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Molecular landscape and prognostic impact of FLT3-ITD insertion site in acute myeloid leukemia: RATIFY study results
Frank G Rücker1, Ling Du2, Tamara J Luck3
1Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
Abstract:
In acute myeloid leukemia (AML) internal tandem duplications of the FLT3 gene (FLT3-ITD) are associated with poor prognosis. Retrospectively, we investigated the prognostic and predictive impact of FLT3-ITD insertion site (IS) in 452 patients randomized within the RATIFY trial, which evaluated midostaurin additionally to intensive chemotherapy. Next-generation sequencing identified 908 ITDs, with 643 IS in the juxtamembrane domain (JMD) and 265 IS in the tyrosine kinase domain-1 (TKD1). According to IS, patients were categorized as JMDsole (n = 251, 55%), JMD and TKD1 (JMD/TKD1; n = 117, 26%), and TKD1sole (n = 84, 19%). While clinical variables did not differ among the 3 groups, NPM1 mutation was correlated with JMDsole (P = 0.028). Overall survival (OS) differed significantly, with estimated 4-year OS probabilities of 0.44, 0.50, and 0.30 for JMDsole, JMD/TKD1, and TKD1sole, respectively (P = 0.032). Multivariate (cause-specific) Cox models for OS and cumulative incidence of relapse using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable identified TKD1sole as unfavorable and HCT as favorable factors. In addition, Midostaurin exerted a significant benefit only for JMDsole. Our results confirm the distinct molecular heterogeneity of FLT3-ITD and the negative prognostic impact of TKD1 IS in AML that was not overcome by midostaurin.
Insights
The FLT3-ITD insertion site in acute myeloid leukemia impacts prognosis. Tyrosine kinase domain-1 (TKD1) sole insertions are linked to poor outcomes, while juxtamembrane domain (JMD) sole insertions benefit from midostaurin.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Internal tandem duplications (ITDs) in the FLT3 gene are a key driver in acute myeloid leukemia (AML).
- FLT3-ITDs are associated with a poor prognosis in AML patients.
- The specific insertion site (IS) of FLT3-ITDs may influence clinical outcomes and treatment response.
Purpose of the Study:
- To investigate the prognostic and predictive impact of FLT3-ITD insertion sites in AML.
- To analyze the association between FLT3-ITD IS and overall survival (OS) and relapse in AML patients treated with midostaurin.
Main Methods:
- Retrospective analysis of 452 AML patients from the RATIFY trial.
- Next-generation sequencing to identify FLT3-ITD insertion sites (juxtamembrane domain [JMD] and tyrosine kinase domain-1 [TKD1]).
- Categorization of patients into JMDsole, JMD/TKD1, and TKD1sole groups.
- Multivariate Cox models to assess prognostic factors and treatment effects.
Main Results:
- Identified 908 FLT3-ITDs with distinct insertion sites: 643 in JMD and 265 in TKD1.
- TKD1sole insertion site was associated with significantly poorer 4-year overall survival (0.30) compared to JMDsole (0.44) and JMD/TKD1 (0.50).
- TKD1sole was identified as an unfavorable prognostic factor, while allogeneic hematopoietic cell transplantation (HCT) was favorable.
- Midostaurin demonstrated a significant survival benefit exclusively in the JMDsole group.
Conclusions:
- FLT3-ITD exhibits distinct molecular heterogeneity based on insertion site.
- TKD1 sole insertion site confers a negative prognostic impact in AML, independent of midostaurin treatment.
- Targeted therapies should consider the specific FLT3-ITD insertion site for optimal patient stratification and treatment selection.
