Summary of our recommendations for ivosidenib and enasidenib administration
| Issue . | Ivosidenib . | Enasidenib . |
|---|---|---|
| Target drug doses | Ivosidenib: 500 mg orally once daily with or without food Levels will be increased by high-fat meals; the drug has a terminal half-life of 94 h | Enasidenib: 100 mg orally once daily with or without food The drug has a terminal half-life of 137 h |
| Optimize dosing | Ivosidenib is primarily metabolized by CYP3A4 Therefore, CYP3A4 inhibitors will increase ivosidenib levels, which could prolong QTc interval If a strong CYP3A4 inhibitor is used, monitor for increased risk of QTc interval prolongation | Not applicable |
| Monitoring and management of DS | IDH inhibitors can induce myeloid proliferation resulting in IDH-DS Assess blood counts and chemistries at least once weekly for the first month, once every other week for the second month, and once monthly for the duration of therapy If differentiation syndrome is suspected • Initiate dexamethasone 10 mg IV or orally every 12 h • Commence hydroxyurea if concomitant noninfectious leukocytosis • Continue for a minimum of 3 days and taper if symptoms improve • Interrupt IDH inhibitor if severe cardiopulmonary symptoms, requirement of hospitalization, and/or renal dysfunction persists for >48 h after initiation of corticosteroids | |
| Noninfectious leukocytosis WBC >25 × 109/L or an absolute increase in WBC >15 × 109/L from baseline | Initiate treatment with hydroxyurea Interrupt IDH inhibitor if leukocytosis not improved with hydroxyurea Resume IDH inhibitor at target dose after resolution | |
| Isolated elevated indirect BR ≥3× ULN | Not applicable | Enasidenib may interfere with bilirubin metabolism through inhibition of UGT1A1 Bilirubin elevations ≥2× ULN may occur in 37%, most commonly within the first month of treatment Reduce enasidenib to 50 mg daily and resume back at 100 mg when BR ≤2× ULN |
| Monitoring for prolonged QT syndrome | If concomitant use of drugs known to prolong the QTc interval (eg, antiarrhythmic medicines, fluoroquinolones, triazole antifungals, 5-HT3 receptor antagonists) cannot be avoided, monitor EKG’s at least weekly for the first 3 wk of therapy then intermittently thereafter If QTc interval >450 ms: correct electrolytes and modify concomitant drugs known to prolong QTc If QTc interval >480 ms: interrupt ivosidenib until QTc ≤480 ms and then resume at 500 mg daily If QTc interval prolongation associated with life-threatening arrhythmia, discontinue ivosidenib permanently | Not applicable |
| Patients with hepatic impairment | No modification of the starting dose is recommended for patients with mild or moderate (Child-Pugh A or B) hepatic impairment; the pharmacokinetics and safety in patients with severe hepatic impairment (Child-Pugh C) are unknown | |
| Patients with renal impairment | No modification of the starting dose is recommended for patients with mild or moderate renal impairment (eGFR ≥30 mL/min/1.73 m2); the pharmacokinetics and safety in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2) are unknown | |
| When to cease therapy? | Ivosidenib: the median time to CR or CRh was 2.8 mo with 92% achieving a first response within 6 mo of initiating therapy If there has not been a meaningful blast reduction or hematologic response after 6 cycles of therapy, consider ceasing treatment if effective alternate options exist | Enasidenib: the median time to CR or CRh was 1.9 mo with 85% achieving a first response within 6 mo of initiating therapy If there has not been a meaningful blast reduction or hematologic response after 6 cycles of therapy, consider ceasing treatment if effective alternate options exist |
| GBS | <1% (2 of 258) in the clinical study developed GBS Monitor for new signs or symptoms of motor and/or sensory neuropathy, paresthesias, or difficulty breathing Permanently discontinue ivosidenib in patients diagnosed with GBS | Not applicable |
| Monitoring for drug resistance mutations at disease progression | Off-target resistance: mutations in K/NRAS, RUNX164,65 On-target resistance: loss of 2-HG suppression associated with second site mutations in IDH66 | |
| Issue . | Ivosidenib . | Enasidenib . |
|---|---|---|
| Target drug doses | Ivosidenib: 500 mg orally once daily with or without food Levels will be increased by high-fat meals; the drug has a terminal half-life of 94 h | Enasidenib: 100 mg orally once daily with or without food The drug has a terminal half-life of 137 h |
| Optimize dosing | Ivosidenib is primarily metabolized by CYP3A4 Therefore, CYP3A4 inhibitors will increase ivosidenib levels, which could prolong QTc interval If a strong CYP3A4 inhibitor is used, monitor for increased risk of QTc interval prolongation | Not applicable |
| Monitoring and management of DS | IDH inhibitors can induce myeloid proliferation resulting in IDH-DS Assess blood counts and chemistries at least once weekly for the first month, once every other week for the second month, and once monthly for the duration of therapy If differentiation syndrome is suspected • Initiate dexamethasone 10 mg IV or orally every 12 h • Commence hydroxyurea if concomitant noninfectious leukocytosis • Continue for a minimum of 3 days and taper if symptoms improve • Interrupt IDH inhibitor if severe cardiopulmonary symptoms, requirement of hospitalization, and/or renal dysfunction persists for >48 h after initiation of corticosteroids | |
| Noninfectious leukocytosis WBC >25 × 109/L or an absolute increase in WBC >15 × 109/L from baseline | Initiate treatment with hydroxyurea Interrupt IDH inhibitor if leukocytosis not improved with hydroxyurea Resume IDH inhibitor at target dose after resolution | |
| Isolated elevated indirect BR ≥3× ULN | Not applicable | Enasidenib may interfere with bilirubin metabolism through inhibition of UGT1A1 Bilirubin elevations ≥2× ULN may occur in 37%, most commonly within the first month of treatment Reduce enasidenib to 50 mg daily and resume back at 100 mg when BR ≤2× ULN |
| Monitoring for prolonged QT syndrome | If concomitant use of drugs known to prolong the QTc interval (eg, antiarrhythmic medicines, fluoroquinolones, triazole antifungals, 5-HT3 receptor antagonists) cannot be avoided, monitor EKG’s at least weekly for the first 3 wk of therapy then intermittently thereafter If QTc interval >450 ms: correct electrolytes and modify concomitant drugs known to prolong QTc If QTc interval >480 ms: interrupt ivosidenib until QTc ≤480 ms and then resume at 500 mg daily If QTc interval prolongation associated with life-threatening arrhythmia, discontinue ivosidenib permanently | Not applicable |
| Patients with hepatic impairment | No modification of the starting dose is recommended for patients with mild or moderate (Child-Pugh A or B) hepatic impairment; the pharmacokinetics and safety in patients with severe hepatic impairment (Child-Pugh C) are unknown | |
| Patients with renal impairment | No modification of the starting dose is recommended for patients with mild or moderate renal impairment (eGFR ≥30 mL/min/1.73 m2); the pharmacokinetics and safety in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2) are unknown | |
| When to cease therapy? | Ivosidenib: the median time to CR or CRh was 2.8 mo with 92% achieving a first response within 6 mo of initiating therapy If there has not been a meaningful blast reduction or hematologic response after 6 cycles of therapy, consider ceasing treatment if effective alternate options exist | Enasidenib: the median time to CR or CRh was 1.9 mo with 85% achieving a first response within 6 mo of initiating therapy If there has not been a meaningful blast reduction or hematologic response after 6 cycles of therapy, consider ceasing treatment if effective alternate options exist |
| GBS | <1% (2 of 258) in the clinical study developed GBS Monitor for new signs or symptoms of motor and/or sensory neuropathy, paresthesias, or difficulty breathing Permanently discontinue ivosidenib in patients diagnosed with GBS | Not applicable |
| Monitoring for drug resistance mutations at disease progression | Off-target resistance: mutations in K/NRAS, RUNX164,65 On-target resistance: loss of 2-HG suppression associated with second site mutations in IDH66 | |
2-HG, 2-hydroxyglutarate; BR, bilirubin; EKG, electrocardiogram; GBS, Guillain-Barré syndrome.