Mutations in Fms-like tyrosine kinase 3 (FLT3) occur in approximately 15 percent of pediatric patients with acute myeloid leukemia (AML). High allelic ratio (HAR) FLT3 internal tandem duplication (FLT3/ITD) mutant AML is associated with poor prognosis in pediatric AML with survival of approximately 25-30 percent. Previous reports have shown the safety of sorafenib, a tyrosine kinase inhibitor, in adults with FLT3-mutant AML. Pediatric patients with HAR FLT3/ITD+ AML could potentially benefit from the addition of sorafenib.
In a new study, investigators sought to examine the feasibility and efficacy of adding sorafenib to standard chemotherapy and as single-agent maintenance therapy in children with this AML subtype. Findings from the Phase III Children's Oncology Group (COG) protocol AAML1031 (NCT01371981) were published in the Journal of Clinical Oncology (2022; doi: 10.1200/JCO.21.01612).
Study Details
In the analysis, Pollard and colleagues screened children with newly diagnosed AML for HAR FLT3/ITD. The study had multiple arms. Patients were randomized to Arm A (standard chemotherapy) or Arm B (standard chemotherapy plus bortezomib) and underwent centralized FLT3/ITD mutation testing. If consented, patients initially randomized to Arm A continued standard chemotherapy with sorafenib, and patients in Arm B discontinued bortezomib when consenting to Arm C. After Arms A and B closed, 19 patients were enrolled on Arm D until FLT3/ITD results returned; a positive FLT3/ITD status allowed patients to enroll in Arm C.
The study enrolled 1,645 patients with newly diagnosed, FLT3/ITD-mutant AML, of which 1,609 were eligible. Of these eligible individuals, 136 (8.5%) of whom had HAR FLT3/ITD+ AML and were eligible for arm C enrollment, 92 patients (68%) consented for enrollment on the arm. Forty-two patients with HAR enrolled on Arm A or B did not participate in Arm C.
Patients with a high FLT3/ITD allelic ratio on Arm C were split into three cohorts. The initial safety phase defined the maximum tolerated dose (MTD) of sorafenib starting in Induction 2. In Arm C cohort 1 (C1), the MTD of sorafenib was 200 mg/m2 once daily. 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 treated with sorafenib at 200 mg/m2 once daily added to standard chemotherapy and used as maintenance therapy (100 mg/m2) and compared with 76 contemporaneously enrolled HAR FLT3/ITD+ patients who received identical chemotherapy without sorafenib.
In terms of safety, dose-limiting toxicities reported in cohort 1 of Arm C included rash (Grade 2, n=1; Grade 3, n=1), Grade 2 hand-foot syndrome (n=1), and Grade 3 fever (n=1). The incidence of targeted toxicities was comparable between all three cohorts of Arm C.
Overall, the data convincingly demonstrated that when comparing long-term outcomes, treatment with sorafenib was associated potent FLT3 kinase inhibitory concentrations, improved event-free survival (EFS), disease-free survival (DFS), and relapse rates compared to the sorafenib-unexposed group. Other details included the following:
* A higher rate of complete remission at end of Induction 1 (75% vs. 57%, P=.028)
* Significantly improved 3-year EFS from entry (55.9% vs. 31.9%, P=.001)
* Significantly improved 3-year DFS (70.9% vs. 49.4%, P=.032) and risk of relapse (17.6% vs. 44.1%, P=.012) from end of Induction 1 in patients with complete remission (CR).
* Despite these gains, overall survival (OS) with sorafenib was no better than controls: 3-year OS from study entry (65.8% vs. 55.3%, P=.244)
* The median follow-up time for patients alive at last contact was 5.3 years, with 32 EFS events among patients who received sorafenib (n=72) and 35 events among patients who did not (n=76).
Although outcomes appeared better overall for children with FLT3/ITD+ AML who received sorafenib, hematopoietic stem cell transplants (HSCT) occurred more often in the experimental arm versus the comparator arm (64% vs. 25%, respectively; P<.001).
In multivariate analysis including HSCT and favorable co-occurring mutations, significantly worse EFS, DFS, and relapse risk were seen in patients who did not receive sorafenib versus those who did (EFS from study entry: HR, 2.37; 95% CI, 1.45-3.88; P<.001; DFS from CR: HR, 2.28; 95% CI, 1.08-4.82; P=.032; relapse risk from CR: HR, 3.03; 95% CI, 1.31-7.04; P=.010). No significant difference in OS was observed (HR=1.21, 95% CI=0.67-2.20, P=.525).
Pharmacokinetics/plasma inhibitory activity data demonstrated that measured plasma concentrations were sufficient to inhibit phosphorylated FLT3. Sub-analysis according to NPM1 status indicated that patients with FLT3-ITD+ and NPM1+ tumors treated with sorafenib did not show a statistically significant improvement in outcomes versus those who did not receive sorafenib.
"These data are the largest analysis of sorafenib efficacy in pediatric FLT3/ITD+ AML. The presently open COG Phase III study, AAML1831, builds on our sorafenib experience by testing gilteritinib in both FLT3/ITD+ AML and children with clinically relevant FLT3-activating mutations," the study authors concluded. "For treatment of pediatric FLT3/ITD+ AML outside of a study context, these data provide compelling support for sorafenib combined with conventional chemotherapy."
Dibash Kumar Das is a contributing writer.