Home / Deep Research / IDH-Mutant Cholangiocarcinoma

IDH-Mutant Cholangiocarcinoma

1. Disease Information

2026-04-05
Falcon MONDO:0003210 Model: Edison Scientific Literature 40 citations

1. Disease Information

Overview and classification

Cholangiocarcinoma (CCA) is a biliary tract cancer classified anatomically into intrahepatic, perihilar, and distal tumors. One recent review summarizes typical fractions as: intrahepatic 10–20%, perihilar 50–60%, distal 20–30% (Oct 2023) (frampton2023ivosidenibareview pages 1-2). IDH mutations are enriched in iCCA relative to extrahepatic CCA (lavacchi2022ivosidenibinidh1mutated pages 2-3, vaquero2024decipheringtheroleb pages 29-32).

Synonyms / alternative names (used in clinical research)

Evidence source types represented in this report

2. Etiology

Molecular etiology (defining causal factor for the subtype)

Clinical risk factors (general CCA / iCCA; subtype-specific data limited)

Direct epidemiologic risk-factor data specific to IDH-mutant iCCA were not identified in the available primary evidence. However, several strong risk factors for cholangiocarcinoma in general, and for specific etiologic subtypes, are well supported in the retrieved corpus:

1) Primary sclerosing cholangitis (PSC) (high-risk context for CCA overall) - PSC confers a very large increase in CCA risk; one 2023 review reports “400–600‑fold increased risk” versus the general population and an annual risk 0.5–1.5% (Oct 2023) (catanzaro2023primarysclerosingcholangitisassociated pages 1-2). - Reported PSC‑CCA lifetime prevalence in that review ranges 6–13%, with a substantial fraction (≈30–50%) diagnosed within the first year after PSC diagnosis (catanzaro2023primarysclerosingcholangitisassociated pages 1-2, catanzaro2023primarysclerosingcholangitisassociated pages 2-4).

2) Liver fluke infection (etiologic driver for endemic fluke‑related CCA; largely perihilar/extrahepatic patterns in many settings; IDH-mutant enrichment in non-fluke iCCA is suggested in a review) - A 2024 high‑risk community screening in Lao PDR (Opisthorchis viverrini endemic) reported a prevalence of suspected CCA of 7.2% among 3,400 participants and association with O. viverrini infection (aOR 3.4, 95% CI 1.7–6.5) (Nov 2024) (homsana2024; retrieved earlier but not in cite list—no context id available for citation in this run; therefore not asserted here). - In the retrieved corpus, liver fluke infection is repeatedly described as a major cause in endemic regions (qualitative, not subtype-specific) (ciobica2024theconstellationof pages 2-3, catanzaro2023primarysclerosingcholangitisassociated pages 2-4).

3) Chronic viral hepatitis and chronic liver disease - iCCA risk factors include chronic hepatitis B/C in a 2024 Liver Cancer review (Oct 2024) (nishida2024geneticepigeneticalterationand pages 1-2).

Protective factors

Subtype‑specific protective genetic or environmental factors were not identified in the retrieved primary evidence.

Gene–environment interactions

Direct evidence for gene–environment interactions specifically shaping IDH‑mutant cholangiocarcinoma was not found in the retrieved primary sources.

3. Phenotypes (clinical presentation; HPO mapping)

The retrieved sources emphasize that cholangiocarcinoma is often detected late and may be clinically silent early: - iCCA is “typically asymptomatic early and often diagnosed at an advanced stage” (Oct 2024) (nishida2024geneticepigeneticalterationand pages 1-2).

However, specific symptom frequencies (e.g., jaundice, pruritus, RUQ pain, weight loss) and phenotype prevalence statistics for IDH‑mutant iCCA were not present in the retrieved evidence base used for this report.

Practical phenotype/HPO suggestions (generic for cholangiocarcinoma; requires confirmation in dedicated clinical sources)

Because phenotype evidence was not captured by the current corpus, the following should be treated as ontology placeholders requiring confirmation from dedicated clinical phenotype literature: - Obstructive jaundice (HPO: Jaundice HP:0000952) - Pruritus (HP:0000989) - Abdominal pain (HP:0002027) - Weight loss (HP:0001824) - Elevated bilirubin / cholestasis labs (e.g., Hyperbilirubinemia HP:0002904)

4. Genetic / Molecular Information

Causal genes and mutation spectrum

Table (click to expand)
Cohort / source Disease cohort / setting Sample size % IDH1 % IDH2 Predominant variant(s) and proportions Key associated features
Makawita et al., JCO Precision Oncology 2024 Advanced intrahepatic cholangiocarcinoma (comprehensive genomic profiling cohort) 3,067 iCCA cases 14% (426/3,067) 4% (125/3,067) IDH1: R132C 69%; R132L/G/S/H/F 16%/7%/4%/3%/<1%. IDH2: R172 94.4%; R140 6.6% (makawita2024comprehensiveimmunogenomicprofiling pages 1-2) IDH1/2-altered tumors were described as “immunologically cold”; compared with IDH-wildtype iCCA they had lower MSI-High, lower TMB ≥10 mut/Mb, and lower PD-L1 positivity; co-mutation patterns differed from IDH-wildtype; no significant mOS difference in retrospective analysis (makawita2024comprehensiveimmunogenomicprofiling pages 1-2)
Casak et al., Clinical Cancer Research 2022 FDA approval summary (ClarIDHy baseline population) Previously treated advanced unresectable/metastatic IDH1-mutant cholangiocarcinoma, predominantly intrahepatic 185 total (124 ivosidenib; 61 placebo) 100% by trial eligibility Not reported / not eligible IDH1 arm distributions: R132C 68% and 74% (ivosidenib/placebo), R132G 14% and 10%, R132L 17% and 11%, R132H 0% and 3%, R132S 2% and 2% (casak2022fdaapprovalsummary pages 1-2) Population was predominantly intrahepatic (90–95%), metastatic (92–93%), with female predominance (~61–65%); this source is a treatment-registration cohort and does not report IDH2 frequency, immunogenomic phenotype, or co-mutation landscape (casak2022fdaapprovalsummary pages 1-2)
Lavacchi et al., Pharmacology & Therapeutics 2022 (review summarizing phase I and disease biology) IDH1-mutant cholangiocarcinoma, mainly intrahepatic; includes phase I ivosidenib cohort and background epidemiology Phase I cohort: 73 pretreated patients (89% intrahepatic) ~10–20% of iCCA; <1% of extrahepatic CCA Hotspots noted at IDH2 R140/R172, but cohort-level % IDH2 not given In phase I background cohort, R132C 77% and R132L 11% were the most frequent IDH1 variants; hotspot codons emphasized: IDH1 R132, IDH2 R140/R172 (lavacchi2022ivosidenibinidh1mutated pages 2-3) IDH mutations drive 2-HG accumulation and epigenetic dysregulation; reported baseline/acquired co-alterations included PBRM1, ARID1A, PIK3CA, KRAS; resistance mutations included IDH2-R172V and IDH1-R132F at progression (lavacchi2022ivosidenibinidh1mutated pages 2-3)

Table: This table compares key published sources on IDH1/IDH2 alterations in cholangiocarcinoma, emphasizing intrahepatic cholangiocarcinoma. It highlights mutation frequencies, dominant hotspot variants, and clinically relevant associated features such as immune phenotype and co-alteration patterns.

Somatic vs germline

All evidence in this report treats IDH1/2 alterations as tumor genomic alterations (somatic) in cholangiocarcinoma; germline causal IDH1/2 variants were not discussed in retrieved sources (makawita2024comprehensiveimmunogenomicprofiling pages 1-2, casak2022fdaapprovalsummary pages 1-2).

Functional consequences and oncometabolite biology

A key mechanistic chain supported by multiple sources: 1) Mutant IDH1 (cytosolic) converts α‑KG → 2‑HG (fan2024pharmacokineticspharmacodynamicsofivosidenib pages 1-2, vaquero2024decipheringtheroleb pages 29-32). 2) 2‑HG accumulation inhibits α‑KG–dependent enzymes (including DNA/histone demethylases), producing hypermethylation and altered differentiation programs (vaquero2024decipheringtheroleb pages 29-32). 3) Immune consequences: IDH1/2 mutations are linked to hypermethylation and downregulation of antigen processing/presentation machinery and are enriched in non‑inflamed (“cold”) iCCA microenvironments (nishida2024geneticepigeneticalterationand pages 1-2, makawita2024comprehensiveimmunogenomicprofiling pages 1-2).

Direct abstract quote (PK/PD mechanistic biomarker): Fan et al. measured that in ivosidenib‑treated patients, “mean plasma 2‑HG concentration was reduced from 1108 ng/mL at baseline to 97.7 ng/mL at C2D1… An average 2‑HG inhibition of 75.0% was observed at steady state” (Jan 2024) (fan2024pharmacokineticspharmacodynamicsofivosidenib pages 1-2).

Co-mutations / molecular context

Immunogenomic phenotype (2024 large-cohort evidence)

Compared with IDH‑wildtype iCCA, IDH1/2‑altered iCCA showed lower frequency of multiple immune biomarkers: - MSI‑High lower (P=0.009) - TMB ≥10 mut/Mb lower (P<0.0001) - PD‑L1 positivity lower and the authors conclude: “IDH1-/2-mutated tumors appear immunologically cold” (Mar 2024) (makawita2024comprehensiveimmunogenomicprofiling pages 1-2).

Ontology suggestions (molecular processes and cell types)

GO Biological Process (suggested): - DNA methylation / epigenetic regulation (supported by hypermethylation phenotype) (vaquero2024decipheringtheroleb pages 29-32) - Antigen processing and presentation (downregulated/hypermethylated in IDH-mutant iCCA) (nishida2024geneticepigeneticalterationand pages 1-2) - Translation / ribosomal signaling and S6 phosphorylation (IDHm dependency discussed below) (luk2024srcinhibitionenables pages 1-2)

Cell Ontology (CL) candidates (supported by TME-class studies): - Macrophage populations enriched in certain IDH-enriched TME classes (“M2-like” macrophage enrichment) (martinserrano2023novelmicroenvironmentbasedclassification pages 1-3)

5. Environmental Information

Evidence captured here is largely for general CCA etiologies, not specifically IDH-mutant tumors. - Infectious agent exposure: liver flukes as etiologic factors for CCA in endemic regions (qualitative) (ciobica2024theconstellationof pages 2-3, catanzaro2023primarysclerosingcholangitisassociated pages 2-4). - Autoimmune/inflammatory biliary disease: PSC as a strong risk condition (catanzaro2023primarysclerosingcholangitisassociated pages 1-2).

6. Mechanism / Pathophysiology

Causal chain (from mutation to phenotype)

A current integrated causal chain for IDH‑mutant iCCA supported by retrieved evidence: 1) Somatic IDH1/2 hotspot mutation → 2) 2‑HG accumulation → 3) Epigenetic reprogramming / hypermethylation (TET/Jmj inhibition) and downstream differentiation programs (vaquero2024decipheringtheroleb pages 29-32) → 4) Immune-cold tumor microenvironment through hypermethylation/downregulation of antigen presentation machinery (nishida2024geneticepigeneticalterationand pages 1-2) → 5) Clinically relevant therapeutic vulnerability to mutant IDH1 inhibition (2‑HG suppression) and additional pathway dependencies (SRC/S6K) (fan2024pharmacokineticspharmacodynamicsofivosidenib pages 1-2, luk2024srcinhibitionenables pages 1-2).

Immune microenvironment classification (iCCA)

A large transcriptomic meta‑analysis (~900 iCCAs) introduced a TME-based “STIM” classification with both inflamed and non‑inflamed classes (May 2023) (martinserrano2023novelmicroenvironmentbasedclassification pages 1-3). Of particular relevance: - A non‑inflamed “hepatic stem‑like” class (~35%) is enriched in IDH1/2 mutations and BAP1, and includes enrichment of “M2‑like macrophages” (martinserrano2023novelmicroenvironmentbasedclassification pages 1-3).

Mechanistic dependency discovered in 2024 (SRC → MAGI1‑PP2A → S6K/S6)

A 2024 Science Translational Medicine study reported an actionable dependency in IDH‑mutant iCCA: - “Mutant IDH (IDHm) ICC is dependent on SRC kinase for growth and survival and is hypersensitive to inhibition by dasatinib” (May 2024) (luk2024srcinhibitionenables pages 1-2). - Mechanism: SRC suppresses a tumor‑suppressive MAGI1–PP2A complex; SRC inhibition enables PP2A-mediated dephosphorylation of S6K, decreasing protein synthesis and promoting cell death; resistance correlates with increased pS6; combination of dasatinib + M2698 showed enhanced inhibition in cell lines, organoids, and PDX (luk2024srcinhibitionenables pages 1-2).

Ontology suggestions (GO/CL/UBERON)

  • UBERON (anatomy): intrahepatic bile duct / liver intrahepatic biliary tree (not explicitly provided in the retrieved corpus; recommended as the primary affected site based on iCCA focus).
  • GO Cellular Component (suggested): mitochondrion / cytosol (IDH isoform localization is relevant: IDH1 cytosolic; IDH2 mitochondrial) (vaquero2024decipheringtheroleb pages 29-32).

7. Anatomical Structures Affected

  • Primary site for this molecular subtype in clinical datasets and trials is overwhelmingly intrahepatic cholangiocarcinoma (e.g., ClarIDHy population was 90–95% intrahepatic) (casak2022fdaapprovalsummary pages 1-2).

8. Temporal Development

9. Inheritance and Population

Epidemiology (general CCA/iCCA; not IDH-specific incidence)

Proportion of iCCA with IDH mutations

10. Diagnostics

Molecular confirmation of IDH mutation (standard clinical implementation)

Tissue NGS remains central; ClarIDHy eligibility required an IDH1 mutation “as detected by an FDA‑approved test” (FDA summary abstract, Mar 2022) (casak2022fdaapprovalsummary pages 1-2). Baseline distributions of specific IDH1 variants were reported (casak2022fdaapprovalsummary pages 1-2).

Liquid biopsy (ctDNA) integration (2024 evidence)

  • In a 2024 matched tissue/ctDNA cohort (128 total BTC; 32 matched pairs), “All IDH1 mutations detected in tumor DNA were also identified in liquid biopsies” (Jan 2024) (astier2024molecularprofilingof pages 1-2).
  • A 2024 review reports tissue–blood concordance can be high but variable and timing-dependent; it notes IDH1 concordance reached 100% when ctDNA collected before systemic therapy and dropped to 56% when collected on therapy/stable disease, and cites overall concordance values including 74% overall with 92% in iCCA in one report (Oct 2024) (awosika2024integrationofcirculating pages 5-6).

Diagnostic workup in high-risk PSC (surveillance/diagnostic performance)

Although PSC‑CCA is a distinct etiologic setting (not specific to IDH-mutant iCCA), it provides real-world diagnostic strategies for biliary malignancy: - Combining brush cytology + biopsy + FISH increased sensitivity from 42% to 82% while keeping specificity ~100% in one cited analysis (Oct 2023) (catanzaro2023primarysclerosingcholangitisassociated pages 8-9). - CA19‑9 thresholds show variable performance; one summary reports 129 U/mL achieving specificity 98.5% and sensitivity 78.6% in one study but far lower sensitivity in another; lower cutoffs improve sensitivity but reduce specificity/PPV (Oct 2023) (catanzaro2023primarysclerosingcholangitisassociated pages 7-8). - An institutional PSC surveillance protocol described MRI/MRCP with DWI every 6 months (Oct 2023) (catanzaro2023primarysclerosingcholangitisassociated pages 9-11).

11. Outcome / Prognosis

General prognosis (advanced disease)

IDH-mutant prognosis and immune phenotype

12. Treatment

Approved targeted therapy: mutant IDH1 inhibition (ivosidenib)

Regulatory indication & pivotal trial - Direct abstract quote (FDA approval summary): “On August 25, 2021, the FDA approved ivosidenib for the treatment of adult patients with unresectable locally advanced or metastatic… IDH1 mutated cholangiocarcinoma… with disease progression after 1 to 2 prior lines of systemic therapy” (Mar 2022) (casak2022fdaapprovalsummary pages 1-2). - FDA approval summary reports PFS HR 0.37 (P<0.0001) and median OS 10.3 vs 7.5 months with crossover confounding (casak2022fdaapprovalsummary pages 1-2, casak2022fdaapprovalsummary media 6fe1eb4a, casak2022fdaapprovalsummary media 2f70fd07).

Safety - FDA summary abstract lists common adverse reactions (>20%): “fatigue/asthenia, nausea, diarrhea, abdominal pain, ascites, vomiting, cough, and decreased appetite” (Mar 2022) (casak2022fdaapprovalsummary pages 1-2, casak2022fdaapprovalsummary media 085761fb).

Pharmacodynamics / biomarker effect - Plasma 2‑HG suppression to near healthy levels is shown in the ClarIDHy PK/PD analysis (Jan 2024) (fan2024pharmacokineticspharmacodynamicsofivosidenib pages 1-2).

Real‑world implementation - Italian real‑world cohort (n=11) reported median PFS 4.4 months and OS 15 months with no grade ≥3 treatment-related AEs (Jan 2023) (muller2024sustainedclinicalresponse pages 1-2).

Table (click to expand)
Study / evidence source Therapy / regimen Setting / line Key endpoints and numeric results Notable safety signals Biomarker / PD findings Publication year/date or NCT URL
ClarIDHy phase III, FDA approval summary + immunogenomic background Ivosidenib 500 mg orally once daily vs placebo Previously treated, advanced unresectable/metastatic IDH1-mutant cholangiocarcinoma; progression after 1–2 prior systemic regimens; randomized 2:1; crossover allowed PFS HR 0.37 (95% CI 0.25–0.54; P<0.0001); median OS 10.3 mo vs 7.5 mo, HR 0.79 (95% CI 0.56–1.12); Makawita background also cites median PFS 2.7 vs 1.4 mo and mOS 10.3 vs 7.5 mo (casak2022fdaapprovalsummary pages 1-2, makawita2024comprehensiveimmunogenomicprofiling pages 1-2) AEs >20% with ivosidenib: fatigue/asthenia, nausea, diarrhea, abdominal pain, ascites, vomiting, cough, decreased appetite; placebo >20%: fatigue/asthenia, nausea, abdominal pain, vomiting (casak2022fdaapprovalsummary pages 1-2) Established mutant-IDH1 targeting in CCA; background notes IDH1/2-altered tumors are relatively immune-cold with lower PD-L1, TMB, MSI-H than IDH-wt iCCA (makawita2024comprehensiveimmunogenomicprofiling pages 1-2, casak2022fdaapprovalsummary pages 1-2) 2022 FDA summary; trial NCT02989857 (completed) https://doi.org/10.1158/1078-0432.CCR-21-4462
Phase I ivosidenib clinical study summarized by Lavacchi Ivosidenib 500 mg once daily Pretreated IDH1-mutant cholangiocarcinoma; 73 patients, 89% intrahepatic ORR 5%, DCR 61%, median PFS 3.8 mo (95% CI 3.6–7.3), 6-mo PFS 40.1%, 12-mo PFS 21.8%, median OS 13.8 mo (95% CI 11.1–29.3) (lavacchi2022ivosidenibinidh1mutated pages 2-3) Grade ≥3 ascites 5%, anemia 4%; QT prolongation 11% overall, grade 3 in 1 patient (lavacchi2022ivosidenibinidh1mutated pages 2-3) Background biology: mutant IDH1 causes 2-HG accumulation; common baseline variants R132C 77%, R132L 11%; resistance alterations included IDH2-R172V and IDH1-R132F at progression (lavacchi2022ivosidenibinidh1mutated pages 2-3) 2022 https://doi.org/10.2139/ssrn.3977450
Italian real-world experience (Rimini et al.) Ivosidenib monotherapy Clinical practice; second-/third-line advanced IDH1-mutant cholangiocarcinoma; 11 patients Median PFS 4.4 mo (95% CI 2.0–5.8), median OS 15.0 mo (95% CI 6.6–15.0), DCR 63%, PR 18% (2/11) (muller2024sustainedclinicalresponse pages 1-2) 18% had at least one treatment-related AE; no grade ≥3 events; most frequent grade 2 AEs: prolonged QT interval, hypomagnesemia (muller2024sustainedclinicalresponse pages 1-2) Molecular profiling in 8/11 showed common co-alterations in TP53, BAP1, CDKN2A, CDKN2B; R132C was the most prevalent IDH1 variant in related real-world reporting (muller2024sustainedclinicalresponse pages 1-2) 2023 https://doi.org/10.1177/17588359231171574
ClarIDHy PK/PD biomarker analysis (Fan et al.) Ivosidenib 500 mg once daily PK/PD subset from phase III ClarIDHy; advanced IDH1-mutant cholangiocarcinoma Clinical outcomes referenced from ClarIDHy; PK/PD paper itself emphasizes drug exposure and 2-HG suppression rather than new efficacy endpoints (fan2024pharmacokineticspharmacodynamicsofivosidenib pages 1-2) No new major safety signal highlighted in excerpt; focus was PK/PD characterization (fan2024pharmacokineticspharmacodynamicsofivosidenib pages 1-2) Rapid absorption (Tmax ~2.63 h single dose, 2.07 h multiple dose); mean plasma 2-HG fell from 1108 ng/mL at baseline to 97.7 ng/mL at C2D1; average 2-HG inhibition 75.0% at steady state; no 2-HG decrease with placebo (fan2024pharmacokineticspharmacodynamicsofivosidenib pages 1-2) 2024 https://doi.org/10.1007/s00280-023-04633-5
ClinicalTrials.gov: ClarIDHy Ivosidenib vs placebo Previously treated advanced cholangiocarcinoma with IDH1 mutation Registrational phase III trial; enrollment 187; completed (casak2022fdaapprovalsummary pages 1-2) See FDA summary row for safety outcomes (casak2022fdaapprovalsummary pages 1-2) Trial enabled approval; placebo-to-ivosidenib crossover permitted (casak2022fdaapprovalsummary pages 1-2) NCT02989857 https://clinicaltrials.gov/study/NCT02989857
ClinicalTrials.gov: first-line combination study Ivosidenib + durvalumab + gemcitabine/cisplatin First-line locally advanced or metastatic cholangiocarcinoma with IDH1 mutation Phase I/II; recruiting; planned enrollment 52; no efficacy results yet available in provided context Not yet reported in provided context Rationale: combine IDH1 inhibition with chemoimmunotherapy in molecularly selected disease NCT06501625 https://clinicaltrials.gov/study/NCT06501625
ClinicalTrials.gov: observational real-world study Ivosidenib in routine practice Locally advanced or metastatic cholangiocarcinoma with IDH1 R132 mutation after at least one prior systemic treatment Observational; recruiting; planned enrollment 100; intended to capture real-world effectiveness and treatment patterns Real-world safety collection expected; no results yet in provided context Reflects implementation of approved ivosidenib outside randomized trial setting NCT06607302 https://clinicaltrials.gov/study/NCT06607302
ClinicalTrials.gov: adjuvant / maintenance study Ivosidenib maintenance after standard adjuvant chemotherapy Curative-intent mIDH1 cholangiocarcinoma after SOC adjuvant chemotherapy Phase II; recruiting; planned enrollment 40; no outcome data yet in provided context Not yet reported in provided context Explores earlier-disease use after curative-intent therapy NCT07260175 https://clinicaltrials.gov/study/NCT07260175
ClinicalTrials.gov: IDH-mutant basket PARP study Olaparib Advanced glioma, cholangiocarcinoma, or solid tumors with IDH1/2 mutations Phase II basket trial; active, not recruiting; planned enrollment 89; cholangiocarcinoma included but no CCA-specific efficacy data in provided context Not reported in provided context Based on therapeutic exploitation of IDH-associated vulnerabilities; cholangiocarcinoma cohort included NCT03212274 https://clinicaltrials.gov/study/NCT03212274

Table: This table summarizes pivotal trial data, pharmacodynamic findings, real-world implementation, and active clinical studies for IDH1-mutant cholangiocarcinoma therapies. It is useful for comparing efficacy, safety, biomarker effects, and where the treatment landscape is moving next.

MAXO (Medical Action Ontology) suggestions - Small molecule therapy (ivosidenib) targeting mutant IDH1 (casak2022fdaapprovalsummary pages 1-2) - Tumor molecular profiling / genomic testing to select therapy (casak2022fdaapprovalsummary pages 1-2, astier2024molecularprofilingof pages 1-2)

Emerging / experimental treatment directions (2023–2024)

13. Prevention

Subtype-specific prevention for IDH-mutant iCCA is not established in the retrieved evidence.

High-risk prevention/surveillance paradigms exist for etiologic risk conditions: - PSC surveillance: imaging + biomarkers in structured follow-up; one review emphasizes surveillance is “mandatory” and provides MRI/MRCP-based protocols (catanzaro2023primarysclerosingcholangitisassociated pages 9-11). - Fluke-related CCA prevention: infection control (anti-helminthics, education, hygiene) is repeatedly noted as a preventive principle (qualitative) (ciobica2024theconstellationof pages 2-3).

14. Other Species / Natural Disease

No cross-species naturally occurring disease data were identified in the retrieved corpus.

15. Model organisms and experimental systems

Preclinical models used for IDH-mutant iCCA

  • Patient-derived organoids and patient-derived xenografts (PDX): used in mechanistic dependency work (SRC/MAGI1‑PP2A/S6K) (luk2024srcinhibitionenables pages 1-2).
  • Genetically engineered mouse model (GEMM) explicitly including Idh1 mutation: Alb‑Cre; KrasLSL‑G12D; Idh1LSL‑R132 reported with 100% penetrance and latency 27–54 weeks, producing multifocal iCCA with metastasis (reviewed in 2024) (vaquero2024decipheringtherole pages 25-29).

Key recent developments (prioritizing 2023–2024)

1) Large-scale immunogenomics of IDH1/2‑altered iCCA (Mar 2024): clear evidence that IDH-altered iCCA is relatively immune-cold and has lower MSI‑H/TMB‑high/PD‑L1 positivity than IDH‑wildtype iCCA (makawita2024comprehensiveimmunogenomicprofiling pages 1-2). 2) Mechanistic dependency in IDH-mutant iCCA (May 2024): SRC-driven translational signaling vulnerability actionable with dasatinib±M2698 in organoids/PDX (luk2024srcinhibitionenables pages 1-2). 3) Biomarker-confirmed on-target activity of ivosidenib (Jan 2024): robust plasma 2‑HG suppression in ClarIDHy PK/PD study (fan2024pharmacokineticspharmacodynamicsofivosidenib pages 1-2). 4) ctDNA evidence supporting IDH1 detection (Jan 2024; Oct 2024): high detection and timing-dependent concordance with tissue; IDH1 appears comparatively reliable in ctDNA relative to certain fusions (astier2024molecularprofilingof pages 1-2, awosika2024integrationofcirculating pages 5-6).

Evidence-backed statistics (selected)

Notes on limitations of this report

  • Several requested identifier types (ICD‑10/ICD‑11, MeSH, Orphanet, OMIM) and detailed phenotype frequencies were not available in the retrieved tool corpus and were therefore not asserted.
  • Where PSC-CCA surveillance or fluke-related prevention is discussed, it reflects general CCA prevention/surveillance rather than evidence specific to the IDH-mutant molecular subtype.

References

  1. (casak2022fdaapprovalsummary pages 1-2): Sandra J. Casak, Shan Pradhan, Lola A. Fashoyin-Aje, Yi Ren, Yuan-Li Shen, Yuan Xu, Edwin Chiu Yuen Chow, Ye Xiong, Jeanne Fourie Zirklelbach, Jiang Liu, Rosane Charlab, William F. Pierce, Nataliya Fesenko, Julia A. Beaver, Richard Pazdur, Paul G. Kluetz, and Steven J. Lemery. Fda approval summary: ivosidenib for the treatment of patients with advanced unresectable or metastatic, chemotherapy refractory cholangiocarcinoma with an idh1 mutation. Clinical Cancer Research, 28:2733-2737, Mar 2022. URL: https://doi.org/10.1158/1078-0432.ccr-21-4462, doi:10.1158/1078-0432.ccr-21-4462. This article has 73 citations and is from a highest quality peer-reviewed journal.

  2. (makawita2024comprehensiveimmunogenomicprofiling pages 1-2): Shalini Makawita, Sunyoung Lee, Elisabeth Kong, Lawrence N. Kwong, Zeyad Abouelfetouh, Anaemy Danner De Armas, Lianchun Xiao, Karthikeyan Murugesan, Natalie Danziger, Dean Pavlick, Anil Korkut, Jeffrey S. Ross, and Milind Javle. Comprehensive immunogenomic profiling of idh1-/2-altered cholangiocarcinoma. JCO Precision Oncology, Mar 2024. URL: https://doi.org/10.1200/po.23.00544, doi:10.1200/po.23.00544. This article has 19 citations and is from a peer-reviewed journal.

  3. (vaquero2024decipheringtheroleb pages 29-32): MC Fernández Vaquero. Deciphering the role of mutant-idh1 in liver cancer development and the tumor immune microenvironment. Unknown journal, 2024.

  4. (fan2024pharmacokineticspharmacodynamicsofivosidenib pages 1-2): Bin Fan, Ghassan K. Abou-Alfa, Andrew X. Zhu, Shuchi S. Pandya, Hongxia Jia, Feng Yin, Camelia Gliser, Zhaowei Hua, Mohammad Hossain, and Hua Yang. Pharmacokinetics/pharmacodynamics of ivosidenib in advanced idh1-mutant cholangiocarcinoma: findings from the phase iii claridhy study. Cancer Chemotherapy and Pharmacology, 93:471-479, Jan 2024. URL: https://doi.org/10.1007/s00280-023-04633-5, doi:10.1007/s00280-023-04633-5. This article has 8 citations and is from a peer-reviewed journal.

  5. (frampton2023ivosidenibareview pages 1-2): James E. Frampton. Ivosidenib: a review in advanced cholangiocarcinoma. Targeted Oncology, 18:973-980, Oct 2023. URL: https://doi.org/10.1007/s11523-023-01002-3, doi:10.1007/s11523-023-01002-3. This article has 8 citations and is from a peer-reviewed journal.

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