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Sorafenib in FLT3/ITD-Positive AML: Impact of Co-occurring Mutations

By: Joseph Fanelli
Posted: Monday, April 6, 2020

According to findings presented in the journal Blood, patients diagnosed with acute myeloid leukemia (AML) with high allelic ratios of FLT3/ITD and WT1 mutations may experience improved outcomes from treatment with sorafenib. Katherine Tarlock, MD, of the Fred Hutchinson Cancer Research Center, Seattle, and colleagues demonstrated that, in line with past findings, these patients treated with sorafenib had better survival than did patients with other ITD-positive disease. “However, sorafenib failed to improve outcomes for NUP98-NSD1–positive patients, further highlighting that novel therapeutic strategies will be needed for this group of patients,” the authors concluded.

In this phase III trial, the authors enrolled 136 patients with a high allelic ratio (> 0.4) and FLT3/ITD mutations. They assessed the safety and efficacy of sorafenib in combination with chemotherapy and hematopoietic stem cell transplantation. Of the patients, 92 were treated with sorafenib, and 42 were not. In addition to conventional karyotyping and mutational profiling, all patients were also tested for NUP98-NDS1 by RNA sequencing and WT1 profiling by next-generation sequencing or hotspot sequencing of exons 7 and 9.

Those patients treated with sorafenib had a combined overall survival of 62%, compared with 68% for those not treated with sorafenib. Those with ITD–positive and NUP9–positive disease had similar 3-year event-free survival regardless of treatment with or without sorafenib (22% vs. 20%, respectively). Furthermore, among those not treated with sorafenib, NUP98-NSD1–positive patients reported significantly inferior outcomes than did NUP98-NSD1–negative patients (event-free survival of 20% vs. 65%). Additionally, treatment with sorafenib did not seem to improve outcomes for patients with a high allelic ratio and ITD-positive status.

“As the addition of FLT3 inhibitors is investigated in [high allelic ratio] FLT3/ITD-positive patients, evaluation of its impact across patients with additional oncogenic mutations will be critical to determine which patients will derive the most benefit from this strategy,” the authors noted.

Disclosure: The authors reported no conflicts of interest.

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