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Venetoclax plus hypomethylating agents for the treatment of chemotherapy-ineligible or high-risk AML

Jan 14, 2021

Patients with newly diagnosed acute myeloid leukemia (AML) who are ineligible or do not respond well to intensive chemotherapy have poor outcomes and reduced therapeutic options.1 Such patients include those of older age or of higher cytogenetic risk, harboring isocitrate dehydrogenase 1/2 (IDH1/2) or TP53 mutations.1-4 Venetoclax (VEN) in combination with hypomethylating agents (HMAs), like azacitidine (AZA) or decitabine (DEC), has shown great promise for such patient subpopulations, leading to high response rates and prolonged survival.1‑4 In fact, VEN in combination with DEC or AZA has been approved by the U.S. Food and Drug Administration (FDA) for patients with newly diagnosed AML, aged ≥ 75 years or with comorbidities that render them ineligible for intestine chemotherapy.1 We hereby summarize recently published data from the longest to date clinical follow-up of patients receiving VEN plus HMAs under the FDA licence.1 Moreover, we have included the latest clinical data presented at the 62nd American Society for Hematology (ASH) Annual Meeting and Exposition on VEN plus HMAs for high-risk patients with IDH1/23 or TP534 mutations.

VEN + HMAs longest clinical follow-up1

Daniel Pollyea and colleagues1 recently published data in American Journal of Hematology from the longest to date clinical follow-up of patients receiving 400 mg VEN plus AZA (75 mg/m2 on Days 1–7) or DEC (20 mg/m2 on Days 1–5), under the FDA licence. Adults ≥ 60 years with newly diagnosed AML ineligible for intensive chemotherapy were enrolled in this phase Ib, open-label, non-randomized trial (NCT02203773), which had safety and response rates as its main endpoints.

Prior analysis of this trial (median follow-up = 15.1 months)2 had demonstrated a complete response (CR)/CR with incomplete hematological recovery (CRi) rate of 73% and median overall survival (OS) had not been reached, when 400 mg VEN was administered with either AZA or DEC.

After a median follow-up of 29 months (range, 0.4–42) and 40 months (range, 0.7–43) for patients receiving VEN + AZA or VEN + DEC, respectively, the efficacy outcomes shown in Table 1 were reported. In brief, patients receiving VEN + AZA achieved a CR/CRi rate of 71%, while those with VEN + DEC achieved a CR/CRi rate of 74%. The responses in both treatment groups were not only deep but also durable, with median durations of response of 21.9 and 15.0 months for VEN + AZA and VEN + DEC, respectively (Table 1). Moreover, the median OS for either group was > 16 months. Patient subgroup analysis revealed good CR/CRi rates with VEN + AZA for patients with TP53 (53%) or IDH1/2 mutations (86%).

Table 1. Efficacy outcomes of VEN plus HMAs1

AML, acute myeloid leukemia; AZA, azacitidine; CI, confidence interval; CR, complete response; CRi, complete response with incomplete hematological recovery; DEC, decitabine; DoR, duration of response; IDH1/2, isocitrate dehydrogenase 1/2; MRD, measurable residual disease; NR, not reached; OS, overall survival; VEN, venetoclax.
*MRD negativity was considered at the 10−3 cut-off and was analyzed only for patients achieving CR/Cri.

Efficacy outcomes for the total cohort

(n = 84)

(n = 31)

CR, n (%)

37 (44)

17 (55)

CR/CRi, n (%)

60 (71)

23 (74)

DoR, months (95% CI)

21.9 (15.1–30.2)

15.0 (7.2–30.0)

Median OS, months (95% CI)

16.4 (11.3–24.5)

16.2 (9.1–27.8)

MRD negativity*, n/N (%)

29/60 (48)

9/23 (39)

Efficacy outcomes by patient subgroup



Patients ≥ 75 years (n = 42)



  CR, n (%)

18 (43)


  CR/CRi, n (%)

27 (64)


  DoR, months (95% CI)

29.5 (15.1–NR)


TP53-positive AML (n = 17)



  CR, n (%)

5 (29)


  CR/CRi, n (%)

9 (53)


  DoR, months (95% CI)

6.5 (1.9–17.3)


IDH1/2-positive AML (n = 22)



  CR, n (%)

10 (46)


  CR/CRi, n (%)

19 (86)


  DoR, months (95% CI)

29.5 (17.9–NR)


With regards to safety, VEN in combination with AZA or DEC, respectively, had manageable toxicity with the most common Grade ≥ 3 hematological adverse events (AEs) being:

  • Febrile neutropenia (39% and 65%)
  • Anemia (30% and 26%)
  • Thrombocytopenia (25% and 23%)
  • Neutropenia (20% and 10%)

The most commonly reported serious AEs, with VEN + AZA or DEC, respectively, were:

  • Febrile neutropenia (31% and 42%)
  • Pneumonia (26% and 29%)
  • Sepsis (4% and 7%)

The 30-day mortality rates for patients receiving VEN + AZA or DEC were 2% (n = 2) and 7% (n = 2), respectively.

These data indicate that VEN in combination with HMAs is an effective first-line treatment for patients who are unfit for induction chemotherapy.

VEN + HMAs for IDH1/2-positive AML3

During the 62nd ASH Annual Meeting and Exposition, a specific analysis on the efficacy and safety of VEN (400 mg) plus AZA (75 mg/m2 on Days 1–7) in older patients with treatment-naïve AML with IDH1/2 mutations, who were unfit for intensive chemotherapy, was presented by Daniel Pollyea.3 The analysis used data from the above phase Ib trial (NCT02203773) and the phase III VIALE-A trial (NCT02993523), where patients unfit for chemotherapy were treated with VEN + AZA or AZA alone. To read more about the study design and findings of VIALE-A, read our summary here. In this analysis, DNA was extracted from bone marrow aspirates that were collected before treatment and were analyzed for the presence or absence of IDH1/2 mutations. The baseline characteristics of patients that received VEN + AZA versus AZA alone were very similar, with no significant differences in age, disease subtypes, Eastern Cooperative Oncology Group (ECOG) performance status, cytogenetic risk, or blast count. The efficacy outcomes of this subanalysis in patients with IDH1/2-positive AML are shown in Table 2. In general, patients receiving VEN + AZA had a significantly higher CR/CRi rate (78.5%) compared with those receiving AZA alone (10.7%). The time to first response was shorter for the VEN + AZA group, with approximately 1 month to response, compared with approximately 2.5–3 months for the AZA group. The VEN + AZA responses were very durable, with a median duration of response of 29.5 months versus 9.5 months for AZA alone (Table 2).

Table 2. Efficacy outcomes for patients with IDH1/2-positive AML3

AZA, azacitidine; CI, confidence interval; CR, complete response; CRi, complete response with incomplete hematological recovery; CRh, complete response with partial hematological recovery; DoR, duration of response; IDH1/2, isocitrate dehydrogenase 1/2; VEN, venetoclax.

Efficacy outcomes in IDH1/2-positive AML

(n = 79)

AZA + placebo
(n = 28)

CR, %



CRi, %



CRh, %



CR/CRh, %



  Median time to first response, months (min, max)

1.0 (0.7, 9.6)

2.6 (2.1, 3.1)

  Median DoR, months (95% CI)

29.6 (16.7–NE)

15.5 (NE)

CR/CRi, %



  Median time to first response, months (min, max)

1.1 (0.7, 8.8)

3.4 (2.1, 7.1)

  Median DoR, months (95% CI)

29.5 (16.7–NE)

9.5 (3.5–15.5)

Median treatment cycles (min, max)

8.0 (1, 37)

2.5 (1, 18)

6-month survival estimate, % (95% CI)

82.3 (71.9–89.1)

50.0 (30.6–66.6)

12-month survival estimate, % (95% CI)

69.3 (57.8–78.3)

35.7 (18.9–53.0)

24-month survival estimate, % (95% CI)

52.4 (40.4–63.1)

12.2 (3.2–27.8)

With regards to AEs, they were similar to the AEs previously observed in the total cohort, indicating that IDH mutation status does not affect AEs with respect to their type or incidence. As previously reported, the VEN + AZA group had higher rates of hematological AEs and infections versus those that received AZA alone.

The above data confirm that VEN in combination with AZA shows great promise for patients with IDH1/2-positive AML and can lead to deep and durable responses with a manageable toxicity profile.

VEN + HMAs for TP53-positive AML4

During the 62nd ASH Annual Meeting and Exposition, Kunhwa Kim presented a post hoc analysis focused on patients aged ≥ 60 years with TP53-positive high-risk AML from a phase II trial (NCT03404193), which investigated the efficacy and safety of VEN (400 mg) plus 10-day DEC (20 mg/m2). Patients received VEN plus DEC as frontline therapy and had either de novo or secondary AML. For more information on the study design and reported outcomes of this phase II trial, read a summary here. Out of a total of 118 patients, 35 had TP53-mutated AML. Most baseline characteristics were similar between TP53-mutated and wild type patients, with the exception of disease diagnosis status and cytogenetic risk. TP53-mutated patients were more likely to have therapy-related AML, less likely to be diagnosed with de novo AML, and had proportionately more adverse/complex cytogenetics. In terms of co-mutations, TP53-mutated patients were less likely to have NPM1, RUNX1, ASXL1, or K/NRAS co-mutations. The efficacy outcomes reported from this analysis are shown in Table 3. Overall, patients with TP53-mutated AML had a significantly lower overall response rate, CR/CRi rate, median OS, and median relapse-free survival, when compared with wild type patients (Table 3).

Table 3. Efficacy outcomes of VEN plus DEC in TP53-mutated AML4

AML, acute myeloid leukemia; CI, confidence interval; CR, complete response; CRi, complete response with incomplete hematological recovery; DEC, decitabine; FCM, flow cytometry; HR, hazard ratio; MLFS, morphologic leukemia-free state; MRD, measurable residual disease; ORR, overall response rate; OS, overall survival; RFS, relapse-free survival; SCT, stem cell transplantation; VEN, venetoclax.

Efficacy outcome, n (%)

TP53-mutated AML
(n = 35)

TP53-wild type AML
(n = 83)

p value


23 (66)

74 (89)



13 (37)

48 (58)



20 (57)

64 (77)



3 (9)

10 (12)


MRD negativity by FCM

7 (20)

44 (53)


No response

12 (34)

9 (11)



2 (6)

0 (0)


Post-treatment SCT

1 (3)

16 (19)


30-day mortality

2 (6)

0 (0)


60-day mortality

9 (26)

3 (4)


Median OS, months



< 0.0001
(HR, 4.67; 95% CI, 2.44–8.93)

Median RFS, months



< 0.0001
(HR, 4.80; 95% CI, 1.97–11.69)

Multivariate analysis revealed the following significant variables for CR:

  • TP53 mutation vs wild type (odds ratio [OR], 0.17; 95% CI, 0.06–0.47; p = 0.001)
  • ECOG performance status ≥ 2 vs < 2 (OR, 0.24; 95% CI, 0.06–0.71; p = 0.010)
  • RUNX1 mutation vs wild type (OR, 0.23; 95% CI, 0.06–0.88; p = 0.031)
  • ASXL1 mutation vs wild type (OR, 0.05; 95% CI, 0.01–0.24)
  • Prior HMA therapy (OR, 0.15; 95% CI, 0.04–0.50)

Multivariate analysis revealed the following significant variables for OS:

  • TP53 mutation vs wild type (HR, 3.17; 95% CI, 1.89–5.32; p < 0.001)
  • Intermediate vs adverse cytogenetic risk (HR, 1.55; 95% CI, 1.02–2.35; p = 0.041)
  • Secondary AML vs de novo AML (HR, 1.99; 95% CI, 1.34–2.95; p = 0.001)
  • DNMT3A mutation vs wild type (HR, 0.61; 95% CI, 0.40–0.95)

The results of this analysis indicate that despite VEN + DEC leading to good responses, these were not durable in patients with TP53-mutated AML. This is also reflected by the short median OS and relapse-free survival observed for this patient subset.


It is evident that VEN combinational therapy with HMAs, like AZA or DEC, provides a safe and efficacious therapeutic option for patients with newly diagnosed AML who are unfit for induction chemotherapy, due to advanced age, comorbidities, or IDH1/2 mutations. Nevertheless, VEN plus DEC does not seem to be an ideal treatment for patients with TP53-mutated AML as it failed to lead to durable responses or greatly prolong survival. This patient subset will need novel therapeutics to be developed. The way in which VEN plus HMA combinational therapy has changed the treatment landscape for patients with AML was further discussed and summarized by Daniel Pollyea in an interview with the AML Hub below.

How have venetoclax combinations changed the way we treat AML?

  1. Pollyea DA, Pratz K, Letai A, et al. Venetoclax with azacitidine or decitabine in patients with newly diagnosed acute myeloid leukemia: Long term follow-up from a phase 1b study. Am J Hematol. 2020. Online ahead of print. DOI: 10.1002/ajh.26039
  2. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in
  3. Pollyea DA, DiNardo CD, Arellano ML, et al. Results of venetoclax and azacitidine combination in chemotherapy ineligible untreated patients with acute myeloid leukemia with IDH 1/2 Oral abstract #461. 62nd American Society of Hematology (ASH) Annual Meeting and Exposition; Dec 6, 2020; Virtual.
  4. Kim K, Maiti A, Kadia TM, et al. Outcomes of TP53-mutant acute myeloid leukemia with venetoclax and decitabine. Oral abstract #693. 62nd American Society of Hematology (ASH) Annual Meeting and Exposition; Dec 7, 2020; Virtual.