Acute Myeloid Leukemia, IDH-Mutated

1. Disease Information (overview; “what is the disease?”)

AML is an aggressive marrow/blood cancer characterized by clonal proliferation of malignant hematopoietic blasts leading to marrow failure, commonly presenting with anemia, infections, and bleeding due to cytopenias. (shimony2023acutemyeloidleukemia pages 1-2, premnath2023paradigmshiftin pages 1-2)

“IDH‑mutated AML” refers to AML cases harboring somatic hotspot missense mutations in IDH1 or IDH2 that drive malignant transformation via production of the oncometabolite (R/D)-2‑hydroxyglutarate (2‑HG) and downstream epigenetic dysregulation and impaired myeloid differentiation. (issa2021acutemyeloidleukemia pages 1-2, fruchtman2024managementofisocitrate pages 1-2)

Classification context (WHO/ICC; blast thresholds)

Recent AML classification systems emphasize molecular genetics. - WHO (2022 revision) generally retains a 20% blast threshold for AML but includes exceptions for some genetically defined AMLs. (shimony2023acutemyeloidleukemia pages 1-2) - ICC (2022) allows genetically defined AML diagnoses at ≥10% blasts for select genetic lesions and introduces an MDS/AML category for 10–19% blasts. (shimony2023acutemyeloidleukemia pages 1-2)

2. Etiology

2.1 Disease causal factors (genetic/mechanistic)

The defining causal factor is somatic gain‑of‑function (“neomorphic”) mutation in IDH1 or IDH2 in leukemic cells. (issa2021acutemyeloidleukemia pages 1-2, fruchtman2024managementofisocitrate pages 1-2)

Hotspot residues / pathogenic variants - IDH1: mutations cluster at R132 (e.g., R132H, R132C, R132L, R132S, R132G). (ivanov2024moleculartargetingof pages 2-4, issa2021acutemyeloidleukemia pages 1-2) - IDH2: mutations cluster at R140 and R172 (notably R140Q and R172K). (ivanov2024moleculartargetingof pages 2-4, fruchtman2024managementofisocitrate pages 1-2)

Frequency in AML - Across reviews, IDH mutations are reported in ~14–20% of AML overall. (fruchtman2024managementofisocitrate pages 1-2) - One treatment‑algorithm review reports an approximate breakdown of ~8% IDH1 and ~12% IDH2 among AML. (issa2021acutemyeloidleukemia pages 1-2)

2.2 Risk factors

No IDH‑specific environmental risk factors were identified in the retrieved sources for this run. Epidemiologically, AML overall is strongly age‑associated (median age ~68–70), which indirectly enriches for IDH‑mutated cases because IDH mutations are frequently found in older AML populations. (fruchtman2024managementofisocitrate pages 1-2, kantarjian2024currentstatusand pages 1-2)

2.3 Protective factors

No IDH‑specific protective factors were identified in the retrieved sources.

2.4 Gene–environment interactions

Not identified in retrieved sources for IDH‑mutated AML specifically.

3. Phenotypes

3.1 Core clinical phenotypes (human)

AML commonly presents with symptoms and signs driven by bone‑marrow failure: - Anemia → fatigue, shortness of breath (HPO suggestion: HP:0001903 Anemia, HP:0012378 Fatigue, HP:0002094 Dyspnea). (premnath2023paradigmshiftin pages 1-2, bill2024impactofidh1 pages 1-6) - Neutropenia/immune dysfunction → fever/infection (HPO: HP:0002719 Recurrent infections, HP:0001945 Fever). (premnath2023paradigmshiftin pages 1-2, bill2024impactofidh1 pages 1-6) - Thrombocytopenia → bleeding/petechiae (HPO: HP:0001873 Thrombocytopenia, HP:0000967 Petechiae, HP:0001892 Bleeding). (bill2024impactofidh1 pages 1-6)

A representative case in a 2023 AML review illustrates typical cytopenias and blast burden (Hb 7.5 g/dL, WBC 2.3×10^9/L, platelets 27×10^9/L; 22% marrow myeloblasts). (shimony2023acutemyeloidleukemia pages 1-2)

3.2 Treatment‑emergent phenotype: IDH‑inhibitor differentiation syndrome (IDH‑DS)

IDH inhibitors can induce a differentiation syndrome characterized by systemic inflammatory/capillary leak manifestations. In an FDA systematic analysis of relapsed/refractory AML trials, adjudicated differentiation syndrome occurred in 19% of patients treated with ivosidenib and 19% with enasidenib; median onset ~20 and 19 days, respectively; and fatal cases occurred (6% and 5% among DS cases, respectively). (norsworthy2020differentiationsyndromewith pages 3-4)

Clinical manifestations used for case identification include dyspnea, unexplained fever, weight gain, hypotension, acute renal failure, and pulmonary infiltrates/pleuropericardial effusion. (norsworthy2020differentiationsyndromewith pages 3-4)

Phenotype ontology suggestion for DS manifestations: - HP:0002094 Dyspnea, HP:0001945 Fever, HP:0004325 Weight gain, HP:0002615 Hypotension, HP:0001919 Acute kidney injury, HP:0002090 Pneumonia/Pulmonary infiltrates, HP:0000967 Edema.

3.3 Functional/QOL impact proxies

Transfusion dependence is a major functional burden; IDH‑directed therapy can restore hematopoiesis. In enasidenib‑treated relapsed/refractory IDH2‑mutant AML, 43.1% of RBC transfusion‑dependent patients and 40.2% of platelet transfusion‑dependent patients achieved transfusion independence. (stein2019molecularremissionand pages 1-4)

4. Genetic/Molecular Information

4.1 Causal genes

• IDH1 (cytosolic/peroxisomal enzyme) and IDH2 (mitochondrial enzyme) are the defining mutated genes. (fruchtman2024managementofisocitrate pages 1-2)

4.2 Pathogenic variants (somatic)

Hotspots: IDH1 R132; IDH2 R140/R172. (ivanov2024moleculartargetingof pages 2-4, fruchtman2024managementofisocitrate pages 1-2)

Somatic origin is typical for AML; the retrieved sources characterize these as acquired driver mutations in leukemia. (issa2021acutemyeloidleukemia pages 1-2, fruchtman2024managementofisocitrate pages 1-2)

4.3 Co-mutations / modifier context

IDH mutational subgroups show distinct co-mutation patterns with clinical implications (e.g., NPM1, DNMT3A, and pathway mutations) and can influence response and resistance. (testa2020isocitratedehydrogenasemutations pages 17-19, lang2023mechanismsofresistance pages 5-7)

A clinically important modifier concept is that IDH2 R140 can behave as a clonal hematopoiesis–like lesion in transplant MRD contexts, with high diagnostic VAF and frequent persistence not necessarily tracking relapse risk. (bill2023impactofidh1andidh2mutationdetection pages 4-5, bill2024impactofidh1 pages 26-30)

4.4 Epigenetic information

IDH mutations promote a hypermethylated state via inhibition of α‑KG–dependent enzymes (TET2 DNA demethylation; histone demethylases), providing a mechanistic basis for epigenetic dysregulation in IDH‑mut AML. (issa2021acutemyeloidleukemia pages 1-2, fruchtman2024managementofisocitrate pages 1-2)

5. Environmental Information

No IDH‑specific environmental contributors were identified in the retrieved sources for this run.

6. Mechanism / Pathophysiology (causal chain)

6.1 Central oncometabolite mechanism

Mutant IDH enzymes lose normal catalytic behavior and acquire neomorphic activity converting α‑ketoglutarate into 2‑hydroxyglutarate (2‑HG). (issa2021acutemyeloidleukemia pages 1-2, fruchtman2024managementofisocitrate pages 1-2)

Accumulated 2‑HG competitively inhibits α‑KG–dependent dioxygenases (including TET2 and histone demethylases), producing DNA/histone hypermethylation and enforcing a myeloid differentiation block that promotes leukemogenesis. (issa2021acutemyeloidleukemia pages 1-2, fruchtman2024managementofisocitrate pages 1-2)

6.2 Additional downstream mechanisms (selected)

• DNA repair and genomic stability: 2‑HG can inhibit DNA repair enzymes and contribute to genetic instability. (fruchtman2024managementofisocitrate pages 1-2)
• BCL‑2 dependence: IDH‑mutant cells show enhanced BCL‑2 dependence, providing biological rationale for venetoclax sensitivity. (nong2024commondrivermutations pages 7-8)

6.3 Model evidence supporting causality and reversibility

• Primary human CD34+ HSPCs: In a 2024 study modeling IDH mutants in normal HSPCs, “CFU ability was dramatically compromised with a complete trilineage block of differentiation,” and “the block was reversed by specific inhibitors,” supporting a direct causal effect and pharmacologic reversibility. (pierangeli2024theleukemicisocitrate pages 1-2)
• Zebrafish AML models (IDH2R140Q or IDH2R172K + FLT3‑ITD): adults developed leukemia with myeloid skewing, differentiation blockade, and transplantable disease; leukemic phenotypes were ameliorated by enasidenib (and quizartinib in combination). (wang2023transgenicidh2r172kand pages 1-2, wang2023transgenicidh2r172kand pages 4-7)
• Mouse models: inducible IDH2R140Q cooperates with other lesions (e.g., HOXA9/MEIS1a, FLT3) in vivo and deinduction of mutant IDH2 affects leukemia maintenance, consistent with a driver/maintenance role. (kats2014protooncogenicroleof pages 1-3)

Suggested ontology terms

• GO Biological Process: hematopoietic cell differentiation; myeloid cell differentiation; regulation of DNA methylation; histone demethylation; cellular response to hypoxia/pseudohypoxia; regulation of apoptotic process (BCL‑2 dependence).
• Cell Ontology (CL): hematopoietic stem cell (HSC); hematopoietic progenitor cell; myeloblast; granulocyte–monocyte progenitor.

7. Anatomical Structures Affected

Organ/tissue level

• Primary site: bone marrow hematopoiesis (UBERON suggestion: UBERON:0002371 bone marrow). (shimony2023acutemyeloidleukemia pages 1-2, bill2024impactofidh1 pages 1-6)
• Peripheral blood involvement: circulating blasts/cytopenias (UBERON: blood). (shimony2023acutemyeloidleukemia pages 1-2)
• Secondary organ involvement: splenomegaly is a prominent feature in AML models (and clinically can occur) (UBERON: spleen). (wang2023transgenicidh2r172kand pages 1-2)

Cell/subcellular localization

• Leukemic clone arises from hematopoietic stem/progenitor compartments and produces immature myeloid blasts (CL: HSPC, myeloblast). (wang2023transgenicidh2r172kand pages 1-2, pierangeli2024theleukemicisocitrate pages 1-2)
• Subcellular: IDH1 is cytosolic/peroxisomal; IDH2 is mitochondrial (GO Cellular Component suggestions: cytosol/peroxisome/mitochondrion). (fruchtman2024managementofisocitrate pages 1-2)

8. Temporal Development

AML often has an acute/subacute presentation due to rapid marrow failure with symptomatic cytopenias. (premnath2023paradigmshiftin pages 1-2)

IDH inhibitor responses can take weeks and reflect differentiation rather than immediate cytotoxicity; in an ivosidenib trial summary the median time to response was ~1.9 months. (fruchtman2024managementofisocitrate pages 3-4)

9. Inheritance and Population

9.1 Epidemiology (AML overall; IDH‑mut AML subset frequency)

• AML overall incidence reported as 4.0 per 100,000; age‑adjusted incidence higher in older adults (e.g., 18.8 per 100,000 in the elderly vs 4.9 per 100,000 in ages 50–64, per one 2024 review). (fruchtman2024managementofisocitrate pages 1-2)
• US AML is primarily a disease of older adults (median age 68–70). (kantarjian2024currentstatusand pages 1-2, premnath2023paradigmshiftin pages 1-2)
• IDH1/2 mutations together occur in ~14–20% of AML in reviews. (fruchtman2024managementofisocitrate pages 1-2)

9.2 Survival statistics (AML overall)

• A 2024 review reports 5‑year survival improved from 9% (1980) to 27% (2017). (fruchtman2024managementofisocitrate pages 1-2)
• A 2023 review reports overall 5‑year survival 30.5% for US cases diagnosed 2012–2018. (premnath2023paradigmshiftin pages 1-2)

10. Diagnostics

10.1 Clinical diagnosis

Diagnosis involves peripheral blood and bone marrow evaluation and includes morphology, immunophenotyping (flow cytometry), cytogenetics, and molecular testing; blast thresholds depend on WHO vs ICC (Section 1). (bill2024impactofidh1 pages 1-6, shimony2023acutemyeloidleukemia pages 1-2)

10.2 Molecular diagnostics for IDH mutations

• IDH1/2 mutations are typically detected by targeted sequencing panels (NGS) and/or hotspot assays (PCR/ddPCR), often on bone marrow samples in AML workups. (bill2024impactofidh1 pages 1-6, bill2023impactofidh1andidh2mutationdetection pages 1-2)
• In a transplant cohort study, diagnostic IDH mutation testing included exon 4 sequencing and NGS verification; the authors note NGS technical sensitivity of ~3% VAF, motivating hotspot ddPCR assays for MRD-level detection. (bill2023impactofidh1andidh2mutationdetection pages 1-2)

IHC limitations: A 2024 review notes IDH1 R132H IHC can miss non‑R132H variants and may have ~5–10% false positives, thus molecular testing is often required. (ivanov2024moleculartargetingof pages 2-4)

10.3 MRD approaches (IDH-specific nuance)

Evidence supports variant‑specific interpretation of persistent IDH mutations: - In a 2023 HSCT cohort, IDH MRD by ddPCR was common at HSCT (75%); persistence of IDH1 R132 or IDH2 R172 was associated with relapse risk, while persistent IDH2 R140 (often high VAF) was less predictive and may reflect clonal hematopoiesis. (bill2023impactofidh1andidh2mutationdetection pages 4-5, bill2024impactofidh1 pages 26-30) - A 2024 cohort (non‑myeloablative alloHCT with PTCy) found no significant association between persistent IDH mutations pre‑alloHCT and 3‑year outcomes, illustrating current uncertainty and the need for standardized thresholds and variant‑aware interpretation. (ravindra2024persistentidhmutations pages 1-4)

11. Outcome/Prognosis

Prognosis in AML is strongly age‑dependent and risk‑stratified by genetics and MRD; older adults historically have poor outcomes even with intensive therapy (e.g., median survival ~9 months and 5‑year survival ≤10% for >60 treated with 7+3 in one 2024 review). (kantarjian2024currentstatusand pages 1-2)

IDH mutation prognostic impact is context‑dependent (co-mutations and variant specifics), and current sources emphasize using broader molecular risk frameworks (e.g., ELN‑style risk) rather than treating IDH mutation alone as a definitive prognostic class. (bill2024impactofidh1 pages 9-13)

12. Treatment

12.1 Targeted therapies (approved)

IDH1 inhibitors - Ivosidenib: in newly diagnosed IDH1‑mutant AML (subgroup, n=34) a 2024 review reports CR 30.3%, CR/CRh 42.4%, median OS 12.6 months; differentiation syndrome occurred 18% (9% grade ≥3). (fruchtman2024managementofisocitrate pages 4-5)

IDH2 inhibitors - Enasidenib: pivotal phase I/II program in relapsed/refractory IDH2‑mutant AML reported ORR 38.8%, CR 19.6%, median OS 8.8 months; grade 3–4 AEs included hyperbilirubinemia 10%, thrombocytopenia 7%, and differentiation syndrome 6%. (stein2019molecularremissionand pages 1-4)

12.2 Combination regimens and real‑world implementation

Ivosidenib + azacitidine (frontline older/unfit; AGILE context) - A health‑economic analysis summarizes that in the randomized AGILE trial, ivosidenib+azacitidine improved event‑free survival (HR 0.33) and overall survival (HR 0.44) vs placebo+azacitidine in newly diagnosed older/unfit IDH1‑mutant AML. (bewersdorf2023costeffectivenessofazacitidine pages 1-2)

Venetoclax + azacitidine (widely used low‑intensity backbone; IDH‑mut subset efficacy) - In pooled phase Ib/III analyses of treatment‑naïve, intensive‑ineligible AML, IDH1/2‑mutant patients had CRc 79% vs 11% (Ven+Aza vs Aza), median OS 24.5 vs 6.2 months, and median duration of remission 29.5 vs 9.5 months. (pollyea2022impactofvenetoclax pages 1-2) - Subgroups: IDH1‑mutant CRc 66.7% (mOS 15.2 months) and IDH2‑mutant CRc 86.0% (mOS not reached). (pollyea2022impactofvenetoclax pages 1-2, pollyea2022impactofvenetoclax pages 5-5)

Adverse events with Ven+Aza in IDH‑mut AML: febrile neutropenia 42.0%, infections 59.3%, pneumonia 27.2%, grade ≥3 AEs 97.5% (in the cited excerpt). (pollyea2022impactofvenetoclax pages 6-7)

12.3 Safety: differentiation syndrome management (expert guidance)

A 2024 review outlines DS pathophysiology and management: prompt respiratory support and corticosteroids (dexamethasone 10 mg IV twice daily) with treatment interruption for severe cases. (fruchtman2024managementofisocitrate pages 3-4)

The FDA analysis describes an operational case‑finding algorithm and recommends dexamethasone 10 mg IV q12h until symptoms resolve (≥3 days), plus cytoreduction/supportive measures (hydroxyurea, diuretics, leukapheresis as needed). (norsworthy2020differentiationsyndromewith pages 3-4)

12.4 Post‑transplant / maintenance

Enasidenib has been studied as post‑alloHCT maintenance; the visual summary of a phase I study indicates no reported differentiation syndrome and provides relapse/survival curves and grade ≥3 AE tables. (fathi2022enasidenibasmaintenance media a35fe258, fathi2022enasidenibasmaintenance media 3bab0af4, fathi2022enasidenibasmaintenance media c85d33dd)

12.5 Ongoing clinical trials (selected; ClinicalTrials.gov)

• NCT03839771 (HOVON150AML): Phase 3, randomized, placebo‑controlled trial adding ivosidenib (IDH1) or enasidenib (IDH2) to intensive induction/consolidation followed by up to 2 years maintenance; endpoints include EFS/OS/MRD‑negative CR and QoL. (NCT03839771 chunk 1)
• NCT06387069 (RAPHAEL): Phase 3, relapsed/refractory IDH1/2‑mutant AML; HMPL‑306 monotherapy vs salvage chemo; cohorts by IDH1 R132 vs IDH2 R140/R172; recruiting. (NCT06387069 chunk 1)
• NCT04603001: Phase 1 covalent IDH inhibitor LY3410738; includes dose‑escalation triplet arm with venetoclax + azacitidine; active not recruiting. (NCT04603001 chunk 1)
• NCT05401097 (I‑DATA): Phase 2 sequencing study comparing IDH inhibitor + azacitidine first vs venetoclax + azacitidine first in newly diagnosed IDH‑mut AML unfit for intensive therapy; recruiting. (NCT05401097 chunk 1)

Suggested MAXO terms (treatment actions)

• Small molecule therapy, targeted therapy, hypomethylating agent therapy, BCL2 inhibitor therapy, allogeneic hematopoietic stem cell transplantation, supportive care (transfusion support, antimicrobial therapy).

13. Prevention

Primary prevention

No established primary prevention strategy specific to IDH‑mutated AML was identified in the retrieved sources.

Secondary/tertiary prevention

• Secondary prevention relies on early recognition of cytopenias and prompt diagnostic evaluation with modern molecular profiling (WHO/ICC emphasize molecular integration). (shimony2023acutemyeloidleukemia pages 1-2)
• Tertiary prevention includes proactive management of infections/cytopenias and vigilance for differentiation syndrome during IDH inhibitor therapy (steroid protocols and supportive care). (fruchtman2024managementofisocitrate pages 3-4, norsworthy2020differentiationsyndromewith pages 3-4)

14. Other Species / Natural Disease

Not established as a naturally occurring veterinary disease entity in retrieved sources; experimental animal models are described below.

15. Model Organisms

Zebrafish

Transgenic IDH2R140Q and IDH2R172K zebrafish (often combined with FLT3‑ITD) develop AML‑like disease with differentiation blockade, splenomegaly, transplantability to recipients, and therapeutic response to enasidenib. (wang2023transgenicidh2r172kand pages 1-2, wang2023transgenicidh2r172kand pages 4-7)

Mouse

Inducible/tissue‑specific IDH2R140Q models cooperate with other lesions to drive acute leukemia and show that deinduction of mutant IDH2 impairs leukemia maintenance. (kats2014protooncogenicroleof pages 1-3)

Primary human HSPCs

Human CD34+ HSPC experimental systems show direct differentiation blockade by IDH mutants with inhibitor reversibility (“complete trilineage block of differentiation” reversed by specific inhibitors). (pierangeli2024theleukemicisocitrate pages 1-2)

16. Real‑world implementation / pharmacovigilance (2024)

A 2024 pharmacovigilance analysis using WHO VigiAccess reported 4,072 adverse event reports for enasidenib and ivosidenib combined (2,776 for enasidenib; 1,296 for ivosidenib). Top reported events included off‑label use, death, fatigue, nausea, diarrhea, AML, drug ineffective, differentiation syndrome, and decreased platelet count. (peng2024arealworldstudy pages 1-2, peng2024arealworldstudy pages 4-6)

Evidence summary table

The following table consolidates high‑yield, evidence‑backed facts (definitions, mechanisms, epidemiology, and treatment outcomes) with DOI URLs:

Table: This table summarizes high-yield, evidence-backed facts for IDH-mutated acute myeloid leukemia, including disease definition, genetics, mechanisms, classification, outcomes, therapies, toxicity, MRD, and epidemiology. It is designed for rapid reuse in a structured disease knowledge base.

Notes on evidence gaps

• Formal disease identifiers (MONDO/MeSH/ICD/Orphanet/OMIM) were not retrieved in this run, so no identifier assertions are made.
• Some key trial-level details (e.g., full AGILE response and toxicity tables) were not directly available in the gathered full text snippets; the report therefore cites secondary summaries where necessary (and flags this limitation). (bewersdorf2023costeffectivenessofazacitidine pages 1-2)
• MRD utility of IDH mutations remains variant‑ and setting‑dependent, with conflicting 2023–2024 cohort conclusions; this uncertainty should be encoded in knowledge base assertions as context‑dependent. (ravindra2024persistentidhmutations pages 1-4, bill2023impactofidh1andidh2mutationdetection pages 4-5)

References

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