Abstract 784: Effect of co-mutations and FLT3-ITD variant allele frequency (VAF) on response to quizartinib or salvage chemotherapy (SC) in relapsed/refractory (R/R) acute myeloid leukemia (AML)
Authors: Perl Alexander E. , Cortes Jorge E. , Ganguly Siddhartha , Khaled Samer K. , Krämer Alwin , Martinelli Giovanni , Russell Nigel H. , Chang Ken C. , Kato Kazunobu , Yan Yuhu , Xu Li-An , Korkhov Sergey , Günnel Tobias , Sumi Hiroyuki , Lesegretain Arnaud , Berisha Flora , Mires Derek , Benzohra Aziz , Isoyama Takeshi , Santos Cedric Dos , Levis Mark J. 
Published: September 2020

Abstract
Introduction: We evaluated the impact of baseline (BL) co-mutations and FLT3-ITD VAF on overall survival (OS) and response (composite complete remission [CRc]) to quizartinib and SC in the phase III QuANTUM-R trial.
Methods: We analyzed 37 recurrently mutated genes in AML in BL samples from 304 patients (pts) (83% of ITT population) with R/R FLT3-ITD-positive AML using next-generation sequencing and a customized Archer® Core Myeloid panel. Positive mutation status was defined as ≥1 mutation detected in the gene region using a VAF cutoff of 2.7%. FLT3-ITD VAF was measured by the Navigate BioPharma FLT3 Mutation Assay (polymerase chain reaction-based, VAF cutoff of 3%). Low and high FLT3-ITD VAF were defined as ≤25% and &gt;25%, respectively.
Results: In addition to FLT3-ITD, the prevalence of key BL co-mutations were 59.9% for DNMT3Amut and 55.3% for NPM1mut. Pts with DNMT3Amut treated with quizartinib had significantly longer OS vs SC (6.3 and 5.4 mos, respectively; hazard ratio [HR], 0.652), p&lt;.05). Pts with NPM1mut treated with quizartinib had a higher CRc rate than with SC, but similar OS (5.1 vs 4.7 mos, respectively; HR, 0.954, p=.82). Pts with NPM1wt/DNMT3Amut treated with quizartinib had the highest CRc rate and longest median OS (9.0 and 4.5 mos, respectively; HR, 0.239, p=.003). OS benefit with quizartinib relative to SC was more pronounced among pts with high FLT3-ITD VAF than low FLT3-ITD VAF. The OS benefit with quizartinib in pts with NPM1wt/DNMT3Amut was maintained in both low and high FLT3-ITD VAF groups. Similarly, for other DNMT3A/NPM1 co-permutations, OS in both low and high FLT3-ITD VAF groups was consistent with OS in the co-mutation group.
Conclusions: Key co-mutations identified here potentially affect treatment response and OS with quizartinib vs SC. Our results suggest that molecular subsets of R/R AML pts may particularly derive clinical benefit from quizartinib.
TableCRc, %Median OS, monthsQuizartinibSCQuizartinibSCHR95% CIITT Population (N = 367)a48276.24.70.760.58-0.98Single Gene Analyses (n = 304)bDNMT3Amut (n = 182)52376.35.40.6520.44-0.97DNMT3Awt (n = 122)40246.04.60.8490.53-1.37NPM1mut (n = 168)48395.14.70.9540.63-1.44NPM1wt (n = 136)47218.55.10.4850.31-0.76TET2mut (n = 98)34326.22.90.6640.38-1.16TET2wt (n = 206)54306.35.40.7280.51-1.05CEBPAmut (n = 46)44428.58.71.9220.80-4.62CEBPAwt (n = 258)48296.24.50.6130.45-0.84IDH1/2mut (n = 49)32275.53.70.4270.20-0.92IDH1/2wt (n = 255)51316.55.10.750.54-1.04Double Gene Analyses (n = 304)NPM1wt/DNMT3Amut (n = 44)61279.04.50.2390.09-0.61NPM1mut/DNMT3Amut (n = 138)50405.45.40.8370.52-1.34FLT3-ITD VAF AnalysesFLT3-ITD high VAF50195.53.90.6890.51-0.93FLT3-ITD low VAF43467.96.10.8570.53-1.40FLT3-ITD VAF Analyses in Selected MutationsDNMT3Amut high VAF53215.82.70.6260.40-0.98DNMT3Amut low VAF526910.26.40.7370.36-1.51NPM1wt/DNMT3Amut high VAF6409.01.50.01790.002-0.16NPM1wt/DNMT3Amut low VAF555011.36.20.3720.11-1.23aN = 367; quizartinib, n = 245; SC, n = 122bBaseline bone marrow samples were available and viable from 304 of 367 pts in the ITT population
Citation Format: Alexander E. Perl, Jorge E. Cortes, Siddhartha Ganguly, Samer K. Khaled, Alwin Krämer, Giovanni Martinelli, Nigel H. Russell, Ken C. Chang, Kazunobu Kato, Yuhu Yan, Li-An Xu, Sergey Korkhov, Tobias Günnel, Hiroyuki Sumi, Arnaud Lesegretain, Flora Berisha, Derek Mires, Aziz Benzohra, Takeshi Isoyama, Cedric Dos Santos, Mark J. Levis. Effect of co-mutations and FLT3-ITD variant allele frequency (VAF) on response to quizartinib or salvage chemotherapy (SC) in relapsed/refractory (R/R) acute myeloid leukemia (AML) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 784.