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

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*

Results¹

• 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*

• 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.

Conclusion

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.