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 >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<.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.

Table

CRc, %Median OS, months
QuizartinibSCQuizartinibSCHR95% CI
ITT Population (N = 367)a 48 27 6.2 4.7 0.76 0.58-0.98 
Single Gene Analyses (n = 304)b 
DNMT3Amut (n = 182) 52 37 6.3 5.4 0.652 0.44-0.97 
DNMT3Awt (n = 122) 40 24 6.0 4.6 0.849 0.53-1.37 
NPM1mut (n = 168) 48 39 5.1 4.7 0.954 0.63-1.44 
NPM1wt (n = 136) 47 21 8.5 5.1 0.485 0.31-0.76 
TET2mut (n = 98) 34 32 6.2 2.9 0.664 0.38-1.16 
TET2wt (n = 206) 54 30 6.3 5.4 0.728 0.51-1.05 
CEBPAmut (n = 46) 44 42 8.5 8.7 1.922 0.80-4.62 
CEBPAwt (n = 258) 48 29 6.2 4.5 0.613 0.45-0.84 
IDH1/2mut (n = 49) 32 27 5.5 3.7 0.427 0.20-0.92 
IDH1/2wt (n = 255) 51 31 6.5 5.1 0.75 0.54-1.04 
Double Gene Analyses (n = 304) 
NPM1wt/DNMT3Amut (n = 44) 61 27 9.0 4.5 0.239 0.09-0.61 
NPM1mut/DNMT3Amut (n = 138) 50 40 5.4 5.4 0.837 0.52-1.34 
FLT3-ITD VAF Analyses 
FLT3-ITD high VAF 50 19 5.5 3.9 0.689 0.51-0.93 
FLT3-ITD low VAF 43 46 7.9 6.1 0.857 0.53-1.40 
FLT3-ITD VAF Analyses in Selected Mutations 
DNMT3Amut high VAF 53 21 5.8 2.7 0.626 0.40-0.98 
DNMT3Amut low VAF 52 69 10.2 6.4 0.737 0.36-1.51 
NPM1wt/DNMT3Amut high VAF 64 9.0 1.5 0.0179 0.002-0.16 
NPM1wt/DNMT3Amut low VAF 55 50 11.3 6.2 0.372 0.11-1.23 
CRc, %Median OS, months
QuizartinibSCQuizartinibSCHR95% CI
ITT Population (N = 367)a 48 27 6.2 4.7 0.76 0.58-0.98 
Single Gene Analyses (n = 304)b 
DNMT3Amut (n = 182) 52 37 6.3 5.4 0.652 0.44-0.97 
DNMT3Awt (n = 122) 40 24 6.0 4.6 0.849 0.53-1.37 
NPM1mut (n = 168) 48 39 5.1 4.7 0.954 0.63-1.44 
NPM1wt (n = 136) 47 21 8.5 5.1 0.485 0.31-0.76 
TET2mut (n = 98) 34 32 6.2 2.9 0.664 0.38-1.16 
TET2wt (n = 206) 54 30 6.3 5.4 0.728 0.51-1.05 
CEBPAmut (n = 46) 44 42 8.5 8.7 1.922 0.80-4.62 
CEBPAwt (n = 258) 48 29 6.2 4.5 0.613 0.45-0.84 
IDH1/2mut (n = 49) 32 27 5.5 3.7 0.427 0.20-0.92 
IDH1/2wt (n = 255) 51 31 6.5 5.1 0.75 0.54-1.04 
Double Gene Analyses (n = 304) 
NPM1wt/DNMT3Amut (n = 44) 61 27 9.0 4.5 0.239 0.09-0.61 
NPM1mut/DNMT3Amut (n = 138) 50 40 5.4 5.4 0.837 0.52-1.34 
FLT3-ITD VAF Analyses 
FLT3-ITD high VAF 50 19 5.5 3.9 0.689 0.51-0.93 
FLT3-ITD low VAF 43 46 7.9 6.1 0.857 0.53-1.40 
FLT3-ITD VAF Analyses in Selected Mutations 
DNMT3Amut high VAF 53 21 5.8 2.7 0.626 0.40-0.98 
DNMT3Amut low VAF 52 69 10.2 6.4 0.737 0.36-1.51 
NPM1wt/DNMT3Amut high VAF 64 9.0 1.5 0.0179 0.002-0.16 
NPM1wt/DNMT3Amut low VAF 55 50 11.3 6.2 0.372 0.11-1.23 

aN = 367; quizartinib, n = 245; SC, n = 122

bBaseline 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.