FMS-like tyrosine kinase 3-internal tandem duplications (FLT3-ITD) measurable residual disease (MRD) represents a clinically relevant biomarker for dynamic disease risk assessment in acute myeloid leukemia (AML), according to research published in the Journal of Clinical Oncology.

Researchers assessed the impact of next-generation sequencing (NGS)-based FLT3-ITD MRD detection on treatment outcome in a cohort of patients with newly diagnosed AML  and evaluated its prognostic value along with those of established prognostic factors at diagnosis, such as mutant NPM1 and FLT3-ITD allelic ratio.

The researchers performed NGS for FLT3-ITD detection at diagnosis and when patients achieved complete response (CR) after intensive remission induction treatment. They correlated FLT3-ITD MRD status with the primary endpoint, cumulative incidence of relapse, and with the secondary endpoint, overall survival (OS).


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A total of 161 patients (51% men and 49% women) with de novo FLT3-ITD AML were included in the study. Patients had a median age of 51 years (range, 19-66). Most patients (76%) had a normal karyotype in cytogenetic analysis. FLT3-ITD low and high allelic ratios were present in 46% and 54% of patients, respectively. NPM1 was mutant in 57% of patients and wild-type in 43% of patients.

The investigators found that NGS-based FLT3-ITD MRD was present in 29% of patients after achieving CR. They demonstrated that the presence of FLT3-ITD MRD was associated with increased risk of relapse (4-year cumulative incidence of relapse, 75% FLT3-ITD MRD v 33% no FLT3-ITD MRD; P <.001) and inferior OS (4-year OS, 31% FLT3-ITD MRD v 57% no FLT3-ITD MRD; P <.001).

Using multivariate analysis, the team demonstrated that detection of FLT3-ITD MRD in patients in CR is an independent prognostic factor for relapse (hazard ratio [HR], 3.55; 95% CI, 1.92-6.56; P <.001) and OS (HR, 2.51; 95% CI, 1.42-4.43; P =.002).

When accounting for FLT3-ITD MRD in the multivariate analysis, they found that NPM1 mutation status and FLT3-ITD allelic ratio at diagnosis lost their prognostic value for relapse (NPM1 mutation status: HR, 1.21; 95% CI, 0.68-2.16; P =.522; FLT3-ITD allelic ratio: HR, 1.76; 95% CI, 1.00-3.09; P =.050) and OS (NPM1 mutation status: HR, 1.30; 95% CI, 0.75-2.23; P =.348; FLT3-ITD allelic ratio: HR, 1.60; 95% CI, 0.96-2.67; P =.070).

“In conclusion, NGS-based detection of FLT3-ITD MRD in CR identifies patients with AML with profound relapse risk and death, and outweighs the prognostic factors that are currently used in AML risk stratification. Therefore, we propose to incorporate FLT3-ITD MRD in AML treatment protocols,” the researchers stated.

Limitations of the study included evaluation of FLT3-ITD MRD at a single time point and in patients treated with intensive chemotherapy only.

The study was presented previously in part at the European Hematology Association 2022 Congress and at the Society of Hematologic Oncology 10th Annual Meeting.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of authors’ disclosures. 

Reference

Grob T, Sanders MA, Vonk CM, et al. Prognostic value of FLT3-internal tandem duplication residual disease in acute myeloid leukemia. J Clin Oncol. Published online October 31, 2022. doi:10.1200/JCO.22.00715