Adverse events of special interest with molecularly targeted therapies and venetoclax
| Adverse event . | Clinical characteristics . | Targeted agent . | Incidence . | Days to onset median (range) . | Management . |
|---|---|---|---|---|---|
| Differentiation syndrome (DS) associated with targeted inhibitors | Dyspnea, pulmonary infiltrates, weight gain, fever, renal failure, hypotension, leukocytosis | Ivosidenib | 11%-19% | 20 (1-78) | Dexamethasone 10 mg twice daily for 72 hours or until improvement in symptoms. Rule out other etiologies for symptoms. Hydroxyurea for co-occurring leukocytosis. For severe cases, temporarily interrupt targeted therapy. |
| Olutasidenib | 14% | 17.5 (1-561) | |||
| Enasidenib | 14%-19% | 19 (1-86) | |||
| Gilteritinib | ∼ 3% | 2-75 | |||
| Quizartinib | Not reported | Not reported | |||
| Revumenib | 16% | 18 (5-41) | |||
| IVO-AZA | 14% | 19.5 (3-33) | |||
| Tumor lysis syndrome | Hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, renal failure, cardiac arrhythmias, seizures | Venetoclax | 3% | Days 1-3 (venetoclax ramp) | Employ venetoclax ramp-up dosing on days 1-3 of initiation of therapy. Administer prophylactic uric acid reducing agents and intravenous fluids when initiating therapy. Monitor chemistry panel every 4–6 hours when initiating therapy. |
| QTc prolongation | Prolongation of the QT interval beyond 450 msec. Grade 3 QT prolongation defined as ≥500 msec or >60 msec change from baseline. | Gilteritinib | 9% | - | Interrupt treatment for QTcF >500 msec and reduce gilteritinib dosage. |
| Quizartinib | 2%-14% | - | Reduce quizartinib dose for QTcF >481-500. Interrupt treatment for QTcF >500 msec and reduce quizartinib dosage. | ||
| Revumenib | 53% (grade 3: 13%) | - | Revumenib interrupted for grade ≥3 QT prolongation and resumed at lower dose-level. | ||
| Ivosidenib | 8%-18% | - | Interrupt treatment for QTcF >480-500 msec. Restart ivosidenib once QTcF <480 and monitor EKG weekly for 2 weeks. | ||
| Hepatic abnormalities | Elevated liver function tests | Olutasidenib | 12% (ALT) 9% (AST) | - | For grade ≥3 AEs, interrupt treatment until ≤ grade 1 and resume at 1 dose-level lower. Can increase to full dose if no recurrence within 30-days after initial event. |
| Hyperbilirubinemia | Enasidenib | 12%-31% | - | Reduce enasidenib to 50 mg/d if bilirubin ≥3 × upper limit of normal. Can resume at 100 mg/d if bilirubin resolves to <2 × upper limit of normal. | |
| Norsworthy et al. CCR 2020;63 Fathi et al. JAMA Onc. 2018;64 de Botton et al. Blood Adv. 2023;65 Fathi et al. AJH 2021 (Differentiation syndrome);66 DiNardo et al. NEJM 2020 (Tumor lysis syndrome),9 Cortez et al. Lancet Haematology 2019,68 Issa et al. Nature 2023;26 Stein et al. Blood 2017;69 Roboz et al. Blood 2020;67 U.S. Package inserts for ivosidenib, olutasidenib, enasidenib, gilteritinib, quizartinib. | |||||
| Adverse event . | Clinical characteristics . | Targeted agent . | Incidence . | Days to onset median (range) . | Management . |
|---|---|---|---|---|---|
| Differentiation syndrome (DS) associated with targeted inhibitors | Dyspnea, pulmonary infiltrates, weight gain, fever, renal failure, hypotension, leukocytosis | Ivosidenib | 11%-19% | 20 (1-78) | Dexamethasone 10 mg twice daily for 72 hours or until improvement in symptoms. Rule out other etiologies for symptoms. Hydroxyurea for co-occurring leukocytosis. For severe cases, temporarily interrupt targeted therapy. |
| Olutasidenib | 14% | 17.5 (1-561) | |||
| Enasidenib | 14%-19% | 19 (1-86) | |||
| Gilteritinib | ∼ 3% | 2-75 | |||
| Quizartinib | Not reported | Not reported | |||
| Revumenib | 16% | 18 (5-41) | |||
| IVO-AZA | 14% | 19.5 (3-33) | |||
| Tumor lysis syndrome | Hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, renal failure, cardiac arrhythmias, seizures | Venetoclax | 3% | Days 1-3 (venetoclax ramp) | Employ venetoclax ramp-up dosing on days 1-3 of initiation of therapy. Administer prophylactic uric acid reducing agents and intravenous fluids when initiating therapy. Monitor chemistry panel every 4–6 hours when initiating therapy. |
| QTc prolongation | Prolongation of the QT interval beyond 450 msec. Grade 3 QT prolongation defined as ≥500 msec or >60 msec change from baseline. | Gilteritinib | 9% | - | Interrupt treatment for QTcF >500 msec and reduce gilteritinib dosage. |
| Quizartinib | 2%-14% | - | Reduce quizartinib dose for QTcF >481-500. Interrupt treatment for QTcF >500 msec and reduce quizartinib dosage. | ||
| Revumenib | 53% (grade 3: 13%) | - | Revumenib interrupted for grade ≥3 QT prolongation and resumed at lower dose-level. | ||
| Ivosidenib | 8%-18% | - | Interrupt treatment for QTcF >480-500 msec. Restart ivosidenib once QTcF <480 and monitor EKG weekly for 2 weeks. | ||
| Hepatic abnormalities | Elevated liver function tests | Olutasidenib | 12% (ALT) 9% (AST) | - | For grade ≥3 AEs, interrupt treatment until ≤ grade 1 and resume at 1 dose-level lower. Can increase to full dose if no recurrence within 30-days after initial event. |
| Hyperbilirubinemia | Enasidenib | 12%-31% | - | Reduce enasidenib to 50 mg/d if bilirubin ≥3 × upper limit of normal. Can resume at 100 mg/d if bilirubin resolves to <2 × upper limit of normal. | |
| Norsworthy et al. CCR 2020;63 Fathi et al. JAMA Onc. 2018;64 de Botton et al. Blood Adv. 2023;65 Fathi et al. AJH 2021 (Differentiation syndrome);66 DiNardo et al. NEJM 2020 (Tumor lysis syndrome),9 Cortez et al. Lancet Haematology 2019,68 Issa et al. Nature 2023;26 Stein et al. Blood 2017;69 Roboz et al. Blood 2020;67 U.S. Package inserts for ivosidenib, olutasidenib, enasidenib, gilteritinib, quizartinib. | |||||
ALT, alanine aminotransferase; AST, aspartate aminotransferase; EKG, electrocardiogram.