venetoclax (Rx)

Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Indicated for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)

Dose ramp-up phase

• Administer dose according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg
• Ramp-up dosing schedule designed to gradually reduce tumor burden and decrease risk of tumor lysis syndrome
• Week 1: 20 mg PO qDay
• Week 2: 50 mg PO qDay
• Week 3: 100 mg PO qDay
• Week 4: 200 mg PO qDay
• Week 5 and beyond: 400 mg PO qDay

Monotherapy

• 400 mg PO qDay after completing the 5-week dose ramp-up schedule
• Continue until disease progression or unacceptable toxicity

Combination with obinutuzumab

• Cycle 1

  • Day 1: Obinutuzumab 100 mg IV
  • Day 2: Obinutuzumab 900 mg IV
  • Days 8 and 15: Obinutuzumab 1000 mg IV
  • Day 22: Start venetoclax according to 5-week ramp up schedule

• Cycle 2

  • Day 1: Obinutuzumab 1000 mg IV
  • Day 28: After completing the ramp-up phase on Cycle 2 Day 28, continue venetoclax 400 mg qDay from Cycle 3 Day 1 until Cycle 12 Day 28

• Cycles 3-6

  • Day 1: Obinutuzumab 1000 mg IV
  • Days 1-28: Continue venetoclax 400 mg PO qDay

• Cycles 7-12

  • Days 1-28: Continue venetoclax 400 mg PO qDay

Combination with rituximab

• Venetoclax

  • Complete 5-week ramp-up dosing to reach 400 mg PO qDay
  • Continue venetoclax 400 mg PO qDay for 24 months from Cycle 1 Day 1 of rituximab

• Rituximab

  • Initiate 375 mg/m² IV after patient has received venetoclax 400 mg/day x 7 days (ie, this will be Day 1 of Cycle 1)
  • 500 mg/m² IV on Day 1 for Cycles 2-6

Acute Myeloid Leukemia

Indicated in combination with azacitidine or decitabine or low-dose cytarabine for treatment in adults (≥75 years) who are newly-diagnosed acute myeloid leukemia (AML) or who have comorbidities that preclude use of intensive induction chemotherapy

Venetoclax dosing depends on the combination agent

Dose ramp-up phase

• Day 1: 100 mg PO qDay
• Day 2: 200 mg PO qDay
• Day 3: 400 mg PO qDay
• Day 4 and beyond (in combination with decitabine or azacitidine): 400 mg PO qDay
• Day 4 and beyond (in combination with low-dose cytarabine): 600 mg PO qDay
• In combination with decitabine, azacitidine, or low-dose cytarabine: Continue until disease progression or unacceptable toxicity

Refer to prescribing information for azacitidine, decitabine, or cytarabine for additionaldosing information

Dosage Modifications

For a dosing interruption >1 week during the first 5 weeks of ramp-up phase or >2 weeks after completing the ramp-up phase, reassess for risk of tumor lysis syndrome (TLS) to determine if reinitiation with a reduced dose is necessary (eg, all or some levels of the dose ramp-up schedule)

Consider discontinuing treatment for patients who require dose reductions to <100 mg for >2 weeks

Dose reduction schedule (CLL/SLL)

• Dose at interruption 400 mg: Restart at 300 mg
• Dose at interruption 300 mg: Restart at 200 mg
• Dose at interruption 200 mg: Restart at 100 mg
• Dose at interruption 100 mg: Restart at 50 mg
• Dose at interruption 50 mg: Restart at 20 mg
• Dose at interruption 20 mg: Restart at 10 mg
• During the ramp-up phase, continue reduced dose for 1 week before increasing the dose

Tumor lysis syndrome

• Modify for any occurrence of blood chemistry changes or symptoms suggestive of TLS
• Withhold the next day’s dose; if resolved within 24-48 hr of last dose, resume at the same dose
• For any blood chemistry changes requiring >48 hr to resolve, resume at a reduced dose
• For any events of clinical TLS, resume at a reduced dose following resolution

Grade 3 or 4 nonhematologic toxicities

• First occurrence: Interrupt dose; once resolved to grade ≤1, resume at same dose; no dose modification is required
• Second and subsequent occurrences: Interrupt dose; follow dose reduction schedule when resuming treatment after resolution; a larger dose reduction may be used at discretion of physician

Hematologic toxicities (CLL/SLL)

• Grade 3 or 4 neutropenia with infection or fever, or grade 4 hematologic toxicities (except lymphopenia)
• First occurrence: Interrupt dose; reduce infection risks with neutropenia by administering G-CSF with venetoclax if clinically indicated; once toxicity resolves to grade ≤1, resume at the same dose
• Second and subsequent occurrences: Interrupt dose; consider using G-CSF as clinically indicated; follow dose reduction schedule when resuming treatment after resolution; a larger dose reduction may be used at discretion of physician

Hematologic toxicities (AML)

• Grade 4 neutropenia with or without fever or infection; or Grade 4 thrombocytopenia
• Occurrence prior to achieving remission: Transfuse blood products, administer prophylactic and treatment anti-infectives as clinically indicated
• First occurrence after remission (last ≥7 days): Delay subsequent treatment cycle of venetoclax and azacitidine, decitabine, or low-dose cytarabine; monitor blood counts; once resolved to Grade 1 or 2, resume all therapy at same dose
• Subsequent occurrence after remission (last ≥7 days): Delay subsequent treatment cycle of venetoclax and azacitidine, decitabine, or low-dose cytarabine; monitor blood counts; once resolved to Grade 1 or 2, resume all therapy at same dose and reduce duration by 7 days for each subsequent cycle

Coadministration with strong CYP3A4 inhibitors

• CLL/SLL

  • Dose ramp-up phase: Contraindicated
  • After ramp-up phase, consider alternative medications or reduce dose to 70 mg (coadministered with posaconazole) and 100 mg (coadministered with other strong CYP3A4 inhibitors)

• AML

  • Day 1: Reduce to 10 mg
  • Day 2: Reduce to 20 mg
  • Day 3: Reduce to 50 mg
  • Day 4: Reduce to 70 mg (coadministered with posaconazole) OR 100 mg (coadministered with other strong CYP3A4 inhibitors
  • Steady daily dose (after ramp-up phase): Reduce dose to 70 mg (coadministered with posaconazole) and 100 mg (coadministered with other strong CYP3A4 inhibitors)
  • Resume venetoclax dose used prior to initiating the CYP3A inhibitor or P-gp inhibitor 2-3 days after discontinuation of inhibitor

Coadministration with moderate CYP3A inhibitor or P-gp inhibitor

• Reduce venetoclax dose by at least 50%
• Resume venetoclax dose used prior to initiating the CYP3A inhibitor or P-gp inhibitor 2-3 days after discontinuation of the inhibitor

Renal impairment

• Mild or moderate (CrCl ≥15 mL/min): No dosage adjustment necessary
• Severe (CrCl <15 mL/min) or patients on dialysis: Recommended dose has not been determined

Hepatic impairment

• Mild or moderate (Child-Pugh A or B): No dosage adjustment; monitor more frequently for signs of toxicity or adverse reactions during initiation and ramp-up phases
• Severe (Child-Pugh C): Reduce venetoclax dose by 50%; monitor

Dosing Considerations

Patients without 17p deletion at diagnosis should be retested at relapse because acquisition of 17p deletion can occur

TLS risk

• Consider all patient comorbidities before final determination of prophylaxis and monitoring schedule
• Assess patient-specific factors for level of risk of TLS and provide prophylactic hydration and antihyperuricemics prior to first dose to reduce risk of TLS
• Perform tumor burden assessments, including radiographic evaluation (eg, CT scan)
• Assess blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine) in all patients and correct preexisting abnormalities prior to initiation; monitor blood chemistries for TLS
• Reassess risk of TLS when reinitiating therapy after a dosage interruption lasting more than 1 week during the ramp-up phase, or more than 2 weeks after completion of ramp-up
• Institute prophylaxis and monitoring as needed

• AML

  • All patients should have WBC<25 x 10⁹/L before to initiation
  • Consider reducing venetoclax starting dose and closely monitor patients with risk factors for TLS (eg, circulating blasts, high burden of leukemia involvement in bone marrow, elevated pretreatment LDH levels, reduced renal function

TLS prophylaxis (CLL/SLL)

• Low tumor burden (all lymph nodes (LNs) <5 cm AND absolute lymphocyte count (ALC) <25 x109/L)

  • Hydration: Oral (1.5-2 L)
  • Give allopurinol or xanthine oxidase inhibitor 2-3 days prior to initiation
  • Administer IV hydration for patients unable to tolerate oral hydration
  • Outpatient monitoring (20-mg or 50-mg dose): Blood chemistry predose, at 6-8 hr, and 24 hr after first dose and predose for subsequent ramp-up doses

• Medium tumor burden (any LN 5 to <10 cm OR ALC ≥25 x109​/L)

  • Hydration: Oral (1.5-2 L, also consider additional IV hydration)
  • Give allopurinol or xanthine oxidase inhibitor (2-3 days prior to initiation)
  • Administer IV hydration for patients unable to tolerate oral hydration
  • Outpatient monitoring (20-mg or 50-mg dose): Blood chemistry predose, at 6-8 hr, and 24 hr after first dose and predose for subsequent ramp-up doses; consider hospitalization for patients with CrCl <80 mL/min at first dose

• High tumor burden (any LN ≥10 cm OR, ALC ≥25 x109​/L AND any LN ≥5 cm)

  • Hydration: Oral (1.5-2 L) and IV (150-200 mL/hr as tolerated)
  • Give allopurinol 2-3 days before initiating venetoclax; consider rasburicase if baseline uric acid is elevated
  • Inpatient monitoring (20-mg or 50-mg dose): Blood chemistry predose, 4, 8, 12, and 24 hr
  • Outpatient monitoring (subsequent ramp-up doses): Blood chemistry at predose, at 6-8 hr, and 24 hr after dose

Orphan Designations

Multiple myeloma

Mantle cell lymphoma

Myelodysplastic syndromes

Sponsor

• AbbVie Inc; 1 Waukegan Road, Dept PA77, Bldg. AP30; North Chicago, Illinois 60044

Safety and efficacy not established