Co-mutations may impact response to quizartinib for relapsed/refractory acute myeloid leukemia
Click Here to Manage Email Alerts
ORLANDO — Quizartinib significantly prolonged survival compared with salvage chemotherapy among patients with relapsed or refractory acute myeloid leukemia and high FLT3-internal tandem duplication variant allele frequency, according to prospective study results presented at ASH Annual Meeting and Exposition.
Additionally, researchers identified baseline co-mutations that may affect treatment response and OS with quizartinib (Daiichi Sankyo), an oral, selective FLT3 inhibitor.
“AML is a molecularly heterogeneous disease with a broad genomic landscape of driver mutations,” Alexander E. Perl, MD, associate professor of medicine at Hospital of University of Pennsylvania, said during a presentation. “FLT3- internal tandem duplication mutations are associated with high relapse rates and reduced OS in patients with AML, but this mutation does not occur in a vacuum. There are other co-mutations with it.”
Results of the randomized phase 3 QuANTUM-R study showed quizartinib improved survival compared with salvage chemotherapy among patients with FLT3-internal tandem duplication (ITD)-positive relapsed or refractory AML. However, the FDA denied approval of the drug for this patient population in June, after the Oncologic Drug Advisory Committee expressed concern over the modest survival results, lack of robust data, high proportion of randomly assigned but untreated patients, and risk for QT prolongation with the treatment.
Perl and colleagues studied the impact of baseline co-mutations and FLT3-ITD variant allele frequency (VAF) on response to quizartinib and OS among participants in the trial.
Researchers evaluated 37 recurrently mutated genes in baseline bone marrow samples from 304 patients in QuANTUM-R (82.8% of the intent-to-treat population) using next-generation sequencing and a customized Archer core myeloid panel (ArcherDX Inc.).
They defined positive mutation status as one or more mutations detected in the gene region using a VAF cutoff of 2.7%. The investigators measured FLT3-ITD VAF separately with the Navigate BioPharma FLT3 Mutation Assay (Navigate BioPharma), and defined it as low ( 25%) or high (> 25%).
Patients had five key co-mutations aside from FLT3-ITD. These included DNMT3A (59.9%, n = 182), NPM1 (55.3%, n = 168), TET2 (32.3%, n = 98), IDH1/2 (16.1%, n = 49) and CEBPA (15.1%, n = 46) mutations.
Results showed longer median OS with quizartinib compared with salvage chemotherapy among patients with mutated DNMT3A (27.3 weeks vs. 23.4 weeks), TET2 (26.9 weeks vs. 12.7 weeks), IDH1/2 (23.7 weeks vs. 16 weeks) and NPM1 (22 weeks vs. 20.4 weeks), but not for those with CEBPA mutations (37 weeks vs. 37.6 weeks).
Composite complete remission rates were higher with quizartinib compared with salvage chemotherapy for all five co-mutations.
Researchers also evaluated permutations of NPM1 and DNMT3A mutations, as 82% of patients with NPM1 mutation also had DNMT3A mutation. They found patients with wild-type NPM1 and mutated DNMT3A had longer median OS with quizartinib compared with salvage chemotherapy (39.3 weeks vs. 19.6 weeks; HR = 0.24; 95% CI, 0.09-0.61). Patients with NPM1 and DNMT3A mutations had lower yet similar median OS with quizartinib vs. salvage chemotherapy (23.6 vs. 23.4 weeks).
Quizartinib conferred a significant OS benefit among patients with high FLT3-ITD VAF (23.9 weeks vs. 17 weeks; P = .0148). Median OS among patients with low FLT3-ITD VAF appeared similar between the two therapies (23.9 vs. 17 weeks; HR = 0.86), but not significantly different.
“[Although] the presence of some mutations may influence front-line therapy choice, this is the first evaluation of the impact of baseline co-mutations on clinical outcomes in a large trial of patients with [this disease] treated with quizartinib,” Perl said. “An independent data set is necessary to validate whether discrete genotypes show survival benefits to quizartinib over salvage chemotherapy.” – by John DeRosier
Reference:
Perl AE, et al. Abstract 737. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
Disclosures:
Perl reports advisory/consultant roles with and honoraria from AbbVie, Actinium Pharmaceuticals, Agios, Daiichi Sankyo, Jazz Pharmaceuticals, NewLink Genetics, Novartis and Takeda, and research funding from Astellas, Bayer, BioMed Valley Discoveries and Fujifilm. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
Back to Top
Michael R. Grunwald, MD
We have three types of approved molecular-targeted therapies in AML, including those that target FLT3 mutations, IDH1 mutations and IDH2 mutations. In some ways, the FLT3 inhibitors are furthest along, with two approvals so far.
We find many other mutations in our patients with AML.
At our institution, we look at 54 genes for mutations in every patient with AML. Other institutions use similar panels, and some institutions use more extensive panels. AML can harbor multiple mutations in an individual patient. So, what does it mean when a patient has a FLT3-ITD mutation and a DNMT3A mutation? How should we treat this patient compared with someone who has a FLT3-ITD mutation and an NPM1 mutation? Or a FLT3-ITD mutation and an IDH2 mutation?
In this study, looking at an array of mutations that commonly co-occur with FLT3-ITD mutations, the investigators sought to determine if some populations fared better than others with the experimental FLT3 inhibitor quizartinib.
Overall, the QUANTUM-R study has shown a small but significant survival benefit, but the drug has not been approved based on this benefit. Digging deeper, one question is whether certain groups of patients achieved more of a benefit than other groups. In this study by Perl and colleagues, patients who have a high allele burden of the FLT3-ITD mutation benefited more from quizartinib than patients with a low allele burden of FLT3-ITD.
In addition, patients with FLT3-ITD who had wild-type NPM1, as well as those patients with FLT3-ITD who had IDH1 or IDH2 mutations, benefited more from quizartinib than other groups of patients.
These findings could lead to further prospective trials that focus on populations expected to achieve benefit with quizartinib.
Click Here to Manage Email Alerts