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Venetoclax use in AML: VIALE-A & VIALE-C Trial Updates

Sonal Agarwal, PharmD
Hematology Oncology Clinical Pharmacist
Yale New Haven Hospital
New Haven, CT

Molly Schiffer, PharmD BCOP
Hematology Oncology Clinical Pharmacist
Yale New Haven Hospital New Haven, CT

Among adult types of acute leukemia, acute myeloid leukemia (AML) is the most common and has the highest mortality rate with a 28.7% five-year relative survival. 1,2 AML is predominantly a malignancy that affects older adults who are at greater risk for complications and co-morbidities.2

Initial treatment management must take into consideration a patient’s performance status, comorbid conditions, cytogenetic and molecular mutations, and age. Intensive induction therapies with cytarabine and an anthracycline are typically offered to young, healthy patients.3 However, due to co-morbidities, older adults, many may not be candidates for intensive therapy.4 Therapeutic options for these individuals have historically included agents such as hypomethylating agents (HMAs), low dose cytarabine (LDAC), gemtuzumab, or best supportive care.4-7

Venetoclax (ABT-199) is a BH3 mimetic that has high selectivity for the B-cell lymphoma-2 (BCL-2) protein. BCL-2, an antiapop-totic protein, has appeared to be an effective target in AML in preclinical studies.8-9 Venetoclax was approved in November 2018 for the treatment of newly-diagnosed AML in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy based on phase Ib and phase II studies assessing the combination of venetoclax with both HMAs and LDAC10,11. The recently published, confirmatory VIALE-A and VIALE-C phase III trials further establish the efficacy and safety of the azacitidine-venetoclax regimen and the LDAC-venetoclax regimen, respectively.

Azacitidine in Combination with Venetoclax: VIALE- A Trial12
VIALE-A study was a confirmatory phase III, multicenter, randomized, double-blind, placebo-controlled trial that evaluated efficacy and safety of venetoclax in combination with azacitidine. All newly diagnosed AML patients who were older than 18 years of age and ineligible to receive intensive chemotherapy regimen were included. Patients were excluded if they had received prior hypomethylating agents, venetoclax, or chemotherapy for myelodysplastic syndrome (MDS), or had favorable cytogenetic risk. Patients were randomized 2:1 to receive azacitidine-venetoclax or azacitidine-placebo (control group) until disease progression or unacceptable toxicity.

The primary endpoint was overall survival (OS), and important secondary endpoints evaluated were event free survival (EFS), composite complete remission (complete remission and complete remission with incomplete hematologic recovery), complete remission, and time to first response. Treatment-related adverse events were assessed in all patients who received at least one dose of therapy.

From February 2017 through May 2019, 431 patients were included, out of which 286 patients were randomized to azacitidine plus venetoclax arm and 145 to azacitidine plus placebo arm. All patients received azacitidine 75 mg/m2 subcutaneously or intrave-nously on days 1 through 7, along with venetoclax target dose of 400 mg or matching placebo oral daily in 28-day cycles. Notably, the recommended venetoclax dose adjustment in combination with a strong CYP3A inhibitor differs between the VIALE-A protocol and the package insert.13 In the AML population, the FDA-approved recommendation is to titrate venetoclax to a maximum of 100mg daily when co-administered with a CYP3A inhibitor; however, the VIALE-A trial took a more conservative approach and utilizes a maximum dose of 50 mg daily. Seventy-five percent of patients had de novo AML and 25% had secondary AML that included history of MDS, chronic myelomonocytic leukemia (CMML), or therapy-related AML. The median duration of follow up was 20.7 months.

The median overall survival was significantly improved with azacitidine-venetoclax (14.7 months vs 9.6 months; hazard ratio for death [HR], 0.66; P<0.001). Composite complete remission achieved was significantly better in the treatment arm (66.4% vs 28.3%; P<0.001); and the complete remission was higher in the treatment arm (36.7% vs 17.9%; P<0.001). Median event-free survival was also significantly improved in the treatment arm (9.8 months vs 7 months; HR 0.63; P<0.001). Time to first response was more rapid in the combination group (1.3 months vs 2.8 months).

For safety analysis, 427 patients were included, out of which 283 patients were in the azacitidine-venetoclax arm and 144 were in the control group. The median number of treatment cycles received in each arm were 7.0 and 4.5 respectively. At least one serious adverse event was reported in 83% of patients in the treatment arm and 73% of patients in the control arm. The most common grade 3 or higher hematologic toxicities in the combination arm versus azacitidine-placebo arm were neutropenia (42% vs 28%), thrombocytopenia (45% vs 38%), febrile neutropenia (42% vs 19%), and anemia (26% vs 20%). Tumor lysis syndrome was seen in 1% of patients during the ramp-up period of venetoclax in combination arm.

Low-Dose Cytarabine in Combination with Venetoclax: VIALE-C Trial 14,15
VIALE-C is a similar confirmatory phase III, multicenter, double-blind, placebo-controlled clinical trial that evaluated the efficacy and safety of venetoclax in combination with LDAC. Adults 18 years or older with newly diagnosed AML and ineligible for intensive chemotherapy were randomized 2:1 to receive LDAC-venetoclax or LDAC-placebo (control group). Patients were considered ineligible for intensive chemotherapy if either they were ≥75 years of age or 18 to 74 years old with at least one criterion that was associated with lack of fitness for intensive chemotherapy regimen. Patients who had previous exposure to hypomethylating agents were included in the study. Excluded patients include those who received prior treatment with cytarabine for MDS, received strong or moderate CYP3A4 inducers seven days prior to the first dose of venetoclax, had known central nervous system involvement, or had WBC >25 x 109/L.

The VIALE-C study took a similarly conservative approach to venetoclax dose adjustments as the VIALE-A study and also had differing recommendations when compared to the package insert.12,13 Primary endpoint was overall survival, and key secondary endpoints included composite complete response and event-free survival.

Overall, 211 patients were enrolled between May 2017 and November 2018; 143 were randomized to LDAC-venetoclax arm and 68 patients were randomized to LDAC-placebo (control) arm. Patients received low-dose cytarabine 20 mg/m2 subcutaneously on days 1 through 10, along with venetoclax target dose of 600 mg (start at 100 mg on day 1 and escalated over 4 days) or matching placebo oral daily in 28-day cycles. Approximately 60% of patients were ≥75 years of age, 38% of patients had secondary AML, and 20% received prior hypomethylating agents.

At planned primary analysis, median overall survival was not significantly higher in the combination arm (7.2 months vs 4.1 months). LDAC-venetoclax arm showed reduction in the risk of death by 25% (HR 0.75; P=0.11) but was not statistically significant. At the six-month update after additional follow up, LDAC-venetoclax reduced the risk of death by 30% and median overall survival was 8.4 months vs 4.1 months in favor of the combination arm (P=0.04). Composite complete response were 48% and 13% in combination arm and control arm, respectively. Median event-free survival significantly improved in the treatment arm (4.7 months vs 2.0 month, P=0.002). A more rapid response was also seen with the combination arm, with a composite complete remission of 34% vs 3% seen after the first cycle in the combination arm and placebo arm, respectively.

For safety analysis, a total of 210 patients (142 in combination arm and 68 in placebo arm) were evaluated. Serious adverse events reported were similar in both arms (65% vs 62%). Most common grade 3 or higher adverse events seen in both arms were neutropenia (47% vs 16%), thrombocytopenia (45% vs 37%), and febrile neutropenia (32% vs 29%). Adverse events leading to death (23% vs 21%) or treatment discontinuation (25% vs 24%) were similar in both arms.

Conclusion
The VIALE-A and VIALE-C trials confirmed previous phase I and II efficacy and safety results and showed the addition of venetoclax to azacitidine or LDAC improved overall survival and resulted in higher composite complete remission and faster response with a tolerable safety profile. This redefined the first-line treatment approach for older patients with newly-diagnosed AML who are unfit to receive intensive induction chemotherapy.

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