Efficacy
DiNardo et al.r confirmed the superiority of the venetoclax-azacitidine (Ven-Aza) combination over azacitidine alone. The median duration of follow-up was 20.5 months, OS was 14.7 months (95% confidence interval [CI], 11.9 to 18.7) compared to 9.6 months (95% CI, 7.4 to 12.7) and a statistically significant (p<0.001) better remission rate for the combination (hazard ratio (HR) for death, 0.66; 95% CI, 0.52 to 0.85; p<0.001). EFS was 9.8 months (95% CI, 8.4 to 11.8) in the combination group and 7.0 months (95% CI, 5.6 to 9.5) in the group receiving azacitidine alone (HR for disease relapse, treatment failure, relapse, or death, 0.63; 95% CI, 0.50 to 0.80; p<0.001). 36.7% of patients receiving combination therapy achieved CR, compared to 17.9% of the patients receiving azacitidine alone (p<0.001), duration of CR was 17.5 months (95% CI, 15.3 to NR) and 13.3 months (95% CI, 8.5 to 17.6). Treatment continued until disease progression or unacceptable toxicity. Patients receiving combination therapy received a median of 7 cycles, compared to 4.5 in the control group.
Figure 1: Overall survivalr
© NEJM 2020
Longer-term follow-up of VIALE-A has been published with 2 years of additional follow-up.r With a median follow-up of 43.2 months, the median overall survival was 14.7 months (95% CI, 12.1 - 18.7) in the Ven-Aza group and 9.6 months (95% CI, 7.4 - 12.7) in the placebo-azacitidine group; (HR 0.58, 95% CI, 0.47-0.72, p<0.001).
Figure 2: Overall survival with longer follow-upr
© Am J Hematol.2024
AML subgroups
Ven-Aza is active in patients with adverse-risk cytogenetics or other high-risk mutations; and confers a survival benefit over azacitidine monotherapy; in all except TP53 mutated patients.r In VIALE-A, longer-term follow-up showed that IDH1/2 mutated patients derived the most significant survival benefit from Ven-Aza, with median OS 19.9 months (95% CI, 12.2-27.7) compared to 6.2 months (95% CI, 2.3-12.7, HR 0.3).r Another study has shown that patients with DNMT3A, NPM1 or SRSF2 mutations had the highest overall response rates (ORR) to hypomethalating agent (HMA) plus venetoclax (63%, 64% and 63% respectively). RUNX1, TP53, complex cytogenetics and del 7q were associated with worse ORR (46%, 36%, 46% and 42% respectively) as well as decreased median OS.r National Comprehensive Cancer Network (NCCN) recommends treatment with Ven-Aza for patients ineligible for intensive chemotherapy regardless of actionable mutations.r Real-world analyses have found similar outcomes, with overall survival of 14.2 months in one study.r
Clinical experience amongst patients with myelofibrosis-associated AML remains minimal, as these patients were excluded from the initial studies. Clinical benefit in myeloproliferative neoplasms (MPNs) in blast phase (MPN-BP) and in accelerated phase (MPN-AP) with venetoclax-HMA therapy has not been clearly seen. It has resulted in increased response rates, but limited survival benefit.r Severe hypoplasia and prolonged pancytopenia has also been noted in such patients. Therefore, it is recommended that patients with extensive myelofibrosis are excluded from treatment until more data is published.
Studies have been undertaken to determine if this regimen could provide effective treatment for younger fitter patients or as a bridge to allogeneic stem cell transplant for younger patients, with some results suggestive of good outcomes.rr