Phase 1/2 Study of Sorafenib Added to Cladribine, High-Dose Cytarabine, G-CSF, and Mitoxantrone in Untreated AML.
Anna B HalpernEduardo Rodríguez-ArbolíMegan OthusKelsey-Leigh A GarciaMary-Elizabeth M PercivalRyan D CassadayVivian G OehlerPamela S BeckerJacob S AppelbaumJanis L AbkowitzJohnnie J OrozcoSioban B KeelPaul C HendrieBart L ScottCristina Maria M GhiuzeliElihu EsteyRoland Bruno WalterPublished in: Blood advances (2023)
The multikinase inhibitor sorafenib improves event-free survival (EFS) when used with 7+3 in younger adults with newly diagnosed acute myeloid leukemia (AML) irrespective of FLT3 mutation status. Here, we evaluated adding sorafenib to CLAG-M (cladribine, high-dose cytarabine, G-CSF, mitoxantrone) in a phase 1/2 trial of 81 adults age ≤60 years with newly diagnosed AML or high-grade myeloid neoplasm. Forty-six patients were treated in phase 1 with escalating doses of sorafenib and mitoxantrone. No maximum tolerated dose was reached, and a regimen including mitoxantrone at 18 mg/m2/day and sorafenib 400 mg twice daily was declared the recommended phase 2 dose (RP2D). Among 41 patients treated at the RP2D, a measurable residual disease-negative complete remission (MRDneg CR) rate of 83% (95% confidence interval [CI]: 68-93%) was obtained. Four-week mortality was 2% (95% CI: 0-13%). One-year overall survival (OS) and EFS were 80% (95% CI: 69-94%) and 76% (95% CI 64-90%), without significant difference in MRDneg CR rates, OS, or EFS between patients with or without FLT3-mutated disease. Comparing outcomes with CLAG-M/sorafenib to a matched cohort of 76 patients treated with CLAG-M alone, multivariable adjusted survival estimates were improved for the 41 patients receiving CLAG-M/sorafenib at RP2D (OS: hazard ratio [HR]=0.24 [95% CI: 0.07-0.82], P=0.023; EFS: HR=0.16 [95% CI: 0.05-0.53], P=0.003). Statistically significant benefit was limited to patients with intermediate-risk disease (in univariate analysis, P=0.01 for OS and P=0.02 for EFS). These data suggest CLAG-M/sorafenib is safe and improves OS and EFS relative to CLAG-M alone, with benefit primarily for patients with intermediate-risk disease. The trial is registered on clinicialtrials.gov as NCT02728050.
Keyphrases
- acute myeloid leukemia
- newly diagnosed
- high dose
- allogeneic hematopoietic stem cell transplantation
- free survival
- high grade
- low dose
- end stage renal disease
- low grade
- stem cell transplantation
- ejection fraction
- bone marrow
- chronic kidney disease
- randomized controlled trial
- study protocol
- cardiovascular events
- skeletal muscle
- open label
- insulin resistance
- adipose tissue
- peritoneal dialysis