Menin Inhibitors in Acute Myeloid Leukemia—What Does the Future Hold?

Abstract

Menin inhibitors constitute a novel class of agents targeting the underlying biology of nucleophosmin (NPM1) mutant and KMT2A (formerly known as MLL1) rearranged (KMT2Ar) acute leukemias. KMT2Ar acute leukemias constitute 5% to 10% of acute leukemias, and NPM1 mutations are identified in 30% of newly diagnosed acute myeloid leukemias (AMLs). In preclinical AML models, small molecule inhibitors of the menin-KMT2A protein-protein interaction induce differentiation, downregulate critical gene expression programs, and confer a survival advantage in patient-derived xenograft models of NPM1 mutant and KMT2Ar AML. Multiple clinical trials evaluating oral menin inhibitors in acute leukemias are ongoing. Preliminary results in relapsed/refractory NPM1 mutant and KMT2Ar AML have shown on-target effects, tolerable toxicity, and promising clinical activity. This review details the current clinical experience of menin inhibitors in AML and discusses how these agents can be successfully integrated into future therapeutic approaches.

Activity of menin inhibitor ziftomenib (KO-539) as monotherapy or in combinations against AML cells with MLL1 rearrangement or mutant NPM1

“…Orally bioavailable, investigational or clinical drug candidate Menin inhibitors (MIs) disrupt binding of Menin to its binding pocket in MLL1/2 and MLL1-FP, which reduces MLL1/2 and MLL1-FP binding to their targets, inhibits HOXA9/MEIS1 activity, represses PBX3, MEF2C, FLT3 and CDK6, as well as induces differentiation and loss of survival of AML with MLL1-r or with mutant (mt)-NPM1 [2,[8][9][10]. In early clinical trials, monotherapy with MI is well tolerated and has achieved objective remissions in patients with previously treated relapsed/ refractory AML harboring MLL1-r or NPM1c [2,11]. However, most patients either fail to respond or eventually relapse [11].…”

“…In early clinical trials, monotherapy with MI is well tolerated and has achieved objective remissions in patients with previously treated relapsed/ refractory AML harboring MLL1-r or NPM1c [2,11]. However, most patients either fail to respond or eventually relapse [11]. Therefore, there is a need to investigate the activity of additional MIs and MIbased combinations that may exhibit superior activity and prevent or abrogate MI-resistance in AML cells with MLL1-r or mtNPM1.…”

Prolonged XPO1 inhibition is essential for optimal antileukemic activity in NPM1-mutated AML

“…Despite its high sensitivity to chemotherapy, NPM1-mutated AML remains an incurable disease in about 50% of patients. Although specific targeting of NPM1c has been so far revealed challenging 2,18 , venetoclax-based regimens and Menin-MLL inhibitors have recently proven effective in NPM1-mutated AML [19][20][21][22][23] . Therefore, there is growing interest in developing new targeted therapies for this entity 24 .…”

Current status and future perspectives in targeted therapy of NPM1-mutated AML

“…Menin inhibitors, including KO-539, SNDX-5613, JNJ-75276617 and DS-1594b, are currently evaluated in clinical trials [100,101]. KO-539 induced CR in 2/6 patients with R/R AML who were evaluable for efficacy analysis.…”

“…KO-539 induced CR in 2/6 patients with R/R AML who were evaluable for efficacy analysis. One of them had an NPM1-mutated AML co-mutated for DNMT3A and KMT2D who received KO-539 at 200 mg/die, as the eight line of therapy, achieving an MRDnegative CR [101]. This trial continues to enroll patients with NPM1-mutated and KTM2A-rearranged AML on the doses of 200 and 600 mg (NCT04067336).…”