Clinical trialPhase 3Blood cancers (leukaemia, lymphoma and myeloma)Leukaemia

Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia

N Engl J Med · 2020431 patients (286 azacitidine + venetoclax, 145 azacitidine + placebo)

DiNardo CD, Jonas BA, Pullarkat V, et al. N Engl J Med. 2020. 383:617-629

A newer report of this study has been published: Long-term follow-up of VIALE-A: Venetoclax and azacitidine in chemotherapy-ineligible untreated acute myeloid leukemia (2024)

Study type: Clinical trial
Study name: VIALE-A
Phase: Phase 3
Design: Randomised, double-blind, placebo-controlled, international multicentre trial (2:1 randomisation)
Sample size: 431 patients (286 azacitidine + venetoclax, 145 azacitidine + placebo)
Source: N Engl J Med · 2020
Trial registration: NCT02993523

In plain words

Many older patients, or patients with other illnesses, cannot tolerate intensive chemotherapy for acute leukaemia. This study showed that adding venetoclax tablets to azacitidine injections (a gentler drug) nearly doubles the chance of remission and also makes patients live meaningfully longer. On the other hand, low blood counts and fever with low white blood cells are seen more often, so regular blood tests and watching for infection are very important with this treatment.

Key results

14.7 vs 9.6 months

Median overall survival

HR for death 0.66 (95% CI 0.52 to 0.85); P<0.001; median follow-up 20.5 months

36.7% vs 17.9%

Complete remission (CR)

P<0.001

66.4% vs 28.3%

Composite complete remission (CR + CRi)

P<0.001

Drugs in this study:Azacitidine (Vidaza)Venetoclax (Venclexta)

Dose and schedule cards

Venetoclax + azacitidine (VIALE-A)

Newly diagnosed AML in patients aged 75 years or older or with comorbidities that preclude intensive chemotherapyCycle length: Every 28 daysOn the page “Leukaemia” · Regimens and dosing in newly diagnosed AML (induction, consolidation and maintenance)

Newly diagnosed AML in patients aged 75 years or older or with comorbidities that preclude intensive chemotherapy

Drug	Dose	Route	Schedule
Cycle 1: ramp-up
Venetoclax	100 mg (Day 1), 200 mg (Day 2), 400 mg (Day 3)	Oral, with food	Days 1–3
Continuation
Venetoclax	400 mg once daily	Oral, with food	Days 1–28 of each cycle
All cycles
Azacitidine	75 mg/m² per day	SC or IV	Days 1–7

Cycle length: Every 28 days
Duration: Until disease progression or unacceptable toxicity

TLS prophylaxis with hydration and a uric acid–lowering agent from before the first dose and throughout the ramp-up; check potassium, uric acid, phosphorus, calcium and creatinine before each new dose, 6 to 8 hours afterward and 24 hours after reaching the final dose. Interactions: with posaconazole, ramp up 10, 20, 50 and then 70 mg; with other strong CYP3A inhibitors, ramp up 10, 20, 50 and then 100 mg; with a moderate CYP3A inhibitor, reduce the dose by at least 50%. Cytopenias before remission are usually not a reason to interrupt treatment (a bone marrow assessment is recommended); grade 4 neutropenia or thrombocytopenia after remission lasting 7 days or longer: delay the next cycle until recovery to grade 1 or 2, and if it recurs, shorten venetoclax administration in each cycle by 7 days (e.g., 21 days instead of 28). Label alternatives: venetoclax 400 mg with decitabine 20 mg/m² IV Days 1–5, or venetoclax 600 mg with cytarabine 20 mg/m² SC Days 1–10. In VIALE-A, febrile neutropenia occurred in 42% vs 19%.

On the page “Leukaemia” · Regimens and dosing in newly diagnosed AML (induction, consolidation and maintenance)

Venetoclax + azacitidine (VIALE-A)

Newly diagnosed AML at age 75 or over, or with comorbidities that preclude intensive chemotherapyCycle length: Every 28 daysOn the page “Acute myeloid leukaemia (AML): 2022 classification, ELN genetic risk and treatment” · Lower-intensity treatment, maintenance and post-transplant treatment

Newly diagnosed AML at age 75 or over, or with comorbidities that preclude intensive chemotherapy

Drug	Dose	Route	Schedule
Cycle 1: ramp-up
Venetoclax	100 mg (day 1), 200 mg (day 2), 400 mg (day 3)	Oral, with food	Days 1 to 3
Continuation
Venetoclax	400 mg once a day	Oral, with food	Days 1 to 28 of each cycle
All cycles
Azacitidine	75 mg/m² a day	Subcutaneous or IV	Days 1 to 7

Cycle length: Every 28 days
Duration: Until disease progression or unacceptable toxicity

Start only with a white cell count below 25×10⁹/L (cytoreduction if needed); hydration and a uric acid-lowering drug from before the first dose until the end of the ramp-up; potassium, uric acid, phosphorus, calcium and creatinine before each new dose, 6 to 8 hours afterwards and 24 hours after reaching the final dose. Interactions: with posaconazole 10, 20, 50, then 70 mg; with other strong CYP3A inhibitors 10, 20, 50, then 100 mg; with a moderate CYP3A inhibitor or a P-gp inhibitor, reduce by at least 50%. Cytopenias before remission are usually not a reason to interrupt (a bone marrow assessment is recommended); grade 4 neutropenia or thrombocytopenia after remission lasting 7 days or more: delay the next cycle until recovery to grade 1 or 2 and, if it recurs, shorten venetoclax by 7 days in each cycle. In VIALE-A, after remission with cytopenias was confirmed at the end of cycle 1, venetoclax was held for up to 14 days or until neutrophils ≥500 and platelets ≥50,000/µL.

On the page “Acute myeloid leukaemia (AML): 2022 classification, ELN genetic risk and treatment” · Lower-intensity treatment, maintenance and post-transplant treatment

Venetoclax + azacitidine or decitabine or low-dose cytarabine (VIALE-A)

Newly diagnosed AML at age 75 or over or with coexisting conditions that preclude intensive induction chemotherapyCycle length: Every 28 daysOn the page “Venetoclax (Venclexta)” · Dose and schedule (FDA label)

Newly diagnosed AML at age 75 or over or with coexisting conditions that preclude intensive induction chemotherapy

Drug	Dose	Route	Schedule
Cycle 1 ramp-up
Venetoclax	Day 1: 100; day 2: 200; day 3: 400 mg; then 400 (with azacitidine or decitabine) or 600 mg (with cytarabine) from day 4	Oral, with food	Daily, days 1 to 28
Option A
Azacitidine	75 mg/m²	IV or subcutaneous	Days 1 to 7
Option B
Decitabine	20 mg/m²	IV	Days 1 to 5
Option C
Low-dose cytarabine	20 mg/m²	Subcutaneous	Days 1 to 10

Cycle length: Every 28 days
Duration: Until progression or unacceptable toxicity

White cell count below 25×10⁹/L before starting (cytoreduction before treatment if needed). Before remission, usually do not interrupt because of cytopenias (bone marrow assessment is recommended).

On the page “Venetoclax (Venclexta)” · Dose and schedule (FDA label)

Aza/Ven

AML, unfit for intensive treatmentEach drug’s schedule in the tableOn the page “Azacitidine with venetoclax in AML”

AML, unfit for intensive treatment

Drug	Dose	Route	Schedule
Azacitidine	75 mg/m²	Subcutaneous or IV	Days 1 to 7
Venetoclax	100 mg on day 1, 200 on day 2, then 400 mg	Oral, with food	Days 1 to 28 (continuous)

Cycle schedule: Every 28 days
Duration: Until progression

As in VIALE-A. With posaconazole, venetoclax 70 mg; with voriconazole 100 mg.

Dose source:.

On the page “Azacitidine with venetoclax in AML”

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Azacitidine + venetoclax

Venetoclax orally once daily with food, continuously on days 1 to 28 of each 28-day cycle; ramp-up in cycle 1: 100 mg day 1, 200 mg day 2 and 400 mg from day 3 (target dose 400 mg).

Azacitidine 75 mg/m² subcutaneously or IV on days 1 to 7 of each 28-day cycle.

Continued until disease progression or unacceptable toxicity. Per the FDA label: tumour lysis syndrome prophylaxis (hydration and a uric acid-lowering agent) and white blood cell count below 25×10⁹/L before starting; with posaconazole a steady dose of 70 mg, and with other strong CYP3A inhibitors a steady dose of 100 mg; grade 4 neutropenia or thrombocytopenia lasting 7 days or more after remission: delay the next cycle and, if it recurs, shorten venetoclax to 21 days per cycle.

2Azacitidine + placebo (control group)

Oral placebo matching venetoclax daily on days 1 to 28, with azacitidine 75 mg/m² subcutaneously or IV on days 1 to 7 of each 28-day cycle, until disease progression or unacceptable toxicity.

Source of the regimen details: Abstract of the paper (NEJM 2020), ClinicalTrials.gov NCT02993523 (eligibility criteria) and the FDA label for venetoclax (DailyMed; 100/200/400 mg ramp-up, tumour lysis prophylaxis and dose modifications)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults with confirmed (WHO criteria), previously untreated acute myeloid leukaemia (AML) who were ineligible for standard cytarabine + anthracycline induction: age 75 years or older, or age 18 to 74 years with at least one of the following: ECOG 2 or 3, heart failure requiring treatment or ejection fraction 50% or less or chronic stable angina, DLCO or FEV1 65% or less, creatinine clearance 30 to less than 45 mL/min, or moderate hepatic impairment (bilirubin more than 1.5 to 3 times the upper limit). ECOG 0 to 2 for age 75 years and older and 0 to 3 for age 18 to 74 years; creatinine clearance at least 30 mL/min; AST and ALT at most 3 times the upper limit. Median age in both groups was 76 years (range 49 to 91).

Endpoints

Primary endpoint: overall survival (OS).

Key secondary endpoints: complete remission (CR) rate, composite complete remission (CR + CRi), transfusion independence and response in molecular subgroups.

Safety and side effects

Grade 3 or higher adverse events with venetoclax versus control: thrombocytopenia 45% versus 38%, neutropenia 42% versus 28% and febrile neutropenia 42% versus 19%. Nausea (any grade) 44% versus 35%. Infections of any grade 85% versus 67% and serious adverse events 83% versus 73%.

Clinical significance and place in guidelines

This study is the basis for full FDA and EMA approval of venetoclax with azacitidine (or decitabine or low-dose cytarabine) for newly diagnosed AML in patients aged 75 years or older or unable to receive intensive induction chemotherapy. The ELN 2022 guideline names venetoclax combined with a hypomethylating agent as the standard first-line treatment for patients unfit for intensive treatment.

Limitations

Candidates for intensive chemotherapy were not enrolled, so the results cannot be generalised to younger patients fit for intensive treatment. The study was sponsored by the manufacturers. Patients with FLT3 mutations or high-risk cytogenetic features were examined in smaller subgroups, and treatment continues until disease progression, which increases the burden of haematological toxicity.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.