Targeting menin in relapsed or refractory acute myeloid leukaemia—where the rubber hits the road

Rearrangements of the lysine methyltransferase 2A [KMT2A, formerly known as mixed lineage leukaemia (MLL)], chromosome locus 11q23—initially established as target for leukaemia therapy by Yokoyama et al. are rare alterations and occur in up to 10% of all acute leukaemias (1). Moreover, it is often associated with pleiotropic drug resistance and high rates of relapse (2). The medium progression-free survival (mPFS) has been reported to be 30–40% with a medium overall survival (mOS) of less than 25% (3). Acute myeloid leukaemias (AMLs) harbouring a KMT2A rearrangement are known to have an aggressive outcome and are associated with early relapse, massive hyperleukocytosis, high incidence of involvement of the central nervous system involvement in most cases, and a very dismal prognosis. In addition, in adults KMT2A rearrangements are typically found in patients with prior treatments with topoisomerase-II (TOPO-II) inhibitors (e.g., etoposide, teniposide) (4). KMT2A rearrangements (with more than 80 fusion partners having been identified so far) have been found in 5–10% of adult AML patients and are very common in infant leukaemia (70–80%) (5).

KMT2A acts as a significant epigenetic gene regulator and plays a major role for the haematopoiesis. In addition, KMT2A is the master regulator for key genes such as HOXA and HOXB, MEIS1, PBX3, MEF2C and CDK6 (6) and thereby promotes self-renewal of myeloid progenitor cells. Of note, KMT2A rearrangements have not only been detected in AML patients, but also can be detected in acute lymphoblastic leukaemia (ALL) and in mixed-phenotype acute leukaemia (MPAL) (7).

Menin is a nuclear scaffold protein which is involved in various biological pathways, and interacts with the N-terminal part of KMT2A, and the menin-KMT2A interaction is required for KMT2A-fusion target gene expression, such as HOXA and MEIS1, which are essential drivers of KMT2A-fusion leukaemogenesis (Figure 1) [reviewed by (10)]. Several preclinical and clinical research papers have provided significant evidence that highly specific menin inhibitors can cause downregulation of the KMT2A-fusion targets such as HOX, PBX3, and MEIS1 genes, which then leads to differentiation of leukaemic blasts (6,11).

Figure 1 The menin-MLL interface is critical for the transcription of the HOX gene which is essential for AMLs harbouring a MLL rearrangement. Small-molecule inhibitors of menin (see Table 1) block the MLL-menin binding side which then results in a shut-down of the HOX gene with subsequent differentiation of leukaemic blasts. Upregulation of this complex leads to the development of AML, disruption of this chromatin complex (by binding of menin inhibitors) leads to inhibition of the leukaemogenic transcription programme (differentiation). The dependency of AML blasts on the menin-KMT2A interaction is associated with a NPM1 mutation (most common genetic alteration in adult AML) (8). Modified after (7,9). MLL, mixed lineage gene; AML, acute myeloid leukaemia.

Nucleophosmin 1 (NPM1) is a chaperone protein and its mutated form serves as a shuttle between the nucleus and the cytoplasm (8). NPM1 mutations frequently co-occur with other genetic alterations, mainly Flt-3 internal tandem duplications (Flt3-ITD) (60%) and DNMT3A mutations (50%) (8,11). Moreover, NPM1 mutations in AML are known to be associated with a favourable prognosis, particularly without concurrent high-risk mutations such as FLT3-ITD. Several clinical trials have provided compelling evidence that AML patients harbouring NPM1 mutations have improved complete response (CR) rates and longer mOS compared to those patients without these mutations (11).

Interestingly, in AML cells harbouring NPM1 mutations (found approximately in 30% of AML patients), rearranged KMT2A is the key oncogenic driver of HOX, MEIS1, and Flt-3 (12). Of note, NPM1 has been shown to bind to specific chromatin targets, which are co-occupied by KMT2A, and menin inhibition has been shown to initiate degradation of mNPM1 resulting in a rapid decrease in gene expression and activating histone modifications (8,12,13) which adds weight to the proposal that mutations of NPM1 are essential targets for the menin-KMT2A inhibition in leukaemias. This important observation adds weight to the proposal that blockage of the menin-KMT2A axis inhibits leukaemias driven by NPM1 mutations for which the expression of KMT2A target genes is essential (14). It should be noted that preclinical results also suggest that the KMT2A inhibition by menin inhibitors may be a novel therapy for AML patients harbouring rearrangements of the nucleoporin 98 gene (NUP98) (mainly associated with infant leukaemias) since NUP98-fusion-driven AML cells were found to be sensitive to menin inhibitors in experimental systems (15,16).

These potential clinical findings prompted several pharmaceutical companies to search for inhibitors targeting the NPM1 mutations in AML which quickly led to the development of novel, oral, highly potent, and specific menin inhibitors (Table 1). All currently available small molecule menin inhibitors are innovative targeted agents currently under clinical evaluation for AML patients harbouring KMT2A and NUP98 rearrangements or NPM1 mutations (17,18).

Most recently, Issa et al. (19) have reported the results of the AUGMENT-101 trial for revumenib in r/r AML patients harbouring KMT2A rearrangements or NPM1 mutations (phase I/II trial, NCT04065399). The primary endpoints in this study were the CR/CRh (complete response with partial hematologic recovery) rate and safety. Revumenib was administered at a dose of 163 mg BID until progression or unacceptable toxicities. Patients enrolled were heavily pretreated, with approximately 44% having received three or more treatment lines including stem cell transplants (median 2, range 1–11). Amongst the 94 patients enrolled, grade ≥3 adverse events were found to be febrile neutropenia (37.2%), differentiation syndrome (16%), and QTc prolongation (13.8%). Revumenib was well tolerated and the observed differentiation syndrome was manageable with steroids and hydroxyurea. A total of 57 patients were eligible for the efficacy evaluation, and the CR/CRh rate was reported to be 22.8% with an overall response rate (ORR) of 63.2%. Of note, 15 of 22 patients (68.2%) had no detectable minimal residual disease (MRD). Interestingly, responses were found to occur rapidly (median of 0.95 months). Since the KMT2A rearrangement is a rare subtype, the trial was conducted as a single-arm study. Moreover, a mutation analysis was not performed following progression, therefore, the underlying resistance mechanisms remain unclear.

Although the mNPM1 part of the trial is still ongoing, the authors concluded that treatment with revumenib has a favourable toxicity profile and is highly active in r/r AML patients harbouring KMT2A rearrangements suggesting that revumenib warrants further evaluation in newly diagnosed AML patients.

In the AUGMENT-101 phase I trial, the most common adverse events included QTc prolongation (25.5% any grade, 13.8% ≥ grade 3), vomiting (30.9%), nausea (44.7% any grade) and febrile neutropenia (38.3% any grade, 37.2% ≥ grade 3). Of note, the differentiation syndrome is a treatment-related event that is seen in almost all clinical trials with menin. The underlying mechanisms are supposed to be cytokine alterations associated with haematopoietic differentiation and can include fever, arthralgias, leukocytosis, pleural or pericardial effusions, and respiratory or renal failure in severe cases (7). It has been reported in 16% of patients in the AUGMENT-101 trial and in 21% (all grades) of ziftomenib-treated patients (KOMET-001, N=83) (20), however, it appeared to be clinically manageable in the AUGMENT-101 trial and did not require dose modifications (19). Based on the results form the AUGMENT-101 trial, FDA approved remuvenib (Revuforj^®) for treatment of r/r AML patients harbouring KMP2A rearrnagements on November 15, 2024.

During the last four to five decades the identified underlying molecular alterations seen in AML patients had not demonstrated any significant impact on the first-line induction chemotherapy. The vast majority clinicians still treat AML patients who are eligible for intensive chemotherapy with an anthracycline (e.g., daunorubicin or idarubicin for 3 consecutive days) plus ara-C (continuous infusion over 7 days) (generally known as the “7 + 3” regimen) (8). A significant breakthrough in terms of mOS benefit was recently demonstrated by a new “7 + 3” formulation (CPX-351, Vyxeos liposomal^®) in patients with secondary AML (21). Until now, several mutation-specific targeted agents such as inhibitors of Flt-3, isocitrate dehydrogenase (IDH1,2), bcl-2, and hedgehog have been approved by FDA and European Medicines Agency (EMA) [reviewed by (11)]. However, despite these advances, it still remains a challenge to treat certain subgroups of AML patients.

The current clinical development of menin inhibitors strongly supports the ongoing paradigm shift towards targeted therapies for treatment of AML patients. These drugs appear to be very innovative molecules and represent a new class of attractive inhibitors of AML driver mutations. Although first results with menin inhibitors used as single agents (Table 1) appear to be very promising, they tend to be insufficient for achieving long and robust improvements in clinical outcome. Early data clearly indicated that AML patients who initially responded to menin inhibitors but then relapsed, were found to have new alterations in the menin gene suggesting that current inhibitors such as revumenib may no longer disrupt menin from binding to KMT2A (9,22). It is conceivable, therefore, that the development of both intrinsic and acquired resistance to menin inhibitors may limit their therapeutic activity, and some researches have provided evidence that up to 40% of these resistant patients are associated with menin gene mutations, whereas the menin gene was found to be unaltered in other studies suggesting that non-mutational resistance mechanisms may also be involved (22,23). Moreover, little is known about the development of resistant clones in terms of the rapid acquisition of treatment failures versus the observed sustainable responses seen in some studies (median duration of 9.1 months) (10).

The majority of clinical studies so far has been conducted in the r/r AML setting (Table 1). More than 22,000 r/r AML patients are diagnosed in Europe every year with an estimated median survival of less than three months (Prof. Giovanni Martinelli, Bologna, Italy, personal communication). For those patients who are not eligible for intensive salvage therapy, very few approved and experimental treatment options with low CR rates (approximately 20–30%) are available (Table 2) indicative of a high unmet medical need for this cohort. Reported CR rates from initial phase I/II trials with menin inhibitors suggest a better treatment outcome with these compounds, however, it is too early to draw definitive conclusions and only a subgroup of r/r AML patients may be selected for treatment. In this regard, an innovative non-cardiotoxic anthracycline derivative (L-annamycin) (24,25) has sparked considerable interest as a combination partner for menin inhibitors.

It is still too early to answer the question how to use menin inhibitors and how to incorporate them into a comprehensive therapeutic strategy. In addition, it is far from being clear whether menin inhibitors should be used as part of large combinations treatments or successions of treatments.

Trials combining menin inhibitors with standard induction chemotherapy or venetoclax-based regimens for both newly diagnosed and r/r AML patients are currently open for recruitment, and final results from these studies are eagerly awaited. Since menin inhibitors appear to have a synergistic effect with many other agents (Flt-3 inhibitors, hypomethylating agents, venetoclax, novel cytostatic drugs etc.), it is conceivable that the combination of both classes of drugs may improve outcomes of AML patients harbouring KMT2A or NPM1 alterations, especially in older patients and in those with r/r AML, and thereby pave the way for better AML therapies in the near future.

Acknowledgments

None.

Footnote

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