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.