Monitoring of minimal residual disease in patients with core binding factor acute myeloid leukemia and the impact ofC-KIT,FLT3, andJAK2mutations on clinical outcome

Abstract

Mutational analysis of C-KIT, fms-like tyrosine kinase 3 (FLT3), and JAK2 genes was performed in 60 patients with core binding factor acute myeloid leukemia (CBF-AML). Patients reaching molecular remission had lower incidence of relapse and better overall survival (OS) than those not achieving molecular remission (p = 0.008 and 0.044, respectively). The overall incidence of C-KIT mutations was 33.3%, FLT3/internal tandem duplication (ITD) 6.6%, FLT3(D835) 10.0% and JAK2(V617F) mutations 3.3%. C-KIT mutations did not predict for clinical/molecular relapse (p = 0.33). OS of patients with C-KIT mutations was identical to patients without them when all patients with CBF-AML were analyzed together (p = 0.58). When AML1/ETO-positive patients were evaluated separately, OS in C-KIT-mutated patients was slightly inferior to unmutated ones (p = 0.14). Patients with CBF-AML with a mutated C-KIT gene were also more prone to extramedullary disease (p = 0.08). Of six patients harboring various FLT3(D835) mutations, four (66.7%) relapsed, whereas among 43 cases without these mutations, 16 relapses (37%) were observed (p = 0.08). Our results on minimal residual disease, C-KIT, and FLT3/ITDs are in line with previous studies. Surprisingly, a possible role for FLT3(D835) mutations was noted in addition. These results need validation in even larger patient cohorts than ours. For routine clinical practice, it may be meaningful to screen for C-KIT mutations in AML1/ETO-positive patients, as well as for FLT3(D835) mutations in CBF-AML.

Prognosis of patients with core binding factor acute myeloid leukemia after first relapse

“…Additionally, in a further analysis based on cytogenetic profile at relapse, we found that those with t(8;21) who had different cytogenetics at relapse had a significantly improved overall survival when they underwent allogeneic HCT after relapse, but those who had the same cytogenetics did not show a benefit from allogeneic HCT. The evaluation of minimal residual disease detected by molecular markers may further stratify treatment strategies for patients with relapsed CBF-AML 19,20 especially among those who did not derive an apparent benefit from allo- geneic HCT after relapse. In addition, genetic profile, including KIT mutation, in patients with CBF-AML may help to guide therapeutic decisions not only in first complete remission but also after first relapse.…”

Initial Diagnostic Workup of Acute Leukemia: Guideline From the College of American Pathologists and the American Society of Hematology

“…This recommendation was supported by 15 studies that met the inclusion criteria for our SR, 18,20,22,91,[294][295][296][297][298][299][300][301][302][303][304] 22,294 Overall, none of these 15 studies were found to have methodological flaws that would raise concerns about the studies' findings. Refer to Supplemental Table 11 for the quality-assessment results of studies for statement 12.…”

“…This recommendation was supported by 2 PCSs 298,339 obtained from our SR. The risk of bias assessment for both was low to moderate.…”

“…100,349 Fewer studies have failed to find mutations of FLT3-ITD to be associated with prognosis, and the significance may be less in pediatric AML. 122,298,[338][339][340] The mutation level was also directly associated with worse survival, 26,342,343 including 2 patient cohort studies, and the level of mutation should be investigated in cases with a mutation detected.…”

“…294,298,301,304 Two of those studies used reverse transcription-PCR (RT-PCR) and were limited to core-binding factor (CBF) AML. 298,304 The other 2 used flow cytometry. 294,301 All showed that MRD was an important factor in relapse-free survival (RFS) and, in some studies, OS.…”