Molecular landscape and prognostic impact of FLT3-ITD insertion site in acute myeloid leukemia: RATIFY study results.
Frank G RückerLing DuTamara J LuckAxel BennerJulia KrzykallaInsa GathmannMaria Teresa Teresa VosoSergio AmadoriThomas W PriorJoseph M BrandweinFrederick R AppelbaumBruno C MedeirosMartin S TallmanLynn SavoieJorge SierraCeline PallaudMiguel Angel SanzJoop H JansenDietger NiederwieserThomas FischerGerhard EhningerMichael HeuserArnold GanserLars BullingerRichard A LarsonClara D BloomfieldRichard M StoneHartmut DöhnerChristian ThiedeKonstanze DöhnerPublished in: Leukemia (2021)
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.
Keyphrases
- acute myeloid leukemia
- tyrosine kinase
- allogeneic hematopoietic stem cell transplantation
- poor prognosis
- end stage renal disease
- newly diagnosed
- ejection fraction
- chronic kidney disease
- peritoneal dialysis
- long non coding rna
- prognostic factors
- clinical trial
- epidermal growth factor receptor
- stem cell transplantation
- gene expression
- single cell
- randomized controlled trial
- phase iii
- squamous cell carcinoma
- open label
- single molecule
- copy number
- study protocol
- genome wide
- rheumatoid arthritis
- acute lymphoblastic leukemia
- systemic lupus erythematosus
- disease activity
- patient reported outcomes
- phase ii
- high dose
- transcription factor
- data analysis
- circulating tumor cells