Sorafenib in Combination With Standard Chemotherapy for Children With High Allelic Ratio FLT3/ITD+ Acute Myeloid Leukemia: A Report From the Children's Oncology Group Protocol AAML1031

Abstract

Purpose: High allelic ratio (HAR) FLT3/ITD (AR > 0.4) mutations confer poor prognosis in pediatric acute myeloid leukemia (AML). COG AAML1031 studied the feasibility and efficacy of adding sorafenib, a multikinase tyrosine kinase inhibitor to standard chemotherapy and as single-agent maintenance therapy in this population.

Materials and methods: Patients were treated in three cohorts. The initial safety phase defined the maximum tolerated dose of sorafenib starting in induction 2. Cohorts 2 and 3 added sorafenib in induction and as single-agent maintenance. Clinical outcome analysis was limited to n = 72 patients in cohorts 2/3 and compared with n = 76 HAR FLT3/ITD+ AML patients who received identical chemotherapy without sorafenib. Sorafenib pharmacokinetics and plasma inhibitory activity were measured in a subset of patients.

Results: The maximum tolerated dose of sorafenib was 200 mg/m² once daily; dose-limiting toxicities included rash (n = 2; 1 grade 3 and 1 grade 2), grade 2 hand-foot syndrome, and grade 3 fever. Pharmacokinetics/plasma inhibitory activity data demonstrated that measured plasma concentrations were sufficient to inhibit phosphorylated FLT3. Although outcomes were superior with sorafenib in cohorts 2 and 3, patients treated with sorafenib also underwent hematopoietic stem-cell transplant more frequently than the comparator population. Multivariable analysis that accounted for both hematopoietic stem-cell transplant and favorable co-occurring mutations confirmed sorafenib's benefit. Specifically, risk of an event was approximately two-fold higher in HAR FLT3/ITD+ patients who did not receive sorafenib (event-free survival from study entry: hazard ratio [HR] 2.37, 95% CI, 1.45 to 3.88, P < .001, disease-free survival from complete remission: HR 2.28, 95% CI, 1.08 to 4.82, P = .032, relapse risk from complete remission: HR 3.03, 95% CI 1.31 to 7.04, P = .010).

Conclusion: Sorafenib can be safely added to conventional AML chemotherapy and may improve outcomes in pediatric HAR FLT3/ITD+ AML.

Trial registration: ClinicalTrials.gov NCT01371981.

FIG 1.

Distribution of HAR FLT3/ITD+ AML patients included in analysis. (A) CONSORT diagram of AAML1031 overall and by Arm C cohort, (B) Flow diagram of AAML1031 Arms A/B (sorafenib-unexposed), and (C) Flow diagram for AAML0531 (sorafenib-unexposed). Alt, alternative donor (donor availability defined for intermediate- and high-risk patients only); AML, acute myeloid leukemia; HAR, high allelic ratio; HSCT, hematopoietic stem-cell transplant; MFD, matched family donor.

FIG 2.

Outcomes for sorafenib-exposed versus -unexposed patients: (A-D) Overall and (E-H) by NPM1 status. (A) OS from study entry, (B) EFS from study entry, (C) DFS from CR, (D) RR from CR, (E) OS from study entry, (F) EFS from study entry by NPM1 status, (G) DFS from CR by NPM1 status, and (H) RR from CR by NPM1 status. CR, complete remission; DFS, disease-free survival; EFS, event-free survival; OS, overall survival; RR, relapse risk; WT, wild-type.

FIG 3.

PK/PD effects of sorafenib. The median and upper range steady-state concentration of sorafenib and the N-oxide metabolite in induction I (n = 23), induction 2 (n = 33), and intensification I (n = 28) is noted in black. PIA median trough inhibition and associated 95% CI are noted in red. Data are contributed by a total of n = 52 patients enrolled at 10 different institutions. PIA, plasma inhibitory activity; PK, pharmacokinetics.