Revuforj (revumenib) / Syndax Pharma - LARVOL DELTA

Revumenib for Relapsed/Refractory Acute Myeloid Leukemia with Susceptible NPM1 Mutation (ASH 2025) - "My presentation will review the FDA approvals for revumenib and ziftomenib for the treatment of patients with R/R AML with a susceptible NPM1 mutation without satisfactory alternative treatment options, discuss why the review teams arrived at these restricted indication statements, and implications for AML drug development."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • NPM1

Ziftomenib for Relapsed/Refractory Acute Myeloid Leukemia with Susceptible NPM1 Mutation (ASH 2025) - "My presentation will review the FDA approvals for revumenib and ziftomenib for the treatment of patients with R/R AML with a susceptible NPM1 mutation without satisfactory alternative treatment options, discuss why the review teams arrived at these restricted indication statements, and implications for AML drug development."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • NPM1

Phase 1/2, multi-center, open-label clinical study to evaluate the safety, pharmacokinetics, and efficacy of Zefamenib combined with chemotherapy or targeted Agents in patients with Acute Myeloid Leukemia (ASH 2025) - P1/2 | "Menin inhibitor revumenib combined with venetoclax and azacitidine have shown complete remission (CR) rate of 88.4% in newly diagnosed AML patients harboring these aberrations...Cohort A and D will enroll untreated AML patients, who will receive zefamenib combined with standard 7+3 chemotherapy for induction and zefamenib combined with high dose cytarabine for consolidation...This study will be the first to clarify the feasibility of zefamenib with intensive chemotherapy or targeted agents in the frontline treatment of AML patients or the efficacy and safety of zefamenib with targeted agents in R/R AML patients harboring NPM1 mutation or KMT2A/NUP98 rearrangements. Results of this study will provide ideas and evidence to improve the prognosis of Chinese AML patients with these genetic aberrations."

Clinical • P1/2 data • PK/PD data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • KMT2A • MEIS1 • NPM1 • NUP98

Real-world AML survival paradox: Early escalation vs. sustained remission (ASH 2025) - "Patients were stratified into two cohorts: Cohort A (early escalation, n=1,460), comprising patients who received either second-line chemotherapy (including fludarabine, cladribine, gilteritinib, enasidinib, revumenib, olutasidenib, etoposide, or clofarabine) or hematopoietic stem cell transplant (HSCT) as salvage therapy within 6 months of completing initial therapy; and Cohort B (no escalation, n=10,540), consisting of patients who received no additional therapy during this same period. Our findings highlight the complex interplay between disease biology and treatment interventions: achieving MRD-negativity remains critical, but when MRD-positivity occurs, subsequent treatment decisions based on disease genetics prove critical. Prospective studies incorporating molecular MRD monitoring are needed to confirm these findings and further optimize post-remission therapy approaches."

Clinical • Real-world • Real-world evidence • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia

Patient assistance for drug cost sharing: Highlighting the variability across pharmaceutical manufacturers of specialty oral anticancer medications for blood cancers (ASH 2025) - "Two of the three manufacturers that did not offer a PAP had discontinued their free-drug program (idelalisib and duvelisib) whereas one never had a free drug program (revumenib). All SOAMs for blood cancer have copay assistance programs for commercially insured and nearly all directly provide free-drugs for select individuals. However, eligibility by insurance type, income level, and associated documentation requirements vary considerably across manufacturers. Future work needs to evaluate whether this variability results in inequitable access across SOAM agents within same indication."

Clinical • Drug cost • HEOR • Hematological Malignancies • Oncology • Oral Cancer

Clinical outcomes in adult AML with KMT2A rearrangements: A comparative analysis with R/R KMT2Ar and NPM1-mutated AML from the Mayo Clinic (ASH 2025) - "While revumenib, a menin inhibitor approved for managing RR KMT2A r acute leukemia, no menin inhibitor is currently approved for NPM1 -mt AML... This single institusion cohort of adult AML with KMT2A r underscores the biological and clinical heterogeneity of this high-risk group. IC was associated with a survival benefit, particularly among younger and fit patients. However, the outcomes following relapse remained poor, highlighting the urgent need for improved post-remission and salvage therapies."

Clinical • Clinical data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • AFDN • CDKN1A • KMT2A • MLLT10 • MLLT3 • NPM1

Cardiac safety of revumenib in children with HOX-driven leukemia: A single-institution cohort (ASH 2025) - P, P1/2 | "Conclusion Revumenib was well tolerated in children with relapsed high-risk leukemia. Cardiac events were infrequent in children and rarely required dose interruption, which supports the safety and continued use of revumenib in this population."

Clinical • Acute Lymphocytic Leukemia • Bone Marrow Transplantation • Heart Failure • Hematological Malignancies • Leukemia • Respiratory Diseases • Septic Shock • KMT2A • NPM1 • NUP98

Azeliragon has significant activity against acute myeloid leukemia blasts (ASH 2025) - "Synergy analysis of OCI-AML3 cells with Combenefit software demonstrated high synergy scores when AZE was combined with cytarabine or venetoclax, medium synergy scores when combined with daunorubicin, and antagonism when combined with azacitidine...The relapse patients included 1 with relapse after 2 bone marrow transplants, 1 with relapse after 7 lines of treatment (including Revumenib), and another 1 with relapse after Revumenib...We conclude that AZE shows promising single agent activity in AML with potential for synergistic combinations with standard agents. Clinical investigation of AZE for the treatment of AML is warranted."

IO biomarker • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Alzheimer's Disease • Bone Marrow Transplantation • CNS Disorders • Hematological Malignancies • Leukemia • Solid Tumor • BCL2 • CD34 • HMGB1 • KMT2A

GB3226, a novel, orally active, first-in-class small molecule inhibitor of ENL-yeats and FLT3 kinase for the treatment of Relapsed/Refractory Acute Myeloid Leukemia (ASH 2025) - "In cell-based assays, GB3226potently inhibited proliferation of both MV4; 11 (IC50=18 nM) and MOLM13 (IC50=32 nM) cell lines andwas additive/synergistic when combined with standard-of-care agents, including venetoclax, gilteritinib,and revumenib. We have developed GB3226, a novel, oral, first-in-class, dual inhibitor of ENL-YEATS and FLT3for the treatment of AML. Preclinical studies demonstrate that GB3226 exhibits potent anti-leukemicactivity and has the potential for combination use with multiple therapeutic agents across diverse AMLgenotypes. GB3226 has shown robust in vitro and in vivo efficacy, along with a favorable preclinical safetyprofile."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • FLT3 • HOXA9 • KIT • MEIS1 • MELK • NTRK3 • TET2

A multicenter phase 1 trial evaluating the safety and preliminary efficacy of revumenib as post-transplant maintenance after allogeneic hematopoietic cell transplant in patients with KMT2A-rearranged or NPM1-mutated acute leukemia (ASH 2025) - P1 | "This proposed phase 1 trial will establish the safety and RP2D for revumenib as post-alloSCTmaintenance therapy for patients with KMT2Ar and high-risk NPM1m acute leukemias. Additionalpharmacokinetic, MRD, and immune profiling studies will also inform RP2D and the future phase 2 trial.The trial is actively recruiting at City of Hope and the Dana-Farber Cancer Institute."

Clinical • P1 data • Post-transplantation • Acute Graft versus Host Disease • Chronic Graft versus Host Disease • Graft versus Host Disease • Immunology • Transplantation • FLT3 • KMT2A • MEIS1 • NPM1

Revumenib in combination with intensive induction and consolidation for newly diagnosed patients with NPM1-mutated or KMT2A-rearranged Acute Myeloid Leukemia: Preliminary results from the Phase 1b etctn 10596 study (ASH 2025) - P1 | "Revumenibwas combined with 7+3 induction (daunorubicin 60mg/m2 Days 1-3 and cytarabine 100mg/m2 Day 1-7)and cytarabine consolidation (1-1.5gm/m2 q12 hours (hrs) x 6 doses Days 1-3 based on age and CrCl).Revumenib dose escalation occurred independently between induction and consolidation on Days 2-28with dose level 1 (DL1) at 226mg q12hr and dose level 2 (DL2) at 276mg q12hr without strong CYP3A4inhibitor azoles. Revumenib combined with 7+3 overall appears to be well-tolerated both with 7+3 inductionand consolidation. However, the grade 5 typhlitis event in induction DL2 occurred on Day 7 of treatment,earlier than expected with 7+3, and thus was deemed possibly related to revumenib. As induction DL1has had no DLTs now in 6 patients, more data will be forthcoming on safety as additional patients havebeen enrolled on DL2."

Clinical • Combination therapy • P1 data • Acute Myelogenous Leukemia • Dermatology • Endocrine Disorders • Febrile Neutropenia • Neutropenia • FLT3 • KMT2A • NPM1

Anti-leukemic efficacy of a novel inhibitor for KMT2A-r/FLT3-driven AML via multi-kinase targeting and synergy with menin inhibition (ASH 2025) - "Synergistic activity with the FDA-approved menin-irevumenib was examined using proliferation assays, immunoblotting, flow cytometry, and qRT-PCRanalyses. LGR3922 demonstrated potent inhibition of oncogenic FLT3 and additional target kinases,resulting in suppressed proliferation and enhanced apoptosis in vitro...In an Mll-ENL knock-in-based NOD.SCID mouse model, LGR3922significantly decreased the Mll-ENL leukemic allelic burden compared to midostaurin... LGR3922 represents a promising candidate for targeted therapy in KMT2A-r/FLT3mut AML,offering a unique multi-kinase mechanism that disrupts key signaling pathways not targeted by currenttherapies. Demonstrated in vivo efficacy, favorable toxicity profile, and synergistic activity with menin-isupport its further development and testing. Since one of the common side effects of menin-i therapy isanemia, the observed erythropoiesis-stimulating effect of LGR3922 as an unexpected side effect could beadvantageous for therapeutic..."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • CDK1 • EIF4E • FLT3 • HDAC4 • HOXA9 • KMT2A • MEF2C • MEIS1 • STAT5

Acute leukemia during pregnancy: A three-decade Mayo Clinic experience (ASH 2025) - "One patient had refractory disease and achieved partial remission after salvage,another had refractory disease and achieved CR after multiple lines of therapy, and a third achieved CRafter FLAG-idarubicin and revumenib...All receivedintensive induction: 7+3 (n=5), 7+3 + ATRA (n=1), 7+3 + gilteritinib (n=1), and 7+3 + nilotinib (n=1)...Notably, 5 (28%) of patients received chemotherapy during pregnancy. Larger,multi-institutional cohorts are warranted to further characterize the incidence and outcomes of AL inpregnancy."

Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Acute Promyelocytic Leukemia • Hematological Malignancies • Hodgkin Lymphoma • Infectious Disease • Leukemia • Lymphoma • Pneumonia • Respiratory Diseases • T Acute Lymphoblastic Leukemia • KMT2A • NUP214

Revumenib for patients with relapsed or refractory (R/R) KMT2Ar acute leukemia: Outcomes by leukemia type in the phase 2 AUGMENT-101 study (ASH 2025) - "Four deaths due to TRAEs occurred (1 event each of intracranial hemorrhage,myocardial ischemia, pneumonia, and respiratory failure), all in pts with AML.CONCLUSIONSRevumenib monotherapy provides clinically meaningful and durable responses, including high rates ofMRD negativity, in heavily pretreated pts with R/R KMT2Ar AL regardless of leukemia type: AML, ALL, orMPAL. The safety profile of revumenib is consistent with prior reports and is generally similar across ALsubtypes."

Clinical • P2 data • Cerebral Hemorrhage • CNS Disorders • Congestive Heart Failure • Febrile Neutropenia • Heart Failure • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Myocardial Ischemia • Neutropenia • Pneumonia • Respiratory Diseases • KMT2A

Detection of MEN1 resistance mutations in cell-free DNA from acute leukemia patients treated with menin inhibitors (ASH 2025) - "Background :Menin inhibitors have demonstrated promising clinical efficacy in multiple subtypes of acute leukemia,with revumenib being the first approved for relapsed/refractory KMT2A-rearranged leukemias...Evaluation of plasma-derived cfDNA with MSK-ACCESS-MEN1 enables non-invasive detection of MEN1resistance mutations in patients treated with menin inhibitors. MEN1 resistance mutations were reliablydetectable in cfDNA from peripheral blood in patients without circulating blasts. Importantly, wedemonstrate that MSK-ACCESS-MEN1 can identify emerging MEN1 resistance mutations prior to clinicalevidence of relapse."

Cell-free DNA • Clinical • Hematological Malignancies • Leukemia • KMT2A • MEN1

Preliminary data from the ongoing Phase 1 study of the menin-MLL inhibitor enzomenib (DSP-5336) in combination with venetoclax and azacitidine in patients with relapsed or refractory Acute Myeloid Leukemia (ASH 2025) - P1/2 | "Median age was 50 yrs (21-76), 56% were female andmedian prior regimens was 2 (1-4); 3 pts (16.7 %) had prior allogeneic stem cell transplant (SCT), 6 pts(33.3%) had prior VEN, and 5 pts (27.8%) received prior menin inhibitor (2 ziftomenib, 1 revumenib, 2enzomenib). Preliminary data show ENZO up to 300 mg BID to be well tolerated in combination withVEN/AZA with no DLTs in 18 pts with R/R KMT2Ar or NPM1m AML. No QT prolongation was reported andthere was 1 report of non-serious DS. Promising preliminary clinical activity has been observed,particularly in pts without prior VEN or menin exposure (100% ORR and 67% CRc rate)."

Clinical • Combination therapy • P1 data • Acute Myelogenous Leukemia • Central Nervous System Leukemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Leukopenia • Neutropenia • Septic Shock • Thrombocytopenia • FLT3 • KMT2A • NPM1

Preliminary Results of A phase 1 study of the safety and tolerability of the combination of revumenib (REV) with gilteritinib (GILT) in Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) (ASH 2025) - P1 | "One pt had successful dose re-escalation after discontinuation of posaconazole without recurrent QTc prolongation. This is the first clinical study evaluating the combination of menin and FLT3 inhibitors fortreatment of R/R AML. We have demonstrated that REV can be safely combined with GILT withencouraging preliminary efficacy. QTc prolongation is a DLT when combined with a strong CYP3A4inhibitor."

Clinical • P1 data • Acute Myelogenous Leukemia • Febrile Neutropenia • Hypotension • Infectious Disease • Neutropenia • Pulmonary Disease • FLT3 • KMT2A • MEIS1 • NUP98

Phase 1 study of revumenib in combination with intensive chemotherapy (IC) in patients (Pts) with newly diagnosed (ND) Acute Myeloid Leukemia (AML) harboring genetic alterations in KMT2A, NPM1, or NUP98: SNDX-5613-0708 (ASH 2025) - P1, P1/2 | "In the dose-escalation phase, pts receive induction withrevumenib and IC (cytarabine and daunorubicin or idarubicin) for up to two 28-day cycles. The safety profile of revumenib in combination with IC was consistent with the knownsafety profile of revumenib. PK findings support exposure targets above the IC90. Early efficacydemonstrated deep responses with all tested pts achieving MRD-negative CR."

Clinical • Combination therapy • P1 data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Febrile Neutropenia • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Neutropenia • Pneumonia • Respiratory Diseases • Septic Shock • KMT2A • NPM1 • NUP98

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 (ASH 2025) - P1/2 | "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 eachsubsequent 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 includeintensive chemotherapy, venetoclax (ven) ± hypomethylating agents, targeted therapies (such as FLT3inhibitors [i], IDH1i, or IDH2i if a corresponding co-mutation is present), and allogeneic hematopoieticstem cell transplant (HSCT). The median DORs by prior treatment were similar to that for the overallpopulation. Given the small subgroup sizes per prior treatment and overlapping confidence intervals,additional data are needed to identify optimal treatment sequences."

Clinical • P2 data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • KMT2A • NPM1

Post-transplant maintenance with revumenib in children with HOX-driven AML (ASH 2025) - P, P1/2 | "Molecular subtypesincluded KMT2Ar (n=8) and NUP98r (n=2); this was the second or greater transplant for five patients.Before transplant, revumenib was administered either as monotherapy per AUGMENT-101(NCT04065399) (n=3) or Expanded Access (NCT05918913) (n=2) or in combination with oral decitabineand venetoclax per the SAVE protocol (NCT05360160) (n=5)...Donor sources included matched sibling donors (n=2),matched unrelated donors (n=2), haploidentical donors (n=3), and unrelated cord blood units (n=3).Conditioning regimens varied by donor and included combinations of fludarabine, busulfan, thiotepa,total body irradiation (TBI), and post-transplant cyclophosphamide (PTCy)...Using revumenib as maintenance post-transplant in children with HOX-driven AML was safe and showedpromising early efficacy. Prospective studies are needed to confirm benefit and define optimal use."

Clinical • Post-transplantation • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Graft versus Host Disease • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Thrombocytopenia • Transplantation • KMT2A • NUP98

Early real-world experience with revumenib outside of a clinical trial setting: A single center retrospective review of efficacy and tolerability (ASH 2025) - "13 (72%) pts receivedhypomethylating agents and venetoclax in combination with revumenib and 1 pt received revumenibwith enasidenib. Early real-world data for revumenib confirms good tolerability with no AEs leading todiscontinuations. Early efficacy data shows excellent activity across molecular and disease subsets.Longer term follow-up data, inclusive of outcomes in molecular subsets, will be presented at the meeting."

Real-world • Real-world evidence • Retrospective data • Review • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Congestive Heart Failure • Heart Failure • Hematological Malignancies • Infectious Disease • Leukemia • Septic Shock • DNMT3A • FLT3 • IDH1 • KMT2A • NPM1 • NUP98 • TET2 • WT1

Setting the stage in KMT2A rearranged acute myelogenous leukemia in the era of menin inhibitors (ASH 2025) - "The recent AUGMENT-101 trial led to the approval of revumenib, a first-in-class drug, in relapsed/refractory KMT2Ar AML, however there is still limited data on outcomes of KMT2ArAML. AHSCT offers the best outcome for KMT2Ar AML. Intensive treatment yielded higher response rates, withmore pts proceeding to AHSCT. The addition of venetoclax to LIT in first-line therapies but not in salvagetherapies improved responses."

Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • IDH1 • KMT2A • NPM1 • TP53

Novel approaches to identify cellular vulnerabilities in TET2-dependent MDS (ASH 2025) - "Other drugs were effective in cells with missenseTET2MT while being completely ineffective in cells with other types of mutations. For example, cells frompatients with nonsense and frameshift TET2MT were more sensitive to the menin inhibitor, revumenib.Analyzing molecular associations, two cases with frameshift and dominant TET2MT which were sensitiveto revumenib also carried NPM1MT.In conclusion, identification of patients with distinctive genomic sub-entities will provide indications forthe investigation of TET2MT patterns (single mutation vs. combinations) predicting novel drugresponsiveness/resistance that can inform mechanistic studies as to the pathophysiologic pathwaysinvolved and the modeling of TET2-dependent conditions."

Acute Myelogenous Leukemia • Myelodysplastic Syndrome • TET2

Syndax Pharmaceuticals…announced that Revuforj (revumenib) was named Best New Drug at the Scrip Awards 2025, held by Citeline. (GlobeNewswire)

Commercial • Acute Myelogenous Leukemia

Therapeutic effect of menin inhibitors is reversible in AML treatment and could be enhanced by the targeting of differentiation associated chromatin complex (ASH 2025) - "In particular, combining the experimental MBD2 inhibitor KCC07 withthe Menin inhibitor Revumenib accelerated differentiation as early as day 3 (vs. day 7 with Revumenibalone)...Our study is the first to demonstrate the reversibility of Menin inhibitor–induced growth inhibition anddifferentiation. More importantly, we identified differentiation associated chromatin complex targeting(such as MBD2 inhibition) as a low-toxicity strategy that enhances and stabilizes Menin inhibitor–induceddifferentiation, offering a promising approach to overcome durability limitations in AML therapy."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • ITGAM • KAT6A • MEIS1 • MEN1