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VIALE-A trial update | Venetoclax and azacitidine combination for the treatment of older patients with newly diagnosed AML

Jul 3, 2020

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VIALE-A (NCT02993523) is a randomized, double-blind, multicenter, placebo-controlled phase III study that compares venetoclax and azacitidine (Ven + Aza) versus placebo + Aza in patients with acute myeloid leukemia (AML) who are not eligible for intensive induction therapy. AML develops mostly in older populations (with a median age between 68–72 years) where treatment options are limited, and survival is poor for patients who are aged ≥ 75 years or have severe comorbidities. These patients are also poor candidates for intensive induction chemotherapy. Low-dose azacitidine, a hypomethylating agent, is associated with low response rates, a longer time to response, and a median overall survival of less than a year. Venetoclax is a highly specific, oral BCL-2 inhibitor for managing overexpression of anti-apoptotic BCL-2 in AML and the AML stem cell population. The combination of venetoclax and hypomethylating agents has been associated with clinical activity in older, treatment-naïve patients with AML. Courtney DiNardo, The University of Texas MD Anderson Cancer Center, Houston, US, presented the results of the VIALE-A study during the 25th European Hematology Association (EHA) Annual Congress, held virtually on June 14, 2020.1

Study Design1

  • Primary endpoints: Overall survival and composite complete remission rate (complete remission [CR] plus CR with incomplete marrow remission [CRi])
  • Secondary endpoints: Event-free survival, CR plus CR with partial hematologic recovery (CRh), transfusion independence, and patient-reported outcomes

The detailed study design can be found here.

Patient characteristics1

  • Median age was 76 years in both treatment groups, and the proportion of patients ≥ 75 years was similar (61% in the Ven + Aza group; 60% in the placebo + Aza group)
  • Patient characteristics were well balanced between treatment groups in terms of AML type (de novo or secondary), Eastern Cooperative Oncology Group (ECOG) performance status (0–1 and 2–3), bone marrow blast count, and poor/intermediate cytogenetic risk
  • The proportion of patients with AML with or without myelodysplasia-related changes was similar between treatment groups
  • The profile of somatic mutations is shown below in Figure 1

 Figure 1. The distribution of somatic mutations among groups

 As of cutoff date, Jan 4, 2020:

  • Median follow-up duration for the Ven + Aza group and the placebo + Aza group was 20.7 months (range, 0.0–30.7) and 20.2 months (0.2–28.8), respectively
  • The number of patients still receiving treatment was 77 (27%) for the Ven + Aza group and 18 (12%) for the placebo + Aza group
  • A total of 336 patients discontinued treatment (209 in the Ven + Aza group and 127 in the placebo + Aza group), mostly due to disease progression or relapse (120 vs 62), withdrawn consent (26 vs 22), physician’s decision (17 vs 9), and death (39 vs 23)
  • The main reason for study discontinuation was death (161 in the Ven + Aza group vs 109 in the placebo + Aza group)


The combination of venetoclax and azacitidine showed a 34% reduction in risk of death (HR, 0.66; 95% CI, 0.52–0.85; p < 0.001) at 20.5 months follow-up compared to azacitidine alone. Median overall survival in the Ven + Aza and placebo + Aza groups were 14.7 and 9.6 months, respectively. Subgroup analyses showed consistent treatment effects and better response rates of CR + CRi in favor of the combination. The combination therapy was associated with substantially higher response rates in all somatic mutations analyzed (see Figure 2). The proportion of patients with transfusion independence was higher in Ven + Aza group compared to placebo + Aza (p < 0.001). The summary of study results and safety analysis are presented in Table 1 and Table 2.

 Table 1. Study results

AML, acute myeloid leukemia; Aza, azacitidine; CR, complete remission; CRh, CR with partial hematologic recovery; CRi, CR with incomplete marrow remission; ECOG, Eastern Cooperative Oncology Group; RBC, red blood cell; Ven, venetoclax

*HR, 0.63; 95% CI, 0.50–0.80; p < 0.001)


Ven + Aza

n = 286

Placebo + Aza

n = 145

Median number of cycles, n (range)

7.0 (1.0–30.0)

4.5 (1.0–26.0)

Composite response rate (CR + CRi), %







Median time to CR/CRi, months (range)

1.3 (0.6–9.9)

2.8 (0.8–13.2)

Median duration of CR/CRi, months



Response rate by CR + CRh, %



Median time to CR/CRh, months (range)

1.0 (0.6–14.3)

2.6 (0.8–13.2)

Median duration of CR/CRh, months



Response rates (CR + CRi) by subgroup, %

Cytogenetic risk



AML subtype

De novo



< 75 years

≥ 75 years

ECOG score

< 2

≥ 2

Bone marrow blasts

20 to < 30%

≥ 30 to < 50%

≥ 50%



































Transfusion independence



RBC and platelet









Median event-free survival, months (range)*

9.8 (8.4–11.8)

7.0 (5.6–9.5)


Figure 2. Response rates (CR + CRi) by somatic mutations

Table 2. The results of safety analysis (as of Jan 4, 2020)

AE, adverse event; Aza, azacitidine; Ven, venetoclax

*≥ 10% occurrence

 †≥ 5% occurrence


Ven + Aza

n = 283

Placebo + Aza

n = 144

All Grade 3/4 AEs*, n (%)

279 (99)

139 (97)

Grade 3/4 hematologic AEs



Febrile neutropenia



233 (82)

126 (45)

119 (42)

118 (42)

74 (26)

58 (21)

98 (68)

55 (38)

41 (29)

27 (19)

29 (20)

17 (12)

Grade 3/4 non-hematologic AEs*



46 (17)

13 (5)

30 (11)

44 (31)

4 (3)

15 (10)

Serious AEs

Febrile neutropenia


235 (83)

84 (30)

47 (17)

105 (73)

15 (10)

32 (22)


≤ 30 days after first dose

≤ 60 days after first dose


21 (7)

43 (15)


9 (6)

24 (17)

Neutropenia, febrile neutropenia, and thrombocytopenia were the most common adverse events leading to dose interruptions and occurred in more patients in the Ven + Aza group compared to the placebo + Aza group (204 [72%] vs 82 [57%]).


The results showed that Ven + Aza combination therapy was associated with higher response rates in difficult-to-treat patient groups, such as older patients (75 years) or those with poor cytogenetic risk. Patients in the combination group reached a faster and more durable response compared to those in the azacitidine alone group. The safety profile was manageable and similar to previous clinical experience. The combination of azacitidine and venetoclax demonstrated both statistically and clinically meaningful improvement in overall survival, response rates, and transfusion independence. Response rates were particularly striking for combination treatment in the subgroup analysis of patients with deleterious somatic mutations, e.g., IDH1, potentially providing a new treatment modality for a personalized medicine approach.

Expert Opinion

  1. DiNardo CJ, Jonas BA, Pullarkat V, et al. A randomized, double-blind, placebo-controlled study of venetoclax with azacitidine vs azacitidine in treatment-naïve patients with acute myeloid leukemia ineligible for intensive therapy-VIALE-A. Oral presentation #303390. EHA25 Virtual Congress; June 14, 2020.


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