Abstract
The aim of this study was to characterize the mutational landscape of patients with FLT3-mutated acute myeloid leukemia (AML) treated within the randomized CALGB 10603/RATIFY trial evaluating intensive chemotherapy plus the multi-kinase inhibitor midostaurin versus placebo. We performed sequencing of 262 genes in 475 patients: mutations occurring concurrently with the FLT3-mutation were most frequent in NPM1 (61%), DNMT3A (39%), WT1 (21%), TET2 (12%), NRAS (11%), RUNX1 (11%), PTPN11 (10%), and ASXL1 (8%) genes. To assess effects of clinical and genetic features and their possible interactions, we fitted random survival forests and interpreted the resulting variable importance. Highest prognostic impact was found for WT1 and NPM1 mutations, followed by white blood cell count, FLT3 mutation type (internal tandem duplications vs. tyrosine kinase domain mutations), treatment (midostaurin vs. placebo), ASXL1 mutation, and ECOG performance status. When evaluating two-fold variable combinations the most striking effects were found for WT1:NPM1 (with NPM1 mutation abrogating the negative effect of WT1 mutation), and for WT1:treatment (with midostaurin exerting a beneficial effect in WT1-mutated AML). This targeted gene sequencing study provides important, novel insights into the genomic background of FLT3-mutated AML including the prognostic impact of co-mutations, specific gene–gene interactions, and possible treatment effects of midostaurin.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2218-2227 |
| Number of pages | 10 |
| Journal | Leukemia |
| Volume | 36 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 2022 |
Funding
The authors thank all institutions and investigators who participated in the CALGB 10603/RATIFY trial and contributed to this study. We thank Dr. Karl-Heinz Holzmann (Genomics Core Facility, Ulm University) for his support with the targeted sequencing analysis. This work was supported in part by Novartis and by the Deutsche Forschungsgemeinschaft (SFB 1074 project B3 to KD and LB), a grant by the BMBF (DRAMA 01KT1603 to HD), and by National Institutes of Health, National Cancer Institute grants U10CA180821 (to the Alliance for Clinical Trials in Oncology Operations Center), U10CA180882 (to the Alliance Statistics and Data Management Center), U24CA196171 (to the Alliance NCTN Biorepository and Biospecimen [CDB]), U10CA180861 (ITSC for Leukemia: Novel Molecular Strategies for NCTN: Individualized Therapies). The authors thank all institutions and investigators who participated in the CALGB 10603/RATIFY trial and contributed to this study. We thank Dr. Karl-Heinz Holzmann (Genomics Core Facility, Ulm University) for his support with the targeted sequencing analysis. This work was supported in part by Novartis and by the Deutsche Forschungsgemeinschaft (SFB 1074 project B3 to KD and LB), a grant by the BMBF (DRAMA 01KT1603 to HD), and by National Institutes of Health, National Cancer Institute grants U10CA180821 (to the Alliance for Clinical Trials in Oncology Operations Center), U10CA180882 (to the Alliance Statistics and Data Management Center), U24CA196171 (to the Alliance NCTN Biorepository and Biospecimen [CDB]), U10CA180861 (ITSC for Leukemia: Novel Molecular Strategies for NCTN: Individualized Therapies). MS has a collaboration with Boehringer Ingelheim. LB was on advisory committees for AbbVie, Amgen, Astellas, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Gilead, Hexal, Janssen, Jazz Pharmaceuticals, Menarini, Novartis, Pfizer, Sanofi, and Seattle Genetics, and has received research support from Bayer and Jazz Pharmaceuticals. RAL has acted as a consultant or advisor to Novartis, AbbVie, Amgen, Ariad/Takeda, Astellas, Celgene/BMS, CVS/Caremark, Epizyme, and MorphoSys, and has received clinical research support to his institution from Novartis, Astellas, Celgene, Cellectis, Daiichi Sankyo, Forty Seven, Gilead, and Rafael Pharmaceuticals, and royalties from UpToDate. FRA serves on advisory boards for Adaptive Biotechnology and Jasper Therapeutics. MH received honoraria from Abbvie, Eurocept, Jazz Pharmaceuticals, Janssen, Novartis, Takeda, funding for institution from Astellas, Bayer Pharma AG, BergenBio, Daiichi Sankyo, Jazz Pharmaceuticals, Karyopharm, Novartis, Pfizer, Roche, and consults Abbvie, Agios, BMS, Daiichi Sankyo, Jazz Pharmaceuticals, Kura Oncology, Novartis, Pfizer, PinotBio, Roche, Tolremo. AG serves on advisory board for Novartis and received research support from Novartis. IG and CP are employees of Novartis. RMS reports personal fees from AbbVie, Actinium, Agios, Argenx, Astellas, AstraZeneca, Biolinerx, Celgene, Daiichi Sankyo, Elevate, Gemoab, Janssen, Jazz, Macrogenics, Novartis, Otsuka, Pfizer, Hoffman LaRoche, Stemline, Syndax, Syntrix, Syos, Takeda, and Trovagene and received research support from AbbVie, Agios, Arog, and Novartis. HD has acted as a consultant or advisor for AbbVie, Agios, Amgen, Astellas, AstraZeneca, Berlin-Chemie, Bristol-Myers Squibb, Celgene, GEMoaB, Gilead, Janssen, Jazz, Novartis, Servier, Syndax and has received institutional research support from AbbVie, Agios, Amgen, Astellas, Bristol-Myers Squibb, Celgene, Jazz Pharmaceuticals, Kronos Bio, Novartis. KD was on advisory committees for Novartis, Janssen Pharmaceutica, Celgene, Bristol-Myers Squibb, and Daiichi Sankyo. The remaining authors declare no competing interests.
ASJC Scopus subject areas
- Hematology
- Oncology
- Cancer Research
