Ivosidenib: IDH1 inhibitor in AML and cholangiocarcinoma
Ivosidenib (brand name Tibsovo) is an oral selective inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). IDH1 mutations are found in about 6 to 10 % of acute myeloid leukaemias (AML) and in about 13 % of intrahepatic cholangiocarcinomas. Ivosidenib was approved in the US in 2018 for relapsed or refractory IDH1 mutated AML, in 2021 for untreated IDH1 mutated AML and in 2022 for previously treated IDH1 mutated cholangiocarcinoma. EMA approval followed in 2023 for the same indications.
Ivosidenib is one of the precision medicine therapies that are only used when a driver mutation has been demonstrated. A validated molecular diagnostic test for the IDH1 mutation, generally next generation sequencing or PCR, is a prerequisite.
Mechanism of action
IDH1 is a cytoplasmic enzyme that normally oxidises isocitrate to alpha ketoglutarate. Mutant IDH1 (frequently the R132H point mutation) acquires a new function: it converts alpha ketoglutarate to D 2 hydroxyglutarate, an oncogenic metabolite. D 2 hydroxyglutarate inhibits numerous alpha ketoglutarate dependent enzymes including histone and DNA demethylases. The consequence is global hypermethylation of DNA and histones, leading to a differentiation block in immature cells.
Ivosidenib selectively binds mutant IDH1 and blocks D 2 hydroxyglutarate production. The epigenetic changes are reversible: differentiation of tumour cells is restored, leading to a reduction of tumour burden. In AML there is classically maturation of leukaemic blasts into functional granulocytes, which clinically allows remission without classical cytotoxic therapy.
Indications
- Acute myeloid leukaemia with IDH1 mutation: as monotherapy in relapsed or refractory disease and in combination with azacitidine as first line therapy in patients unfit for intensive chemotherapy
- Intrahepatic cholangiocarcinoma with IDH1 mutation: after prior gemcitabine based chemotherapy
- Other IDH1 mutated tumours: myelodysplastic syndrome, chondrosarcoma, glioma in clinical development
Dosing and administration
Standard dose: 500 mg orally once daily, continuously, until disease progression or unacceptable toxicity.
The tablets are taken at the same time each day, preferably on an empty stomach or with a light meal. A high fat meal can increase bioavailability and lead to more adverse events.
Dose modification: with specific toxicities (differentiation syndrome, QT prolongation, raised liver enzymes) pause therapy or reduce dose. With repeated severe reactions discontinue.
Monitoring: differential blood count, electrolytes, liver enzymes, ECG before start and during the first 3 months every 1 to 2 weeks, then monthly. In AML additional bone marrow aspirate to assess response.
Adverse effects
Very common: diarrhoea, fatigue, nausea, vomiting, anorexia, mouth pain, peripheral oedema, dyspnoea, QT prolongation, anaemia, abdominal pain.
Common: dizziness, cough, pruritus, rash, arthralgia, myalgia, raised liver enzymes, hyperuricaemia.
Uncommon: differentiation syndrome, tumour lysis syndrome, hyponatraemia, liver failure, respiratory failure.
Differentiation syndrome:
- Specific and potentially life threatening adverse event of IDH inhibitors in AML
- Onset usually in the first 1 to 3 months
- Symptoms: dyspnoea, peripheral oedema, pleural or pericardial effusion, fever, rash, hypotension, renal failure, liver dysfunction
- Treatment: high dose steroids (dexamethasone 10 mg twice daily), diuretics, treatment interruption if needed, supportive measures
- Patients and relatives must be informed about early signs, since rapid response can be life saving
QT prolongation: ECG before start and regularly during therapy. With QTc above 500 ms interrupt therapy and correct electrolyte disturbances.
Interactions
- Strong CYP3A4 inhibitors (itraconazole, ketoconazole, clarithromycin, ritonavir): raised levels, caution or dose reduction
- Strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, St John's wort): reduced levels, avoid the combination if possible
- QT prolonging substances: additive effect, ECG monitoring
- Sensitive CYP3A4 substrates (e.g. hormonal contraceptives): reduced levels because ivosidenib induces CYP3A4, recommend alternative contraception
Special considerations
Pregnancy: contraindicated, teratogenic potential. Reliable contraception during therapy and for at least 1 month after the end of therapy; hormonal contraceptives may be impaired in efficacy.
Breastfeeding: contraindicated.
Before starting therapy: molecular evidence of the IDH1 mutation, ECG, electrolytes, liver and renal function, pregnancy test, blood count, bone marrow aspirate in AML.
During therapy: regular checks as described above, imaging in cholangiocarcinoma every 6 to 12 weeks, bone marrow aspirate in AML to assess remission.
Patient communication: ivosidenib enables targeted therapy with oral administration. Information about differentiation syndrome is essential, since patients and relatives must recognise early signs and seek prompt medical help.
State of research: combinations with azacitidine, venetoclax or classical chemotherapy are in trials and partly approved. Trial results are awaited in IDH1 mutated gliomas as well.
Related substances
- Sotorasib, KRAS G12C inhibitor as another example of precision medicine
- Dasatinib, BCR ABL inhibitor in CML
- Regorafenib, multikinase inhibitor in mCRC and HCC
- Fruquintinib, highly selective VEGFR TKI
Frequently asked questions
Who is eligible for ivosidenib?
Patients with AML or intrahepatic cholangiocarcinoma in whom an IDH1 mutation has been demonstrated by molecular diagnostics. The mutation must be confirmed by validated tests. Without the mutation the therapy is not effective.
What is differentiation syndrome?
A specific, potentially life threatening adverse event of IDH inhibitors in AML. The sudden differentiation of leukaemic blasts into granulocytes can cause massive inflammatory reactions with dyspnoea, oedema and renal or hepatic problems. Early recognition and treatment with steroids are decisive.
Does ivosidenib work against all IDH1 mutations?
Efficacy data exist mainly for the common mutations such as R132H, R132C and R132G. For rarer IDH1 mutations efficacy is less well established; an individual judgement at a molecular tumour board is sensible.
How is response assessed?
In AML by bone marrow aspirate and trends in blood counts. In cholangiocarcinoma by CT or MRI imaging every 6 to 12 weeks, tumour markers and clinical symptoms. A measurable reduction of D 2 hydroxyglutarate in serum can be a pharmacodynamic marker.
Sources
- EMA Tibsovo (ivosidenib) EPAR
- BfArM German Federal Institute for Drugs and Medical Devices
- AWMF guidelines AML and cholangiocarcinoma
- Gelbe Liste ivosidenib monograph
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