FormalPara Key Summary Points

Menin inhibitors are novel targeted agents currently in clinical development mainly for the treatment of subsets of acute leukemia driven by rearrangement of the lysine methyltransferase 2A (KMT2Ar) gene or by mutation of the nucleophosmin 1 (NPM1mt) gene.

The first clinical trials with the menin inhibitors SNDX-5613 (revumenib) and KO-539 (ziftomenib) demonstrated encouraging efficacy with approximately 30% response rates in patients with NPM1mt, and 27% with revumenib and 5.6% with ziftomenib in KMT2Ar-driven leukemias.

The safety profile of menin inhibitors appears easily manageable.

Menin inhibitors have the potential to reach a larger subset of acute leukemia with similar dependency on the menin–KMT2A interaction, which could be identified using precision approaches testing characteristic gene expression.

Introduction

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by uncontrolled clonal expansion of hematopoietic progenitor cells. It is a highly complex disorder involving cytogenetic and epigenetic changes [1]. There has been substantial progress in our knowledge of AML, especially the biology of the disease. Clinical options are currently changing with the identification of new molecular markers and new therapeutic agents. The US Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA) recently approved several mutation-specific targeted agents, including Fms-like tyrosine kinase 3 (FLT3) inhibitors [2, 3] and isocitrate dehydrogenase (IDH) inhibitors [4, 5], as well as venetoclax, a B cell leukemia/lymphoma 2 (BCL-2) inhibitor [6, 7], and glasdegib, an inhibitor of the hedgehog (Hh)/glioma-associated oncogene homolog signaling pathway [8]. Despite these advances, many subsets of acute leukemia remain challenging to treat.

Menin inhibitors are novel targeted agents currently in clinical development mainly for the treatment of subsets of acute leukemia driven by rearrangement of the lysine methyltransferase 2A (KMT2A) gene, previously known as mixed-lineage leukemia (MLL), or by mutation of the nucleophosmin 1 (NPM1) gene [9]. Approximately 10–30% of patients with AML harbor at least one of these germline predispositions. Menin inhibitors exert a therapeutic effect by preventing the binding of the menin protein and KMT2A complex, thus switching off the pathway and promoting the differentiation of leukemic immature cells.

This review describes the biological properties of small molecule menin inhibitors and summarizes the current available data regarding their ongoing clinical development in the treatment of AML.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by the author.

Discovery of Menin–KMT2A Interaction Small Molecule Inhibitors

Historically, menin was identified as an essential oncogenic factor of leukemogenesis driven by KMT2A rearrangement (KMT2Ar), after discovery of germline mutations in the gene responsible for the multiple endocrine neoplasia type 1 syndrome (MEN1) [10,11,12,13]. From 2012, the first small molecule menin inhibitors were developed and preclinical activities were demonstrated in KMT2Ar leukemia [13, 14] and consecutively in NPM1 mutated (NPM1mt) AML [15, 16]. The structure and biological mechanisms of these menin inhibitors have been recently reviewed [17]. The hydroxymethyl and aminomethyl piperidine compounds represent the first generation of the small molecule inhibitors of menin–MLL1 interactions. A series of hydroxymethyl and aminomethyl piperidine compounds were tested against various malignancies [18], including M-525 [19], M-808 [20], M-89 [21, 22], and M-1121 [23] targeting HOXA9 and MEIS1. Although these compounds displayed strong inhibitory activity, their poor metabolic stability limits the in vivo pharmacodynamic research. A new type of small molecule inhibitor, corresponding to thiophenpyrimidine inhibitors, with good oral bioavailability and strong target binding activity, was then identified and called the second generation of menin inhibitors [19, 24]; these include compounds such as MI-2, MI-3, MI-136, MI-538, MI-463, MI-503, and MI-1481, which target HOXA9 and MEIS1, VTP-50469 targeting MEIS1 and FLT3, BAY-155 targeting MEIS1, KO-539 targeting MEIS1, FLT3, and PBX3, and MI-3454 targeting HOXA9, MEIS1, and FLT3. These menin inhibitors display good biological activity with no hematopoietic function damage, and no obvious tissue and organ toxicity in mice [23, 24]. Macrocyclic peptide-like inhibitors were obtained via other methods and were inhibitors directly based on the menin–KMT2A interaction, with reduced molecular weight of the inhibitor [25]. They included MCP-1, which targets HOXA9 and MEIS1 [26]. Subsequent optimizations led to the development of menin–KMT2A inhibitors by pharmaceutical companies, such as SNDX-5613, KO-539, DSP-5336, DS-1594, BN104, BMF-219, and JNJ-75276617, which were introduced in the first clinical trials in acute leukemias from 2020 [9].

Mechanism of Action

KMT2Ar occurs in 5–10% of acute leukemias and is particularly common in infant leukemia (70–80%) [9]. More than 80 fusion partners of KMT2A have been identified [27]. Fusion partners influence the leukemia phenotype: t(9;11) (p21;q23), known as KMT2A-MLLT3 or AF9, is most common in AML, while t(4;11) (q21;q23), known as KMT2A-MLLT2 or AF4, is most common in acute lymphoblastic leukemia (ALL) [28]. KMT2Ar is associated with a poor prognosis due to increased resistance to chemotherapy and higher rates of relapse [29]. KMT2Ar leukemias are characterized by the aberrant overexpression of HOX genes along with their cofactor MEIS1 [30]. NPM1mt AML is detected in 20–30% of cases at diagnosis. This AML subset has a gene expression profile similar to KMT2Ar leukemias with upregulation of HOX genes (specifically HOXA and MEIS1). KMT2Ar and NPM1mt cause blood cells to regress or dedifferentiate and behave like the stem cells they arose from. This results in the formation of a hematopoietic differentiation block and leukemic transformation [31]. The cellular programs hijacked by these gene changes require menin, which binds to the protein produced by KMT2A. The complex formed by these proteins in turn binds to chromatin and turns on the aberrant communication pathways triggered by the altered KMT2A or NPM1 (Fig. 1).

Fig. 1
figure 1

Schematized mechanism of action of small molecule menin inhibitors in KMT2Ar AML and NPM1mt AML. Menin regulates gene expression through interaction with various transcription factors and chromatin regulators, and binds to KMT2A. The binding site is preserved throughout all KMT2A fusion proteins and is an essential cofactor for binding to HOX gene promotors. KMT2Ar leukemias are characterized by the aberrant overexpression of HOX genes along with their cofactor MEIS1. NPM1, which turns exclusively cytoplasmic when mutated (NPM1c), has a gene expression profile similar to KMT2Ar leukemias with upregulation of HOX genes. This causes a hematopoietic differentiation block and leukemic transformation. Revumenib and ziftomenib are menin inhibitors disrupting the same menin–KMT2A interaction. Disruption of this chromatin complex leads to inhibition of the aberrant leukemogenic transcription program and apoptosis, without affecting normal hematopoiesis. Sec super elongation complex, DOTL1 DOT1-like histone lysine methyltransferase, LEDGF lens epithelium-derived growth factor

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Menin was first described after discovery of germline mutations in the MEN1 gene [32]. The gene containing 10 exons is located on chromosome 11q13 and has demonstrated a tumor suppressor function in endocrine glands. Menin is primarily a nuclear protein, which regulates gene expression through interaction with various transcription factors and chromatin regulators [33, 34]. Menin binds to KMT2A which, along with partner proteins forming the KMT2A complex, regulates gene expression through epigenetic modulation of transcription. The binding site is preserved throughout all KMT2A fusion proteins and is an essential cofactor for binding to HOX gene promotors. In animal models, genetic ablation of menin reversed aberrant HOX gene expression, leading to abrogation of the differentiation arrest and the oncogenic properties of KMT2Ar. Menin appears therefore as an essential oncogenic cofactor for leukemogenesis driven by KMT2Ar [35]. An extensive overview has been recently published regarding normal and pathologic functions of menin, and its role in driving leukemia [9].

The discovery that the cofactor menin is necessary for KMT2A to bind HOX gene promoters has led to the development of potent small molecule inhibitors of the menin–KMT2A interaction [10, 36]. Disruption of this chromatin complex leads to inhibition of the aberrant leukemogenic transcription program and apoptosis, without affecting normal hematopoiesis (Fig. 1). In NPM1mt AML, the interaction between KMT2A and menin leads to HOX- and MEIS1-mediated leukemogenic transcription. NPM1mt AMLs have an overexpression of HOXA9 and its cofactor MEIS1, leading to leukemogenesis via CCAAT enhancer-binding protein alpha (CEBPα) and KMT2A. KMT2A acts as a transcriptional regulator that binds to menin and then regulates HOXA9. Therefore, targeting the menin–KMT2A interaction could be also a therapeutic strategy in NPM1mt leukemia [9, 16, 37]. Menin inhibitors work differently from other targeted therapies. Instead of blocking the activity of dysfunctional proteins, they stop the genes affected by the altered KMT2A or NPM1 from being expressed in the first place. When the menin–KMT2A complex cannot bind to chromatin, the cells that had acted like haywire stem cells either turn back into normal cells or die. Preclinical studies in mouse models showed that menin inhibitors reverse aberrant gene expression mediated by HOX genes and their cofactor MEIS1 leading to leukemia regression in KMT2Ar or NPM1mt leukemias [15, 16, 30, 36]. However, other leukemias overexpressing HOX genes may also respond to menin inhibitors [38].

The dependency on menin in AML is linked to overexpression of HOXA and/or HOXB genes and their cofactor MEIS1. This expression signature is also shared by other leukemia genotypes or recurrent cytogenetic abnormalities than NPM1mt and KMT2Ar leukemias. Preclinical results suggest that menin–KMT2A inhibition may represent a targeted therapy for patients with leukemia and rearrangement of the nucleoporin 98 gene (NUP98), a common and adverse genotype among children. NUP98-fusion-driven leukemia was shown to be sensitive to the menin–KMT2A inhibitor VTP50469 [38]. AML subsets with translocations involving the MN1 gene that result in high expression of MN1 are also aggressive AML. They are characterized by an aberrant myeloid precursor-like gene expression program that shares features of KMT2Ar leukemia, including high levels of HOXA and MEIS1 gene expression [39]. While the mechanism of response remains unclear, a complete response has been reported in a patient with mutations in RUNX1 and SETD2 genes after treatment with the menin inhibitor KO-529 [40]. This suggests that the activity of another critical transcription factor could result from targeting menin disruption [9].

Clinical Investigations

Given the strong preclinical rationale, seven orally administered menin inhibitors are currently in the clinical stage for AML treatment: SNDX-5613 (revumenib), KO-539 (ziftomenib), DSP-5336, DS-1594, BN104, BMF-219, and JNJ-75276617. These agents have been mostly tested towards relapsed/refractory (R/R) acute leukemias as monotherapy. However, combination trials with drugs in the standard of care treatments are underway. The main ongoing and planned studies are summarized in Table 1.

Table 1 Main ongoing and planned clinical trials involving small molecule menin inhibitors in the treatment of AML
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Monotherapies

SNDX-5613 (Revumenib)

Revumenib phase 1/2 pivotal trial (AUGMENT-101 trial) is running in R/R AML with NPM1mt or KMT2Ar (NCT04065399). In this multicenter phase 1/2 dose-escalation and expansion study, revumenib was administered orally either in capsule or liquid formulation every 12 h in 28-day continuous cycles. The primary objective of the phase 1 was to identify the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D). The objective of the phase 2 was to assess the safety and efficacy of SNDX-5613 in three cohorts: KMT2Ar ALL or mixed-phenotype acute leukemia (MPAL), KMT2Ar AML, and NPM1mt AML. Sixty adults and eight children with leukemia joined the phase 1 trial. There were 56 patients (82%) with R/R AML, 11 (16%) with ALL, and one with MPAL (2%). The median age was 42.5 years. Patients had received a median of four prior treatments, and almost half had already undergone stem cell transplantation (SCT). The only dose-limiting toxicity (DLT) observed was grade 3 asymptomatic prolongation of the QT interval. Overall, 18 of the 60 patients who had a KMT2Ar or NPM1mt experienced a complete remission (CR) with a full or partial recovery (CRp), which lasted for a median of 9 months. Fourteen of those patients (78%) achieved measurable residual disease (MRD) negativity, as assessed by multiparameter flow cytometry. The overall response rate (ORR) [including CR/CRp/complete remission with incomplete hematologic recovery (CRh)/complete remission with incomplete count recovery (CRi)] was 53%. The ORR was 59% and 36% in patients with R/R KMT2Ar and NPM1mt, respectively. The median time to CR/CRh was 1.9 months (0.9–4.9 months). Twelve of the participants received SCT after going into remission. With a median follow-up of 11.9 months after achieving CR/CRh, the median duration of response was 9.1 months [41,42,43]. In the AUGMENT-101 trial, patients who achieved a CR, morphological leukemia-free state (MLFS), or partial remission (PR) could undergo hematopoietic SCT without leaving the study. Revumenib was stopped before the SCT conditioning regimen but could be resumed after transplant if the patient achieved CR. To date, nine patients with AML resumed revumenib, eight after SCT and one after a stem cell boost. Revumenib was resumed 59–180 days after SCT. Dose was reduced in four patients to mitigate adverse events, and revumenib was discontinued in four patients because of progressive disease or cytopenias. At the time of analysis, revumenib duration of treatment in the maintenance setting ranged from 23 to 588 days, with treatment ongoing for five of the nine patients. CR was maintained in six patients after SCT and maintenance revumenib. One patient converted to MRD-negative status following initiation of revumenib maintenance therapy. Overall, MRD-negative remissions were maintained in five patients [44].

A phase 1 open-label study (NCT05406817) is currently recruiting to evaluate the absorption, metabolism, and excretion (AME) of orally administered carbon-14 ([14C])-SNDX-5613 in participants with R/R acute leukemia.

KO-539 (Ziftomenib)

Ziftomenib phase 1/2 registration trial (KOMET-001) is running in R/R AML with NPM1mt AML (NCT04067336). This phase 1/2 multicenter first-in-human study comprises a phase 1a dose-escalation study included any patients with R/R AML, while the phase 1b dose-validation/expansion study included patients with KMT2Aror NPM1mt. The phase 2 assessed tolerability and efficacy in patients with KMT2Ar and NPM1mt. As of the data cutoff in April 2023, 35% of the patients with NPM1mt AML treated at the RP2D of 600 mg achieved CR [40].

DSP-5336

DSP-5336 is an investigational, orally administered small molecule designed to inhibit the menin and MLL protein interaction. A phase 1/2 study of DSP-5336 is being conducted in patients with R/R acute leukemia (NCT04988555) [45]. The dose escalation phase consists of two parallel arms (arm A, without concomitant antifungal azole therapy; and arm B, with concomitant azole therapy). Patients were eligible with R/R AML, ALL, or acute leukemia of ambiguous lineage without a limit on number of prior therapies, with a focus on those with KMT2Ar and NPM1mt. Accrual is ongoing with 24 patients enrolled as of April 2023: 14 patients in arm A and 10 patients in arm B. Patients had received a median of 3 (1–9) prior treatments, and six had received prior allogeneic SCT. No DLTs have been observed. Most adverse events were grade 1/2. One possible grade 4 differentiation syndrome was observed. Out of the six patients enrolled with NMT2Ar, one achieved CRi with a duration of therapy of 5.1 months, one achieved MLFS with a duration of therapy of 6.2 months or more, and one remained stable with clearance of peripheral blasts, recovery of peripheral counts, resolution of leukemic gingival infiltration, and reduction in bone marrow blasts from 85% to 31%. Of the four enrolled patients with NPM1mt, two remained stable with complete clearance of peripheral blasts and bone marrow blasts reduced by 66% and 83%, respectively. Data to date suggests that azoles may not have a significant effect on DSP-5336 exposure.

JNJ-75276617

JNJ-75276617 is an orally bioavailable, potent, and selective protein–protein interaction inhibitor of the binding between KMT2A and menin, with activity in leukemic cell lines and samples derived from patients with primary leukemia or those with either KMT2Ar or NPM1mt. The primary goal of this first-in-human ongoing study (NCT04811560) is to establish the RP2D of JNJ-75276617 with an acceptable safety profile [46]. To date, 58 patients received JNJ-75276617: 56 (97%) had R/R AML and 2 (3%) had R/R ALL. The median number of prior lines of treatment was 2 (1–7), including 10 patients with a prior allogeneic SCT. KMT2Ar or NPM1mt was present in 33 (57%) and 25 (43%) patients, respectively. Grade 3 or higher adverse events were observed in 17 (29%) patients including neutropenia (10%), anemia and thrombocytopenia (7% each), differentiation syndrome (5%), and liver transaminase increase (3%). DLTs were observed in 5 (9%) patients, with differentiation syndrome in 2 (3%) patients. In 26 of the 41 patients (63%) with disease evaluation data, there was a reduction in bone marrow disease burden. A more than 50% decrease in bone marrow blasts was observed in 16 patients (39%). Across all cohorts there were 12 responders, including one MRD negative CR. One responder discontinued treatment for allogeneic SCT, while eight responders continue on treatment. Preliminary pharmacodynamic data among responders show biologic activity as indicated by reduction in expression of menin–KMT2A target genes (MEIS1, HOXA9, FLT3) and induction of genes associated with differentiation (ITGAM, MNDA). Compared to baseline, the percentage of KMT2A-altered cells or NPM1 variant allele frequency (VAF) was reduced in responders.

BMF-219

A phase 1 (COVALENT-101) first-in-human dose-escalation and dose-expansion study (NCT05153330) of BMF-219, an oral covalent menin inhibitor, is currently ongoing in adult patients with AML, ALL with KMT2Ar or NPM1mt, diffuse large B cell lymphoma (DLBCL), multiple myeloma (MM), and chronic lymphocytic lymphoma (CLL)/small lymphocytic lymphoma (SLL) [47]. In July 2023, 26 patients with R/R acute leukemia (24 AML and 2 ALL) were enrolled, 17 male and 9 female with a median age of 57.5 years. There was a median of 4 prior lines of therapy (1–8) and 11 patients had a prior history of SCT. Patients received BMF-219 daily for continuous 28-day cycles until progression/intolerability. BMF-219 has generally been well tolerated with no DLTs observed and no discontinuations due to treatment-related toxicities. Common side effects included vomiting (13%) and differentiation syndrome (13%). The first results demonstrated early signs of clinical activity in the different genomic subgroups [48].

BN104

This phase 1/2 trial (NCT06052813) is to learn the safety, pharmacokinetics, and preliminary efficacy of BN104 taken orally once daily or twice daily in patients with ALL or AML. The study is divided into two phases. The phase 1 dose-escalation study aims to evaluate safety and tolerance of BN104 in patients with R/R acute leukemia to determine the MTD and the RP2D, including patients with KMT2Ar or NPM1mt enrolled at dose optimization phase. The phase 2 expansion study will be conducted at the selected dose level to further evaluate the safety and tolerability of BN104, as well as preliminary efficacy in KMT2Ar or NPM1mt acute leukemia. Study drug will be administered in 28-day cycles until disease progression or unacceptable toxicity.

Combination Therapies

Beyond addressing an unmet medical need, this novel class of small molecule menin inhibitors has further potential in taking up more prominent roles in the AML treatment paradigm through building synergies with current standard of care treatments. Preclinical studies demonstrate that co-treatment with menin inhibitors and BCL-2 inhibitors (such as venetoclax), CDK6 inhibitors (such as abemaciclib), or CDK9 inhibitors (such as enitociclib) induces synergistic lethality in AML cells harboring DMT2Ar or NPM1mt [49, 50]. Treatment with ziftomenib plus venetoclax/azacitidine has induced prolonged durable remissions in mice with KMT2Ar AML xenografts [51]. The combination of RAS/MAPK targeting using the MEK1/2 inhibitor selumetinib was evaluated with VTP-50469, a close analogue of revumenib, in leukemia cell lines harboring both KMT2Ar and RAS mutations and cells from a xenograft model derived from samples from a patient with AML [52]. This combination resulted in a synergistic decrease in viability, a G0/G1 cell cycle arrest, and an increase in apoptosis. Similarly ziftomenib, in combination with selinexor, synergistically inhibited the growth of KMT2Ar AML cell lines [53]. Several menin inhibitors (DS-1594, KO-539, SNDX-5613, and JNJ-75276617) are currently being evaluated in patients as a combination therapy with standard of care treatments to allow their further inclusion into earlier lines of therapy.

KO-539 (Ziftomenib)

Given the monotherapy activity seen to date, the development of ziftomenib in combination with standard-of-care chemotherapies or FLT3 inhibitors may provide increased clinical benefit for patients with R/R AML and KMT2Ar or PM1mt with or without concurrent FLT3 mutations (FLT3mt).

The KOMET-007 trial (NCT05735184) is expected to evaluate the safety and efficacy of ziftomenib in combination with venetoclaxplus azacitidine or the 7 + 3 chemotherapy regimen for patients with newly diagnosed or R/R NPM1mt and KMT2Ar menin-dependent AML. The objectives were to establish the minimum biologically effective DLT and RP2D, and to establish preliminary anti-leukemic efficacy [51].

KOMET-008 (NCT05735184) is an open-label, dose escalation, and expansion study to determine the safety, tolerability, and preliminary efficacy of ziftomenib when combined with standard-of-care regimens (FLAG-idarubicin, low-dose cytarabine, gilteritinib for NPM1mt and FLT3mt) for the treatment of either NPM1mt (arm A) or KMT2Ar (arm B) R/R AML [54].

SNDX-5613 (Revumenib)

The AUGMENT-102 trial (NCT05326516), combining revumenib with fludarabine and cytarabine chemotherapy, is currently recruiting.

The SAVE study (NCT053601600) is a phase 1/2 trial designed for KMT2Ar, NPM1mt, and NUP98r leukemias. The aim of phase 1b of this clinical research study is to find the highest tolerable dose of SNDX-5613 that can be given in combination with ASTX727 (a combination of the drugs decitabine/cedazuridine) and venetoclax for patients with AML or MPAL, and to determine the safety, tolerability, and RP2D of SNDX-5613 in this setting. The phase 2 trial aims to learn if the dose of study drugs found in phase 1b can help to control AML/MPAL [55]. Dose escalation followed a 3 + 3 design. ASTX727 was administered at 35 mg/100 mg on days 1–5, venetoclax at 400 mg on days 1–14, and revumenib 113 mg/12 h (dose level [DL] 0) or 163 mg/12 h (DL1, used in phase 2 monotherapy) on days 1–28. Preliminary data regarding the first eight enrolled patients (eight at DL0 and two at DL1) showed a morphological response in all seven evaluable patients: one CR, three CRh, three CRp, one PR, and one MLFS. MRD was undetectable by flow cytometry (sensitivity at 10−4) in three of seven patients (43%). Three patients underwent SCT following response, two are in continued remission, one has started maintenance, and one died of SCT complications prior to starting maintenance. Grade 3 or higher treatment-related adverse events were febrile neutropenia (63%), decreased platelets count (25%), and decreased neutrophil count (25%). There was one DLT (grade 4 thrombocytopenia and neutropenia) at DL0. Two patients developed a grade 2 differentiation syndrome, which resolved with steroids [55].

A phase 1b trial (NCT05886049) has been designed to test the safety, side effects, and best dose of SNDX-5613 when given in combination with a standard intensive 7 + 3 chemotherapy in newly diagnosed AML with NPM1mt or KMT2Ar. Adding SNDX-5613 to the standard chemotherapy may be able to shrink or stabilize leukemia for longer than the standard chemotherapy alone. Patients will receive revumenib orally every 12 h on days 2–28, daunorubicin on days 1–3, and cytarabine by continuous infusion on days 1–7 as induction therapy. Patients with persistent disease will continue to re-induction treatment with revumenib on days 2–28, daunorubicin on days 1–2, and cytarabine on days 1–5. Patients who achieve a response to induction or re-induction treatment will continue to consolidation with revumenib on days 2–28 and cytarabine on days 1–3 in the absence of disease progression or unacceptable toxicity.

A phase 2 trial (NCT05761171) has been designed to test the safety and best dose of revumenib when given together with chemotherapy in infants and young children with R/R leukemia with KMT2Ar. Drugs used in chemotherapy are vincristine, prednisone, asparaginase, fludarabine, and cytarabine. This trial is being done to find out if the combination of revumenib and chemotherapy may help to treat the cancer cells better than either treatment alone.

DS-1594b

The effectiveness of the menin inhibitor DS-1594b in combination with the BCL-2 antagonist venetoclax (ABT-199) was evaluated in a patient-derived xenograft model of NPM1mt acute leukemia [56]. The combination exhibited promising anti-leukemic activity and held potential as a therapeutic strategy for patients with AML and NPM1mt. DS-1594b is currently combined with venetoclax and azacitidine or mini-Hyper-CVD (cyclophosphamide, vincristine, dexamethasone) in an open-label phase 1/2 trial in R/R AML ad ALL (NCT04752163).

JNJ-75276617

A phase 1b study (NCT05453903) has been designed to determine the RP2D of JNJ-75276617 in combination with AML directed therapies. The aim of this study is to determine the RP2D, safety, pharmacokinetic, pharmacodynamic, and preliminary clinical activity of JNJ-75276617 in combination with standard of care treatments for adult participants with R/R or newly diagnosed AML with NPM1mt or KMT2Ar and will include dose selection and subsequent combination specific dose expansion.

Main Adverse Events

In the AUGMENT-101 phase 1 trial, the most common adverse events included QT prolongation (56% any grade), nausea (50%), vomiting (40%), and febrile neutropenia (31%). Therapy with revumenib was associated with a low frequency of grade 3 or higher treatment adverse events [42]. The most frequent treatment-emergent adverse events of grade 3 or higher were febrile neutropenia (31%), thrombocytopenia (19%), and sepsis (18%). Asymptomatic prolongation of the QT interval was identified as the only DLT.

Differentiation syndrome is a notable treatment-related adverse event shared by menin inhibitors in their phase 1 trials. It is caused by cytokine alterations associated with hematopoietic differentiation and can include fever, arthralgias, leukocytosis, pleural or pericardial effusions, and respiratory or renal failure in severe cases, as differentiation syndrome previously observed after IDH inhibitors, arsenic trioxide, or all-trans retinoic acid administration [57, 58]. Detection of differentiation syndrome justifies the evidence of a successful reversal of the differentiation block caused by KMT2Ar through menin inhibition. It occurred in 16% of revumenib recipients and in 57.5% of ziftomenib recipients with 30% of grade 3 or higher [40, 42]. In the phase 1 with revumenib, all cases with differentiation syndrome resolved following treatment with steroids, and the addition of hydroxyurea in case of leukocytosis. Differentiation syndrome arose at a median time of 18 days (5–41 days).

Discussion

The treatment of AML is undergoing rapid changes. Identification of mutations in genes coding for epigenetic regulators, kinases, cell cycle regulators, and transcription factors has recently received particular interest both in terms of prognosis and therapeutic approaches with the development of specific targeted therapy. Many drugs have become available with the potential to change the standard of care for patients with AML. Whenever available, targeted drugs can be used as a single agent or added to treatment strategies involving other targeted agents, low-intensity therapy, or intensive chemotherapy. In this setting, small molecule menin inhibitors represent a promising group of novel agents, currently in clinical development. To date, these agents appear to be most effective for KMT2Ar and NPM1mt acute leukemias, although it is possible that a subset of leukemias with other genetic markers may respond as well. Biomarkers such as HOX or MEIS1 expression would predict response or could be used to identify and target a larger population of patients who may benefit from menin inhibitors. At the RP2D level following phase 1 clinical trials, SNDX-5613 (revumenib) and KO-539 (ziftomenib) demonstrated encouraging efficacy with approximately 30% response rates (CR/CRh) in patients with NPM1mt. KMT2Ar-driven leukemias, known for their poor prognosis and a huge clinical need, showed a response rate of 27% with revumenib, but only a response rate of 5.6% with ziftomenib. In both cases, the safety profile was easily manageable.

Major questions remain on how to use menin inhibitors and how to incorporate them in a global therapeutic strategy. Should they be used as single agents or in combination therapies, or as part of large combinations or successions of treatments? During the phase 1/2 treatment with revumenib, less activity of genes that drive leukemia and more activity of genes associated with healthy blood cell differentiation were demonstrated. Although very promising, first results with menin inhibitors used as single agents tend to be insufficient for achieving serious outcome improvements. Some patients, for whom AML initially responded to menin but then started rising again, displayed new changes in the MEN1 gene, which encodes menin. These changes meant that revumenib could no longer disrupt menin from binding to KMT2A.

The development of both innate and acquired resistance to menin inhibitors could limit their therapeutic potential. While studies have found that approximately 40% of these resistant cases can be traced back to mutations in the menin gene, the menin gene remains unaltered in other majorities, suggesting the presence of other mechanisms driving resistance. PRC1.1 was identified as a key epigenetic driver of menin-MLL resistance through a KMT2A target gene-independent mechanism which involves aberrant activation of MYC. AML cells with loss of PRC1.1 are hypersensitive to the BCL-2 inhibitor venetoclax, which can be used to overcome the resistance to menin–MLL inhibition [59].

The good tolerance profile in the first phase 1/2 trials makes menin inhibitors serious candidates for combination therapy. The incorporation into conventional chemotherapy backbones, potentially including other novel agents, or low-intensity treatments should produce opportunities to assess the feasibility of such combinations in terms of tolerability and treatment efficacy. Combinations of several drugs might reduce the risk of resistant clonal outgrowth. However, it is currently not known whether the use of sequential administration is or not more adapted than a concurrent administration in order to avoid potential toxicities. Trials combining menin inhibitors with standard induction chemotherapy or venetoclax-based regimens for both newly diagnosed and relapsed/refractory AML are being developed, and final results from these studies are eagerly awaited.

Activation of a KMT2A-like signature through upregulation of HOXA9 and MEIS1 has been demonstrated at relapse after venetoclax-based therapies [60]. Menin inhibitors could therefore become a promising therapy in this setting. It will also be important to study menin inhibitors in patients with relapsed AML with NPM1 and FLT3-ITD co-mutations, as responses to FLT3 inhibitors alone are often not durable. The combination of menin inhibitors with low-intensity therapies should certainly improve the outcomes in patients with AML considered unfit for intensive treatment. As shown with other novel targeted agents, low-intensity combinations may be also used on their own in younger patients and also served as bridge to transplant.

Another unanswered question is whether or not menin inhibitors have an effect on leukemia stem cells (LSCs). When quiescent, leukemia-initiating cells do not respond to cell cycle-specific cytotoxic agents, and contribute to treatment failure. An important feature for new therapeutic strategies might therefore focus on exploiting targets governing stem cell renewal and differentiation. Characteristics that are relevant to therapy may differ depending on the origin of the malignant cell. The identification of menin inhibitor efficacy on driver genes that regulate self-renewal might provide a main issue for therapeutic intervention, particularly if these gene requirements are more critical for self-renewal in LSCs than hematopoietic stem cells.

KMT2Ar results in a genetically unique subtype of AML characterized by chromosomal translocations involving the KMT2A gene and over 80 fusion partners, including AF9 as one of the most common partners. The oncogenic KMT2A fusion proteins interact with multiple transcription and chromatin regulators, such as menin, to induce leukemogenic stem cell gene programs and transform hematopoietic stem and progenitor cells. The enhanced purine metabolism emerges as a crucial dependency for LSCs, providing potential targets for novel therapeutic strategies in treating KMT2Ar leukemia [61].

Conclusion

Early therapeutic data regarding new therapeutic approaches with menin inhibitors in AML have shown highly encouraging results. In contrast to previous proposed targeted therapies that concerned a small fraction of patients with AML, menin inhibitors by their efficacy in NPM1mt leukemias can lead to wider application in therapeutic strategies. Furthermore their manageable toxicity suggests the use of combinations with low-intensity treatment or standard intensive chemotherapy, which could improve potency and optimize promising new treatment strategies.