Genetic alterations and measurable residual disease in core binding factor acute myeloid leukemia

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• Measurable residual disease (MRD) is a critical prognostic indicator in Core Binding Factor (CBF) Acute Myeloid Leukemia (AML).
• The prognostic significance of KIT and FLT3 mutations in CBF AML, particularly when considering MRD, remains incompletely understood.

Purpose of the Study:

• To evaluate the prognostic value of genetic alterations, including KIT and FLT3 mutations, in adult CBF AML patients while accounting for early MRD response.
• To determine if specific genetic mutations impact relapse risk independently of MRD levels.

Main Methods:

• Analysis of data from the retrospective multicenter RetroCBF study (training set) and the prospective CBF-2006 trial (validation set).
• Centralized high-throughput sequencing of 36 genes in 656 adult CBF AML patients in first complete remission (CR).
• Utilized a LASSO-penalized model to assess the combined prognostic value of MRD and genetic alterations.

Main Results:

• KIT-TKD mutations in RUNX1::RUNX1T1 and FLT3-ITD mutations in CBFB::MYH11 were associated with an increased risk of relapse in the training cohort.
• In the training cohort, patients with low MRD and without these mutations had a 3-year cumulative incidence of relapse of 22%, compared to 53% in high-risk patients.
• These findings were validated in the independent CBF-2006 cohort, confirming the independent adverse prognostic value of these mutations.

Conclusions:

• KIT-TKD mutations (in RUNX1::RUNX1T1) and FLT3-ITD mutations (in CBFB::MYH11) significantly worsen prognosis in CBF AML.
• These genetic alterations impact relapse risk independently of MRD status.
• Inclusion of KIT-TKD and FLT3-ITD mutations in risk stratification models is crucial for improved management of CBF AML patients.