with t(8;21)(q22;q22.1). Despite sharing a common pathogenic mechanism involving rearrangements of the CBF transcriptional complex, there is growing evidence for considerable genotypic heterogeneity. We comprehensively characterized the mutational landscape of 350 adult CBF-AML [inv(16): n = 160, t(8;21): n = 190] performing targeted sequencing of 230 myeloid cancer-associated genes. Apart from common mutations in signaling genes, mainly NRAS, KIT, and FLT3, both CBF-AML entities demonstrated a remarkably diverse pattern with respect to the underlying cooperating molecular events, in particular in genes encoding for epigenetic modifiers and the cohesin complex. In addition, recurrent mutations in novel collaborating candidate genes such as SRCAP (5% overall) and DNM2 (6% of t(8;21) AML) were identified. Moreover, aberrations altering transcription and differentiation occurred at earlier leukemic stages and preceded mutations impairing proliferation. Lasso-penalized models revealed an inferior prognosis for t(8;21) AML, trisomy 8, as well as FLT3 and KIT exon 17 mutations, whereas NRAS and WT1 mutations conferred superior prognosis. Interestingly, clonal heterogeneity was associated with a favorable prognosis. When entering mutations by functional groups in the model, mutations in genes of the methylation group (ie, DNMT3A, TET2) had a strong negative prognostic impact.

Prognostic impact of c-KIT mutations in core binding factor acute myeloid leukemia

2011 ◽  
Vol 35 (10) ◽  
pp. 1376-1383 ◽  
Author(s):  
Sang Hyuk Park ◽  
Hyun-Sook Chi ◽  
Sook-Kyung Min ◽  
Borae G. Park ◽  
Seongsoo Jang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Impact ◽  
Core Binding Factor ◽  
Binding Factor ◽  
Acute Myeloid

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

2005 ◽  
Vol 23 (24) ◽  
pp. 5705-5717 ◽  
Author(s):  
Guido Marcucci ◽  
Krzysztof Mrózek ◽  
Amy S. Ruppert ◽  
Kati Maharry ◽  
Jonathan E. Kolitz ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Gene Profiling ◽  
Prognostic Impact ◽  
Core Binding Factor ◽  
Cytogenetic Abnormalities ◽  
Binding Factor ◽  
Group B ◽  
Leukemia Group ◽  
Acute Myeloid

Purpose 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. Patients and Methods 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. Results 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. Conclusion 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.

scholarly journals Complete Molecular Risk Stratification of De Novo Acute Myeloid Leukemia with Intermediate Cytogenetics Using an Eight-Gene Panel

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2333-2333
Author(s):  
Maya Thangavelu ◽  
Ryan Olson ◽  
Li Li ◽  
Wanlong Ma ◽  
Steve Brodie ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Direct Sequencing ◽  
Core Binding Factor ◽  
Binding Factor ◽  
Molecular Abnormality ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Background: Refining risk stratification of acute myeloid leukemia (AML) using molecular profiling, especially those with intermediate cytogentic risk, is becoming standard of care. However, current WHO and ELN classifications are focused on few markers, mainly FLT3, NPM1, and CEBPA. While these abnormalities are relatively common, not all patients with AML and intermediate or normal cytogenetics will have abnormalities in these genes leaving large percentage of patients without refined risk stratification. We demonstrate that using 8 different AML-related genes are adequate to provide one or more molecular markers to further risk stratify patients with de novo AML. Method: Using direct sequencing we analyzed 211 samples referred from community practice with the diagnosis AML for molecular analysis. All samples were evaluated prospectively for mutations in FLT3, NPM1, IDH1, IDH2, CEBPA, WT1, RUNX1, and TP53 using direct sequencing. Fragment length analysis was used in addition to sequencing for FLT3 and NPM1. Available morphology, cytogenetics, and clinical data along with history were reviewed. Results: Of the 211 samples tested 103 (49%) had at least one or more molecular abnormality adequate for refining the risk classification. The mutations detected in these 103 patients were as follows: 27 (26%) FLT-ITD, 10 (10%) FLT3-TKD, 30 (29%) NPM1, 7 (7%) CEBPA, 14 (14%) IDH1, 13 (13%) IDH2, 10 (10%) WT1, 38 (37%) RUNX1, and 2 (2%) TP53. There was significant overlap and most patients had more than one mutation as illustrated in the graph below. However, if the testing was restricted to FLT3, NPM1, CEBPA and DNMT3A, only 56 (54%) would have had refined risk classification and 46% of patients would have remained without subclassification. The most striking finding was that all the remaining patients, who had no molecular abnormality detected in any of these 8 genes, had either history of MDS evolved to AML, therapy-related AML, or cytogenetic abnormalities other than intermediate (multiplex cytogenetic abnormalities or core-binding factor abnormality). Conclusion: Using FLT3, NPM1, CEBPA, and DNMT3A is inadequate for the molecular characterization of patients with AML. Patients with de novo AML and intermediate risk cytogenetics can be adequately prognostically subclassified and molecularly studied by testing only 8 genes. More importantly, this data confirms that the molecular biology driving de novo AML is significantly different from that driving MDS, AML with myelodysplasia-related changes, therapy-related AML, or AML with core binding factor or multiplex cytogenetics. Unlike de novo AML, these entities should be molecularly studied using MDS-specific driver genes. Furthermore, this data suggests that different therapeutic approaches should be developed for MDS and MDS-related AML. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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