REPORTING FROM ASH 2017
ATLANTA (FRONTLINE MEDICAL NEWS) – Mitoxantrone, etoposide, and cytarabine (MEC) in combination with the second-generation proteasome inhibitor ixazomib was well tolerated and effective in a phase 1 expansion study of patients with relapsed or refractory acute myeloid leukemia.
The overall response rate in 30 patients enrolled in the study and treated with the novel combination was 53%; 11 patients had a complete response (CR), and 5 had a complete response with incomplete blood count recovery (CRi). The median overall survival was 4.9 months, Anjali S. Advani, MD , reported at the annual meeting of the American Society of Hematology.
Thirteen patients proceeded to allogeneic hematopoietic cell transplant (AHCT), and one received a donor lymphocyte infusion. Seven of these 14 patients are alive with a median follow-up of 14.5 months, said Dr. Advani of Taussig Cancer Institute, Cleveland Clinic.
The patients, who had a median age of 58 years (range of 18-70 years), were eligible for the study if they had relapsed/refractory acute myeloid leukemia (AML), adequate organ function, and cardiac ejection fraction of at least 45%. The median time from initial diagnosis to enrollment was 7.6 months.
Eight patients had a history of an antecedent hematologic disorder; 14 were in their first relapse; and 13 had disease that was refractory to their last treatment. Two had received a prior AHCT; seven had FLT3 internal tandem duplication (ITD) mutations indicative of particularly poor prognosis; and seven had adverse cytogenetics, she said.
They received one cycle of the therapy, which included 8mg/m2 of mitoxantrone, 80 mg/m2 of etoposide, and 1,000 mg/m2 of cytarabine given intravenously on days 1-6, plus ixazomib at doses of 1 mg (27 patients) or 2 mg (3 patients) given orally on days 1, 4, 8, and 11. An additional 18 patients were treated at the maximum tolerated dose (1 mg, as determined in phase 1 of the trial), Dr. Advani said.
The treatment was well tolerated in most patients. Grade 3-5 nonhematologic toxicities occurred in at least 15% of patients and included infection in 74%, febrile neutropenia in 85%, hypotension in 18%, hypoxia in 19%, mucositis in 15%, hypokalemia in 33%, and hypoalbuminemia in 30%, she said. The early mortality rate was 10%.
Of note, prior studies have demonstrated that the number of mutations in DNMT3A, TP53, ASXL1, and NRAS is associated with a worse response to salvage therapy. Of 21 patients in the current study who had available data, 10 patients had at least one of these mutations, and 8 of those 10 patients achieved CR or CRi, Dr. Advani said.
“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.
The findings are encouraging and suggest that results from gene expression profiling may help identify resistant patients and provide further therapeutic targets, she said, noting that in vitro studies are planned to clarify whether the use of ROR-alpha agonists may help sensitize resistant cells to treatment.
Dr. Advani reported receiving research funding from Takeda/Millenium, and serving as a consultant for Pfizer.