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.

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.

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 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 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.

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].

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.

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.

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].

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.

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).

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.