Revuforj (revumenib) / Syndax Pharma - LARVOL DELTA

Acute myeloid leukemia management and research in 2025. (PubMed, CA Cancer J Clin) - "Since 2017, a turning point in AML research, 12 agents have received regulatory approval for AML in the United States: venetoclax (BCL2 inhibitor); gemtuzumab ozogamicin (CD33 antibody-drug conjugate); midostaurin, gilteritinib, and quizartinib (fms-like tyrosine kinase 3 inhibitors); ivosidenib, olutasidenib, and enasidenib (isocitrate dehydrogenase 1 and 2 inhibitors); oral azacitidine (a partially absorbable formulation); CPX351 (liposomal encapsulation of cytarabine:daunorubicin at a molar ratio of 5:1); glasdegib (hedgehog inhibitor); and recently revumenib (menin inhibitor; approved November 2024). Oral decitabine-cedazuridine, which is approved as a bioequivalent alternative to parenteral hypomethylating agents in myelodysplastic syndrome, can be used for the same purpose in AML. Menin inhibitors, CD123 antibody-drug conjugates, and other antibodies targeting CD123, CD33, and other surface markers are showing promising results. Herein, the authors review the..."

IO biomarker • Journal • Review • Acute Myelogenous Leukemia • Acute Promyelocytic Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation • CD123 • CD33 • FLT3 • IDH1 • IL3RA

A Multi-Site Break through Cancer Trial: Phase II Study Investigating Dual Inhibition of BCL2 and Menin in AML MRD Using the Combination of Venetoclax and Revumenib (Trial In Progress) (ASH 2024) - P2 | "This study may identify a novel strategy to eradicate MRD using combination targeted therapies which may decrease recurrence and improve remission duration. In addition, this study could improve detection of MRD, and our understanding of MRD biology."

IO biomarker • P2 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • KMT2A • NPM1 • NUP98

Oncogenic Potential and Sensitivity to Menin Inhibitors of a Novel Fusion KAT6B::NUTM2B in Congenital Myeloid Sarcoma with Bone Marrow Involvement (ASH 2024) - "To test the sensitivity to the menin inhibitor SNDX-5613, varying concentrations of SNDX-5613 were added to CFU medium...Whole transcriptome analysis of the KN-positive case demonstrated a transcriptomic profile similar to that of KAT6A and KMT2A fusions and activation of HOXA9/10 genes. Furthermore, our in vitro study indicated a dramatic proliferative potential and oncogenic transformation of KN-positive cells and sensitivity to menin inhibitor, suggesting a promising new therapeutic approach for KAT6B-associated fusions."

Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Prostate Cancer • Rare Diseases • Sarcoma • Solid Tumor • CD123 • CD133 • CD14 • CD34 • HOXA10 • HOXA9 • IL3RA • ITGAM • ITGAX • KAT6A • KAT6B • KIT • KMT2A • NUTM2B

Identifying 'Druggable' Targets and Preclinically Overcoming Non-Genetic/Adaptive Resistance to Menin Inhibitors in AML with MLL1r or mtNPM1 (ASH 2024) - "These MITR cells exhibited cross-resistance to other MIs, including ziftomenib and DS1594b...Notably, in a luciferized MLL1r MITR AML PDX model, compared to treatment with each agent alone, co-treatment with FHD-286 and SNDX-5613 or OTX015 for 8-weeks yielded significantly superior survival of the NSG mice (p < 0.05). These findings demonstrate that co-treatment with FHD-286 overcomes in vitro and in vivo MI-resistance, while significantly improving in vivo efficacy of BETi in the cell-line xenograft and PDX models of MITR AML cells. They also show that combinations of epigenetically targeted agents may be effective in MI-sensitive or -resistant AML with MLL1r or mtNPM1."

IO biomarker • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • BRD4 • CDK6 • CLEC12A • CREBBP • EP300 • FLT3 • HOXA9 • IGF2BP2 • MEF2C • MEIS1 • NPM1 • PBX3 • SMARCA4

Discovery of BTC-86, a Novel Second-Generation Menin-MLL Inhibitor to Overcome the Acquired Resistance in MEN1 for R/R Acute Leukemia (ASH 2024) - "BTC-86 is the most potent one in inhibition of menin-MLL1 binding against all the MEN1 acquired mutations among all five clinical molecules, including SNDX-5613, JnJ-75276617, and KO-539. IND-enabling study of BTC-86 is in progress. Further studies in clinical setting are warranted to confirm BTC-86 as a second-generation menin-MLL inhibitor for overcoming acquired resistance in MEN1."

Preclinical • Biliary Tract Cancer • Hematological Malignancies • Leukemia • Oncology • KMT2A • MEIS1 • MEN1 • NPM1

Targeting Menin in T-Lineage Acute Lymphoblastic Leukemia (ASH 2024) - "Menin inhibitors (e.g., revumenib, ziftomenib) had remarkable single-agent activity for KMT2A-rearranged (KMT2A-r) and NPM1-mutant leukemias in early phase clinical trials. These data provide evidence for preclinical activity of menin inhibitors in T-ALL with high p-MEF2C. Additional studies investigating combination strategies and the use of p-MEF2C as a biomarker of ziftomenib response in T-ALL are ongoing."

Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • T Acute Lymphoblastic Leukemia • ABL1 • CD7 • CDK1 • CDK6 • KMT2A • MEF2C • MEIS1 • MLLT10 • NPM1 • NUP214 • NUP98

REM-422, a Small Molecule MYB mRNA Degrader, Demonstrates Anti-Leukemic Activity As Monotherapy and in Combination with Standards of Care in Preclinical Models of AML (ASH 2024) - P1 | "The activity of REM-422 was assessed in vitro in combination with AML standards of care by co-treating leukemia cell lines with REM-422 and other agents including venetoclax, gilteritinib, revumenib, and azacitidine. The REM-422 and revumenib combination arm demonstrated more durable activity with delayed tumor regrowth kinetics after cessation of dosing compared to the monotherapy arms. Altogether, these data support the therapeutic potential for REM-422 in AML patients both as monotherapy and in combination therapy."

Combination therapy • IO biomarker • Monotherapy • Preclinical • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Adenoid Cystic Carcinoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Oncology • ANXA5 • BCL2 • CD14 • FLT3 • ITGAM • KMT2A • MYB

The Histone Acetyltransferase MOZ (KAT6A) Is a Molecular Dependency and Therapeutic Target in NUP98-Rearranged Acute Myeloid Leukemia (ASH 2024) - "In combination with SNDX-5613, PF9363 increased median latency by 50% compared to vehicle and by 18% compared to PF9363 alone. In summary, our studies show that MOZ is a therapeutic vulnerability in NUP98 FO-driven AML and that MOZ inhibitor treatment may improve responses to Menin inhibition."

Epigenetic controller • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • HOXA13 • HOXA9 • JADE2 • KAT6A • KDM5A • KMT2A • MEIS1 • NSD1 • NUP98 • PRRX1 • SETBP1

Discerning the Landscape of Menin Inhibitor Resistance (ASH 2024) - "With higher dose MI therapy, only 1 of 5 mice developed a MEN1 mutation and in the remaining mice MEN1 WT cells persisted and slowly expanded over the course of ≥6 months of therapy despite on-target gene expression changes : decreased MEIS1 and HOXA cluster genes, increased CD11b, CD13, CD14.Given that CRISPR-Cas9 base editing previously predicted some of the MEN1 mutations that arose with revumenib, we utilized improved base editing technology to help discern the landscape of MEN1 acquired mutations for four additional MIs currently in clinical trials (DS-1594, DSP-5336, JNJ-75276617, ziftomenib). An in vitro technique leveraging large starting cell numbers validates this base editor screening approach, which resulted in rapid development of resistant MEN1 mutant clones in less than 4 weeks of treatment. Identifying MEN1 mutations in patients receiving MIs is important because there may be opportunities for patients with select MEN1 mutations to derive benefit from an..."

Hematological Malignancies • Leukemia • Oncology • ANPEP • CD14 • ITGAM • KMT2A • MEIS1 • MEN1 • NPM1

Phase I/II Study of the All-Oral Combination of Revumenib (SNDX-5613) with Decitabine/Cedazuridine (ASTX727) and Venetoclax (SAVE) in R/R AML (ASH 2024) - P1/2 | "ASTX727 (decitabine/ cedazuridine) was administered at 35 mg/100 mg PO daily days 1-5, venetoclax at 400 mg (target dose) PO daily days 1-14, and revumenib 113 mg PO Q12h (dose level [DL] 0) or 163 mg PO Q12h (DL 1, used in phase II monotherapy), days 1-28 with either posaconazole or voriconazole (strong CYP3A4 inhibitors). Conclusions : The all-oral combination SAVE results in high rates of remission in pts with R/R AML with KMT2Ar, NPM1mt or NUP98r. In addition to the R/R cohort, a frontline cohort is now enrolling pts."

IO biomarker • P1/2 data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Metabolic Disorders • Nephrology • Neutropenia • Oncology • Renal Disease • Respiratory Diseases • Thrombocytopenia • KMT2A • NPM1 • NUP98

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 (ASH 2024) - P1/2 | "Pts were heavily pretreated (median of 2 prior therapies [range, 1-11]), with 51 (44%) receiving ≥3 prior lines, 73 (63%) receiving prior venetoclax, and 59 (51%) underwent prior hematopoietic stem cell transplant (HSCT). The safety profile of revumenib with this longer follow-up is consistent with prior reports. This trial represents the largest evaluation of a targeted therapy for pts with R/R KMT2Ar acute leukemias to date."

Clinical • P2 data • Anemia • Bone Marrow Transplantation • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Neutropenia • Oncology • Septic Shock • KMT2A

Revumenib As Pre-Emptive Therapy for Measurable Residual Disease in NPM1 mutated or KMT2A-rearranged Acute Myeloid Leukemia: A Domain of the Multi-Arm ALLG AMLM26 Intercept Platform Trial (ASH 2024) - P, P1/2 | "Median age was 62 years (range 19-85), 7 were in CR1, 3 had prior venetoclax exposure and 6 prior intensive therapy. In preliminary analysis, NPM1m ≥1 log10 MRD reduction was recorded in 62.5% (n=5) of pts, including 37.5% (n=3) achieving MRD negativity. Further updates will be presented at the meeting."

Residual disease • Acute Myelogenous Leukemia • Anemia • Febrile Neutropenia • Neutropenia • Thrombocytopenia • KMT2A • NPM1

Additional Results from R/R mNPM1 AML Patients in Pivotal Phase 2 Portion of AUGMENT-101 (PRNewswire) - P1/2 | N=413 | AUGMENT-101 (NCT04065399) | Sponsor: Syndax Pharmaceuticals | "Syndax announced today additional results from the Phase 2 cohort of R/R mNPM1 AML patients in the AUGMENT-101 trial....Subgroup analyses from the Phase 2 protocol-defined R/R mNPM1 efficacy population (N=64) show that CR/CRh responses were observed across all major subgroups....The CR+CRh rate was 25% (4/16) among patients with 1 prior line of therapy, 20% (5/25) among patients with 2 prior lines of therapy, and 26% (6/23) among patients who had received three or more prior lines of therapy....Among the 84 patients enrolled in the...Phase 2...cohort, 77 met the efficacy evaluable criteria requiring patients to have blast counts >5% measured within 28 days prior to treatment and a centrally confirmed NPM1 mutation. In this expanded post-hoc efficacy analysis, 48% (37/77; 95% CI: 37%, 60%) achieved an overall response, and 26% (20/77; 95% CI: 17%, 37%) achieved a CR/CRh."

P2 data • Acute Myelogenous Leukemia

Revumenib: “The all-oral SAVE [revumenib (SNDX-5613), oral decitabine/cedazuridine (ASTX727) and venetoclax] - acceptable safety and high efficacy in children and adults with R/R AML susceptible to menin inhibition”; ”Acute myeloid leukemia (Syndax) - ASH 2024: “ORR 82%, CR/CRh 48% - MRD-neg 88% in responders. Median DOR not reached”

P1/2 data • Acute Myelogenous Leukemia • Hematological Malignancies • Oncology

Revumenib: “Clinical outcomes of Aza/Ven/Rev”; Acute myeloid leukemia (Syndax) - ASH 2024: “Overall Response rate = 100% in 37 evaluable patients”

P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Oncology

Revumenib: “In this updated phase 2 analysis, revumenib continues to consistently provide clinically meaningful responses in heavily pretreated patients with R/R KMT2Ar acute leukemias, including high rates of MRD negativity and ability to proceed to HSCT”; :Acute myeloid leukemia" (Syndax) - ASH 2024: “The safety profile of revumenib is manageable; no patients discontinued due to differentiation syndrome or QTc prolongation”

P2 data • Acute Myelogenous Leukemia • Hematological Malignancies • Oncology

Revumenib: “Revumenib demonstrated compelling efficacy in R/R mNPM1 AML patients in Ph 2 portion of AUGMENT-101”; Acute myeloid leukemia (Syndax) - ASH 2024: “77 of 84 enrolled patients met the efficacy evaluable criteria (i.e., blast counts >5% measured within 28 days prior to treatment and centrally confirmed mNPM1)”

P2 data • Acute Myelogenous Leukemia • Hematological Malignancies • Oncology

Updated Data from BEAT-AML Trial of Revumenib in Combination with Venetoclax and Azacitidine in Newly Diagnosed AML Patients (PRNewswire) - P1/2 | N=2,000 | BEAT-AML (NCT03013998) | Sponsor: Beat AML, LLC | "The efficacy evaluable population includes 37 patients across both dose levels with an ORR of 100% (37/37) and CRc rate of 95% (35/37). The rate of MRD negativity was 95% (35/37). 27% (10/37) of patients proceeded to hematopoietic stem cell transplant (HSCT). Revumenib was generally well tolerated at both the 113 mg and 163 mg q12h dose in combination with venetoclax and azacitidine. In the safety population (N=46), 15% (7/46) of patients experienced differentiation syndrome with two (4%) Grade 3 or greater events. 43% (20/46) of patients experienced QTc prolongation with five (11%) Grade 3 or greater events...The Company plans to initiate a pivotal trial with this combination in front-line newly diagnosed patients by year-end 2024."

P1 data • Acute Myelogenous Leukemia

Pyoderma gangrenosum-like neutrophilic dermatosis as an adverse effect of menin-KMT2A inhibitor therapy for acute myeloid leukaemia. (PubMed, Ann Hematol) - "A 71 years old woman received the MENi revumenib (REV) for relapsed/refractory NPM1m AML...However, to our knowledge, this is the first report ever of MENi induced PG-like ND and cutaneous involvement of DS. This report highlights the fact that ND such as PG, as a manifestation of DS, are a possibly severe adverse effect of MENi."

Adverse events • Journal • Acute Myelogenous Leukemia • Dermatology • Hematological Malignancies • Leukemia • Oncology • Pyoderma Gangrenosum • KMT2A

Results from Phase 1/2 SAVE Trial of Revumenib in Combination with Venetoclax and Decitabine/Cedazuridine in R/R AML (PRNewswire) - P1b/2 | N=43 | SAVE (NCT05360160) | "The all-oral combination resulted in high rates of remission in patients with KMT2Ar, mNPM1, and NUP98r with an overall response rate (ORR)1 of 82% (27/33) and a CR/CRh rate of 48% (16/33). In patients with minimal residual disease (MRD) status available, 65% (17/26) who achieved a response were MRD negative, and among patients who achieved a CR/CRh response, 88% (14/16) were MRD negative. 39% (13/33) of patients proceeded to HSCT following this combination, with 54% (7/13) of patients resuming revumenib post-HSCT....With a median follow-up of 9.3 months (N=33), the 6-month overall survival (OS) was 68% (95% CI: 47%, 80%); median OS was not reached. The median duration of CR/CRh response was also not reached....The most common (>20%) Grade 3 or higher treatment-emergent adverse events (TEAEs) were febrile neutropenia (33%) and lung infection (33%)."

P1/2 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Data from Phase 2 Portion of the AUGMENT-101 Trial of Revumenib in R/R KMT2Ar Acute Leukemia (PRNewswire) - P1/2 | N=413 | AUGMENT-101 (NCT04065399) | Sponsor: Syndax Pharmaceuticals | "During the oral session at the ASH meeting, the Company presented additional data from this larger data set showing that responses were observed across all major subgroups, including heavily pretreated patients, patients with prior venetoclax exposure, and patients of all ages. The updated analyses also show that of the 21 responders who proceeded to HSCT, 67% (14/21) went to transplant in CRc [38% (8/21) in CR/CRh and 29% (6/21) in CRp/CRi] and 33% (7/21) went to transplant in MLFS. Of the patients who proceeded to transplant in CRc and had MRD results available, 82% (9/11) were MRD negative....Time to response was rapid with a median time to ORR of 1.0 months (range: 0.9-3.1) and median time to CR/CRh of 2.0 months (range: 0.9-4.6). As previously reported, the median duration of CR/CRh was 6.4 months among the 22 CR/CRh responders."

P2 data • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Bezlotoxumab As Treatment for Recurrent/Chronic Clostridioides Difficile Infection in Stem Cell Transplant Recipients (ASH 2024) - "However, the safety and efficacy of bezlotuxumab has not been studied in pediatric patients undergoing a SCT, and no data exists to detail its impact on common immunosuppressants such as tacrolimus and mycophenolate mofetil (MMF)...Following relapse of AML, the patient enrolled on a clinical trial to receive a KMT2A inhibitor, revumenib, achieved remission, and eventually proceeded to a second SCT using a single cord donor. The patient's post-SCT course was complicated by Streptococcus mitis/oralisbacteremia, resulting in a long course of broad-spectrum antibiotics with vancomycin and meropenem...At this recurrence, she was hospitalized for dehydration and treated with oral vancomycin, subsequently transitioning to oral fidaxomicin over a 21-day taper...All patients were confirmed to have no gastrointestinal GVHD causing the diarrhea, and no recurrence of diarrhea occurred after bezlotoxumab. This case series strongly suggests the potential utility of bezlotoxumab..."

Clinical • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Gastroenterology • Gastrointestinal Disorder • Graft versus Host Disease • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Oncology • Pediatrics • Pneumonia • Respiratory Diseases • Transplantation • DEK • KMT2A • NUP214

Efficacy and Safety of Revumenib in the Treatment of Acute Myeloid Leukemia with KMT2A Rearrangements or NPM1 Mutations: A Systematic Review (ASH 2024) - "These findings highlight Revumenib as a potential new standard of care for this challenging subset of AML, pending further validation from larger, more comprehensive studies. Revumenib offers promising outcomes for relapsed/refractory AML patients with KMT2A rearrangements or NPM1 mutations, supporting its integration into clinical practice."

Clinical • Review • Acute Myelogenous Leukemia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology • KMT2A • NPM1

Lintuzumab-Ac225 Exerts Mutation Agnostic Antileukemic Activity in Preclinical Models of AML (ASH 2024) - "In clinical trials, lintuzumab-Ac225 has demonstrated promising therapeutic responses when added to CLAG-M chemotherapy in heavily pretreated relapsed/refractory AML patients, including high risk populations with venetoclax failures and TP53 mutations...Although the single agent cytotoxicity of FLT3 inhibitors (gilteritinib, quizartinib) and KMT2A inhibitors (revumenib, ziftomenib) was observed with varied sensitivity in both MV-4-11 and MOLM-13 FLT3/KMT2A mutation-carrying cells, the combinations with lintuzumab-Ac225 were additive at all studied dose levels (p<0.01)...CD33-targeted radiation-induced damage improves AML control in adverse-risk settings, and further potentiates response durability when added to standard-of-care, including molecularly targeted therapy. Collectively, these data support the backbone therapy potential of lintuzumab-Ac225 in a mutation agnostic manner, warranting further clinical evaluation in difficult to treat relapsed/refractory AML."

Preclinical • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CD33 • CDKN1A • FLT3 • IDH1 • IDH2 • KMT2A • NPM1 • TP53

A Phase II Study of the Menin Inhibitor Revumenib in Leukemia Associated with Upregulation of HOX Genes: Trial in Progress (ASH 2024) - P2 | "If this occurs, expansion cohorts in those subsets will be started. In addition, HOX/MEIS1 expression may become a genotype-agnostic method of identifying patients who will benefit from menin inhibition."

P2 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CDX2 • CREBBP • ETV6 • KAT6A • KMT2A • MEIS1 • MEN1 • MLLT10 • MN1 • NPM1 • NUP214 • NUP98 • RUNX1