MENIN inhibitor-based therapy in acute leukemia: latest updates from the 2024 ASH annual meeting

Abstract

Menin inhibitors (MENINis) represent a novel and promising class of therapeutic agents for acute leukemia (AL). AL subtypes driven by overexpressed HOXA9/MEIS1, such as those characterized by KMT2A-rearranged (KMT2Ar) or NPM1-mutated (NPM1m) AL, display sensitivity to MENINi. Consequently, approximately 40–50% of acute myeloid leukemia (AML) and 5–15% of acute lymphoblastic leukemia (ALL) patients may potentially benefit from MENINi-based therapy. At the 2024 ASH annual meeting, updated clinical data regarding monotherapy with MENINis in AL, including revumenib, bleximenib, enzomenib and BN104, were presented. Moreover, combination therapies based on MENINis were also reported to be highly effective in refractory/relapsed, or newly diagnosed KMT2Ar- and NPM1m-AML patients. Evidently, MENINis have demonstrated a considerable efficacy in KMT2Ar- and NPM1m-AML patients with a well-tolerance. Furthermore, the therapeutic effects of venetoclax plus azacitidine or "3 + 7" regimens were further enhanced by the addition of MENINis in KMT2Ar- and NPM1m-AML patients. Therefore, MENINis offer new therapeutic prospects for AML patients, particularly for those with high-risky and poor-prognostic on-target subtypes.

To the editor

MENINis represent a novel and promising class of therapeutic agents for AL. It is widely recognized that KMT2Ar-/NPM1m-AL exhibits sensitivity to MENINi. In fact, additional subtypes driven by overexpressed HOXA9/MEIS1 may also be potential candidates for MENINi treatment [1]. Recently, revumenib became the first MENINi approved by FDA for refractory/relapsed KMT2Ar-AL, marking a significant milestone in the translation of MENINi from bench to bed. This paper highlights updates on MENINi for AL treatment as presented at the 2024 ASH annual meeting.

MENINi as monotherapy

To our knowledge, more than seven distinct types of MENINis, including revumenib (SNDX-5613), ziftomenib (KO-539), bleximenib (JNJ-75276617), enzomenib (DSP-5336), icovamenib (BMF-219), BN104, and HMPL-506, are currently undergoing clinical trials [2]. Moreover, a number of studies have updated their results this year (Table 1).

Table 1.

Updates of MENINi monotherapy for refractory/relapsed AL treatment in the 2024 ASH annual meeting

Inhibitor	Phase	Registration	Disease1	Genetic subtypes	Efficacy outcomes						Safety profile	Ref
					Evaluated cases2	ORR	cCR	CR/CRh	mTTFR3 (months)	mDoR (months)
Revumenib	2	NCT04065399	AML, ALL, MPAL	KMT2Ar	97	64% (62/97)	42% (41/97)	23% (22/97)	/	6.4 in CR/CRh	Grade ≥ 3 febrile neutropenia (39%), anemia (20%), thrombocytopenia (16%), DS (15%), neutropenia (15%), leukopenia (15%), QTc prolongation (13%)	[3]
Bleximenib	1	NCT04811560	AML, ALL, other AL	KMT2Ar, NPM1m	150 mg BID: 20 90/100 mg BID: 20 45 mg BID: 13	50% (10/20) 50% (10/20) 39% (5/13)	40% (8/20) 40% (8/20) 23% (3/13)	30% (6/20) 35% (7/20) 23% (3/13)	/ 1.0 /	/ 6.4 /	All grade DS (13%), neutropenia (12%), thrombocytopenia (11%), QTc prolongation (0.8%)	[4]
Enzomenib	1	NCT04988555	AML, ALL	KMT2Ar, NPM1m, Others	KMT2Ar: 22 NPM1m: 13 CALM-AF10: 1	59% (13/22) 54% (7/13) 100% (1/1)	23% (5/22) 23% (3/13) 100% (1/1)	/	1.0	/	All grade febrile neutropenia (22.2%), DS (11.1%), QTc prolongation (5.0%)	[5]
BN104	1/2	NCT06052813	AML	KMT2Ar, NPM1m, NUP98r	11	89% (8/9)	33% (3/9)	/	0.9	/	All grade febrile neutropenia (20%), DS (10%), QTc prolongation (10%)	[6]

¹The type of disease for current enrolled patients;

²The number of patients whose efficacy was evaluable;

³The definition of mTTFR: median time to first response, in which “response” referred to objective response

In the AUGMENT-101 study, continued treatment and follow-up data were updated after the interim analysis [3]. 97 refractory/relapsed KMT2Ar-AL patients were treated with revumenib. The ORR, cCR, or CR/CRh was 64%, 42% or 23%, respectively. The mDoR for CR/CRh patients was 6.4 months. 34% of patients with therapeutic responses proceed to HSCT.

Bleximenib was evaluated in refractory/relapsed KMT2Ar-/NPM1m-AL patients [4]. The ORR, cCR or CR/CRh were 50% vs. 50% vs. 39%, 40% vs. 40% vs. 23%, or 30% vs. 35% vs. 23% in 150 mg BID vs. 90/100 mg BID vs. 45 mg BID group, respectively. The mDoR in 90/100 mg BID group was 6.4 months.

Enzomenib was investigated in refractory/relapsed AL patients with KMT2Ar, NPM1m or other HOXA9/MEIS1 driven subtypes, and 36 patients receiving active doses were evaluated [5]. The ORR and CR/CRh were 59.1% and 22.7% in KMT2Ar patients, while the ORR and CR/CRh were 53.8% and 23.1% in NPM1m patients.

BN104, a novel non-covalent MENINi, was evaluated in refractory/relapsed AML patients [6]. The ORR or CR/CRh was 89% or 33% in 9 KMT2Ar/NPM1m patients, respectively.

In comparison to NPM1m-AL, the therapeutic options for re-induction in KMT2Ar-AL are limited. Notably, MENINis offered a novel and effective therapeutic choice for KMT2Ar-AL patients.

MENINi-based combination therapy

The investigation of revumenib and ziftomenib, two leading MENINis in clinical trials, extended beyond monotherapy, and bleximenib followed. Reports have also emerged regarding the outcomes of their combination therapy in AML treatments (Table 2).

Table 2.

Updates of MENINi-based combination therapy for AML treatment in the 2024 ASH annual meeting

Inhibitor	Combination	Phase	Registration	Indication	Genetic subtype	Efficacy outcomes							Ref
						Evaluated cases1	ORR	cCR	CR/CRh	mDoR	RFS	OS
Revumenib	ASTX727, Venetoclax	1/2	NCT05360160	Refractory/ Relapsed	KMT2Ar, NPM1m, NUP98r	26	88% (23/26)	69% (18/26)	58% (15/26)	Not reached in CR/CRh	59% for 6-month	74% for 6-month	[7]
Ziftomenib	Azacitidine, Venetocalx	1a	NCT05735184	Refractory/ Relapsed	KMT2Ar, NPM1m	NPM1m 200 mg: 5 NPM1m 400 mg: 6 KMT2Ar 200 mg: 7 KMT2Ar 400 mg: 6	100% (5/5) 67% (4/6) 43% (3/7) 33% (2/6)	80% (4/5) 50% (3/6) 29% (2/7) 17% (1/6)	/	/	/	/	[8]
Ziftomenib	Cytarabine, Daunorubicin	1a	NCT05735184	Newly diagnosed	KMT2Ar, high risky NPM1m	NPM1m 200 mg: 8 NPM1m 400 mg: 7 KMT2Ar 200 mg: 10 KMT2Ar 400 mg: 8	/	100% (8/8) 86% (6/7) 90% (9/10) 63% (5/8)	/	/	/	/	[9]
Bleximenib	Cytarabine, Daunorubicin/Idarubicin	1b	NCT05453903	Newly diagnosed	KMT2Ar, NPM1m	14	93% (13/14)	/	86% (12/14)	/	/	/	[10]

¹The number of patients whose efficacy was evaluable

Refractory/relapsed AML

The SAVE regimen (revumenib[SNDX-5613], ASTX727 and venetoclax) was specifically designed for refractory/relapsed AML [7]. The ORR was 88%, with a CR/CRh of 58%. 12 patients proceeded to HSCT. As follow-up, the 6-month RFS was 59% and OS was 74%. The mDoR had not been reached in CR/CRh patients.

In the KOMET-007 study [8], ziftomenib plus VA regimen was administrated to refractory/relapsed KMT2Ar-/NPM1m-AML patients. For NPM1m patients, the ORR was 100% at 200 mg and 67% at 400 mg; the cCR was 80% at 200 mg and 50% at 400 mg. For KMT2Ar patients, the ORR was 43% at 200 mg and 33% at 400 mg; the cCR was 29% at 200 mg and 17% at 400 mg.

ND AML

In the KOMET-007 study [9], ND high-risk KMT2Ar-/NPM1m-AML patients were treated with ziftomenib plus "3 + 7" regimen. For NPM1m patients, the cCR were 100% at 200 mg and 86% at 400 mg, respectively. For KMT2Ar patients, the cCRR were 90% at 200 mg and 63% at 400 mg, respectively.

Bleximenib plus "3 + 7" regimen was also investigated in ND KMT2Ar-/NPM1m-AML patients [10]. 14 patients achieved an ORR of 93% and a CR/CRh of 86%.

As indicated, the addition of VA potentially only enhanced the therapeutic responses of MENINis in NPM1m-AML rather than KMT2Ar-AML among refractory/relapsed patients [8]. In contrast, the "3 + 7" regimen plus MENINi showed a durable and high response in both KMT2Ar-/NPM1m-AML among ND patients [9].

MENINis were well-tolerant, with their majority of AEs being manageable. As reported, gastrointestinal symptoms and cytopenias emerged as the most prevalent AEs. However, two relatively uncommon yet clinically significant AEs, DS and QTc prolongation, demand heightened clinical vigilance due to their potentially profound implications for patient safety and treatment outcomes.

Highlights from the 2024 ASH annual meeting regarding MENINi treatment for AL primarily focused on the monotherapy of novel MENINis and MENINis-based combination therapies with VA or "3 + 7" regimen. Notably, the addition of MENINi to standard therapies further improved therapeutic responses of KMT2Ar-/NPM1m-AML patients. These findings established its critical therapeutic role and held significant promise for KMT2A-MENIN-dependent AL. In the future, MENINis-based combination therapy still needed to be optimized and personalized for different AL subtypes.

Abbreviations

AL

Acute leukemia

AEs

Adverse effects

ALL

Acute lymphoblastic leukemia

AML

Acute myeloid leukemia

ASH

American Society of Hematology

cCR

Composite complete remission

CR/CRh

CR plus CR with partial hematologic recovery

DS

Differentiation syndrome

FDA

Food and Drug Administration

HSCT

Hematopoietic stem cell transplantation

KMT2Ar

KMT2A-rearranged

KMT2Ar-/NPM1m

KMT2A-rearranged and NPM1-mutated

MPAL

Mixed phenotype acute leukemia

mDoR

Median duration of response

MENINi

MENIN inhibitor

mTTFR

Median time to first response

NPM1m

NPM1-mutated

ND

Newly diagnosed

ORR

Overall response rate

OS

Overall survival

RFS

Relapse-free survival

VA

Venetoclax and azacitidine

Author contributions

Jiewen Sun collected and summarized materials. Xiang Zhang wrote the manuscript. Wenjuan Yu revised the paper.

Funding

This study was funded by National Natural Science Foundation of China (82200183).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.