Minor clones with internal tandem duplication of the FLT3 gene in NPM1-positive acute myeloid leukemia

Introduction. Internal tandem duplication (ITD) in the FMS-like tyrosine kinase 3 (FLT3) gene is a poor prognostic factor in acute myeloid leukemia (AML). Identification of a group of such patients raises the question of prescribing targeted therapy to them.

Aim: to assess the significance of minor FLT3-ITD clones in AML with NPM1 mutation.

Materials and methods. The study included 58 patients belonging to the intermediate or favorable risk group. Patients underwent therapy according to the AML-21 protocol. Molecular genetic diagnostics of FLT3 mutations was performed by polymerase chain reaction (PCR) with fragment analysis (PCR-FA), PCR-FA with double label and tandem duplication PCR (TD-PCR), NPM1 mutations — by PCR-FA (primary diagnostics) and allele-specific PCR to assess minimal residual disease (MRD).

Results. Using double-labeled PCR-FA and TD-PCR, allowed to identify minor FLT3-ITD clones in 12 (36 %) of 33 patients in whom these clones were not detected by the standard method. We also identified additional FLT3-ITD mutations in 13 (52 %) of 25 FLT3-positive patients. In the studied cohort no significant association of minor FLT3-ITD clones with the dynamics of MRD reduction, the percentage of patients achieving MRD-negative status, overall and relapse-free survival among patients with NPM1(+) AML was found.

Conclusion. The association of minor FLT3-ITD clones with clinical features of the disease in patients with AML and NPM1 gene mutations is minimal or absent. It can be assumed that these patients do not require the use of additional more sensitive methods for detecting FLT3-ITD mutations at the primary stage of diagnosis and the inclusion of tyrosine kinase inhibitors in program therapy. However, final conclusions can be made if it is shown that the detection of minor clones with FLT3-ITD mutation at the onset is not associated with the occurrence of relapses, taking into account the treatment protocol.

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