Idhifa (enasidenib) / BMS, Royalty, Servier, Schrodinger - LARVOL DELTA

Enasidenib plus venetoclax in patients with IDH2-mutated relapsed or refractory acute myeloid leukaemia or myelodysplastic syndrome (ENAVEN-AML): a multicentre, single-arm, phase 1b/2 trial. (PubMed, Lancet Haematol) - P1/2 | "Enasidenib plus venetoclax is safe, with no unexpected TEAEs or treatment-related deaths, and shows preliminary activity in patients with relapsed or refractory IDH2-mutated AML and MDS."

IO biomarker • Journal • P1/2 data • Acute Myelogenous Leukemia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology • Pneumonia • Respiratory Diseases • Septic Shock • Thrombocytopenia • ARG1 • IDH2

Overall survival by IDH2 mutant allele (R140 or R172) in patients with late-stage mutant-IDH2 relapsed or refractory acute myeloid leukemia treated with enasidenib or conventional care regimens in the phase 3 IDHENTIFY trial. (ASCO 2022) - P3 | "Pts were preselected to a CCR (azacitidine, intermediate- or low-dose Ara-C, or supportive care), and were then randomized 1:1 to ENA 100 mg/d or CCR in 28d cycles. Mutational burden and co-mutational profiles differed between pts with mIDH2-R140 and mIDH2-R172 R/R AML. ENA improved survival outcomes for pts with IDH2-R172 mutations, with median OS and 1-year survival rate approximately double those in the CCR arm."

Clinical • P3 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • DNMT3A • FLT3 • IDH2 • JAK2 • NPM1 • RUNX1 • SRSF2 • TMB • TP53

Phase Ib/2 Study of Oral Decitabine/Cedazuridine (ASTX727) and Venetoclax in Combination with the Targeted Mutant IDH1 Inhibitor Ivosidenib or the Targeted Mutant IDH2 Inhibitor Enasidenib in IDH Mutated Acute Myeloid Leukemia (ASH 2022) - "(Table 1) In the R/R cohort, 78% (n=11) patients had received prior treatment with either an HMA (azacitidine or decitabine), BCL2i and/or IDHi, with a median of 2 prior treatments...There were two patients with possible/probable differentiation syndrome which resolved with medical management (dexamethasone and diuresis)...AEs are anticipated and tolerable. Enrollment to this study is ongoing."

Combination therapy • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Febrile Neutropenia • Hematological Malignancies • Hepatology • Mucositis • Myelodysplastic Syndrome • Neutropenia • Transplantation • IDH1

Mutations in IDH1 and IDH2 portend a poor prognosis in adult patients with acute lymphoblastic leukemia (ASH 2025) - "One pt with IDH1mut T-ALL and 2 ptsIDH2mut T-ALL received ivosidenib and enasidenib, respectively, in salvage: the IDH1mut pt had noresponse and the 2 IDH2mut pts achieved CR with a median duration of response of 17 months (3-31)before relapsing.The median event-free survival (EFS) for IDHmut pts was 16 months, with a 3-year EFS rate of 28%, vs. amedian EFS of 69 months and a 3-year EFS rate of 60% in IDHwt pts (p=0.0005). Co-occurring mutations include DNMT3A, NOTCH1, and NRAS, which were enriched inpts with T-ALL. Novel therapeutic strategies, including venetoclax and IDH inhibitors, are warranted inthis high-risk subgroup."

Clinical • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • T Acute Lymphoblastic Leukemia • BCOR • DNMT3A • IDH1 • IDH2 • IKZF1 • JAK1 • KRAS • NOTCH1 • NRAS • SRSF2 • TET2 • TP53

Postmarketing Safety Signals of Revumenib (Menin-KMT2A Inhibitor) vs Acute Myeloid Leukemia-Targeted Therapies: A Class-Restricted Disproportionality Analysis of the FDA Adverse Event Monitoring System (2016–2026) (SOHO 2026) - " AE reports (January 2016–April 2026) were extracted for revumenib (n = 716) and eight targeted AML therapies (n = 70179): ziftomenib, enasidenib, ivosidenib, olutasidenib, gilteritinib, midostaurin, quizartinib, and venetoclax. Analysis of 716 revumenib reports (median age, 50 years; 50.2% male; 57.5% US-sourced; 55.6% serious) identified AML as the recorded indication in 59.2% of cases. Eleven AEs qualified as robust signals. Established toxicities included differentiation syndrome (n = 32; ROR, 9.12; 95% CI, 6.31–13.20), QTc prolongation (n = 29; ROR, 8.88; 95% CI, 6.03–13.08), and decreased platelet count (n = 113; ROR, 3.91; 95% CI, 3.19–4.79)."

Adverse events • Clinical • P4 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • KMT2A

Outcomes of Frontline Triplet Regimens With a Hypomethylating Agent, Venetoclax, and Isocitrate Dehydrogenase Inhibitor for Intensive Chemotherapy-Ineligible Patients With Isocitrate Dehydrogenase-Mutated AML. (PubMed, J Clin Oncol) - P1/2 | "Given the excellent outcomes of IDH-triplet therapy for newly diagnosed, IC-ineligible IDH-mutant AML, further prospective studies comparing IDH-triplet versus IDH-doublet regimens are warranted."

Journal • Acute Myelogenous Leukemia • Transplantation • IDH1 • IDH2

Novel targeted therapy and cellular immunotherapy enabling allogeneic hematopoietic stem cell transplantation for relapsed/refractory acute myeloid leukemia. (PubMed, Chin Med J (Engl)) - "For R/R AML patients with mutated FMS-related tyrosine kinase 3 (FLT3), sorafenib and quizartinib have shown encouraging therapeutic effects either in combination with chemotherapy for bridging to transplantation or as maintenance therapy after HSCT. Ivosidenib and enasidenib, which are inhibitors that target mutated isocitrate dehydrogenase (IDH) 1 and 2, respectively, have been approved by the US Food and Drug Administration (FDA) for the treatment of IDH1/IDH2-mutated R/R AML. Venetoclax, an inhibitor of B-cell lymphoma-2 (BCL2), is widely used in the salvage treatment of R/R AML and has better therapeutic effects and controllable drug toxicity than traditional chemotherapy. In addition, chimeric antigen receptor (CAR) T-cell immunotherapy (targeting CD33, CD123, and CLL1) has achieved encouraging clinical response rates in phase I and phase II clinical trials for R/R-AML, and subsequent bridging HSCT has significantly improved patient survival."

IO biomarker • Journal • Acute Myelogenous Leukemia • B Cell Lymphoma • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Lymphoma • Oncology • Transplantation • BCL2 • CD123 • CD33 • FLT3 • IDH1 • IDH2 • IL3RA

A Risk-Adapted Study to Assess the Efficacy of Enasidenib and Subsequent Response-Driven Addition of Azacitidine for Newly Diagnosed IDH2-Mutant AML Patients: 3-Year Follow-up (ASH 2022) - P1/2 | "At three-year follow-up, ENAm continues to be a safe and well-tolerated therapy in ND patients ≥ 60 years old with IDH2m AML both alone and with the risk-adapted addition of AZA. CR/CRi rates are high (48%, adjusted 95% CI 30.3-60.5) and remissions are durable (11.1 months, 95% CI 5.6-41.4). The composite CR (cCR) rate of ENAm appears comparable to the cCR rate achieved with ENA + AZA in AG221-AML-005, a phase 2 study comparing ENA + AZA to AZA alone in ND AML."

Clinical • Acute Myelogenous Leukemia • Anemia • Bone Marrow Transplantation • Hematological Disorders • Oncology • Renal Disease • Transplantation • ENAM • IDH2

DNMT3A as an Epigenetic Scaffold in Acute Myeloid Leukemia: Synergistic Mutational Landscapes and Therapeutic Implications (SOHO 2026) - "In Patient 1, the identification of IDH2 allowed for a triple combination therapy (azacitidine/venetoclax+enasidenib), successfully achieving clinical remission after intensive chemotherapy failure. : Our findings emphasize that DNMT3A mutations serve as a critical epigenetic scaffold for secondary mutations. Comprehensive NGS profiling identifies these synergistic clusters, enabling a shift from standard 7+3 protocols to personalized, targeted combinations (eg, IDH inhibitors) that can overcome epigenetic block in relapsed/refractory AML. 7+3: cytarabine given daily for 7 days and daunorubicin given daily for 3 days, AMP: Association for Molecular Pathology, ASCO: American Society of Clinical Oncology, CAP: College of American Pathologists, CGC: Cancer Genomics Consortium, ClinGen: Clinical Genome Resource, DNMT3A: DNA methyltransferase 3 alpha, FLAG-IDA: fludarabine, cytarabine, granulocyte colony–stimulating factor plus idarubicin, IDH1/2: isocitrate dehydrogenase 1..."

Acute Myelogenous Leukemia • Breast Cancer • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • DNMT3A • IDH1 • IDH2 • NPM1 • TET2 • TP53

Clinical Outcomes Using Frontline “Triplet“ Regimens for Newly Diagnosed IDH-Mutated Acute Myeloid Leukemia (AML): A Pooled Analysis of Two Phase Ib/2 Clinical Trials (ASH 2024) - P1/2 | "Targeted IDH inhibitors (IDHi) such as ivosidenib (IVO) and enasidenib (ENA) are also effective, either as single agents or in combination with azacitidine (AZA)...In this pooled analysis, we report the clinical outcomes and patterns of relapse among pts with newly diagnosed (ND) IDH mutant AML who are not eligible for intensive chemotherapy treated with frontline triplet regimens containing a HMA + venetoclax (VEN) + IDHi...Pts received either frontline AZA + VEN + IVO or oral Decitabine/Cedazuridine (ASTX727) + VEN + IVO/ENA (arms for IDH1 or IDH2 mutant disease, respectively)...Given these promising frontline results, prospective studies comparing triplet versus doublet regimens for IDH mutant AML are warranted. Enrollment on both HMA + VEN + IDHi triplet trials is ongoing."

Clinical data • Retrospective data • Acute Myelogenous Leukemia • Hepatology • Mucositis • ETNK1 • FLT3 • GNAS • IDH1 • IDH2 • KRAS • NPM1 • NRAS • SETBP1 • TET2 • TP53

A PHASE IB/2 TRIAL OF AN ALL-ORAL "TRIPLET" REGIMEN FOR IDH-MUTATED MYELOID MALIGNANCIES: DECITABINE/CEDAZURIDINE AND VENETOCLAX IN COMBINATION WITH IVOSIDENIB/ENASIDENIB (EHA 2025) - P1/2 | "An all-oral triplet regimen of DEC-C+VEN+IVO/ENA demonstrated an impressive CRc rate in both ND and R/R pts with IDH mutant myeloid neoplasms with no new safety signals."

Combination therapy • Acute Myelogenous Leukemia • Hepatology • Infectious Disease • Myelodysplastic Syndrome • IDH1 • IDH2 • TP53

Targeted therapy with the mutant IDH2 inhibitor enasidenib for high-risk IDH2-mutant myelodysplastic syndrome. (PubMed, Blood Adv) - P2 | "Enasidenib is an effective treatment option for mIDH2 MDS, both in combination with azacitidine for treatment naïve high-risk MDS, and as a single agent after prior HMA therapy. This trial is registered at www.clinicaltrials.gov as NCT03383575."

Clinical • Journal • Acute Myelogenous Leukemia • Constipation • Fatigue • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Hepatology • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology • UGT1A1

Survival and Toxicity Trade-Offs With Anthracycline-Based Induction vs Non-Anthracycline Therapy in Newly Diagnosed Acute Myeloid Leukemia: A Real-World Propensity-Matched Analysis (SOHO 2026) - "Anthracycline cohort (n = 9727): daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone. Nonanthracycline cohort (n = 6649): azacitidine, decitabine, venetoclax, glasdegib, gilteritinib, enasidenib, ivosidenib, midostaurin; anthracyclines excluded... Anthracycline induction was associated with 27% lower 3-year mortality but higher acute toxicity—36% more hospitalization, 23% bleeding, 13% VTE, 11% MACE—reflecting the risk-benefit profile of intensive induction. Selection of fitter patients with favorable AML biology likely contributes through residual confounding despite PSM. These findings reinforce integrating fitness, cytogenetic/molecular risk, and patient preference into the frontline regimen choice."

Clinical • Real-world • Real-world evidence • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3

V-FAST Master Trial: Subgroup Analysis of Outcomes with CPX-351 Plus Midostaurin in Adults with Newly Diagnosed Acute Myeloid Leukemia By FLT3 Mutation Type (ASH 2022) - P1b | "V-FAST (Vyxeos – First Phase Assessment with Targeted Agents) is an open-label, multicenter, multi-arm, nonrandomized, phase 1b master trial (NCT04075747) to evaluate the safety and preliminary efficacy of CPX-351 combined with targeted agents (MID, venetoclax, enasidenib)...In conclusion, preliminary results from the V-FAST trial suggest the combination of CPX-351 + MID is feasible with a manageable safety profile and promising remission rates in adults with newly diagnosed, FLT3-mutated AML. Although conclusions are limited by the small numbers of patients in each subgroup, results are generally consistent for patients with FLT3 ITD and TKD mutations."

Clinical • Acute Myelogenous Leukemia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Leukopenia • Myelodysplastic Syndrome • Neutropenia • Oncology • Thrombocytopenia • Transplantation • FLT3

Phase Ib/2 Study of Oral Decitabine/Cedazuridine (ASTX727) and Venetoclax in Combination with the Targeted Mutant IDH1 Inhibitor Ivosidenib or the Targeted Mutant IDH2 Inhibitor Enasidenib: 2023 Update (ASH 2023) - "AEs were anticipated and tolerable. Enrollment is ongoing."

Combination therapy • Acute Myelogenous Leukemia • Hepatology • Mucositis • CYP3A4 • IDH1 • IDH2

Beat AML: Study of Biomarker-Based Treatment of Acute Myeloid Leukemia (clinicaltrials.gov) - P2/3 | N=3000 | Recruiting | Sponsor: Beat AML, LLC | Phase classification: P1/2 ➔ P2/3 | Trial completion date: Dec 2028 ➔ Dec 2032 | Trial primary completion date: Dec 2028 ➔ Dec 2032

Biomarker • Phase classification • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • NPM1

Molecularly Targeted Combination Therapy for Advanced Phase Myeloproliferative Neoplasm: MPN-RC 119 (ASH 2022) - P2 | "Combination treatment with ruxolitinib and enasidenib appear safe with manageable toxicity profile. The majority of grade 3/4 AEs were hematologic as expected in this advanced patient population. Results are encouraging and warrant continued evaluation of this IDH2 mutant defined poor prognostic group."

Combination therapy • Bone Marrow Transplantation • Febrile Neutropenia • Hematological Disorders • Hepatology • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Transplantation

Multicenter Pilot Clinical Trial of Enasidenib As Maintenance Therapy after Allogeneic Hematopoietic Cell Transplantation in Patients with Acute Myeloid Leukemia (AML) Carrying IDH2 Mutations (ASH 2022) - P1 | "GVHD prophylaxis consisted of post-transplant cyclophosphamide-based (60%; n=9) or tacrolimus-based (40%; n=6) regimens (Tac/Siro= 4 and Tac/MTX= 2). While treatment delays and dose reductions were common, the majority of the study patients remained on the protocol therapy. Droplet digital PCR testing on bone marrow was done to study clearance of IDH2 clones post-HCT and these results will be available by December 2022."

Clinical • Acute Graft versus Host Disease • Acute Myelogenous Leukemia • Anemia • Chronic Graft versus Host Disease • Graft versus Host Disease • Hematological Malignancies • Immunology • Lymphoma • Multiple Myeloma • Neutropenia • Thrombocytopenia • Transplantation • IDH1 • IDH2

Enasidenib as Maintenance following Allogeneic Hematopoietic Cell Transplantation for IDH2-Mutated Myeloid Malignancies. (PubMed, Blood Adv) - P1 | "Enasidenib is safe, well-tolerated, with preliminary activity as maintenance therapy following HCT, and merits additional study. The study was registered at ClinicalTrials.gov (NCT03515512)."

Journal • Acute Graft versus Host Disease • Acute Myelogenous Leukemia • Chronic Graft versus Host Disease • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Novel Coronavirus Disease • Oncology • Transplantation • IDH2

Multicenter Pilot Clinical Trial of Enasidenib As Maintenance Therapy after Allogeneic Hematopoietic Cell Transplantation (alloHCT) in Patients with Acute Myeloid Leukemia (AML) Carrying IDH2 Mutations (TCT-ASTCT-CIBMTR 2024) - P1 | "In conclusion, post-HCT maintenance therapy with enasidenib is safe and feasible with highly favorable survival outcomes in mIDH2 AML. Treatment delays and dose reductions were commonly seen; however, most patients completed their 2-years maintenance."

Clinical • Acute Graft versus Host Disease • Acute Myelogenous Leukemia • Anemia • Chronic Graft versus Host Disease • Graft versus Host Disease • Hematological Malignancies • Immunology • Neutropenia • Thrombocytopenia • Transplantation • IDH1 • IDH2

A Study of Enasidenib in People With T-Cell Lymphoma (clinicaltrials.gov) - P2 | N=2 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Recruiting ➔ Active, not recruiting | N=25 ➔ 2

Enrollment change • Enrollment closed • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • IDH2

Cost-Effectiveness of Epigenetic Drugs in Oncology: A Systematic Review of Economic Evaluations. (PubMed, Value Health) - "This systematic review offers a comprehensive synthesis of current economic evaluations of epidrugs in oncology. The wide variability in ICERs and methodological approaches underscores the need for more standardized and robust evaluations to clarify the economic value of epigenetic drugs."

HEOR • Journal • Review • Hematological Disorders • Oncology

Host systemic metabolism and cancer metabolic vulnerabilities: mechanisms and therapeutic opportunities. (PubMed, Front Oncol) - "FDA-validated targets include IDH1/2 (ivosidenib, enasidenib, vorasidenib-August 2024), HIF-2α (belzutifan), and mTOR (everolimus). Future advances require AI-driven genome-scale metabolic modelling for patient stratification, single-cell and spatial metabolomics to resolve intra-tumoral metabolic heterogeneity, and rational combination strategies targeting multiple metabolic nodes simultaneously to preempt adaptive resistance. Integration of circadian pharmacology, host metabolic comorbidity management (obesity, diabetes, gut microbiome modulation), and TME metabolic normalisation into cancer treatment frameworks will drive the next generation of precision metabolic oncology."

Journal • Review • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Oncology • EPAS1 • FASN • HIF1A • IDH1 • IDH2 • KRAS • LDHA • PKM • STAT3 • TP53

Enasidenib for Patients With Clonal Cytopenia of Undetermined Significance and Mutations in IDH2A Decentralized Trial (clinicaltrials.gov) - P2 | N=15 | Recruiting | Sponsor: Washington University School of Medicine | Trial completion date: Feb 2029 ➔ Jun 2029 | Trial primary completion date: Jan 2028 ➔ May 2028

Trial completion date • Trial primary completion date • Hematological Disorders

IDEAL Study: IDH2 (AG 221) Inhibitor in Patients With IDH2 Mutated Myelodysplastic Syndrome (clinicaltrials.gov) - P2 | N=68 | Active, not recruiting | Sponsor: Groupe Francophone des Myelodysplasies | Trial completion date: Mar 2026 ➔ Dec 2026

Trial completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • IDH2