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 >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.
. | CRc, % . | Median OS, months . | ||||
---|---|---|---|---|---|---|
. | Quizartinib . | SC . | Quizartinib . | SC . | HR . | 95% 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 | 0 | 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 . | ||||
---|---|---|---|---|---|---|
. | Quizartinib . | SC . | Quizartinib . | SC . | HR . | 95% 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 | 0 | 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.