Summary of our recommendations for venetoclax administration
| Issue . | Management . |
|---|---|
| Target drug doses | Venetoclax 400 mg/d × 28 d + azacitidine 75 mg/m2 days 1-7 or decitabine 20 mg/m2 daily days 1-5 subcutaneously or IV OR Venetoclax 600 mg/d × 28 d + LDAC 20 mg/m2 daily days 1-10 subcutaneously |
| Prevention of TLS | Identify patients with higher risk of TLS: WBC >25 × 109/L, uric acid above 7.5 mg/dL (446 μmol/L), creatinine above 1.4 mg/dL (124 μmol/L) All patients, especially those with an elevated risk of TLS should be hospitalized until at least completion of ramp-up dosing Prior to commencing venetoclax • For patients with hyperleukocytosis, commence hydroxycarbamide or flat-dose ara-C, eg, 100-1000 mg IV daily until the WBC is <25 × 109/L prior to starting venetoclax • Commence TLS prophylaxis with prehydration and uricosuric agents and normalize potassium, inorganic phosphorus, and uric acid levels according to institutional practice • For some molecularly defined AML subsets with high sensitivity to venetoclax, eg, newly diagnosed NPM1 or IDH mutation, we have noticed TLS may even occur in patients with a WBC <25 × 109/L; such patients should be monitored carefully for rapid cytoreduction and early onset of severe hyperkalemia; in such cases, we also consider lowering the starting WBC <10 × 109/L to lower TLS risk prior to initiation of venetoclax Ramp-up initial venetoclax dosing in steps: 100 mg day 1, 200 mg day 2, 400 mg day 3 (for HMA), 600 mg day 4 (for LDAC) Monitor for TLS complications predose (<4 h) and 6-8 h after each ramp-up dose with additional monitoring until normalization of abnormal biochemistry If significant biochemical or clinical TLS is observed, delay further venetoclax dosing until resolution |
| Optimize venetoclax dosing | Take venetoclax within 30 min after a meal with ∼1 cup of water If HMA used, consider antiemetic prophylaxis (eg, ondansetron) Before commencing venetoclax, patients should have at least a 3-day washout from drugs with CYP3A4 inhibitor activity, as well as grapefruit juice, Seville oranges, and starfruit11 ; CYP3A4 inducers should be avoided; the venetoclax dose ramp-up should reach 400 mg before combination with CYP3A4 inhibitors is commenced; for combination with moderate CYP3A4 inhibitors (eg, ciprofloxacin, fluconazole, or isavuconazole), reduce the venetoclax daily dose by 50% (eg, from 400 mg to 200 mg); if strong CYP3A4 inhibitors are used (eg, voriconazole or posaconazole), we recommend reducing the venetoclax daily dose by at least 75% (eg, from 400 mg to 100 mg); pharmacokinetic studies have shown that venetoclax 50 mg daily when coadministered with posaconazole 300 mg daily most closely resembles the pharmacokinetic characteristics of venetoclax 400 mg daily without posaconazole11 ; therefore, for patients with persistent venetoclax-related adverse events (eg, neutropenia) when coadministered with strong CYP3A4 inhibitors, a further dose reduction of venetoclax to 50 mg should be considered. |
| Preventing infection | Severe and prolonged neutropenia is common with these regimens, even after achieving remission. For patients with grade 4 neutropenia (<0.5 × 109/L), antifungal prophylaxis according to institutional practice; if CYP3A4 inhibitors are used (eg, ciprofloxacin and/or azole antifungals), venetoclax dose adjustment is required (see optimizing venetoclax dosing) Hospitalization until hematologic recovery should be considered for selected patients with a high risk of complications or inadequate social support networks to enable safe outpatient management Treatment-related neutropenia may occur in the later part of the cycle and recover rapidly with commencement of G-CSF |
| Managing myelosuppression | Postinduction marrow assessment should be performed on days 21-28; if blast excess persists, commence the next cycle without treatment dose interruption If marrow blasts <5%, hold venetoclax and start next cycle when there has been at least partial hematologic recovery (neutrophils ≥0.5 × 109/L and platelets ≥50 × 109/L); G-CSF may be used to accelerate neutrophil recovery if neutrophils <0.5 × 109/L In subsequent cycles (for patients with <5% marrow blasts), monitor blood counts ∼ weekly; if treatment-related grade 4 neutropenia persists for >7 days, or the patient develops severe complications, interrupt venetoclax dosing, and start G-CSF until neutrophil recovery We do not reduce the venetoclax dose to manage myelosuppression Consider shortening venetoclax duration for subsequent cycles if hematologic recovery takes >14 days after interrupting venetoclax for neutropenia and/or thrombocytopenia; the following stepwise reductions could be considered 28 days → 21 days → 14 days; consider reducing HMA dose intensity by 50% if marrow cellularity is 15% to 30%, or to 33% dose intensity if marrow cellularity <15% in the setting of clinical response with delayed or lack of hematologic recovery Prophylactic G-CSF after HMA (day 8) or LDAC (day 11) could be considered for patients with recurrent dose delays due to neutropenia |
| Patients with hepatic impairment | In subjects with severe hepatic impairment (Child-Pugh C), reduce venetoclax dose by 50% |
| Patients with renal impairment | If GFR >30 mL/min, no venetoclax dose adjustment is necessary If GFR <30 mL/min, no literature exists on venetoclax pharmacokinetics |
| When to cease therapy? | Median time to response is 1-2 cycles with venetoclax combinations; if there has not been a meaningful blast reduction or hematologic response after 3-4 cycles of therapy, consider ceasing treatment if effective alternate options exist |
| Markers associated with outcome | The presence of NPM1 and/or IDH mutation is associated with high rates of clinical response The presence of signaling mutations, particularly FLT3-ITD, and/or biallelic TP53mut may be enriched at relapse (C.D.D. and A.H.W., manuscript submitted, October 2019) |
| Issue . | Management . |
|---|---|
| Target drug doses | Venetoclax 400 mg/d × 28 d + azacitidine 75 mg/m2 days 1-7 or decitabine 20 mg/m2 daily days 1-5 subcutaneously or IV OR Venetoclax 600 mg/d × 28 d + LDAC 20 mg/m2 daily days 1-10 subcutaneously |
| Prevention of TLS | Identify patients with higher risk of TLS: WBC >25 × 109/L, uric acid above 7.5 mg/dL (446 μmol/L), creatinine above 1.4 mg/dL (124 μmol/L) All patients, especially those with an elevated risk of TLS should be hospitalized until at least completion of ramp-up dosing Prior to commencing venetoclax • For patients with hyperleukocytosis, commence hydroxycarbamide or flat-dose ara-C, eg, 100-1000 mg IV daily until the WBC is <25 × 109/L prior to starting venetoclax • Commence TLS prophylaxis with prehydration and uricosuric agents and normalize potassium, inorganic phosphorus, and uric acid levels according to institutional practice • For some molecularly defined AML subsets with high sensitivity to venetoclax, eg, newly diagnosed NPM1 or IDH mutation, we have noticed TLS may even occur in patients with a WBC <25 × 109/L; such patients should be monitored carefully for rapid cytoreduction and early onset of severe hyperkalemia; in such cases, we also consider lowering the starting WBC <10 × 109/L to lower TLS risk prior to initiation of venetoclax Ramp-up initial venetoclax dosing in steps: 100 mg day 1, 200 mg day 2, 400 mg day 3 (for HMA), 600 mg day 4 (for LDAC) Monitor for TLS complications predose (<4 h) and 6-8 h after each ramp-up dose with additional monitoring until normalization of abnormal biochemistry If significant biochemical or clinical TLS is observed, delay further venetoclax dosing until resolution |
| Optimize venetoclax dosing | Take venetoclax within 30 min after a meal with ∼1 cup of water If HMA used, consider antiemetic prophylaxis (eg, ondansetron) Before commencing venetoclax, patients should have at least a 3-day washout from drugs with CYP3A4 inhibitor activity, as well as grapefruit juice, Seville oranges, and starfruit11 ; CYP3A4 inducers should be avoided; the venetoclax dose ramp-up should reach 400 mg before combination with CYP3A4 inhibitors is commenced; for combination with moderate CYP3A4 inhibitors (eg, ciprofloxacin, fluconazole, or isavuconazole), reduce the venetoclax daily dose by 50% (eg, from 400 mg to 200 mg); if strong CYP3A4 inhibitors are used (eg, voriconazole or posaconazole), we recommend reducing the venetoclax daily dose by at least 75% (eg, from 400 mg to 100 mg); pharmacokinetic studies have shown that venetoclax 50 mg daily when coadministered with posaconazole 300 mg daily most closely resembles the pharmacokinetic characteristics of venetoclax 400 mg daily without posaconazole11 ; therefore, for patients with persistent venetoclax-related adverse events (eg, neutropenia) when coadministered with strong CYP3A4 inhibitors, a further dose reduction of venetoclax to 50 mg should be considered. |
| Preventing infection | Severe and prolonged neutropenia is common with these regimens, even after achieving remission. For patients with grade 4 neutropenia (<0.5 × 109/L), antifungal prophylaxis according to institutional practice; if CYP3A4 inhibitors are used (eg, ciprofloxacin and/or azole antifungals), venetoclax dose adjustment is required (see optimizing venetoclax dosing) Hospitalization until hematologic recovery should be considered for selected patients with a high risk of complications or inadequate social support networks to enable safe outpatient management Treatment-related neutropenia may occur in the later part of the cycle and recover rapidly with commencement of G-CSF |
| Managing myelosuppression | Postinduction marrow assessment should be performed on days 21-28; if blast excess persists, commence the next cycle without treatment dose interruption If marrow blasts <5%, hold venetoclax and start next cycle when there has been at least partial hematologic recovery (neutrophils ≥0.5 × 109/L and platelets ≥50 × 109/L); G-CSF may be used to accelerate neutrophil recovery if neutrophils <0.5 × 109/L In subsequent cycles (for patients with <5% marrow blasts), monitor blood counts ∼ weekly; if treatment-related grade 4 neutropenia persists for >7 days, or the patient develops severe complications, interrupt venetoclax dosing, and start G-CSF until neutrophil recovery We do not reduce the venetoclax dose to manage myelosuppression Consider shortening venetoclax duration for subsequent cycles if hematologic recovery takes >14 days after interrupting venetoclax for neutropenia and/or thrombocytopenia; the following stepwise reductions could be considered 28 days → 21 days → 14 days; consider reducing HMA dose intensity by 50% if marrow cellularity is 15% to 30%, or to 33% dose intensity if marrow cellularity <15% in the setting of clinical response with delayed or lack of hematologic recovery Prophylactic G-CSF after HMA (day 8) or LDAC (day 11) could be considered for patients with recurrent dose delays due to neutropenia |
| Patients with hepatic impairment | In subjects with severe hepatic impairment (Child-Pugh C), reduce venetoclax dose by 50% |
| Patients with renal impairment | If GFR >30 mL/min, no venetoclax dose adjustment is necessary If GFR <30 mL/min, no literature exists on venetoclax pharmacokinetics |
| When to cease therapy? | Median time to response is 1-2 cycles with venetoclax combinations; if there has not been a meaningful blast reduction or hematologic response after 3-4 cycles of therapy, consider ceasing treatment if effective alternate options exist |
| Markers associated with outcome | The presence of NPM1 and/or IDH mutation is associated with high rates of clinical response The presence of signaling mutations, particularly FLT3-ITD, and/or biallelic TP53mut may be enriched at relapse (C.D.D. and A.H.W., manuscript submitted, October 2019) |
ara-C, cytarabine; GFR, glomerular filtration rate; TLS, tumor lysis syndrome. See Table 2 for expansion of other abbreviations.