Subgroup Analyses Confirm Clinically Meaningful Revumenib Responses in AML Across Mutational Profiles

Treatment with revumenib (Revuforj) elicited clinically meaningful responses across groups of patients with relapsed/refractory, NPM1-mutated acute myeloid leukemia (AML) and high-risk co-mutation profiles, as well as pediatric and young adult patients with KMT2A-rearranged acute leukemia, according to findings from subgroup analyses of the phase 1/2 AUGMENT-101 trial (NCT04065399) presented at the 2026 EHA Congress.^1,2

At a data cutoff of February 19, 2026, among 54 adult patients with centrally confirmed NPM1 mutation and next-generation sequencing results, the overall response rate (ORR) was 48.1%, including best responses of complete response (CR; 20.4%), CR with partial hematologic recovery (CRh; 5.6%), CR with incomplete platelet recovery (CRp; 1.9%), CR with incomplete count recovery (CRi; 1.9%), morphologic leukemia-free state (14.8%), and partial response (PR; 3.7%).¹ The ORRs across co-mutation subgroups were as follows:

• FLT3 and IDH1/2 (n = 8): 75.0%
• IDH1/2 (n = 14): 71.4%
• DNMT3A and IDH1/2 (n = 9): 66.7%
• Spliceosome co-mutations (n = 8): 62.5%
• DNMT3A and FLT3 (n = 15): 60.0%
• TP53 (n = 4): 50.0%
• NRAS (n = 2): 50.0%
• FLT3 (n = 23): 47.8%
• Common secondary AML co-mutations (n = 19): 42.1%
• TET2 (n = 17): 35.3%

Among the subgroups, the CR/CRh rates were highest in patients with FLT3 and IDH1/2 (62.5%), IDH1/2 (64.3%), and DNMT3A and IDH1/2 (55.6%) co-mutations.

“Revumenib demonstrated deep, clinically meaningful responses in patients with high-risk co-mutation profiles across the broad and heterogeneous relapsed/refractory NPM1-mutated AML population, including those associated with adverse outcomes,” James Blachly, MD, lead author on the NPM1 co-mutation analysis, and colleagues wrote in the poster presentation.

Blachly is an associate professor in the Department of Internal Medicine and a member of the Leukemia and Hematologic Malignancies Program at the Ohio State University Comprehensive Cancer Center – James in Columbus.

Additionally, at the same data cutoff, among 36 pediatric and young adult patients with acute leukemia, the CR/CRh rate was 27.8% (95% CI, 14.2%-45.2%), with a median duration of 32.3 months (95% CI, 1.8-not reached [NR]) and a median time to CR/CRh of 1.9 months (95% CI, 1.0-5.6).² Furthermore, the composite CR (CRc) rate was 30.6% (95% CI, 16.3%-48.1%), the ORR was 55.6% (95% CI, 38.1%-72.1%), the median event-free survival (EFS) was 3.6 months (95% CI, 1.9-6.6), and the median overall survival (OS) was 6.4 months (95% CI, 2.9-34.2).

In this analysis, among the patients with AML (n = 26), the CR/CRh rate was 30.8% (95% CI, 14.3%-51.8%), with a median duration of 32.3 months (95% CI, 2.7-NR) and a median time to CR/CRh of 1.9 months (95% CI, 1.0-5.6). The CRc rate was 34.6% (95% CI, 17.2%-55.7%), the ORR was 57.7% (95% CI, 36.9%-76.6%), the median EFS was 4.5 months (95% CI, 2.3-11.7), and the median OS was 6.9 months (95% CI, 2.9-NR).

“There was [previously] no hope for these patients,” lead author of the KMT2A-rearranged subgroup analysis, Branko Cuglievan, MD, said in an interview with OncLive®. “The cure rate was under 30% in [the relapsed population], and now we’re seeing that many of these children can be cured with 1 pill or solution, so it’s a game changer completely, and we’re excited about that.”

Cuglievan is an associate professor in the Department of Leukemia in the Division of Cancer Medicine, as well as an associate professor and section chief of Leukemia/Lymphoma in the Department of Pediatrics—Patient Care in the Division of Pediatrics at The University of Texas MD Anderson Cancer Center in Houston.

What is the current role of revumenib in the acute leukemia treatment paradigm?

In October 2025, the FDA approved revumenib for the treatment of adult and pediatric patients at least 1 year of age with relapsed/refractory AML and a susceptible NPM1 mutation who have no satisfactory alternative treatment options.³ This regulatory decision was based on data from AUGMENT-101, in which the CR/CRh rate in the overall population (n = 65) was 23.1% (95% CI, 13.5%-35.2%), with a median duration of 4.5 months (95% CI, 1.2-8.1).^3,4

In the present NPM1 co-mutation analysis, investigators noted that patients with NPM1-mutated AML had a median of 4 co-mutations (range, 0-11), many of which are associated with poor prognosis and higher relapse rates, and that a similar number of co-mutations are seen at relapse.¹ Previously, a post hoc analysis from AUGMENT-101 showed that at a data cutoff of September 18, 2024, revumenib monotherapy generated an ORR of 48.1%, a CR/CRh rate of 26.0% (95% CI, 16.6%-37.2%), a cCR rate of 32.5% (95% CI, 22.2%-44.1%), and, among CR/CRh responders with available minimal residual disease (MRD) status, an MRD-negativity rate of 63.2%.⁵

Revumenib was also FDA approved in November 2024 for the treatment of adult and pediatric patients at least 1 year of age with relapsed/refractory acute leukemia harboring a KMT2A translocation.⁶ This regulatory decision was also supported by findings from AUGMENT-101, showing a CR/CRh rate of 21.2% (95% CI, 13.8%-30.3%) and a median duration of CR/CRh of 6.4 months (95% CI, 2.7-not evaluable).

Investigators from the KMT2A rearrangement analysis noted that these rearrangements represent the most frequently occurring chromosomal rearrangement in pediatric acute leukemia and are associated with poor prognosis.²

In the posters presented at EHA 2026, the investigators sought to further characterize the efficacy of revumenib as monotherapy in patients with NPM1 co-mutations that may be prognostic of adverse outcomes, as well as show long-term follow-up findings with the agent in relapsed/refractory, KMT2A-rearranged acute leukemia.^1,2

What was the design of AUGMENT-101?

The ongoing open-label, dose-escalation and -expansion AUGMENT-101 trial is investigating revumenib in pediatric and adult patients with relapsed/refractory NPM1-, KMT2A, or NUP9-rearranged acute leukemia.^1,2

In the phase 1 dose-escalation portion, all patients received revumenib orally at the recommended phase 2 dose (RP2D) of 160 mg every 12 hours (or 95 mg/m² if weighing <40 kg) in combination with a strong CYP3A4 inhibitor in 28-day cycles. The phase 2 pivotal trial portion included patients with KMT2A-rearranged acute lymphoblastic leukemia (ALL)/mixed-phenotype acute leukemia (MPAL), or AML, as well as those with NPM1-mutated AML. Patients received revumenib at the FDA-approved RP2D, or at 270 mg every 12 hours (or 160 mg/m² if weighing <40 kg) without a strong CYP3A4 inhibitor in 28-day cycles. Patients who achieved a PR or better had the option to receive hematopoietic stem cell transplant (HSCT); if they had a CRc with HSCT, they could receive optional revumenib maintenance therapy.

CR/CRh rate and safety/tolerability served as the trial’s primary end points. Secondary end points included CRc rate, ORR, duration of response, and time to response.

Notably, outcomes based on NPM1 co-mutation status are descriptive, as the study was not powered for statistical comparisons between these groups.¹

The KMT2A-rearranged pediatric/young adult analysis included patients 30 days to less than 21 years of age pooled from phases 1 and 2 who were treated at the RP2D and had baseline morphologic blast levels of at least 5%.²

What baseline characteristics from the AUGMENT-101 trial subgroup analyses presented at EHA 2026 are important to note?

Among the overall population of patients in the NPM1 co-mutation analysis, the median age was 65.0 years (range, 19-84), 59% were White, 57% were female, and patients had a median of 3 co-mutations (range, 1-8).¹ Patients had also received a median of 2 prior lines of therapy (range, 1-7), including venetoclax (Venclexta; 74%), HSCT (26%), FLT3 inhibitors (48%), IDH1 inhibitors (4%), and IDH2 inhibitors (6%).

In the KMT2A rearrangement analysis, the median duration of follow-up was 6.9 months for patients with AML (n = 27), 2.9 months for those with ALL (n = 8), and 5.7 months for those with MPAL (n = 3).² Additionally, 7 patients were still on study as of the data cutoff. Most patients were 2 years to under 12 years of age (55%).

How did MRD-negativity rates correspond with response outcomes in AUGMENT-101 subgroups?

In the NPM1 co-mutation analysis, most patients who achieved CR/CRh and had available MRD status achieved MRD negativity.¹ In the overall population, the CR/CRh rate was 25.9% (95% CI, 15.0%-39.7%), and the MRD-negativity rate among evaluable patients who achieved CR/CRh (n = 14) was 64.3%. Additionally, the CRc rate was 29.6% (95% CI, 18.0%-43.6%), and the MRD-negativity rate among evaluable patients who achieved CRc (n = 15) was 66.7%. MRD-negativity rates among patients with CR/CRh and CRc in the co-mutation subgroups were as follows:

• FLT3 and IDH1/2: 100% and 100%, respectively
• IDH1/2: 88.9% and 88.9%
• DNMT3A and IDH1/2: 100% and 100%
• Spliceosome co-mutations: 75.0% and 80.0%
• DNMT3A and FLT3: 100% and 100%
• TP53: 0% and 0%
• FLT3: 100% and 100%
• Common secondary AML co-mutations: 60.0% and 66.7%
• TET2: 75.0% and 75.0%

In the total population of the KMT2A rearrangement analysis, the MRD negativity rates were 87.5% among patients who achieved CR/CRh and 88.9% among those who achieved CRc.² These rates were as follows in each disease subtype:

• AML: 85.7% and 87.5%, respectively
• ALL: 0% and 0%
• MPAL: 100% and 100%

What is the safety profile of revumenib in NPM1 co-mutated and KMT2A-rearranged acute leukemia?

NPM1 co-mutations analysis:

In the co-mutations analysis, the most frequently reported treatment-emergent adverse effects (TEAEs) were QTcF prolongation, vomiting, and febrile neutropenia (n = 21 each).¹ Additionally, grade 3 or higher differentiation syndrome was observed in 15% of patients, consistent with prior reports. No grade 5 differentiation syndrome or QTcF prolongation occurred. TEAEs led to dose interruptions, reductions, and discontinuation in 65%, 13%, and 37% of patients, respectively. Treatment-related AEs (TRAEs) led to these dosing outcomes in 50%, 13%, and 6% of patients, respectively.

“Overall, these findings continue to support revumenib as a treatment option for relapsed/refractory NPM1-mutated AML regardless of co-mutation profile,” the authors concluded.

KMT2A rearrangement pediatric/young adult analysis:

Among patients in the total population of the KMT2A rearrangement analysis (n = 38), any-grade TEAEs (97%), grade 3 or higher TEAEs (92%), any-grade TRAEs (74%), grade 3 or higher TRAEs (37%), and serious AEs (79%) were seen.²

TEAEs leading to dose reduction or interruption occurred in 8% and 32% of patients, respectively. Eight percent of patients had a TEAE leading to treatment discontinuation; all 8 patients had AML, and these TEAEs included febrile neutropenia, septic shock, and sepsis. Additionally, 13% of patients experienced TEAEs leading to death.

TRAEs led to dose reduction and interruption in 3% and 11% of patients, respectively. No TRAEs led to revumenib discontinuation or death in this population.

In the total population, 34% of patients had differentiation syndrome, but the protocol did not mandate prophylaxis, and no patients discontinued treatment due to differentiation syndrome. Most patients with differentiation syndrome had a maximum differentiation syndrome severity of grade 2 (69%); additionally, 23% of these patients had a maximum severity of grade 3, and 1 of these patients (8%) had a maximum severity of grade 4. The median time to initial differentiation syndrome onset was 7.0 days (range, 3.0-41.0), and the median duration of the initial event was 14.5 days (range, 4.0-30.0).

Moreover, QTcF prolongation was reported in 21% of patients. All patients experienced recovery or resolution of QTcF prolongation, and no patients discontinued treatment due to this AE. Half of patients with this AE experienced it at a maximum severity of grade 2 or 3. The median time to initial QTcF prolongation onset was 4.0 days (range, 1.0-56.0), and the median duration was 1.0 day (range, 1.0-18.0).

“To see some of these children alive is amazing, and the key now is to move this to the frontline setting,” Cuglievan concluded in the interview. “The quicker we go to the frontline setting, the better. What we are learning is which combinations to use. Hopefully, we can cure more of these children soon.”

References

1. Blachly JS, Stein E, Issa G, et al. Efficacy of revumenib in acute myeloid leukemia harboring NPM1-mutated co-mutations: post hoc analysis of AUGMENT-101. Presented at: 2026 EHA Congress; June 11-14, 2026; Stockholm, Sweden. Abstract PF514.
2. Cuglievan B, Shukla N, Karras N, et al. Long-term follow-up of pediatric/young adult patients with relapsed/refractory KMT2AR acute leukemia treated with revumenib in AUGMENT-101. Presented at: 2026 EHA Congress; June 11-14, 2026; Stockholm, Sweden. Abstract PF508.
3. FDA approves revumenib for relapsed or refractory acute myeloid leukemia with a susceptible NPM1 mutation. FDA. October 24, 2025. Accessed June 12, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-revumenib-relapsed-or-refractory-acute-myeloid-leukemia-susceptible-npm1-mutation
4. Revuforj. Prescribing information. Syndax. Updated October 2025. Accessed June 12, 2026. https://cms.syndax.com/wp-content/uploads/Revuforj-full-prescribing-info.pdf
5. Revumenib for patients with relapsed or refractory (R/R) nucleophosmin 1–mutated (NPM1m) acute myeloid leukemia (AML): updated results from the phase 2 AUGMENT-101 study. Presented at: 2025 SOHO Annual Meeting; September 3-6, 2025; Houston, TX. Abstract AML-110.
6. FDA approves revumenib for relapsed or refractory acute leukemia with a KMT2A translocation. FDA. November 15, 2024. Accessed June 12, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-revumenib-relapsed-or-refractory-acute-leukemia-kmt2a-translocation