High-frequency type I/II mutational shifts between diagnosis and relapse are associated with outcome in pediatric AML: implications for personalized medicine.
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.
Bachas
Costa
C
Department of Pediatric Oncology/Hematology,VU University Medical Center, Amsterdam, The Netherlands.
Schuurhuis
Gerrit Jan
GJ
Hollink
Iris H I M
IH
Kwidama
Zinia J
ZJ
Goemans
Bianca F
BF
Zwaan
C Michel
CM
van den Heuvel-Eibrink
Marry M
MM
de Bont
Eveline S J M
ES
Reinhardt
Dirk
D
Creutzig
Ursula
U
de Haas
Valerie
V
Assaraf
Yehuda G
YG
Kaspers
Gertjan J L
GJ
Cloos
Jacqueline
J
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
D014408:Biomarkers, Tumor; D017931:DNA Primers; D004273:DNA, Neoplasm; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3