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The addition of sorafenib to conventional chemotherapy was safe and demonstrated evidence of improved outcomes in pediatric patients with FLT3-ITD–positive acute myeloid leukemia.
The addition of sorafenib (Nexavar) to conventional chemotherapy was safe and demonstrated evidence of improved outcomes in pediatric patients with FLT3-ITD–positive acute myeloid leukemia (AML), according to findings from the phase 3 Children’s Oncology Group (COG) Protocol AAML1031 (NCT01371981) published in the Journal of Clinical Oncology.1
The median follow-up time for patients alive at last contact was 5.3 years (range, 0.3-13.1). There were 32 event-free-survival (EFS) events among patients who received sorafenib (n = 72) and 35 events among patients who did not (n = 76).
Additionally, treatment with sorafenib was associated with improved EFS from study entry (P = .001) as well as disease-free survival (DFS; P = .032) and relapse risk from complete remission (CR; P = .012) but not overall survival (OS; P = .244).
“These data demonstrate that sorafenib dosing of 200 mg/m2 [per] day was tolerable in conjunction with conventional chemotherapy, significantly improved EFS, relapse risk, and DFS, and provided potent FLT3 inhibition,” lead study author Jessica A. Pollard, MD, a physician at Dana-Farber Cancer Institute, and coauthors wrote in the publication. “For treatment of pediatric FLT3-ITD–positive AML outside of a study context, these data provide compelling support for sorafenib combined with conventional chemotherapy.”
High allelic ratio FLT3-ITD mutations are associated with poor prognosis in pediatric AML, but chemotherapy remains the standard of care. Prior studies have shown sorafenib is safe in adults with FLT3-mutant AML. Following documentation of sorafenib’s ease of administration in the pediatric population, investigators sought to examine its use in combination with chemotherapy.
The study enrolled 1,645 patients with newly diagnosed, FLT3-ITD–mutant AML, of which 1,609 were eligible. Patients were randomized to 1 of 4 arms: standard chemotherapy consisting of asparaginase, cytarabine, daunorubicin, and etoposide (arm A); asparaginase, bortezomib (Velcade), cytarabine, daunorubicin, and etoposide (arm B); asparaginase, cytarabine, daunorubicin, etoposide, and sorafenib (arm C); or cytarabine, daunorubicin, and etoposide (arm D).2
At enrollment, patients were randomized to arm A or arm B and underwent centralized FLT3-ITD mutation testing. Patients with a high FLT3-ITD allelic ratio (> 0.4) were eligible for enrollment on arm C, which was split into 3 cohorts. 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; if positive, patients were eligible for arm C.
Of the 1,609 patients enrolled, 8.5% (n = 136) had high allelic ratio FLT3-ITD–positive AML and were eligible for enrollment in arm C, of which 68% (n = 92) of patients consented. Another 42 patients with high allelic ratio enrolled on arm A or B did not participate in arm C.
During the safety phase, sorafenib was given at a dose of 200 mg/m2 once daily; this dose was determined to be the recommended dosing for sorafenib given the absence of protocol defined dose-limiting toxicities requiring treatment de-escalation. Following completion of the first cohort, the study was amended such that cohort 2 started sorafenib on day 11 of induction 1 and received the agent concomitantly with chemotherapy thereafter.
A preliminary signal of increased cardiac toxicity was reported in 22% (n = 7) of patients in cohort 2 of arm C as defined by grade 3 ejection fraction decline (n = 3), grade 2 ejection fraction decline (n = 2), grade 3 left-ventricular systolic dysfunction (n = 1), grade 2 cardiac other (shortening fraction decline, n = 1), and grade 1 cardiac other (shortening fraction decline, n = 1).
Two patients met the criteria for permanent discontinuation of sorafenib and both tolerated restart. The remaining five discontinued treatment before retreatment was possible. This safety signal led investigators to start sorafenib after completion of standard chemotherapy in each cycle.
A year of sorafenib maintenance, administered after hematopoietic stem cell transplant (HSCT) or completion of chemotherapy was added for patients enrolled in cohort 2 given early evidence of the activity of maintenance therapy. Maintenance dosing was 100 mg/m2 daily with a potential for escalation to a maximum dose of 150 mg/m2 twice daily.
Only 80 patients received sorafenib maintenance in cohorts 2 and 3 of arm C; 38% (n = 30) received at least 1 cycle and 25% (n = 20) completed all maintenance treatment. Maintenance toxicity rates were comparable to those of earlier treatment cycles.
Additional findings from secondary analyses, in which patients who were sorafenib-treated and -naïve were censored at the date of last contact, demonstrated similar outcomes as did censoring of both groups at the time of elective withdrawal.
Furthermore, subanalysis according to NPM1 status indicated that patients with FLT3-ITD–positive and NPM1-positive tumors treated with sorafenib did not show a statistically significant improvement in outcomes vs those who did not receive sorafenib (EFS: P = .399; DFS: P = .715; relapse risk: P = .607; OS: P = .783).
Although outcomes appeared better overall for children with FLT3-ITD–positive AML who received sorafenib, they also underwent HSCT more frequently than the comparator population (64% vs 25%, respectively; P < .001).
In multivariable analysis including NPM1 status and HSCT as a time-varying covariate, significantly worse EFS, DFS, and relapse risk was seen in patients who did not receive sorafenib vs 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).
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 3 cohorts of arm C.
Patients initially enrolled on arm A before switching to arm C (n = 53) were compared with patients who remained on arm A (n = 34). Targeted toxicities were comparable overall as well as across cohorts and treatment phases for patients in arm C who initially were treated on arm A. Additionally, the incidence of chemotherapy-related dose reduction and intensive care unit admission were similar. Notably, patients in arm C were more likely to receive dexrazoxane as a cardioprotectant with anthracycline therapy during induction (P = .006). No significant unanticipated toxicities were reported in the sorafenib cohort.
Ultimately, the cardiac toxicity reported in arm C was similar to that of arm A. Differences in median ejection fraction were also similar between arms C and A and across arm C cohorts.
“These data are the largest analysis of sorafenib efficacy in pediatric FLT3-ITD–positive AML. The presently open COG phase 3 study, AAML1831 [NCT04293562], builds on our sorafenib experience by testing gilteritinib in both FLT3-ITD–positive AML and children with clinically relevant FLT3-activating mutations,” the study authors concluded.