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FLT3 Internal Tandem Duplication Measurable Residual Disease in Complete Remission Identifies Patients with AML with Profound Risk for Relapse and Death

Impact of NGS-based detection of FLT3 internal tandem duplication measurable residual disease on treatment outcome in newly diagnosed acute myeloid leukaemia
07 Nov 2022
Haematologic malignancies;  Personalised medicine

A comprehensive analysis investigated the impact of persistence of FLT3 internal tandem duplication in complete remission after induction chemotherapy and treatment outcome in a cohort of patients with newly diagnosed acute myeloid leukaemia (AML), enrolled in multicentre prospective phase III HOVON-SAKK clinical trials. The results reveal FLT3 internal tandem duplication measurable residual disease as a strong independent prognostic factor that identifies patients with AML with profound risk of relapse and death.

Furthermore, FLT3 internal tandem duplication measurable residual disease outcompetes the impact of other currently established prognostic factors, including the NPM1 mutation status and FLT3 internal tandem duplication allelic ratio at diagnosis and residual disease measurements in complete remission. The findings are reported by Peter J.M. Valk, PhD of the Department of Hematology, Erasmus University Medical Centre Rotterdam in Rotterdam, the Netherlands and colleagues on 31 October 2022 in the Journal of Clinical Oncology.

The authors explained in the background that internal tandem duplications in the FLT3 receptor gene are among the most common genetic molecular aberrations in patients with AML. In FLT3 internal tandem duplication AML, the FLT3 kinase is constitutively activated resulting in uncontrolled proliferation of leukaemic blasts. FLT3 internal tandem duplications are generally considered late-event mutations in leukaemogenesis and are frequently preceded by the appearance of mutations in DNMT3A and NPM1.

FLT3 internal tandem duplication has been suggested to characterise an aggressive leukaemic phenotype with early relapse and inferior treatment outcome. Several features present at diagnosis have been postulated to modify the prognostic effect of FLT3 internal tandem duplication, including the presence of concurrent NPM1 mutation and the FLT3 internal tandem duplication clone size, ie, allelic ratio.

Increasing evidence indicates that treatment outcome prediction can be improved by assessing the kinetics and depth of response during treatment by detection of measurable residual disease. Advances in sequencing technology now enable accurate molecular detection of FLT3 internal tandem duplication measurable residual disease.

Clonal evolution studies revealed that late-event mutations in activated signaling genes, such as those in FLT3, are often subclonal and can be unstable during relapse in up to 25% of patients with AML, which may disqualify these markers for measurable residual disease detection. Systematic studies evaluating the applicability of FLT3 internal tandem duplication measurable residual disease detection as a prognostic biomarker in AML are lacking.

It prompted the study team to perform NGS in 161 patients with de novo FLT3 internal tandem duplication AML at diagnosis and in complete remission after intensive remission induction treatment. FLT3 internal tandem duplication measurable residual disease status was correlated with the cumulative incidence of relapse and overall survival (OS).

NGS-based FLT3 internal tandem duplications measurable residual disease was present in 47 of 161 patient (29%) with AML. Presence of FLT3 internal tandem duplications measurable residual disease was associated with increased risk of relapse with 4-year cumulative incidence of relapse of 75% in FLT3 internal tandem duplications measurable residual disease versus 33% in case of no FLT3 internal tandem duplications measurable residual disease (p < 0.001) and inferior OS with 4-year OS of 31% in FLT3 internal tandem duplications measurable residual disease versus 57% in case of no FLT3 internal tandem duplications measurable residual disease (p < 0.001).

In multivariate analysis, detection of FLT3 internal tandem duplications measurable residual disease in complete remission conferred independent prognostic significance for relapse (hazard ratio [HR] 3.55; p < 0.001) and OS (HR 2.51; p = 0.002).

FLT3 internal tandem duplications measurable residual disease exceeded the prognostic value of most generally accepted clinical and molecular prognostic factors, including the FLT3 internal tandem duplications allelic ratio at diagnosis and measurable residual disease assessment by multiparameter flow cytometry or NGS-based detection of NPM1 mutation.

The authors concluded that NGS-based detection of FLT3 internal tandem duplications measurable residual disease in complete remission identifies patients with AML with profound risk for relapse and death and outweighs the prognostic factors that are currently used in AML risk stratification. Therefore, they proposed to incorporate FLT3 internal tandem duplications measurable residual disease in AML treatment protocols.

The study was previously presented in part at the European Hematology Association 2022 Congress in Vienna, Austria and at the Society of Hematologic Oncology 10th Annual Meeting from 28 September to 1 October 2022 in Houston, TX, US.

The study was supported by grants from the Queen Wilhelmina Fund Foundation of the Dutch Cancer Society.

Reference

Grob T, Sanders MA, Vonk CM, et al. Prognostic Value of FLT3-Internal Tandem Duplication Residual Disease in Acute Myeloid Leukemia. JCO; Published online 31 October 2022. DOI: 10.1200/JCO.22.00715

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