title: High-frequency type I/II mutational shifts between diagnosis and relapse are associated with outcome in pediatric AML: implications for personalized medicine.
abstract: Although virtually all pediatric patients with acute myeloid leukemia (AML) achieve a complete remission after initial induction therapy, 30%-40% of patients will encounter a relapse and have a dismal prognosis. To prevent relapses, personalized treatment strategies are currently being developed, which target specific molecular aberrations. To determine relevance of established AML type I/II mutations that may serve as therapeutic targets, we assessed frequencies of these mutations and their persistence during disease progression in a large group (n = 69) of paired diagnosis and relapse pediatric AML specimens. In 26 of 42 patients (61%) harboring mutations at either stage of the disease, mutation status changed between diagnosis and relapse, particularly in FLT3, WT1, and RAS genes. Presence or gain of type I/II mutations at relapse was associated with a shorter time to relapse (TTR), whereas absence or loss correlated with longer TTR. Moreover, an adverse outcome was found for patients with activating mutations at relapse, which was statistically significant for FLT3/ITD and WT1 mutations. These findings suggest that mutational shifts affect disease progression. We hence propose that risk stratification, malignant cell detection, and selection of personalized treatment should be based on status of type I/II mutations both at initial diagnosis and during follow-up.
authors.affiliation: Department of Pediatric Oncology/Hematology,VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Costa
authors.initials: C
authors.lastname: Bachas
authors.forename: Gerrit Jan
authors.initials: GJ
authors.lastname: Schuurhuis
authors.forename: Iris H I M
authors.initials: IH
authors.lastname: Hollink
authors.forename: Zinia J
authors.initials: ZJ
authors.lastname: Kwidama
authors.forename: Bianca F
authors.initials: BF
authors.lastname: Goemans
authors.forename: C Michel
authors.initials: CM
authors.lastname: Zwaan
authors.forename: Marry M
authors.initials: MM
authors.lastname: van den Heuvel-Eibrink
authors.forename: Eveline S J M
authors.initials: ES
authors.lastname: de Bont
authors.forename: Dirk
authors.initials: D
authors.lastname: Reinhardt
authors.forename: Ursula
authors.initials: U
authors.lastname: Creutzig
authors.forename: Valerie
authors.initials: V
authors.lastname: de Haas
authors.forename: Yehuda G
authors.initials: YG
authors.lastname: Assaraf
authors.forename: Gertjan J L
authors.initials: GJ
authors.lastname: Kaspers
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Cloos
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D016162:Genes, Wilms Tumor; D011905:Genes, ras; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000145:classification / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D008297:Male; D009154:Mutation; D057285:Precision Medicine; D011379:Prognosis; D012008:Recurrence; D013997:Time Factors; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D017931:DNA Primers; D004273:DNA, Neoplasm; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3