Revumenib: a new potential targeted therapy for KMT2A-rearranged acute leukemia

Despite major therapeutic advances over the last decades, acute leukemia still represents an aggressive disease with a poor prognosis, especially for patients who are either considered unfit for intensive treatment or with relapsed or refractory disease. Thus relapsed/refractory acute leukemia remains an unsolved therapeutic problem, for which therapies with alternative mechanism of action are needed.

Thanks to a better understanding of mechanisms governing leukemia biology, the recent years have seen the development of many trials investigating targeted drugs, of which some have shown promising results able to change the standard of care in the treatment of patients with high-risk leukemia. In this setting, several mutation-specific targeted agents have been recently approved by the US and/or the European health agencies. These novel agents include Fms-like tyrosine kinase 3 (FLT3) inhibitors (1,2), isocitrate dehydrogenase (IDH) inhibitors (3,4), and venetoclax, a B cell leukemia/lymphoma 2 (BCL-2) inhibitor (5,6).

Menin inhibitors are novel targeted agents in acute leukemias. They target acute leukemias with rearrangement of the lysine methyltransferase 2A (KMT2A) gene (previously known as mixed-lineage leukemia) and those with mutation of the nucleophosmin 1 (NPM1) gene (7). Menin acts as a scaffolding protein/adaptor protein, providing a platform for other proteins to interact and regulate gene expression, particularly in the context of HOX genes. Menin binds to KMT2A, a histone methyltransferase, which is critical for the proper methylation of histone marks associated with HOX gene activation. Regulation of gene expression involves interaction with various transcription factors and chromatin regulators. The binding site is a cofactor for binding to HOX gene promoters. The overexpression of HOX genes and their cofactor MEIS1 participates to leukemic transformation through a blockage of differentiation (8). While NPM1 gene mutations are often considered as having a favorable prognosis, rearrangements of KMT2A, common in infants and children with acute leukemia, are especially associated with poor outcomes after conventional chemotherapy. They occur in up to 10% of acute leukemias (rearrangements of KMT2A occur in 80% of infant acute lymphoblastic leukemia and 5–15% of children and adults with acute myeloid, lymphoblastic or mixed phenotype leukemia) and definitively require the development of alternative therapies (9). Until now no targeted therapies were approved for these unfavorable molecular abnormalities.

In a recent issue of the Journal of Clinical Oncology, Issa and colleagues (10) reported findings from a phase 2 study of 94 patients, with relapsed or refractory KMT2A-rearranged acute leukemia of any lineage, given revumenib, an oral small molecule inhibitor of the menin-KMT2A interaction, administered as monotherapy (163 mg once every 12 hours, with a strong cytochrome P450 inhibitor, in 28-day cycles). Revumenib led to high remission rates with an overall response rate of 63.2% and a complete remission (CR) plus CR with partial hematologic recovery (CRh) rate of 22.8% (24.5% in acute myeloid leukemia and 14.3% in acute lymphoblastic leukemia) that exceeded the null hypothesis of expected remission rates for this patient population, even in heavily pretreated patients. Measurable residual disease (MRD)-negative response was observed in 70% of evaluable patients with CR plus CRh. The median duration of CR plus CRh was 6.4 months and the median overall survival was 8 months. The safety profile was acceptable showing grade ≥3 adverse events in 86% including essentially febrile neutropenia (37.2%), differentiation syndrome (16%), and QTc prolongation (13.8%) that generally resolved with dose adjustment and without treatment discontinuation. Overall, this paper confirmed the importance of the menin inhibitor revumenib in this molecularly defined sub-population of patients with relapsed/refractory acute leukemia.

This study demonstrates that menin inhibitor revumenib as monotherapy can provide clinical benefit in KMT2A-rearranged acute leukemias. Following these encouraging results, some issues should be mentioned.

Results should be interpreted with caution considering the relatively small number of patients included in the study, the short follow-up period, and the lack of control group although as mentioned by the authors this was not feasible due to the low frequency of the rearranged KMT2A leukemia subtype.

Although efficacy was noted with revumenib as monotherapy, a major issue concerns a potential better efficacy in combination with other available treatments. The good tolerance profile of revumenib pleads for the use of such therapeutic strategies, which might also reduce the risk of resistant clonal outgrowth. Furthermore, combinations should lead to deeper responses, and increased uptake of allogeneic stem cell transplantation (SCT), which remains the main therapeutic goal in relapsed/refractory patients. An emerging point was therefore the feasibility of SCT after revumenib therapy. In Issa et al.’ study (10), 38.9% of patients achieving response could proceed to allogeneic SCT, of which half followed post-transplant maintenance therapy with revumenib. In fit patients, studies incorporating revumenib into conventional intensive induction and consolidation chemotherapy backbones are currently ongoing (NCT05886049, NCT05761171). In unfit patients, preliminary data suggest high response rates when combining revumenib with venetoclax and a hypomethylating agent (NCT05360160) (11). Studies are also investigating combinations with other inhibitors, such as FLT3 inhibitors (gilteritinib, midostaurin) (NCT06222580, NCT06313437). All these studies should demonstrate feasibility and increased treatment efficacy. Question then will remain about best to use the combination therapy as part of a large combination or succession of treatments.

A notable treatment-related adverse event observed with revumenib therapy was differentiation syndrome, which is a common side effect observed with low-intensity targeted therapy. Symptoms are similar to those previously observed after other low-intensity treatments such as IDH inhibitors (12). This syndrome is mainly due to various cytokine alterations. Detection of differentiation syndrome justifies a successful reversal of the differentiation block. In Issa et al.’ study, differentiation syndrome was successfully managed with corticosteroids and hydroxyurea in case of leukocytosis. There were no treatment discontinuations (10).

In addition to revumenib, several other menin inhibitors are currently under investigation as monotherapy in a relapsed/refractory setting: KO-539 (ziftomenib) (NCT04067336), JNJ-75276617 (NCT04811560), DSP-5336 (NCT04988555), BMF-219 (NCT05153330), BN104 (NCT06052813) (13). Some of those agents are also currently tested in combination with other targeted agents or low-intensity therapy in unfit patients, or with intensive chemotherapy in patients considered fit: JNJ-75276617 with venetoclax and azacitidine (NCT05453903), ziftomenib with venetoclax, azacitidine, intensive chemotherapy, low-dose cytarabine, or gilteritinib (NCT05735184), DS-1594b with venetoclax and azacitidine (NCT04752163). All menin inhibitors should demonstrate efficacy in acute leukemias sharing the same dependency on the menin-KMT2A interaction. This includes leukemias displaying the NPM1 mutation and other less common subtypes (14,15). They could therefore have a larger application since acute myeloid leukemia with NPM1 mutations are seen in up to 40% of cases. Furthermore, preliminary results with revumenib are very encouraging in this setting (21% CR/CRh) and final findings should confirm those observed in KMT2A-rearranged leukemia (8).

Finally, as for all new agents, a major question is to understand whether revumenib has an effect on leukemia stem cells (LSCs). LSCs play a key role in the development and maintenance of acute leukemia (16). Quiescent leukemia-initiating cells escape to cytotoxic cancer agents which target rapidly proliferating cells, contributing then to treatment failure. Strategies for targeting LSCs hold then the promise to identify a more effective therapeutic approach to cure acute leukemia. Genes involved in self-renewal might represent rational targets for therapeutic intervention. Accumulating evidence suggests that KMT2A-rearranged leukemias originate from an uncommitted precursor (17). Stem cell-like blasts have been demonstrated in KMT2A-rearranged leukemias (18) and stem cell factor have been involved in KMT2A-rearranged leukemogenesis (19). A common theme in the various forms of KMT2A rearrangements is that KMT2A fusion proteins aberrantly upregulate the expression of HOX genes. Those ones play an essential role in the regulation of hematopoiesis and are highly expressed in hematopoietic stem cells and early progenitors (20). Their overexpression was shown to be sufficient for the initiation of leukemic transformation (21). Furthermore, up to 15% of patients with mixed phenotype acute leukemia (MPAL), which are position in the spectrum of immature leukemias, have rearrangements of KMT2A (22). In Issa et al.’s study (10), decreased expressions of MEIS1, HOXA9, PBX3, and FLT3 were noted. These findings are consistent with a potential action on LSCs. However, this decreased gene expression pattern was observed in both responders and non-responders to revumenib therapy and warrants confirmation in larger studies.

Much improvement is still needed in the treatment of high-risk patients with acute leukemia. Many drugs have become available that have the potential to change the standard of care for patients with acute leukemia. Because of their specific mechanism of action and their acceptable tolerance, menin inhibitors might be one of those effective new therapeutic strategies. They should rapidly be approved by health authorities for the treatment of leukemias with KMT2A-rearrangement or NPM1 mutation. Further inclusion into schedules combining several therapeutic agents might hold the promise of substantial benefit.

Acknowledgments

None.

Footnote

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