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 - Funding Information:
This work was supported in part by the MD Anderson Cancer Center Support Grant (CCSG) CA016672, the MD Anderson Cancer Center Leukemia SPORE CA100632, the Charif Souki Cancer Research Fund, and generous philanthropic contributions to the MD Anderson Moon Shots Program.
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 - 33681815
AN - SCOPUS:85127348488
SN - 2643-3230
VL - 2
SP - 125
EP - 134
JO - Blood cancer discovery
JF - Blood cancer discovery
IS - 2
ER -