Revumenib for patients with relapsed or refractory (R/R) KMT2Ar acute leukemia: Outcomes by leukemia type in the phase 2 AUGMENT-101 study

Blood · 2025-11-03 · 3 citations

Abstract BACKGROUND Patients (pts) with lysine methyltransferase 2A–rearranged (KMT2Ar)acute leukemia (AL) have a poor prognosis. The menin-KMT2A interaction is a key driver of leukemogenesis. Revumenib is a first-in-class, oral, selective inhibitor of the menin-KMT2A interaction. The AUGMENT-101 phase 2 analysis included pts with different leukemia types: ALL, AML, and mixed-phenotype AL (MPAL). Recent results (data cutoff [DCO]: Feb 29, 2024; efficacy-evaluable population, n=97; safety population, N=116) showed a complete remission (CR) or CR with partial hematologic recovery (CR+CRh) rate of 23% and an overall response rate (ORR) of 64% as well as a generally well-tolerated safety profile (Aldoss et al. ASH 2024. Abstract 211). Here we report outcomes by AL subtype (ALL, AML, and MPAL) in pts with KMT2Ar AL from the DCO (Feb 29, 2024).METHODS Pts aged ≥30 d with R/R KMT2Ar AL were eligible to enroll and receive revumenib 163 mg (95 mg/m2 if body weight <40 kg) every 12 h with a strong CYP3A4 inhibitor in 28-d continuous cycles. Treatment continued until unacceptable toxicity, disease progression, or lack of response after ≤4 cycles. Primary endpoints were CR+CRh rate, safety, and tolerability. Key secondary endpoints included ORR (composite CR+MLFS+partial remission) and duration of response (DOR). Pts with centrally confirmed KMT2Ar AL and ≥5% baseline bone marrow blasts within 28 d prior to the start of study treatment made up the efficacy-evaluable population. Measurable residual disease (MRD) was assessed locally by flow cytometry or PCR at investigators' discretion. The analysis of outcomes by AL type was descriptive and was not powered for statistical comparisons. RESULTS As of the DCO, 97 pts comprised the efficacy-evaluable population (AML, 78 pts [80%]; ALL, 13 [13%]; MPAL, 6 [6%]). Median (range) age was 38 y (1-75) in pts with AML, 37 y (1-73) in pts with ALL, and 16 y (1-53) in pts with MPAL; 14 pts (18%) with AML, 3 (23%) with ALL, and 3 (50%) with MPAL were pediatric pts (aged <18 y). Median (range) number of prior lines of therapy was 2 (1-11) in pts with AML, 3 (1-8) in pts with ALL, and 2 (1-4) in pts with MPAL. In the efficacy-evaluable population, ORR was 67% (95% CI, 55%–77%) in pts with AML, 46% (95% CI, 19%–75%) in pts with ALL, and 67% (95% CI, 22%–96%) in pts with MPAL. CR+CRh rate was 23% (18/78 pts; 95% CI, 14%–34%) in pts with AML, 23% (3/13; 95% CI, 5%–54%) in pts with ALL, and 17% (1/6; 95% CI, 0%–64%) in pts with MPAL. Median DOR (95% CI) was 7.7 mo (3.4–not reached [NR]), NR (0.9–NR), and 1.8 mo (NR–NR), respectively. Among pts who achieved CR/CRh, 18 had MRD status available (17 by flow; 1 by PCR) and 11 achieved MRD negativity. For evaluable responders with AML, ALL, and MPAL, MRD negativity was 64% (9/14), 33% (1/3), and 100% (1/1), respectively. Twenty-one pts proceeded to HSCT while in remission, including 19 with AML and 2 with MPAL; 9 pts with AML resumed revumenib post HSCT as maintenance. In the safety population (N=116 [AML, n=95; ALL, n=15; MPAL, n=6]), 88 pts with AML (93%), 12 pts with ALL (80%), and 6 pts with MPAL (100%) experienced a grade ≥3 treatment-emergent AE (TEAE); 55 pts (58%), 4 pts (27%), and 4 pts (67%), respectively, experienced a grade ≥3 treatment-related AE (TRAE). In pts with AML, the most common (≥15%) grade ≥3 TRAEs were differentiation syndrome (DS; 14 [15%]), febrile neutropenia (FN; 14 [15%]), and QTc prolongation (15 [16%]; all grade 3). In pts with ALL, the most common (≥10%) grade ≥3 TRAEs were FN, DS, and nausea (2 [13%] each). In pts with MPAL, the most common (occurring in ≥2 pts) TRAEs were FN, anemia, decreased platelet count, and decreased neutrophil count (2 [33%] each). Six pts (5%) discontinued treatment due to a TRAE (AML, 5 pts [1 event each of cardiac failure, intracranial hemorrhage, myocardial ischemia, pneumonia, and respiratory failure]; ALL, 1 pt [nausea and vomiting]). DS events were experienced by 28% of pts with AML, 13% with ALL, and 33% with MPAL. Four deaths due to TRAEs occurred (1 event each of intracranial hemorrhage, myocardial ischemia, pneumonia, and respiratory failure), all in pts with AML. CONCLUSIONS Revumenib monotherapy provides clinically meaningful and durable responses, including high rates of MRD negativity, in heavily pretreated pts with R/R KMT2Ar AL regardless of leukemia type: AML, ALL, or MPAL. The safety profile of revumenib is consistent with prior reports and is generally similar across AL subtypes.

Expanding the Landscape of Dual Action Antifolate Antibacterials through 2,4-Diamino-1,6-dihydro-1,3,5-triazines

ACS Infectious Diseases · 2025-02-14 · 4 citations

Antibiotics that operate via multiple mechanisms of action are a promising strategy to combat growing resistance. Previous studies have shown that dual action antifolates formed from a pyrroloquinazolinediamine core can inhibit the growth of bacterial pathogens without developing resistance. In this work, we expand the scope of dual action antifolates by repurposing the 2,4-diamino-1,6-dihydro-1,3,5-triazine (DADHT) cycloguanil scaffold to a variety of derivatives designed to inhibit dihydrofolate reductase (DHFR) and disrupt bacterial membranes. Dual mechanism DADHTs have activity against a variety of target pathogens, including Mycobacterium tuberculosis, Mycobacterium abscessus, and Pseudomonas aeruginosa, among other ESKAPEE organisms. Through X-ray crystallography, we confirmed engagement of the Escherichia coli DHFR target and found that some DADHTs stabilize a previously unobserved conformation of the enzyme but, broadly, bind in the occluded conformation. Using in vitro inhibition of purified E. coli and Staphylococcus aureus DHFR and disruption of E. coli membranes, we determined that alkyl substitution of dihydrotriazine at the 6-position best optimizes the DADHT’s two mechanisms of action. By employing both mechanisms, the DADHT spectrum of activity was extended beyond the scope of traditional antifolates. We are optimistic that the dual mechanism approach, particularly through the action of antifolates, offers a unique means of combating hard-to-treat bacterial infections.

POSTER: AML-110 Patients With Relapsed or Refractory (R/R) Nucleophosmin 1–Mutated (NPM1m) Acute Myeloid Leukemia (AML): Updated Results From the Revumenib Phase 2 AUGMENT-101 Study

Clinical Lymphoma Myeloma & Leukemia · 2025-08-28

AML-112: Revumenib Activity in Patients With Acute Leukemia With NUP98r: Results From the AUGMENT-101 Phase 1 Study

Clinical Lymphoma Myeloma & Leukemia · 2025-08-28 · 1 citations

Menin inhibition with revumenib for <i>NPM1</i>-mutated relapsed or refractory acute myeloid leukemia: the AUGMENT-101 study

Blood · 2025-05-07 · 40 citations

ABSTRACT: The prognosis for relapsed or refractory (R/R) nucleophosmin 1-mutated (NPM1m) acute myeloid leukemia (AML) is poor and represents an urgent unmet medical need. Revumenib, a potent, selective menin inhibitor, was recently approved for the treatment of R/R acute leukemia with a KMT2A translocation in patients aged ≥1 year based on results from the phase 1/2 AUGMENT-101 study. Here, we present results from patients with R/R NPM1m AML enrolled in the phase 2 portion of AUGMENT-101. Enrolled patients received revumenib with or without a strong CYP3A4 inhibitor every 12 hours in 28-day cycles. Primary end points were rate of complete remission (CR) or CR with partial hematologic recovery (CRh; CR + CRh), safety, and tolerability. Secondary end points included overall response rate (ORR) and duration of response. As of 18 September 2024, 84 patients received ≥1 dose of revumenib. Median age was 63 years; 1 patient was aged <18 years. The protocol-defined, efficacy-evaluable population for the primary analysis included 64 adult patients (≥3 previous lines of therapy, 35.9%; previous venetoclax, 75.0%). The CR + CRh rate was 23.4% (1-sided P = .0014); the ORR was 46.9%. Median duration of CR + CRh was 4.7 months. Of 30 responders, 5 (16.7%) proceeded to hematopoietic stem cell transplant (HSCT) and 3 resumed revumenib after HSCT. Treatment-related adverse events led to treatment discontinuation in 4 patients (4.8%). Revumenib demonstrated clinically meaningful responses in this heavily pretreated, older population with NPM1m AML, including remissions that enabled HSCT. The safety profile of revumenib was consistent with previously reported results. This trial was registered at www.clinicaltrials.gov as #NCT04065399.

Exploring the Influence of Respiratory Therapy Students in Interprofessional Simulations for Critical Care Patient Mobilization

Respiratory Care · 2025-06-04 · 1 citations

Background: Early mobility (EM) of mechanically ventilated patients in ICUs is essential to improve patient outcomes, yet its adoption faces barriers. Interprofessional education (IPE) simulations offer a controlled environment for health care students to develop skills in airway management and foster teamwork, which are crucial for implementing EM practices. Including respiratory therapists in these simulations is particularly important, as they bring specialized expertise in airway management. Their involvement ensures that all team members are proficient in critical skills, enhancing patient safety and the effectiveness of EM strategies in ICU settings.

AML-111: Updated Results and Longer Follow-Up From the AUGMENT-101 Phase 2 Study of Revumenib in All Patients With Relapsed or Refractory (R/R) KMT2Ar Acute Leukemia (AL)

Clinical Lymphoma Myeloma & Leukemia · 2025-08-28

Revumenib for patients with relapsed or refractory (R/R) Nucleophosmin 1–Mutated (NPM1m) Acute Myeloid Leukemia (AML): Outcomes by prior treatment in the phase 2 AUGMENT-101 study

Blood · 2025-11-03

Abstract BACKGROUND NPM1m AML accounts for ~30% of newly diagnosed adult AML and 12% of R/R AML cases. Approximately 50% of adult patients with NPM1m AML experience progressive disease or death after frontline treatment. Historical data suggest that only 48% and 10% of patients achieve complete remission (CR) after first salvage with high- or low-intensity treatments, respectively; CR rates decrease with each subsequent line (CR with second salvage, 30% and 8%; CR with subsequent salvage, 11% and 2%). Current standard of care varies depending on patient and disease characteristics and may include intensive chemotherapy, venetoclax (ven) ± hypomethylating agents, targeted therapies (such as FLT3 inhibitors [i], IDH1i, or IDH2i if a corresponding co-mutation is present), and allogeneic hematopoietic stem cell transplant (HSCT). Despite these available options, the prognosis for patients with R/R NPM1m AML remains poor, with a 1-year survival rate of only 16%. Novel treatments are needed. The menin–lysine methyltransferase 2A (KMT2A) interaction is a critical driver of leukemogenesis in NPM1m AML. Revumenib is a first-in-class, oral, selective inhibitor of the menin-KMT2A interaction. Safety (safety population, N=84) and clinical outcomes (efficacy-evaluable population, n=77) from the phase 2 AUGMENT-101 study in patients with R/R NPM1m AML have been previously reported and demonstrated clinically meaningful responses across a range of prior treatments, including ven, FLT3i, IDH1i, IDH2i, and HSCT (NCT04065399; Arellano et al. EHA 2025. PS1467). Here, we present additional characterization of clinical outcomes, including duration of response (DOR), by prior treatment. METHODS Patients aged ≥30 d with R/R NPM1m AML were eligible to receive revumenib 163 mg (95 mg/m2 if body weight [bw] &amp;lt;40 kg) every 12 h (q12h) with a strong CYP3A4i or 276 mg (160 mg/m2 if bw &amp;lt;40 kg) q12h without a strong CYP3A4i in 28-d cycles. Patients with centrally confirmed NPM1m AML status and ≥5% blasts in bone marrow at baseline within 28 d prior to the start of study treatment were included in the efficacy-evaluable population. Treatment continued until unacceptable toxicity, disease progression, or lack of response after ≤4 cycles. Primary endpoints were rate of CR or CR with partial hematologic recovery (CR+CRh), safety, and tolerability. Secondary endpoints included overall response rate and DOR. Post hoc analysis of DOR by prior treatment was conducted. This analysis was descriptive and not powered to allow statistical comparisons. RESULTS As of September 18, 2024, 77 patients met efficacy-evaluable criteria. Median age was 63 y (range, 11–84 y; 38 patients were ≥65 y). Of these patients, 57 (74.0%) had received prior ven, 31 (40.3%) had prior FLT3i, 5 (6.5%) had prior IDH1i, 5 (6.5%) had prior IDH2i, and 18 (23.4%) had previously undergone HSCT. Overall, the CR+CRh rate was 26.0% (20/77; 95% CI, 16.6%–37.2%) and median duration of CR/CRh was 4.7 mo (95% CI, 2.1–8.2). The CR+CRh rate based on prior treatment was 19.3% (11/57; 10.0%–31.9%) with ven; 12.9% (4/31; 3.6%–29.8%) with FLT3i; 40.0% (2/5; 5.3%–85.3%) with IDH1i; 60.0% (3/5; 14.7%–94.7%) with IDH2i; and 27.8% (5/18; 9.7%–53.5%) with HSCT. Median (95% CI) duration of CR/CRh based on prior treatment was 3.9 mo (1.0–8.2) with ven; 4.3 mo (0.9–NR) with FLT3i; 3.9 mo (NR–NR) with IDH1i; 8.2 mo (NR–NR) with IDH2i; and 5.6 mo (1.8–NR) with HSCT. Safety data from the safety population (N=84) were reported previously; 66 patients (78.6%) experienced a treatment-related AE (TRAE); TRAEs led to treatment discontinuation in 4 patients (4.8%) and death in 1 (1.2%). CONCLUSIONS These findings further characterize outcomes in patients with R/R NPM1m AML treated with revumenib monotherapy in AUGMENT-101. The median DORs by prior treatment were similar to that for the overall population. Given the small subgroup sizes per prior treatment and overlapping confidence intervals, additional data are needed to identify optimal treatment sequences.

POSTER: AML-111 Updated Results and Longer Follow-Up From the AUGMENT-101 Phase 2 Study of Revumenib in All Patients With Relapsed or Refractory (R/R) KMT2Ar Acute Leukemia (AL)

Clinical Lymphoma Myeloma & Leukemia · 2025-08-28

POSTER: AML-112 Revumenib Activity in Patients With Acute Leukemia With NUP98r: Results From the AUGMENT-101 Phase 1 Study

Clinical Lymphoma Myeloma & Leukemia · 2025-08-28