Journal: Leukemia
This study evaluated how specific genetic lesions add to MRD-based risk stratification in adult core-binding factor (CBF) AML in first complete remission (CR).
Design:
- Combined cohorts: Two large CBF-AML cohorts were analyzed:
- Retrospective multicenter series (RetroCBF; n=461) as the training set.
- Prospective trial (CBF-2006; n=195) as the validation set.
- Total sample size: n=656.
- Patient population: All patients had CBF-AML (either RUNX1::RUNX1T1 or CBFB::MYH11) and were in first complete remission.
- Molecular profiling: Centralized 36‑gene next-generation sequencing was performed.
- Statistical modeling: A LASSO-penalized model examined the prognostic impact of genetic alterations while adjusting for early MRD response.
Key findings:
- Mutations predicting relapse (training cohort, adjusted for MRD):
- KIT tyrosine kinase domain (TKD) mutations in RUNX1::RUNX1T1 AML.
- FLT3-ITD in CBFB::MYH11 AML.
- Risk groups combining MRD and mutations:
- Low-risk: MRD low AND no KIT-TKD (RUNX1::RUNX1T1) or FLT3-ITD (CBFB::MYH11).
- 3-year cumulative incidence of relapse: 22% (95% CI 13–33%).
- High-risk: all other patients.
- 3-year cumulative incidence of relapse: 53% (95% CI 46–60%).
- Subdistribution HR for relapse high- vs low-risk: 3.21 (95% CI 1.83–5.62, p<0.0001).
- Low-risk: MRD low AND no KIT-TKD (RUNX1::RUNX1T1) or FLT3-ITD (CBFB::MYH11).
- Validation: These associations and the combined risk stratification were confirmed in the prospective validation cohort.
Clinical implication:
- Independent adverse markers: KIT-TKD mutations in RUNX1::RUNX1T1 AML and FLT3-ITD in CBFB::MYH11 AML worsen prognosis independently of MRD.
- Refined risk assessment: Risk assessment in CBF-AML should incorporate both MRD and these specific mutations to more accurately identify patients at high relapse risk.
- Treatment guidance: This combined stratification can guide intensification strategies (e.g., transplant or targeted approaches) in first remission.