Targeting the undruggable: menin inhibitors ante portas

Acute myeloid leukaemias harbouring a rearrangement of the mixed lineage leukaemia gene (MLL) are aggressive haematopoietic malignancies that relapse early and have a poor prognosis (event-free survival less than 50%). Menin is a tumour suppressor, however, in MLL-rearranged leukaemias it functions as a co-factor which is mandatory for the leukaemic transformation by interaction with the N-terminal part of MLL, which is maintained in all MLL-fusion proteins. Inhibition of menin blocks leukaemogenesis and leads to differentiation and, in turn, to apoptosis of leukaemic blasts. Furthermore, nucleophosmin 1 (NPM1) binds to specific chromatin targets, which are co-occupied by MLL, and menin inhibition has been shown to trigger degradation of mNPM1 resulting in a rapid decrease in gene expression and activating histone modifications. Therefore, disruption of the menin-MLL axis blocks leukaemias driven by NPM1 mutations for which the expression of menin-MLL target genes (e.g., MEIS1, HOX etc.) is essential. To date at least six different menin-MLL inhibitors are undergoing clinical evaluation as first- and second-line monotherapy in acute leukaemias: DS-1594, BMF-219, JNJ-75276617, DSP-5336, revumenib, and ziftomenib, however, only for revumenib and ziftomenib early clinical data have been reported. In the revumenib phase I/II AUGMENT-101 trial (N = 68) with very heavily pretreated AML patients the ORR was 53% with a CR rate of 20%. The ORR in patients harbouring MLL rearrangement of mNPM1 was 59%. Patients who achieved a response had a mOS of 7 months. Similar results have been reported for ziftomenib in the phase I/II COMET-001 trial. ORR was 40% and CRc was 35% in AML patients with mNPM1. However, outcome was worse in AML patients with a MLL rearrangement (ORR 16.7%, CRc 11%). Differentiation syndrome was a notable adverse event. The clinical development of novel menin-MLL inhibitors is well in line with the currently ongoing paradigm shift towards targeted therapies seen in the AML treatment landscape. Moreover, the clinical assessment of combinations of these inhibitors with established therapy options in AML could be the fuel for an improved outcome of MLL/NPM1 patients.

 

Comments:

The passage discusses the role of the menin-MLL axis in acute myeloid leukemias (AML) with rearrangements of the mixed lineage leukemia gene (MLL) and the potential of menin-MLL inhibitors as targeted therapies for these aggressive hematopoietic malignancies.

AMLs with MLL rearrangements are known to be aggressive and have a poor prognosis. Menin, typically a tumor suppressor, acts as a co-factor in MLL-rearranged leukemias, promoting leukemic transformation through its interaction with the N-terminal part of MLL. Inhibition of menin has been shown to block leukemogenesis, induce differentiation, and lead to apoptosis of leukemic blasts.

Additionally, nucleophosmin 1 (NPM1) plays a role in these leukemias by binding to specific chromatin targets that are co-occupied by MLL. Menin inhibition triggers degradation of NPM1, resulting in decreased gene expression and activating histone modifications. As a result, disrupting the menin-MLL axis can block leukemias driven by NPM1 mutations, where the expression of menin-MLL target genes (e.g., MEIS1, HOX) is essential.

Several menin-MLL inhibitors are currently being evaluated in clinical trials as monotherapy for the treatment of acute leukemias. These inhibitors include DS-1594, BMF-219, JNJ-75276617, DSP-5336, revumenib, and ziftomenib. However, early clinical data have only been reported for revumenib and ziftomenib.

The revumenib phase I/II AUGMENT-101 trial included heavily pretreated AML patients and showed an overall response rate (ORR) of 53%, with a complete response (CR) rate of 20%. In patients with MLL rearrangements or NPM1 mutations, the ORR was 59%. The median overall survival (mOS) for patients who achieved a response was 7 months.

Similar results were reported for ziftomenib in the phase I/II COMET-001 trial. The ORR was 40%, with a complete response with incomplete hematologic recovery (CRc) rate of 35% in AML patients with NPM1 mutations. However, outcomes were worse in AML patients with MLL rearrangements, with an ORR of 16.7% and CRc rate of 11%.

It is worth noting that differentiation syndrome was observed as a notable adverse event in these trials.

The development of menin-MLL inhibitors aligns with the current trend toward targeted therapies in AML treatment. Further clinical evaluation of these inhibitors, including combination approaches with established therapy options, may contribute to improved outcomes for patients with MLL/NPM1 rearrangements in AML.