Midostaurin in patients with acute myeloid leukemia and FLT3-TKD mutations: a subanalysis from the RATIFY trial

Abstract

The results from the RATIFY trial (ClinicalTrials.gov: NCT00651261; CALGB 10603) showed that midostaurin combined with standard chemotherapy significantly improved outcomes in patients with FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML), compared with placebo. In this post hoc subgroup analysis from the trial, we evaluated the impact of midostaurin in 163 patients with FLT3-tyrosine kinase domain (TKD) mutations. At a median follow-up of 60.7 months (95% CI, 55.0-70.8), the 5-year event-free survival (EFS) rate was significantly higher in patients treated with midostaurin than in those treated with placebo (45.2% vs 30.1%; P = .044). A trend toward improved disease-free survival was also observed with midostaurin (67.3% vs 53.4%; P = .089), whereas overall survival (OS) was similar in the 2 groups. Patients with AML and NPM1mut/FLT3-TKDmut or core binding factor (CBF)-rearranged/FLT3-TKDmut genotypes had significantly prolonged OS with or without censoring at hematopoietic cell transplantation (HCT), compared with NPM1WT/CBF-negative AMLs. The multivariable model for OS and EFS adjusted for allogeneic HCT in first complete remission as a time-dependent covariable, revealed NPM1 mutations and CBF rearrangements as significant favorable factors. These data show that NPM1 mutations or CBF rearrangements identify favorable prognostic groups in patients with FLT3-TKD AMLs, independent of other factors, also in the context of midostaurin treatment.

Conflict of interest statement

Conflict-of-interest disclosure: M.T.V. has received research funding and is a member of the Speakers Bureau for Celgene. R.A.L. has served on independent data safety monitoring committees and acted as a consultant or advisor and has received clinical research support from Novartis. D.J. has received clinical research support from Novartis. G.M. has acted as a consultant or advisor for trials supported by Novartis. J.K. has acted as a consultant or advisor for Amgen, Astellas, Bristol-Myers Squibb, Daiichi Sankyo, and Pfizer. M.H. has acted as a consultant or advisor for AbbVie, Daiichi Sankyo, Novartis, Pfizer, and Bayer Pharma and has received clinical research support from Pfizer, Daiichi Sankyo, Karyopharm, BerGenBio, Bayer Pharma, Novartis, and Astellas. J.N. has acted as consultant or advisor for Novartis. A.W. has received clinical research support from Novartis. A.H.W. has acted as a consultant or advisor for Novartis, Astellas, Pfizer, MacroGenics, AbbVie, Genentech, Servier, Celgene, Takeda, and Argenix; has consulted for Amgen, AstraZeneca, and Janssen; is a member of the speakers bureau for AbbVie/Genentech and Novartis; has received research funding from Novartis, Celgene, AbbVie, Servier, AstraZeneca, and Amgen; and is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax. J.S. has acted as a consultant or advisor for Pfizer, Daiichi Sankyo, AbbVie, Novartis, Astellas, and Roche and is a member of the speakers’ bureau for Novartis, Pfizer, Daiichi Sankyo, and AbbVie. M.A.S. has acted as a consultant or advisor for Teva Pharmaceutical Industries, Daiichi Sankyo, Orsenix, AbbVie, Novartis, and Pfizer. J.M.B. has acted as a consultant or advisor for Novartis, Celgene, Pfizer, Astellas, Teva, and Roche and has received research funding from Celgene. T.M.d.W. has acted as a consultant or advisor for Novartis, Celgene, Johnson & Johnson, and Incyte and has received clinical research support from Novartis, Celgene, and Johnson & Johnson. D.N. reports support from Cellectis and Daiichi and has participated in a Novartis speakers’ bureau outside the scope of the submitted work. B.C.M. has acted as a consultant or advisor for Celgene, Novartis, and Astellas and is currently employed by Roche/Genentech. M.S.T. has acted as a consultant or advisor for AbbVie, BioLineRx, Daiichi Sankyo, Orsenix, KAHR Medical, Rigel Pharmaceuticals, Nohla, Delta Fly Pharma, Tetraphase, Oncolyze, and Jazz Pharmaceuticals; has received clinical research funding from AbbVie, Cellerant Therapeutics, Orsenix, ADC Therapeutics, and BioSight; and has received royalties from UpToDate. R.F.S. has acted as a consultant or advisor for Pfizer and Daiichi Sankyo; is a member of the speakers’ bureau for Novartis, Pfizer, and Daiichi Sankyo; and has received clinical research funding from Pfizer, Daiichi Sankyo, PharmaMar, AstraZeneca, and Roche. A.G. has received clinical research support from Novartis. S.A. has acted as a consultant or advisor for Novartis and Daiichi Sankyo. Y.C., Y.M.C., and L.D. disclose employment with Novartis Pharmaceuticals Corporation. C.D. discloses employment with Novartis Pharma AG. C.T. is the Chief Executive Officer and a co-owner of Agendix, a company performing molecular diagnostics; has acted as a consultant or advisor for Novartis and Astellas; and has received clinical research support from Bayer. K.D. has acted as a consultant or advisor for Astellas, Celgene, Daiichi Sankyo, Janssen, Novartis, and Roche and has received clinical research support from Astex, Celgene, and Novartis. R.M.S. has acted as a consultant or advisor for AbbVie, Actinium, and Agios; has received personal fees from Amgen, Arogargenx, AROG, Astellas, AstraZeneca, BiolinerxBioLineRx, Celgene, Cornerstone, Daiichi Sankyo, Fujifilm, Janssen, Juno, MacrogenicsJazz Pharmaceuticals, MacroGenics, Novartis, Ono/Theradex Oncology, Orsenix, Otsuka/Astex, Pfizer, Roche, Stemline, Sumitomo Therapeutics, Takeda, and Trovagene; and has received institutional research support (to the institution) for clinical trials sponsored by AbbVie, Agios, AROG, and Novartis. H.D. has acted as a consultant or advisor for AbbVie, Agios, Amgen, Astellas, Astex Pharmaceuticals, Celgene, Janssen, Jazz Pharmaceuticals, Novartis, Roche, and Seattle Genetics and has received institutional research support from Amgen, AROG Pharmaceuticals, Bristol-Myers Squibb, Celgene, Jazz Pharmaceuticals, Novartis, Pfizer, and Sunesis. F.L.-C. discloses honoraria and a consulting or advisory role from Teva Pharmaceuticals Industries and Lundbeck. The remaining authors declare no competing financial interests.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Survival in patients with FLT3-TKDmutAML, according to treatment arm (n = 163 patients). HR and 95% CI are shown. OS (A), EFS (B), DFS (C), CIR (D).

Figure 2.

Estimated prognostic effect of NPM1 status and treatment effect. The figures show HR and 95% CI, censored at allogeneic HCT or not, for 134 FLT3-TKD mutated patients, grouped for NPM1 mutation status (mutated vs WT) (A) and according to treatment (midostaurin vs placebo) (B). The size of the boxes indicates the precision of the estimates.

Figure 3.

Survival outcomes (not censored at allogeneic HCT) by NPM1 mutation status and treatment arm (n = 134 patients). OS (A), EFS (B), DFS (C), CIR (D).

Figure 4.

Survival outcomes, according to CBF rearrangements (n = 20 patients), NPM1mut(n = 79 patients), and other genotypes (n = 26 patients). Other genotypes includes patients with intermediate (n = 11) and adverse karyotypes (n = 15 patients). OS (A), EFS (B), DFS (C), CIR (D).