TY - JOUR
T1 - Patterns of Resistance Differ in Patients with Acute Myeloid Leukemia Treated with Type I versus Type II FLT3 Inhibitors
AU - Alotaibi, Ahmad S.
AU - Yilmaz, Musa
AU - Kanagal-Shamanna, Rashmi
AU - Loghavi, Sanam
AU - Kadia, Tapan M.
AU - DiNardo, Courtney D.
AU - Borthakur, Gautam
AU - Konopleva, Marina
AU - Pierce, Sherry A.
AU - Wang, Sa A.
AU - Tang, Guilin
AU - Guerra, Veronica
AU - Samra, Bachar
AU - Pemmaraju, Naveen
AU - Jabbour, Elias
AU - Short, Nicholas J.
AU - Issa, Ghayas C.
AU - Ohanian, Maro
AU - Garcia-Manero, Guillermo
AU - Bhalla, Kapil N.
AU - Patel, Keyur P.
AU - Takahashi, Koichi
AU - Andreeff, Michael
AU - Cortes, Jorge E.
AU - Kantarjian, Hagop M.
AU - Ravandi, Farhad
AU - Daver, Naval
N1 - Publisher Copyright:
©2020 American Association for Cancer Research.
PY - 2021/3/1
Y1 - 2021/3/1
N2 - Despite promising results with FLT3 inhibitors (FLT3i), response durations remain short. We studied pretreatment and relapse bone marrow samples from patients with FLT3-mutated acute myeloid leukemia (AML) treated with FLT3i-based therapies (secondary resistance cohort), and pretreatment bone marrow samples from patients with no response to FLT3ibased therapies (primary resistance cohort). Targeted next-generation sequencing (NGS) at relapse identified emergent mutations involving on-target FLT3, epigenetic modifiers, RAS/MAPK pathway, and less frequently WT1 and TP53. RAS/MAPK and FLT3-D835 mutations emerged most commonly following type I and II FLT3i-based therapies, respectively. Patients with emergent mutations at relapse had inferior overall survival compared with those without emergent mutations. Among pretreatment RAS-mutated patients, pretreatment cohort-level variant allelic frequencies for RAS were higher in nonresponders, particularly with type I FLT3i-based therapies, suggesting a potential role in primary resistance as well. These data demonstrate distinct pathways of resistance in FLT3-mutated AML treated with type I versus II FLT3i.
AB - Despite promising results with FLT3 inhibitors (FLT3i), response durations remain short. We studied pretreatment and relapse bone marrow samples from patients with FLT3-mutated acute myeloid leukemia (AML) treated with FLT3i-based therapies (secondary resistance cohort), and pretreatment bone marrow samples from patients with no response to FLT3ibased therapies (primary resistance cohort). Targeted next-generation sequencing (NGS) at relapse identified emergent mutations involving on-target FLT3, epigenetic modifiers, RAS/MAPK pathway, and less frequently WT1 and TP53. RAS/MAPK and FLT3-D835 mutations emerged most commonly following type I and II FLT3i-based therapies, respectively. Patients with emergent mutations at relapse had inferior overall survival compared with those without emergent mutations. Among pretreatment RAS-mutated patients, pretreatment cohort-level variant allelic frequencies for RAS were higher in nonresponders, particularly with type I FLT3i-based therapies, suggesting a potential role in primary resistance as well. These data demonstrate distinct pathways of resistance in FLT3-mutated AML treated with type I versus II FLT3i.
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U2 - 10.1158/2643-3230.BCD-20-0143
DO - 10.1158/2643-3230.BCD-20-0143
M3 - Article
C2 - 34238762
AN - SCOPUS:85127348488
SN - 2643-3230
VL - 2
SP - 125
EP - 134
JO - Blood cancer discovery
JF - Blood cancer discovery
IS - 2
ER -