A Phase I/II Trial of MEC (Mitoxantrone, Etoposide, Cytarabine) in Combination with Ixazomib for Relapsed Refractory Acute Myeloid Leukemia.

Purpose: The prognosis of patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) remains poor, and novel therapies are needed. The proteasome pathway represents a potential therapeutic target. A phase I trial of the second-generation proteasome inhibitor ixazomib in combination with MEC (mitoxantrone, etoposide, and cytarabine) was conducted in patients with R/R AML.

Patients And Methods: Dose escalation of ixazomib was performed using a standard 3 × 3 design. Gene-expression profiling was performed on pretreatment and posttreatment bone marrow or blood samples.

Results: The maximum tolerated dose of ixazomib in combination with MEC was 1.0 mg. The dose limiting toxicity was thrombocytopenia. Despite a poor risk population, the response rate [complete remission (CR)/CR with incomplete count recovery (CRi)] was encouraging at 53%. Gene-expression analysis identified two genes, IFI30 (γ-interferon inducible lysosomal thiol reductase) and RORα (retinoic orphan receptor A), which were significantly differentially expressed between responding and resistant patients and could classify CR.

Conclusions: These results are encouraging, but a randomized trial is needed to address whether the addition of ixazomib to MEC improves outcome. Gene-expression profiling also helped us identify predictors of response and potentially novel therapeutic targets.