Addition of venetoclax to azacitidine improves outcomes for subset of patients with AML
Click Here to Manage Email Alerts
Treatment with venetoclax plus azacitidine conferred better outcomes than azacitidine alone among select patients with acute myeloid leukemia, according to study results presented at ASH Annual Meeting and Exposition.
Patients with poor-risk cytogenetics and wild-type TP53 who received the venetoclax (Venclexta; Genentech, AbbVie) regimen had higher remission rates and longer duration of remission and OS. In addition, researchers reported similar outcomes among patients who were wild type for TP53 and had poor risk cytogenetics and those with intermediate-risk cytogenetics who received venetoclax plus azacitidine.
Conversely, improved response rates did not translate to longer duration of remission or OS for patients with poor-risk cytogenetics and TP53 mutations who received venetoclax with azacitidine vs. azacitidine alone.
“We know that poor-risk cytogenetics are associated with worse outcomes in patients treated with conventional therapies. We also know that TP53 mutations frequently co-occur with poor-risk cytogenetics. Therefore, we wanted to learn whether poor-risk cytogenetics drive worse outcomes in patients treated with venetoclax plus azacitidine, or if this is due to the strong association between poor-risk cytogenetics and TP53 mutations,” Daniel A. Pollyea, MD, MS, clinical director of leukemia services, associate professor of medicine and hematology and Robert H. Allen MD chair in hematology research at University of Colorado Anschutz Medical School, told Healio.
The analysis included treatment-naive patients with AML who had been deemed unfit for intensive chemotherapy either because of age or comorbidities. Researchers pooled data from an ongoing phase 3 study comparing treatment with venetoclax plus azacitidine or placebo, and a phase 1b study of patients who received venetoclax and azacitidine.
Treatment consisted of 400 mg venetoclax daily and 75 mg/m2 azacitidine on days 1 to 7 of 28-day cycles.
Among the 546 patients in the pooled analysis, 353 received venetoclax plus azacitidine and 145 received azacitidine. About one-third of patients (n = 127) in the venetoclax-azacitidine group had poor-risk cytogenetics, 50 had wild-type TP53 and 54 had TP53 mutations. In the azacitidine group, 56 patients (39%) had poor-risk cytogenetics, 22 had wild-type TP53 and 18 had TP53 mutations.
Among 401 patients who received venetoclax plus a hypomethylating agent, 38% (n = 152) had poor-risk cytogenetics, 61 had wild-type TP53 and 68 had TP53 mutations.
Median age of patients in each group ranged from 74 to 77 years.
Results showed patients with poor-risk cytogenetics and wild-type TP53 who received venetoclax plus azacitidine vs. azacitidine alone had a higher composite remission rate (70% vs. 23%), longer median duration of remission (18.37 months vs. 8.51 months) and longer median OS (23.43 months vs. 11.29 months).
Researchers noted the results among patients with poor-risk cytogenetics and wild-type TP53 were comparable to those of patients with intermediate-risk cytogenetics and wild-type TP53.
Among patients with poor-risk cytogenetics and TP53 mutations who received venetoclax plus azacitidine vs. azacitidine alone, researchers reported composite remission rates of 41% vs. 17%, median duration of remission of 6.54 months vs. 6.7 months and median OS 5.17 months vs. 4.9 months.
Grade 3 or higher adverse events among patients with poor-risk cytogenetics and wild-type TP53 who received venetoclax plus azacitidine vs. azacitidine alone included thrombocytopenia (36% in both groups), febrile neutropenia (32% vs. 14%), anemia (26% vs. 6%), neutropenia (24% vs. 27%) and pneumonia (18% vs. 23%). In patients with poor-risk cytogenetics and TP53 mutations, adverse events with venetoclax plus azacitidine vs. azacitidine included febrile neutropenia (43% vs. 22%), thrombocytopenia (28% in both groups), neutropenia (26% vs. 17%), anemia (13% vs. 32%) and pneumonia (26% vs. 33%).
“Although poor-risk cytogenetics predict poor outcomes with conventional therapies, there is no such association with venetoclax plus azacitidine if there is no TP53 mutation,” Pollyea said. “Patients with poor-risk cytogenetics who were wild type for TP53 had similar response rates, response duration and OS as patients with intermediate-risk cytogenetics who were wild type for TP53. However, patients with TP53 mutations continue to do poorly, even with venetoclax plus azacitidine. Although the response rates for venetoclax with azacitidine were higher than for azacitidine alone in this group, there were no differences in duration of response and OS.”
For more information:
Daniel A. Pollyea, MD, MS, can be reached at Division of Hematology, University of Colorado Anschutz Medical School, Fitzsimons Building, 13001 E. 17th Place, Aurora, CO 80224; email: daniel.pollyea@cuanschutz.edu.
Perspective
Back to Top
Douglas Tremblay, MD
Despite the established role of venetoclax with hypomethylating agents, this study suggests the combination may not be able to overcome the negative prognostic impact on survival of TP53 mutations in AML. In contrast, for patients with poor-risk cytogenetics without a TP53 mutation, there still seems to be added benefit to adding venetoclax to hypomethylating agents.
This study is not entirely unsurprising given the extremely poor survival we see clinically in patients with AML who harbor a TP53 mutation.
In patients who harbor a TP53 mutation and have poor-risk cytogenetics, there may be more reluctance to add venetoclax to hypomethylating agents. However, in practice, venetoclax is likely still going to be employed in this setting, given higher response rates observed in this study, particularly among patients who may be eligible for allogeneic stem cell transplantation. Further studies are needed to identify agents that are active in TP53-mutated AML and can be combined with a backbone of a hypomethylating agent and venetoclax.
Icahn School of Medicine at Mount Sinai
Collapse
Pollyea DA, et al. Abstract 224. Presented at: ASH Annual Meeting and Exposition; Dec. 11-14, 2021; Atlanta.
Click Here to Manage Email Alerts