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MRD response in patients with newly diagnosed AML treated with venetoclax and azacitidine in the VIALE-A trial

Jul 9, 2021

The phase III VIALE-A trial (NCT02993523) is a randomized, double-blind study investigating the use of venetoclax + azacitidine (Ven+Aza) for the treatment of patients with newly diagnosed acute myeloid leukemia (AML). This study has previously been reported on the AML Hub and demonstrated that patients treated with Ven+Aza had higher rates of composite complete remission (CRc; complete remission [CR] + CR with incomplete hematologic recovery) and measurable residual disease response (MRD <10−3) compared with those treated with azacitidine alone (23.4% vs 7.6%; p < 0.001).

As there is limited evidence of the clinical significance of MRD monitoring in patients receiving low-intensity chemotherapy, Keith Pratz and colleagues investigated the prognostic impact of MRD <10−3 on the outcome of patients from the VIALE-A study who were treated with Ven+Aza. The results of this study were presented during the European Hematology Association (EHA)2021 Virtual Congress and are summarized below.

Study design and patient characteristics1

  • Enrolled patients were ≥18 years of age and unfit for intensive chemotherapy.
  • Dosage: Venetoclax 400 mg orally on Days 1–28; azacitidine 75 mg/m2 on Days 1–7/28-day cycle.
  • MRD was assessed from bone marrow aspirates taken at baseline, end of Cycle 1, and every 3 cycles thereafter, by multiparametric flow cytometry using the integrated leukemia-associated immunophenotypes and different than normal method.
  • Outcomes evaluated: Duration of remission (DoR) for CRc, overall survival (OS), and event-free survival (EFS).
  • Of the 286 patients treated with Ven+Aza, 164 patients had a CRc and had samples evaluable for MRD analysis.
    • Of these patients, 67 (41%) achieved MRD <10−3, while 97 (59%) had an MRD ≥10−3.
  • Baseline characteristics of the patients included in this analysis can be seen in Table 1.
    • MRD responses were seen in all subsets of patients.
    • Of note, MRD response was seen in 33% of patients with poor risk cytogenetics, 30% of patients with TP53 mutations, and 88% of patients with NMP1 mutations.

Table 1. Baseline patient characteristics*

Characteristic, n

CRc + MRD <10−3
(n = 67)

CRc + MRD ≥10−3
(n = 97)

Age group, years



              18 to <65



              65 to <75






Gender, male/female



ECOG performance score









Cytogenetic risk









Type of AML



              De novo AML



              Secondary AML



Molecular mutations



              FLT3 ITD/TKD












*Data from Pratz et al.1
AML, acute myeloid leukemia; CRc, composite complete response; ECOG, Eastern Cooperative Oncology Group; ITD, internal tandem duplication; MRD, minimal residual disease; TKD, tyrosine kinase domain.



  • Median follow-up was 22.1 months for patients who achieved MRD <10−3 and 20.8 months for those with CRc + MRD ≥10−3.
  • Patients with an MRD response were treated for a median of 16 cycles, while those with MRD ≥10−3 had a median of 9 cycles.
  • Median DoR, EFS, and OS were not reached in patients with an MRD response (Table 2).
    • 18-month estimates for DoR, EFS, and OS were better for those who achieved an MRD response compared with those who did not.

Table 2. Responses*


18-month estimate, % (95% CI)

Median response, months (95% CI)

CRc + MRD <10−3

CRc + MRD 10−3

CRc + MRD <10−3

CRc + MRD ≥10−3


69.6 (55.9–79.8)

33.5 (22.9–44.5)

NR (19.3–NR)

9.7 (8.0–15.8)


73.7 (61.1–82.8)

33.9 (24.4–43.6)

NR (19.7–NR)

10.6 (9.0–13.9)


84.6 (73.3–91.4)

50.1 (39.6–59.8)

NR (24.4–NR)

18.7 (12.9–NR)

*Data from Pratz et al.1

CI, confidence interval; CRc, composite complete response; DoR, duration of response; EFS, event free survival; MRD, minimal residual disease; NR, not reached; OS, overall survival.

  • Multivariate Cox regression analysis of OS revealed two covariates associated with OS; MRD response (hazard ratio, 0.285; 95% confidence interval, 0.159–0.510; p < 0.001) and cytogenetic risk (hazard ratio, 2.062; 95% confidence interval, 1.260–3.374; p = 0.004)
  • The timing of MRD response generally occurred later than achievement of clinical response.
    • 25% of patients achieved an MRD response by the end of Cycle 1.
    • 21% of patients achieved an MRD response by the end of Cycle 7.
  • Patients who achieved MRD response had a higher rate of ≥Grade 3 febrile neutropenia, neutropenia, and thrombocytopenia compared with those who did not achieve an MRD response (Figure 1).
    • Serious adverse events were similar across both groups.

Figure 1. Adverse events* 

*Adapted from Pratz et al.1
AE, adverse event; CRc, composite complete response; MRD, minimal residual disease.



Patients with newly diagnosed AML treated with Ven+Aza who achieved CRc and an MRD response <10−3 had a longer DoR, EFS, and OS compared with those who did not achieve an MRD response (≥10−3). Higher rates of neutropenia were observed in patients that achieved an MRD response compared with those who did not. MRD response was also a significant predictor of OS, however, further studies are required to investigate the role of MRD response in clinical management.

  1. Pratz KW, Jonas BA, Pullarkat V, et al. Measurable residual disease response in acute myeloid leukemia treated with venetoclax and azacitidine. Oral abstract #S137. European Hematology Association (EHA)2021 Virtual Congress; Jun 11, 2021; Virtual.