Addition of Ixazomib to MEC Chemotherapy Promising in R/R AML

Anjali S. Advani

Anjali S. Advani

The addition of ixazomib (Ninlaro) to a combination of mitoxantrone, etoposide, and cytarabine (MEC) demonstrated a promising rate of responses among patients with relapsed or refractory acute myeloid leukemia (AML), according to the results of a phase I/II trial.

“…Our study demonstrates that the regimen of MEC and ixazomib was well tolerated and associated with a clinical response rate that was higher than expected in the context of salvage therapy for relapsed/refractory patients with poor-risk disease features,” the study authors, led by Anjali S. Advani, MD, wrote in their report published inClinical Cancer Research.

The study enrolled 30 patients who were treated at the Cleveland Clinic and University Hospitals of Cleveland between October 2014 and January 2017.

Patients received 8 mg/m²of mitoxantrone, 80 mg/m²of etoposide, 1000 mg/m²of cytarabine, all intravenously plus oral ixazomib on days 1, 4, 8, and 11 in escalating doses of 1.0, 2.0, or 3.0 mg. Eighteen patients were to be treated at the maximum tolerated dose. In total, 27 patients were treated with 1.0 mg of ixazomib and 3 were treated at 2.0 mg.

The median age of the patients was 58 years (range, 31-70) and 53% of the patients were male. Fourteen patients were in their first relapse and 13 were refractory to their most recent treatment. Seven patients hadFLT3-ITD mutations and another 7 had adverse cytogenetics. Two patients had undergone a prior allogeneic hematopoietic stem cell transplant.

The overall response rate was 53% consisting of 11 complete responses (CR) and 5 complete responses with incomplete count recovery (CRi). The median overall survival (OS) was 4.5 months (95% CI, 2.9-13.8), and at 1 year, the OS rate was 30.0% (95% CI, 17.4%-51.8%). Among patients who achieved a CR or CRi, the median OS was 11.1 months (95% CI, 4.9-not available [NA]) and the OS rate at 1 year was 50.0% (95% CI, 30.6%-81.6%).

Thirteen patients (43%) went on to receive an allogeneic hematopoietic stem cell transplant. Of these patients, the median OS was 38.3 months (95% CI, 5.0-NA) and at 1 year the OS rate was 63.6% (95% CI, 40.7%-99.5%). At 1 year, the rate of relapse-free survival was 77.8% (95% CI, 54.9%-100%) and the median was not reached.

Eight of 10 patients with mutations inDNTMT3A, TP53, ASXL1,andNRAS, which are associated with worse responses to salvage therapy and characterized the poor-risk status of many of the patients, achieved a CR/CRi.

The most common grade ≥3 nonhematologic toxicities were infection (74%), febrile neutropenia (85%), hypotension (18%), hypoxia (19%), and mucositis (15%). Adverse effects related to ixazomib were mostly gastrointestinal and neurologic, including constipation (grade 1/2 at 1.0 mg, 7%; grade 1/2 at 2.0 mg, 33%), other gastrointestinal symptoms (grade 1/2 at 1.0 mg, 4%; at 2.0 mg, 0%), and neurologic symptoms (grade 1/2 at 1.0 mg, 7%; grade 3 at 1.0 mg, 3%; at 2.0 mg, 0%). Dose delays due to increased bilirubin and diarrhea were needed for 2 patients.

One dose-limiting toxicity of grade 4 thrombocytopenia was observed with 1.0 mg of ixazomib. Two patients who received 2.0 mg developed grade 4 thrombocytopenia 50 days before initiation of chemotherapy. The maximum tolerated dose was set as 1.0 mg of ixazomib as a result.

The study authors noted that patients who were refractory to the combination regimen had a higher white blood cell count prior to trial therapy, a higher incidence ofFLT3mutations than those who responded to treatment, and a shorter median time from diagnosis to registration in the trial. Additionally, patients who were refractory were more likely to have a prior antecedent hematologic disorder, more likely to be refractory to their last treatment, and were less likely to be in first relapse.

The investigators also identified that the IFI30 and RORα genes were significantly different between responding and responding and resistant patients. “If this is validated, we could potentially increase the response rate to this regimen even further by ‘pre-selecting’ patients who are most likely to benefit based on specific gene expression features,” Advani et al noted in the report.

A larger randomized phase II trial is planned to further investigate the combination of ixazomib and MEC in patients with relapsed/refractory AML.

Reference:

Advani AS, Cooper B, Visconte V, et al. A Phase I/II Trial of MEC (Mitoxantrone, Etoposide, Cytarabine) in Combination with Ixazomib for Relapsed Refractory Acute Myeloid Leukemia.Clin Cancer Res. 2019;25(14):4231-4237. doi: 10.1158/1078-0432.CCR-18-3886.