Olutasidenib (Rezlidhia): A Targeted Drug for IDH1-Mutated Relapsed/Refractory AML

　　Detailed Drug Introduction

　　Olutasidenib is an oral IDH1 mutation inhibitor developed by Rigel Pharmaceuticals,with the trade name Rezlidhia.It was approved for marketing by the US FDA in 2022,mainly used for the treatment of adult patients with relapsed or refractory acute myeloid leukemia(AML)harboring IDH1 mutations.As a precise targeted drug,its mechanism of action is to highly selectively inhibit the activity of mutant IDH1 enzyme,significantly reduce the level of the oncogenic metabolite 2-hydroxyglutarate(2-HG)in the body,restore the normal differentiation ability of bone marrow cells,and promote the maturation and natural apoptosis of leukemia cells.Compared with traditional chemotherapy,it has fewer severe side effects such as myelosuppression and better tolerability.

　　The definite indication of this drug is:adult patients with IDH1 mutations who have relapsed or refractory AML after receiving at least one line of treatment.Confirmation of IDH1 mutation through an FDA-approved companion diagnostic test is required before use,and it is not applicable to AML with IDH2 mutations or wild-type IDH1.

　　The standard dosage is 150mg twice daily,taken orally,with an interval of about 12 hours between doses.It can be taken with or without food,and each capsule must be swallowed whole,without crushing,chewing or opening.Treatment should be continued until disease progression or the occurrence of intolerable toxic reactions.If a dose is missed and the time to the next dose is more than 8 hours,the missed dose should be taken as soon as possible;if it is less than 8 hours,the missed dose should be skipped,and no double dose is needed;if vomiting occurs after taking the medicine,no supplementary dose is needed,and the next dose should be taken as planned.

　　Dose adjustment should be carried out according to the occurrence of adverse reactions:when grade 3 non-hematological toxicity(such as QTc prolongation,abnormal liver function)occurs for the first time,administration should be suspended until the toxicity is reduced to≤grade 1,and then treatment should be resumed at the same dose;when the above toxicity occurs for the second time,the dose should be reduced to 150mg once daily after resuming treatment;when it occurs for the third time or the reduced dose is intolerable,permanent drug withdrawal is required.If differentiation syndrome(manifested as fever,dyspnea,hypotension,etc.)occurs,administration must be suspended immediately and dexamethasone should be given for treatment.If necessary,hydroxyurea should be added to control white blood cells,and treatment should be resumed at the same dose after symptoms are relieved.

　　The following precautions should be noted during medication:first,be alert to differentiation syndrome,which may occur in AML patients using IDH inhibitors.In addition to the above symptoms,it may also be accompanied by pulmonary infiltration,weight gain,etc.Patients should be informed in advance to seek medical attention immediately once relevant symptoms appear.The conventional treatment plan is dexamethasone 10mg every 12 hours.Second,monitor QTc interval prolongation.Olutasidenib may cause QTc prolongation.Electrocardiogram and electrolytes(potassium,magnesium)should be monitored every 2 weeks before and during treatment.If QTc>500ms,administration should be suspended.Third,pay attention to hepatotoxicity.Regularly monitor ALT,AST and bilirubin levels.If ALT>3 times ULN and total bilirubin>2 times ULN,administration should be suspended.Fourth,pay attention to embryo-fetal toxicity.Women of childbearing age should take effective contraceptive measures during treatment and within 1 month after drug withdrawal,and breastfeeding women are not recommended to use the drug.

　　Special populations should follow the following principles for medication:among patients with liver insufficiency,no dose adjustment is needed for mild to moderate(Child-Pugh A/B),and there is no relevant medication data for severe(Child-Pugh C),so it should be used with caution;among patients with renal insufficiency,no dose adjustment is needed for mild to moderate(eGFR≥30),and there is no relevant medication data for end-stage renal disease;no dose adjustment is needed for elderly patients(≥65 years old),but close monitoring of the occurrence of hepatotoxicity and hypertension is required.

　　In terms of drug interactions,olutasidenib is a CYP3A4 substrate.When used in combination with strong CYP3A4 inhibitors(such as posaconazole,clarithromycin),close monitoring of toxic reactions is required,and the dose may need to be reduced to 150mg once daily;combined use with strong CYP3A4 inducers(such as rifampicin,phenytoin)may reduce efficacy,so concurrent use should be avoided;at the same time,it is necessary to avoid combining with grapefruit,star fruit and their products to avoid interfering with drug metabolism.

　　In terms of efficacy data,the 5-year follow-up results of the key Phase II study(NCT02719574)showed that the overall response rate of olutasidenib in the treatment of relapsed/refractory IDH1-mutated AML was 48%,of which the complete response rate was 20%.The median duration of response for all responders was 15.5 months,and the median duration of response for patients with complete response could reach 25.3 months.Some patients could be bridged to hematopoietic stem cell transplantation through this drug,creating possibilities for potential cure.