On November 21, 2018, venetoclax (Venclexta) was granted accelerated approval for use in combination with azacitidine or decitabine or low-dose cytarabine for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients aged ≥ 75 years or who have comorbidities that preclude the use of intensive induction chemotherapy.^1,2

Ongoing phase III studies, VIALE-A (ClinicalTrials.gov identifier NCT02993523) and VIALE-C (NCT03069352), are evaluating venetoclax in combination with azacitidine or low-dose cytarabine with overall survival as the primary endpoint and are intended as the confirmatory trials.

Supporting Efficacy Data

Approval was based on the rate and duration of complete remission in two single-arm trials that included patients with newly diagnosed AML who were ≥ 75 years old or had comorbidities that precluded the use of intensive induction chemotherapy.

In study M14-358 (NCT02203773),^2,3 oral venetoclax was given in combination with azacitidine in 67 patients and in combination with decitabine in 13 patients. Venetoclax was given via a daily ramp-up to a final dose of 400 mg once daily. During the ramp-up, patients received prophylaxis against tumor-lysis syndrome and were hospitalized for monitoring. Azacitidine was given intravenously (IV) or subcutaneously at 75 mg/m² on days 1 to 7 of each 28-day cycle beginning on cycle 1 of day 1. Decitabine was given at 20 mg/m² IV on days 1 to 5 of each 28-day cycle beginning on cycle 1 of day 1.

Complete remission was achieved in 25 (37%) of 67 patients receiving venetoclax plus azacitidine; the median observed time in remission (time from the start of complete remission to the data cutoff date or relapse) was 5.5 months (range = 0.4–30 months). Complete remission with partial hematologic recovery was observed in an additional 16 patients (24%). Complete remission was achieved in 7 (54%) of 13 patients receiving venetoclax plus decitabine; the median observed time in remission was 4.7 months (range = 1.0–18 months). One additional patient (8%) achieved complete remission with partial hematologic recovery.

In study M14-387 (NCT02287233),² 61 patients, including those with previous exposure to a hypomethylating agent for an antecedent hematologic disorder, received venetoclax in combination with low-dose cytarabine. Venetoclax was given via daily ramp-up to a final dose of 600 mg once daily; during the ramp-up, patients received tumor-lysis syndrome prophylaxis and were hospitalized for monitoring. Cytarabine was given subcutaneously at 20 mg/ m² once daily on days 1 to 10 of each 28-day cycle beginning on cycle 1 of day 1.

Complete remission was achieved in 13 (21%) of 61 patients; the median observed time in remission was 6 months (range = 0.03–25 months). Complete remission with partial hematologic recovery was achieved in an additional 13 patients (21%).

How It Works

Venetoclax is a selective small-molecule inhibitor of the antiapoptotic protein BCL-2. BCL-2 has been found to be overexpressed in chronic lymphocytic leukemia and AML cells, where it mediates tumor cell survival and has been associated with resistance to chemotherapeutics. Venetoclax helps to restore apoptosis by binding directly to the BCL-2 protein, displacing proapoptotic proteins such as BIM, and triggering mitochondrial outer membrane permeability and activation of caspases. In preclinical studies, venetoclax showed cytotoxic activity in tumor cells that overexpress BCL-2.

How It Is Used

In patients with AML, the recommended venetoclax dose depends upon the combination regimen used. The venetoclax ramp-up phase consists of 100, 200, and 400 mg given on days 1, 2, and 3, respectively; for day 4 and beyond, the venetoclax dose is 400 mg/d when given in combination with azacitidine or decitabine and 600 mg/d when given in combination with low-dose cytarabine. Treatment should be continued until disease progression or unacceptable toxicity.

Patients receiving venetoclax are at risk for tumor-lysis syndrome, and product labeling provides detailed information on risk assessment and prophylaxis for this complication. All patients with AML should have white blood cell counts < 25 × 10⁹/L prior to initiation of treatment. Cytoreduction prior to treatment may be required. Prophylactic measures including adequate hydration and antihyperuricemic agents should be provided prior to the first venetoclax dose and continued during the ramp-up phase.

Prior to the initiation of treatment, blood chemistry should be assessed and preexisting abnormalities corrected. Blood chemistry should be monitored for tumor-lysis syndrome before each dose, at 6 to 8 hours after each new dose during ramp-up, and at 24 hours after reaching the final dose. For patients with risk factors for tumor-lysis syndrome—eg, circulating blasts, a high burden of leukemia involvement in bone marrow, elevated pretreatment lactate dehydrogenase levels—additional measures should be considered, including increased laboratory monitoring and reduction of the venetoclax starting dose.

Product labeling provides instructions on dose modification for hematologic toxicity in patients with AML as well as instructions on dose modification and management of drug-interaction risks in patients with AML receiving concomitant posaconazole (Noxafil) or other strong CYP3A inhibitors (eg, ketoconazole, conivaptan [Vaprisol], clarithromycin), moderate CYP3A inhibitors (eg, erythromycin, ciprofloxacin, diltiazem), and P-glycoprotein inhibitors (eg, amiodarone, captopril, cyclosporine). Coadministration with strong or moderate CYP3A inducers should be avoided. P-glycoprotein substrates should be taken at least 6 hours before venetoclax.

Safety Profile

In patients with AML receiving venetoclax in combination with azacitidine or decitabine or low-dose cytarabine, the most common adverse events of any grade (≥ 30% of patients) were nausea, diarrhea, thrombocytopenia, constipation, neutropenia, febrile neutropenia, fatigue, vomiting, peripheral edema, pyrexia, pneumonia, dyspnea, hemorrhage, anemia, rash, abdominal pain, sepsis, back pain, myalgia, dizziness, cough, oropharyngeal pain, and hypotension.

In the 67 patients receiving venetoclax in combination with azacitidine, serious adverse events occurred in 75% of patients, with the most frequent (≥ 5%) being febrile neutropenia, pneumonia (excluding fungal), sepsis (excluding fungal), respiratory failure, and multiple organ dysfunction syndrome. Adverse events led to treatment discontinuation in 21% of patients, with the most frequent causes (≥ 2%) being febrile neutropenia and pneumonia (excluding fungal). Adverse events led to dose interruption in 61% of patients and dose reductions in 12%.

In the 13 patients receiving venetoclax in combination with decitabine, serious adverse events occurred in 85% of patients, with the most frequent (≥ 5%) being febrile neutropenia, sepsis (excluding fungal), pneumonia (excluding fungal), diarrhea, fatigue, cellulitis, and localized infection. Adverse events led to treatment discontinuation in 38% of patients, with the most frequent cause (≥ 5%) being pneumonia (excluding fungal). Adverse events led to dose interruption in 62% of patients and dose reduction in 15%.

In the 61 patients receiving venetoclax in combination with low-dose cytarabine, serious adverse events occurred in 95% of patients, with the most frequent (≥ 5%) being febrile neutropenia, sepsis (excluding fungal), hemorrhage, pneumonia (excluding fungal), and device-related infection. Adverse events led to treatment discontinuation in 33% of patients, with the most common causes (≥ 2%) being hemorrhage and sepsis (excluding fungal). Adverse events led to dose interruption in 52% of patients and dose reduction in 8%.

Venetoclax carries warnings/precautions for tumor-lysis syndrome, neutropenia, immunization, and embryofetal toxicity. Tumor-lysis syndrome should be anticipated, and risk should be assessed in all patients. No live attenuated vaccines should be given prior to, during, or after venetoclax treatment. Patients should be advised not to breastfeed during venetoclax therapy. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA approves venetoclax in combination for AML in adults.Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm626499.htm. Accessed December 5, 2018.

2. Venclexta (venetoclax) tablets prescribing information, AbbVie Inc and Genentech Inc, November 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2018/208573s009lbl.pdf. Accessed December 5, 2018.

3. DiNardo CD, Pratz K, Pullarkat V, et al: Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. October 25, 2018 (early release online).