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

A Study of Gilteritinib in Combination With Ivosidenib or Enasidenib in People With Acute Myeloid Leukemia (AML) (clinicaltrials.gov) - P1 | N=18 | Recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | N=36 ➔ 18

Enrollment change • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • IDH1 • IDH2

FACT Complex — A gatekeeper of differentiation in AML (AACR 2026) - "Available differentiation therapies are limited to specific subtypes of AML, for example, All-Trans Retinoic Acid (ATRA) for Promyelocytic Leukemia (PML) and Enasidenib for IDH2-mutated AML.To identify genes encoding druggable proteins essential in maintaining the undifferentiated state of AML, we designed a creative CRISPR screen...In the present study, our goal is to explore the mechanistic role of FACT complex in AML differentiation. We also intend to exploit the dependency of the FACT complex in AML to develop therapeutic approaches to target AML."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • IDH2

Targeted Therapy in Acute Myeloid Leukemia: Current Approaches and Novel Directions. (PubMed, J Pers Med) - "Here, we detail the current targeted therapies available for AML: specifically, those targeting the BCL2 family (venetoclax), FLT3 (midostaurin, gilteritinib, quizartinib), IDH1/2 (enasidenib, ivosidenib), and MENIN (revumenib, ziftomenib). In addition, we outline potential mechanisms of resistance against these therapies, as well as efforts being taken to prevent or bypass them."

IO biomarker • Journal • Review • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • FLT3 • IDH1 • IDH2

Targeting cytosolic mutant IDH1 by hyperactivation to induce cancer cytotoxicity (AACR 2026) - "Although FDA-approved inhibitors such as ivosidenib and enasidenib effectively suppress 2HG, fewer than half of patients respond, and resistance invariably develops. In parallel, we found that activation of mitochondrial 2HG production in IDH1-mutant cancer cells triggers profound metabolic collapse, leading to impaired cell growth in vitro and in vivo. Together, these results suggest that direct or indirect hyperactivation of the mutant IDH1 pathway may represent a new therapeutic strategy --- targeting cytosolic IDH1 mutations by driving cancer cells beyond their metabolic limits."

Acute Myelogenous Leukemia • Brain Cancer • Glioma • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • IDH1 • IDH2

Epigenetic remodeling of BCOR-PRC1.1 complex dictates response and resistance to IDH inhibitors in AML (AACR 2026) - "IDH2 mutation establishes an epigenetic blockade marked by promoter hypermethylation, 5hmC loss, and loss of BCOR-PRC1.1 occupancy, enabling aberrant activation of stemness programs. Enasidenib reverses these defects by restoring 5hmC, promoter methylation balance, BCOR binding, and PRC1.1-mediated repression. These data support a model in which IDH-inhibitor-induced differentiation requires intact BCOR function and repression of BCOR targets such as JUNB and WNT11, defining how IDH-mutant epigenetic dysregulation and BCOR loss converge to limit therapeutic efficacy."

Acute Myelogenous Leukemia • Oncology • BCOR • CEBPA • CEBPB • IDH1 • IDH2 • JUNB • TET2 • WNT11

FLAG-VENETOCLAX-ENASIDENIB SALVAGE FOR 7+3 FAILURE (EBMT 2026) - "The patient underwent standard induction with the "7+3" regimen (Cytarabine/Idarubicin) plus venetoclax...Consequently, a salvage regimen comprising FLAG (Fludarabine, Cytarabine, G-CSF), venetoclax, and the IDH2-inhibitor enasidenib (100 mg daily) was initiated... This case demonstrates that NGS is indispensable in the management of refractory AML-MRC, specifically for identifying targets like IDH2 when standard venetoclax-based induction fails. The addition of enasidenib to FLAG-based salvage provided a crucial bridge to transplant. Furthermore, for patients who have failed intensive induction, NMA conditioning offers a viable, reduced-toxicity platform for allogeneic HSCT, allowing for successful engraftment and survival in a resource-limited setting."

IO biomarker • Acute Myelogenous Leukemia • B Cell Lymphoma • Bone Marrow Transplantation • Hematological Disorders • Leukemia • Lymphoma • Myelodysplastic Syndrome • ASXL1 • RUNX1 • SRSF2

Differentiation Syndrome in Acute Myeloid Leukemia: Molecular Mechanisms, Clinical Spectrum, and Emerging Therapeutic Paradigms. (PubMed, Int J Mol Sci) - "While differentiation therapy revolutionized acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), its extension into non-APL AML has been limited until recent targeted agents...IDH1/2 inhibitors (ivosidenib, enasidenib, olutasidenib) yield overall response rates (ORRs) of 30-94% in AML with DS in 10-19%. Menin inhibitors (revumenib, ziftomenib, enzomenib, bleximenib) achieve ORRs of 33-88% in KMT2A-rearranged or NPM1-mutated AML, with DS in 10-25% and QT prolongation as key toxicities. FLT3 inhibitors (gilteritinib, quizartinib) improve survival in FLT3-mutated AML with DS in 1-5%...Improved recognition of DS and rational combination approaches will be essential to maximize the therapeutic benefit. Future research should address mechanisms of resistance and biomarkers to achieve cures beyond APL."

Journal • Review • Acute Myelogenous Leukemia • Acute Promyelocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • IDH1 • IDH2 • KMT2A • NPM1

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

Νοvel Therapies in High-Risk Myelodysplastic Syndromes. (PubMed, Eur J Haematol) - "Recent advances have led to the development of novel therapeutic strategies, such as BCL-2 inhibitors (venetoclax), IDH1/2 inhibitors (ivosidenib, enasidenib), CD47 inhibitors (magrolimab), TIM-3 inhibitors (sabatolimab), XPO1 inhibitors (eltanexor), NEDD8-activating enzyme inhibitors (pevonedistat), TP53-targeted agents (eprenetapopt), liposomal chemotherapy (CPX-351), and oral HMA formulations. Combinations of hypomethylating agents with these new drugs, as first-line treatment, have to date not proven more efficacious than HMA monotherapy. This review summarizes the current therapeutic landscape on novel therapies for HR-MDS, highlighting their mechanism of action, efficacy, and demonstrates the unmet clinical need for more effective therapies."

Journal • Review • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation • HAVCR2 • IDH1 • IDH2

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

Enasidenib (AG-221) Maintenance Post Allogeneic HCT in Patients With IDH2 Mutation (clinicaltrials.gov) - P2 | N=35 | Recruiting | Sponsor: City of Hope Medical Center | Suspended ➔ Recruiting

Enrollment open • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation

Clinical Approach to Relapsed or Refractory Lower-Risk Myelodysplastic Syndromes (ICKSH 2026) - "In the phase 3 COMMANDS trial (ESA -naïve TD LR -MDS; IPSS -R very low/low/intermediate; sEPO <500 U/L; <5% blasts; del(5q) excluded), luspatercept significantly improved the primary endpoint (RBC -TI for ≥12 weeks with concurrent mean hemoglobin [Hb] increase ≥1.5 g/dL during weeks 1–24) versus epoetin alfa (60.4% vs 34.8%; p<0.0001). Evidence -based sequencing begins with early ESA use when appropriate, transitions to luspatercept when response is lost, but consider this agent not only in R/R cases, but also as an effective and durable first -line option (with subgroup -consistent benefit), for TD ESA -naïve LR -MDS who do not have probability to respond to ESAs and incorporates imetelstat as a potentially disease -modifying therapy in ESA -failed/ESA -ineligible and lus patercept -failed TD LR - MDS , especially if with high transfusion burden . Molecularly targeted agents and cytogenetically defined approaches (e.g., lenalidomide in del(5q) ,..."

Clinical • Cardiovascular • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Neutropenia • Thrombocytopenia • ACVR2A • IDH1 • IDH2 • SF3B1

The Care and Cure of the Leukemias in 2026. (PubMed, Am J Hematol) - "Currently, most leukemias are effectively treated with immunotherapies (highly effective monoclonal antibodies targeting CD19 [blinatumomab], or CD22 [inotuzumab ozogamicin]), BCR::ABL1 tyrosine kinase inhibitors (TKIs; e.g., dasatinib, ponatinib), Bruton TKIs (e.g., ibrutinib, acalabrutinib), BCL-2 inhibitors (venetoclax), IDH1/2 inhibitors (ivosidenib, olutasidenib, and enasidenib), FLT3 inhibitors (e.g., midostaurin, quizartinib, and gilteritinib), menin inhibitors (revumenib, ziftomenib), and chimeric antigen receptor T-cell therapies. Herein, we provide a high-level overview of prominent clinical developments across all leukemias. In contemporary times, harnessing the benefits of novel targeted therapies and the evolving treatment landscape bolster the optimistic view that most, if not all, leukemias are curable."

IO biomarker • Journal • Review • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Chronic Lymphocytic Leukemia • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • ABL1 • CD22 • FLT3 • IDH1 • IDH2 • KMT2A • TP53

ESMART: European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors (clinicaltrials.gov) - P1/2 | N=285 | Recruiting | Sponsor: Gustave Roussy, Cancer Campus, Grand Paris

New P1/2 trial • Hematological Malignancies • Oncology • Pediatrics

ESMART: European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors (clinicaltrials.gov) - P1/2 | N=455 | Recruiting | Sponsor: Gustave Roussy, Cancer Campus, Grand Paris | Trial completion date: Aug 2027 ➔ Feb 2031 | Trial primary completion date: Aug 2027 ➔ Feb 2031

Trial completion date • Trial primary completion date • Hematological Malignancies • Oncology • Pediatrics

ESMART: European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors (clinicaltrials.gov) - P1/2 | N=397 | Recruiting | Sponsor: Gustave Roussy, Cancer Campus, Grand Paris | N=285 ➔ 397 | Trial completion date: Dec 2020 ➔ Jan 2022 | Trial primary completion date: Dec 2020 ➔ Jan 2022

Enrollment change • Trial completion date • Trial primary completion date • Pediatrics

ESMART: European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors (clinicaltrials.gov) - P1/2 | N=460 | Recruiting | Sponsor: Gustave Roussy, Cancer Campus, Grand Paris | Trial completion date: Jan 2022 ➔ Aug 2027 | Trial primary completion date: Jan 2022 ➔ Aug 2027

Trial completion date • Trial primary completion date • Hematological Malignancies • Oncology • Pediatrics

Management of Acute Myeloid Leukemia: A Review. (PubMed, Cancers (Basel)) - "Targeted therapies have improved outcomes in molecularly defined subsets of AML, with menin, IDH and FLT3 inhibitors representing major advances. However, TP53-mutated AML continues to carry a dismal prognosis, underscoring the need for more effective therapeutic strategies. Continued biomarker-driven research, novel drug combinations, and mechanistic insights will be essential to further refine AML treatment and improve long-term survival across disease subsets."

Journal • Review • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • FLT3 • KMT2A • NPM1

Comparing New Treatments for People With Newly Diagnosed Acute Myeloid Leukemia That Has an IDH2 Gene Change (A MyeloMATCH Treatment Trial) (clinicaltrials.gov) - P2 | N=93 | Recruiting | Sponsor: National Cancer Institute (NCI) | Suspended ➔ Recruiting

Enrollment open • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • ABL1 • BCR • IDH2

Enasidenib (AG-221) Maintenance Post Allogeneic HCT in Patients With IDH2 Mutation (clinicaltrials.gov) - P2 | N=35 | Suspended | Sponsor: City of Hope Medical Center | Recruiting ➔ Suspended

Trial suspension • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation

A Study of Gilteritinib in Combination With Ivosidenib or Enasidenib in People With Acute Myeloid Leukemia (AML) (clinicaltrials.gov) - P1 | N=36 | Recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Feb 2026 ➔ Feb 2027 | Trial primary completion date: Feb 2026 ➔ Feb 2027

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • IDH1 • IDH2

AG120-221-C-001: Safety Study of AG-120 or AG-221 in Combination With Induction and Consolidation Therapy in Participants With Newly Diagnosed Acute Myeloid Leukemia (AML) With an IDH1 and/or IDH2 Mutation (clinicaltrials.gov) - P1 | N=90 | Recruiting | Sponsor: Agios Pharmaceuticals, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • IDH1 • IDH2 • UGT1A1

AG-221-AML-005: A Study to Assess the Safety and Efficacy of Two Combinations of Isocitrate Dehydrogenase (IDH) Mutant Targeted Therapies Plus Azacitidine in Participants With Newly Diagnosed Acute Myeloid Leukemia (AML) Harboring IDH Mutations Who Are Not Candidates to Receive Intensive Induction Chemotherapy (clinicaltrials.gov) - P1/2 | N=272 | Recruiting | Sponsor: Celgene Corporation | Not yet recruiting ➔ Recruiting | N=150 ➔ 272

Enrollment change • Enrollment open • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

AG120-221-C-001: Safety Study of AG-120 or AG-221 in Combination With Induction and Consolidation Therapy in Participants With Newly Diagnosed Acute Myeloid Leukemia (AML) With an IDH1 and/or IDH2 Mutation (clinicaltrials.gov) - P1 | N=120 | Recruiting | Sponsor: Agios Pharmaceuticals, Inc. | N=90 ➔ 120

Enrollment change • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • IDH1 • IDH2 • UGT1A1

AG-221-AML-005: A Study to Assess the Safety and Efficacy of Two Combinations of Isocitrate Dehydrogenase (IDH) Mutant Targeted Therapies Plus Azacitidine in Participants With Newly Diagnosed Acute Myeloid Leukemia (AML) Harboring IDH Mutations Who Are Not Candidates to Receive Intensive Induction Chemotherapy (clinicaltrials.gov) - P1/2 | N=130 | Active, not recruiting | Sponsor: Celgene | Phase classification: P1b/2 ➔ P1/2

Phase classification • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology