Study Investigates Diverse Molecular Mechanisms Driving Treatment Resistance in AML

Researchers evaluated the primary mechanisms governing drug resistance and relapse in patients treated with crenolanib, an FLT3 inhibitor.

Comprehensive mutational sequencing should be carried out on patient samples at the start and during treatment of acute myeloid leukemia (AML), according to a new study published in the journal Nature Communications. In addition, it is imperative that potential sub-clones with resistant mutations be identified in order to recognize and pre-emptively target problematic clones, the researchers found.

Investigators studied the primary mechanisms governing drug resistance and relapse in patients treated with crenolanib, a potent and selective FLT3 inhibitor. They performed whole exome sequencing of AML patient samples before and after crenolanib treatment. Based on data from other FLT3 inhibitors, they expected that secondary mutations in FLT3 would help explain many causes of resistance. However, they determined that this was not the case.

“We were surprised that very few cases could be explained in this way. Instead, we found that the AML tumors underwent a selective process of clonal evolution, and tumor subclones that had accumulated mutations in other genes and pathways were the primary cause of resistance,” said study investigator Jeffrey W. Tyner, PhD, of the Division of Hematology and Medical Oncology at OHSU Knight Cancer Institute in Portland.

Mutations of NRAS and IDH2 occurred mostly as FLT3-independent subclones. However, TET2 and IDH1 mutations predominantly co-occurred with FLT3-mutant clones, and these mutations were found to be enriched in poor-responders to crenolanib. In a cohort of 51 crenolanib-treated patients, only 3 patients (5.9%) demonstrated FLT3 secondary mutations, and 5 patients (9.8%) showed concomitant TET2 truncation mutations. A total of 15 patients (29.4%) were found to have mutations in alternative signaling pathways.

Tyner and his colleagues also identified three distinct patterns of mutation dynamics during the treatment of crenolanib. They found that each clonal evolutionary pattern appeared to represent a distinct prognosis, suggesting that tailored strategies will be required to circumvent drug resistance.

“Combination therapies are absolutely required, and choosing the right combination therapy may necessitate in-depth studies upfront to understand the clonal diversity that is present prior to therapy, such that a drug combination regimen can be tailored not just to a patient's dominant tumor clone, but also to problematic subclones,” Tyner told Cancer Network.

Although single-agent therapy with FLT3 inhibitors may be of some clinical benefit to patients with high VAF of FLT3 mutations, it appears that a combination approach with a FLT3 inhibitor and chemotherapy or agents targeting cooperative lesions will be required to achieve deep and durable remission, the researchers concluded.

Mark Levis, MD, PhD, a professor of oncology and the director of the Adult Leukemia Program at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, said these findings may help lead to new combination therapies that produce more durable remission rates.

“This is an important paper and the data are applicable to most FLT3 inhibitors, not just crenolanib. The results are consistent with other emerging data regarding mechanisms of resistance to targeted agents in AML,” Levis told Cancer Network.