Addition of Sorafenib to Chemotherapy May Improve Outcomes in Pediatric HAR FLT3/ITD1+ AML

Pediatric patients with high allelic ratio FLT3/ITD–positive acute myeloid leukemia may benefit from treatment with sorafenib plus chemotherapy.

Pediatric patients with high allelic ratio FLT3/ITD-positive acute myeloid leukemia (AML) could potentially benefit from the addition of sorafenib (Nexavar) to chemotherapy, according to a study published in The Journal of Clinical Oncology.

Patients in the sorafenib arm experienced superior outcomes, however hematopoietic stem-cell transplants (HSCT) occurred more often in the experimental arm vs the comparator arm. Sorafenib’s was confirmed in the multivariable analysis, which accounted for HSCT and favorable co-occurring mutations. The multivariate analysis from study entry also identified a 2-fold higher risk of an event occurring in patients who did not receive sorafenib (event-free survival [EFS]; HR, 2.37; 95% CI, 1.45-3.88; P <.001). Similar findings were observed with regard to disease-free survival (DFS) from complete remission (CR; HR, 2.28; 95% CI, 1.08-4.82; P = .032) and relapse risk from CR (HR, 3.03; 95% CI, 1.31-7.04; P = .010). Patients also had sufficient plasma concentrations to inhibit phosphorylated FLT3.

The study had multiple arms: arm A administered standard chemotherapy and arm B administered standard chemotherapy plus bortezomib. Patients enrolled on arm C following initial treatment in arm A which included the use of sorafenib. Patients enrolled on arm D after arms A and B closed and until FLT3/ITD results returned; a positive FLT3/ITD status allowed patients to enroll in arm C. A total of 1609 de-novo patients were eligible for treatment, 136 of whom had high allelic ratio FLT3/ITD-positive AML, and were eligible for arm C enrollment; 92 patients consented for enrollment on the arm. In arms A and B, an additional 42 patients with high allelic ratio FLT3/ITD-positive AML enrolled. A total of 24 patients in arm C who were randomly assigned to receive bortezomib prior to enrollment, and 19 patients received it in close proximity to sorafenib.

In arm C cohort 1 (C1), the maximum tolerated dose of sorafenib was 200 mg/m2 once daily. Grade 3 toxicities in the cohort included rash (n = 1) and fever (n = 1).

To limit confounding influence of bortezomib, the toxicities of the 53 patients enrolled in arm C were compared with the 34 patients in arm A who were HAR FLT/ITD–positive who declined to enroll in arm C or were treated in arm A while arm C was closed. Patients had similar rates of chemotherapy dose reduction and intensive care unit admission. During induction, patients in arm C were more likely to receive dexrazoxane as a cardioprotectant with anthracycline (P = .006).

In arm C cohort 2 (C2), 7 patients experienced preliminary signals of increased cardiac toxicity, which was defined as grade 3 ejection fraction decline (n = 3), grade 3 ejection fraction decline (n = 2), grade 2 cardiac fraction decline (n = 2), grade 3 left-ventricular systolic dysfunction (n = 1), grade 2 shortening fraction decline (n = 1), and grade 1 shortening fraction decline (n = 1). In total, 2 patients met criteria for permanent discontinuation, 2 tolerated treatment restart, and 5 continued to protocol therapy. The toxicity in arm C was comparable to arm A.

In cohorts 2 and 3 in cohort C, sorafenib was administered to 80 patients, 30 of whom received at least 1 cycle and 20 completed all maintenance treatment. In total, 62% of patients did not undergo maintenance treatment, 56% went off protocol therapy, and 6% did not meet eligibility criteria.

Characteristics were similar between those exposed to sorafenib and those who were not, excluding Hispanic pediatric patients, as the population was more likely to be unexposed to sorafenib and more frequently received HSCT. A morphologic complete response (CR) was more often found in patients taking sorafenib. The population also had less persistent disease. Minimal residual disease rates were not significantly different between groups.

The median follow-up for patients alive at last contact was 5.3 years, with 32 EFS events in the sorafenib-exposed group vs 35 events for those who were not exposed. When comparing with long-term outcomes, investigators determined that exposure to sorafenib allowed for improved EFS, DFS, and relapse risk from a CR, but not overall survival.

At the prescribed dosing, during the first 3 courses of therapy, sorafenib was able to target FLT3 in a subset of patients and inhibit its function. This was found through a plasma inhibitor assay with a median trough of FLT3 inhibition being 92%, 91%, and 81% during the first 3 courses of therapy, respectively.


Pollard JA, Alonzo TA, Gerbing R, et al. 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. J Clin Oncol. Published Online March 29, 2022. doi:10.1200/JCO.21.01612