“To identify a signature predictive of response to treatment, we performed RNA sequencing on pretreatment samples from 17 patients, and on posttreatment samples from 11 patients,” she said. “We found that genes were differentially expressed between resistant and responding patients in 314 genes in the pretreatment samples, in 217 genes in the posttreatment samples, and in 72 genes at both time points.”
Gene set enrichment analysis identified significantly differentially expressed genes clustering in heme-metabolism and erythroblast differentiation, inflammatory response, cytokine/STAT signaling, nuclear factor-kappa beta (NF-kappaB), and hypoxia. Two genes – gamma-interferon–inducible lysosomal thiol reductase (IFI30) and retinoic acid–related orphan receptor A (ROR-alpha) – were found to be significantly different between responding and resistant patients, and could potentially classify response, she noted.
“IFI30, which may increase the levels of antioxidants and lead to a decreased ER [endoplasmic reticulum] stress response to therapy, was more highly expressed in resistant patients, and ROR-alpha, a tumor-suppressor gene, was down regulated in resistant patients,” she said.
Ixazomib was combined with the AML salvage regimen MEC in this study because proteasome inhibitors like ixazomib induce cell death in AML cells through inhibition of NF-kappaB, and also increase chemosensitivity to anthracyclines and cytarabines, Dr. Advani explained.