Revumenib for KMT2Ar (MLLr) and NPM1-Mutated AML

ASH 2022: Revumenib Leads to Long-Lasting Responses in KMT2Ar(MLLr) and NPM1-Mutated AML

Posted: Dec 14, 2022

At the 64th Annual Meeting of the American Society of Hematology (ASH 2022), Ghayas C. Issa, MD, an expert on AML, talked about the first phase of the AUGMENT-101 trial. The study looked at how safe and effective Revumenib was as a single drug for people with relapsed or resistant acute leukemia with KMT2Ar (MLLr) or NPM1 mutations.

Currently, there are no approved targeted treatments for NPM1-mutated acute myeloid leukemia (which is found in 30% of people with newly diagnosed AML) or mixed lineage leukemia-rearranged (MLLr, currently called KMT2Ar, 10% of AML), a type of acute leukemia that often doesn't respond to standard treatments and is caused by spontaneous translocations at the MLL1 gene. Revumenib stops the mechanisms of both types of AML, NMP1-mutated AML and KMT2Ar (MLLr) AML.

Revumenib (also called SNDX-5613) is a powerful and selective KMT2Ar-Menin inhibitor that stops the interaction of KMT2Ar proteins that strongly bind to the protein Menin. This stops the abnormal gene expression and kills the AML cells.

Methods

Arm A	Arm B
Had not taken strong antifungal drugs (CYP3A4 inhibitors)	Had taken strong antifungal drugs (CYP3A4 inhibitors)
Revumenib was taken by mouth every 12 hours in cycles of 28 days.
Safety Group	Efficacy Group
Patients who got at least one dose of Revumenib	Only patients with MLLr (also called KMT2A) or mNPM1

Patients Included in the Study

Total	Median Age Adults	Median Age Pediatric	Patients with AML	KMT2Ar (MLLr)	NPM1
68	50.5 years old	2.5 years old	82% (56/68)	48/68	14/68

Between November 2019 and March 2022, 68 patients with Relapsed/Refractory acute leukemia (including 60 patients with KMT2Ar or NPM1) joined the study's arm A or arm B
Patients in this study had been through a lot of treatment before, with a median of 4 (range: 1–12) prior lines of therapy and 46% having had a transplant before

Side Effects Reported

No side effects caused people to stop treatment or pass away
The side effect that limited the dosage that could be given safely was asymptomatic QTc prolongation, the extension of the time between when the heart contracts and relaxes, which happened in almost 5% of patients
Some treatment-related side effects of grade 3 (in 2-3% of the patients) were: diarrhea, fatigue, anemia, tumor lysis syndrome, low neutrophils, low platelets, calcium excess, and low potassium
Differentiation syndrome (grade 2) is a group of symptoms that includes shortness of breath, fluid buildup in the lungs or heart, swelling, chest pain, and other symptoms. It was found in 11 patients (16%) and was successfully treated with steroids and/or hydroxyurea

Responses to Revumenib

Group	Overall Response Rate (Patients number)	Complete Response (CR & CRh)	FLT3 co-mutation
Efficacy group	53% (32/60)	30% (18/60)	5/32
KMT2Ar (MLLr)	59% (27/46)	33% (15/46)	2/27
NPM1	36% (5/14)	21% (3/14)	3/5

Efficacy Group’s	Months
Median Follow-Up	4.6
Median Duration of Response	9.1
Median Overall Survival	7

The rate of complete response (all kinds) was 38% (23/60)
78% of the people with complete responses (all kinds) were MRD negative
Patients with wild-type KMT2A and NPM1 had genotypes that were not sensitive to menin inhibition, and did not respond to Revumenib therapy
All responders with an FLT3 co-mutation had been previously treated with an FLT3 inhibitor

Take Away Points

These results show that blocking KMT2a-menin with Revumenib is a successful way to treat acute leukemia with KMT2Ar (MLLr) or NPM1
The treatment was well tolerated and had a low rate of grade ≥3 side effects
Revumenib led to long-lasting remissions in patients with leukemia that hadn’t responded to almost 4 lines of therapy and a history of stem cell transplant, prolonging the median Overall Survival with previously available therapies from 3 months to 7 months.
For more information about this ongoing clinical trial, click here.

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about the author
Arturo Hurtado

Arturo Hurtado is an International Medical Graduate who joined HealthTree in 2020 as part of the Patient Experience team. He helps patients understand their disease panorama and navigate their AML through the tools and resources that HealthTree provides. He is an enthusiastic photographer, tech nerd, and aspiring food explorer who loves to travel and find new exciting experiences.