Patterns of Resistance Differ in Patients with Acute Myeloid Leukemia Treated with Type I versus Type II FLT3 Inhibitors
Ahmad S. Alotaibi, Musa Yılmaz, Rashmi Kanagal‐Shamanna, Sanam Loghavi, Tapan M. Kadia, Courtney D. DiNardo, Gautam Borthakur, Marina Konopleva, Sherry Pierce, Sa A. Wang, Guilin Tang, Veronica Guerra, Bachar Samra, Naveen Pemmaraju, Elias Jabbour, Nicholas J. Short, Ghayas C. Issa, Maro Ohanian, Guillermo Garcia‐Manero, Kapil N. Bhalla, Keyur P. Patel, Koichi Takahashi, Michael Andreeff, Jörge E. Cortes, Hagop M. Kantarjian, Farhad Ravandi, Naval Daver
Abstract
Abstract 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 FLT3i-based 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. Significance: Sequential NGS-based mutational analysis at relapse after FLT3i-based therapies showed distinct pathways of secondary resistance between type I and II FLT3i. FLT3 mutations may be lost at relapse after FLT3i-based therapies. Pretreatment RAS/MAPK mutations may also be associated with primary resistance in patients treated with type I FLT3i. See related commentary by Shastri et al., p. 113.