Novel agents: management of selected adverse events
| Agent . | AE requiring special attention (incidence all grades) . | Management . |
|---|---|---|
| Midostaurin | QT prolongation (10%) | Dose interruption/reduction, substitution of QT prolonging co-medication if possible, otherwise additional ECG controls |
| Gilteritinib | Transaminase elevation (81%) | Dose interruption/reduction (if grade ≥ 3) |
| QT prolongation (9%) | Dose interruption/reduction, substitution of QT prolonging co-medication if possible | |
| PRES (1%) | Discontinuation | |
| Ivosidenib | Differentiation syndrome (25% single agent, 17% in combination with azacitidine) | Dexamethasone, hydroxyurea for co-occurring leukocytosis, Dose interruption/reduction |
| QT prolongation (21% single agent, 26% combination with azacitidine) | Dose interruption/reduction, substitution of QT prolonging co-medication if possible | |
| Enasidenib | Differentiation syndrome (14% single agent, 10% in combination with azacitidine) | Dexamethasone, hydroxyurea for co-occurring leukocytosis, Dose interruption/reduction |
| Bilirubin elevation (81%) | Dose interruption/reduction | |
| Gemtuzumab ozogamicin | Transaminase elevation (24.5%)* Bilirubin elevation (13%)* | Dose interruption/reduction |
| VOD/SOS (2.9-4.6%) | Dose interruption, supportive care, fluid management, possibly defibrotide | |
| Venetoclax | Neutropenia Thrombocytopenia | Early response assessment, eg, on day 14-21 of cycle 1, if bone marrow blasts < 5%, cease venetoclax for up to 14 d to allow count recovery to ≥ CRh. If neutropenia does not recover with 7 d of ceasing venetoclax, addition of G-CSF may augment recovery. Subsequent cycles: azacitidine 75 mg/m2 SC/IV d1-7 (or d1-5 + d8-9) or decitabine 20 mg/m2 IV d1-5 plus venetoclax 400 mg QD, or LDC 20 mg/m2 SC d1-10 plus venetoclax 600 mg QD q4 wk until progression. Delayed count recovery or recurrent treatment-emergent grade 4 neutropenia/thrombocytopenia lasting ≥ 7 d require reductions in the duration of administered venetoclax (from 28 to 21 or 14 d, or even less) and/or reductions in the dose of azacitidine, decitabine, or LDC if severe bone marrow hypoplasia. |
| Tumor lysis syndrome | Dose ramp up in cycle 1; hydration, the prophylactic use of uric acid lowering drugs, close electrolyte monitoring and reduction of WBC to < 25 × 109/L (< 25 000/µL) is recommended. | |
| Interaction with CYP3A inhibitors | • Moderate CYP3A inhibitors (eg, ciprofloxacin): reduce the venetoclax dose by at least 50%; ramp-up phase: 50 mg on d1, 100 mg on d2, 200 mg PO QD from d3 • Strong CYP3A inhibitors (eg, posaconazole): ramp-up phase: 10 mg on d1, 20 mg on d2, 50 mg on d3, 100 mg (or less‡)207 QD PO from d4. | |
| Glasdegib | Muscle spams (15%) QT prolongation (8.3%) | Dose interruption/reduction Dose interruption/reduction, substitution of QT prolonging co-medication if possible |
| CPX-351 | Prolonged myelosuppression† | Consequent anti-infectious prophylaxis |
| CC-486/oral azacitidine | Neutropenia (44%) Thrombocytopenia (33%) Nausea (65%), vomiting (60%), diarrhea (50%) | Dose interruption/reduction, myeloid growth factors Prophylactic anti-emetics |
| Agent . | AE requiring special attention (incidence all grades) . | Management . |
|---|---|---|
| Midostaurin | QT prolongation (10%) | Dose interruption/reduction, substitution of QT prolonging co-medication if possible, otherwise additional ECG controls |
| Gilteritinib | Transaminase elevation (81%) | Dose interruption/reduction (if grade ≥ 3) |
| QT prolongation (9%) | Dose interruption/reduction, substitution of QT prolonging co-medication if possible | |
| PRES (1%) | Discontinuation | |
| Ivosidenib | Differentiation syndrome (25% single agent, 17% in combination with azacitidine) | Dexamethasone, hydroxyurea for co-occurring leukocytosis, Dose interruption/reduction |
| QT prolongation (21% single agent, 26% combination with azacitidine) | Dose interruption/reduction, substitution of QT prolonging co-medication if possible | |
| Enasidenib | Differentiation syndrome (14% single agent, 10% in combination with azacitidine) | Dexamethasone, hydroxyurea for co-occurring leukocytosis, Dose interruption/reduction |
| Bilirubin elevation (81%) | Dose interruption/reduction | |
| Gemtuzumab ozogamicin | Transaminase elevation (24.5%)* Bilirubin elevation (13%)* | Dose interruption/reduction |
| VOD/SOS (2.9-4.6%) | Dose interruption, supportive care, fluid management, possibly defibrotide | |
| Venetoclax | Neutropenia Thrombocytopenia | Early response assessment, eg, on day 14-21 of cycle 1, if bone marrow blasts < 5%, cease venetoclax for up to 14 d to allow count recovery to ≥ CRh. If neutropenia does not recover with 7 d of ceasing venetoclax, addition of G-CSF may augment recovery. Subsequent cycles: azacitidine 75 mg/m2 SC/IV d1-7 (or d1-5 + d8-9) or decitabine 20 mg/m2 IV d1-5 plus venetoclax 400 mg QD, or LDC 20 mg/m2 SC d1-10 plus venetoclax 600 mg QD q4 wk until progression. Delayed count recovery or recurrent treatment-emergent grade 4 neutropenia/thrombocytopenia lasting ≥ 7 d require reductions in the duration of administered venetoclax (from 28 to 21 or 14 d, or even less) and/or reductions in the dose of azacitidine, decitabine, or LDC if severe bone marrow hypoplasia. |
| Tumor lysis syndrome | Dose ramp up in cycle 1; hydration, the prophylactic use of uric acid lowering drugs, close electrolyte monitoring and reduction of WBC to < 25 × 109/L (< 25 000/µL) is recommended. | |
| Interaction with CYP3A inhibitors | • Moderate CYP3A inhibitors (eg, ciprofloxacin): reduce the venetoclax dose by at least 50%; ramp-up phase: 50 mg on d1, 100 mg on d2, 200 mg PO QD from d3 • Strong CYP3A inhibitors (eg, posaconazole): ramp-up phase: 10 mg on d1, 20 mg on d2, 50 mg on d3, 100 mg (or less‡)207 QD PO from d4. | |
| Glasdegib | Muscle spams (15%) QT prolongation (8.3%) | Dose interruption/reduction Dose interruption/reduction, substitution of QT prolonging co-medication if possible |
| CPX-351 | Prolonged myelosuppression† | Consequent anti-infectious prophylaxis |
| CC-486/oral azacitidine | Neutropenia (44%) Thrombocytopenia (33%) Nausea (65%), vomiting (60%), diarrhea (50%) | Dose interruption/reduction, myeloid growth factors Prophylactic anti-emetics |
AE, adverse event; LDC, low-dose cytarabine; PRES, posterior reversible encephalopathy syndrome; SmPC, Summary of Product Characteristics; SOS, sinusoidal obstructive syndrome, VOD, veno-occlusive disease.
Single agent.
Median times to absolute neutrophil count ≥ 0.5 × 109/L (≥500/µL) were 35 and 29 days; and median times to platelet count ≥ 50 × 109/L (≥50 000/µL) were 36.5 and 29 days after CPX-351 vs “7 + 3,” respectively, in patients who achieved CR/CRi after initial induction chemotherapy.
In the VIALE-A and VIALE-C trials, an adjusted venetoclax dose of 50 mg was used in the presence of a strong CYP3A4 inhibitor. This venetoclax dose is supported by a pharmacokinetic study examining venetoclax in the presence of posaconazole.207