A Phase 1/2 Trial of MEC (Mitoxantrone, Etoposide, Cytarabine) in Combination with Ixazomib for Relapsed/ Refractory Acute Myeloid Leukemia
2019
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 1 trial of the second generation proteasome inhibitor, ixazomib in combination with MEC (mitoxantrone, etoposide, and cytarabine) was conducted in patients with R/R AML. Experimental design: Dose escalation of ixazomib was performed using a standard 3x3 design. Gene expression profiling was performed on pre- and post-treatment 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 2 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.
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