Current available therapies for patients with acute myeloid leukemia ( AML ) who are ineligible for intensive therapy yield limited responses with poor survival.
Venetoclax ( Venclyxto ) is a selective small-molecular inhibitor of BCL-2. Clinical data from a prior phase 1b study showed that Venetoclax and Azacitidine combination had promising efficacy with an acceptable safety profile.
Researchers have evaluated efficacy of Azacitidine + Venetoclax combination regimen compared to Azacitidine + Placebo in treatment-naïve patients with acute myeloid leukemia ineligible for intensive therapy.
This phase 3, randomized, double-blinded, multicenter, placebo-controlled study included patients with confirmed acute myeloid leukemia who were ineligible for intensive induction therapy due to medical comorbidities and/or age more than 75 years.
Prior treatment with a hypomethylating agent for an antecedent hematologic disorder was excluded.
Patients were randomized to 2:1 Azacitidine + Venetoclax or Azacitidine + placebo. Patients on Azacitidine + Venetoclax received Azacitidine 75 mg/m2 subcutaneous or intravenous on days 1-7 per 28-day cycle and once daily 400 mg Venetoclax orally on days 1–28 with a 3-day ramp up in cycle 1.
Patients on Azacitidine + Placebo received Azacitidine 75 mg/m2 on days 1-7 per 28-day cycle and once daily Placebo orally on days 1–28.
The primary endpoint was to compare overall survival ( OS ). Secondary endpoints were rates of: composite complete remission [ complete remission ( CR ) + CR with incomplete count recovery ( CRi ) ], CR+CRi by initiation of cycle 2, CR, transfusion independence [ red blood cells ( RBC ) or platelets ], CR+CRi and OS by molecular subgroups, and event-free survival ( EFS ).
A sample size of 400 was estimated to detect a hazard ratio ( HR ) of 0.7 in overall survival with 2-sided alpha of 4% and power of 87%.
Overall survival and event-free survival were analyzed by the Kaplan-Meier method and compared between arms using the log-rank test stratified by age ( 18 to less than 75 vs 75 or more ) and cytogenetic risk ( intermediate vs poor ).
As of 04 Jan 2020, 431 patients ( median age 76 years, range 49-91 ) were randomized to Azacitidine + Venetoclax ( n=286 ) or Azacitidine + Placebo ( n=145 ).
With median follow-up of 20.5 months, the median overall survival was 14.7 months in Azacitidine + Venetoclax and 9.6 months in Azacitidine + Placebo ( hazard ratio, HR=0.66, 95% CI: 0.52–0.85, p less than 0.001 ) respectively, representing a 34% reduction in risk of death.
Patiens received a median number of 7.0 ( range: 1-30 ) and 4.5 ( 1-26 ) cycles of study drug in Azacitidine + Venetoclax and Azacitidine + Placebo.
CR + CRi rates in Azacitidine + Venetoclax / Azacitidine + Placebo were 66/28% ( p less than 0.001 ) respectively.
Median time ( 95% CI ) to first CR or CRi response was 1.3 ( 0.6-9.9 ) / 2.8 ( 0.8-13.2 ) months and duration of CR + CRi was 17.5/13.4 months respectively.
Response rates in patients with poor and intermediate cytogenetic risk was 53/23% and 74/32% respectively.
Response rates in patients with de novo and secondary acute myeloid leukemia were 66/30% and 67/23% respectively.
Grade 3 or more hematological adverse events included ( Azacitidine + Venetoclax / Azacitidine + Placebo ) thrombocytopenia ( 45/38% ), neutropenia ( 42/29% ), febrile neutropenia ( 42/19% ), anemia ( 26/20% ), and leukopenia ( 21/12% ).
All grade gastrointestinal adverse effects were common with nausea ( 44/35% ), constipation ( 43/39% ), diarrhea ( 41/33% ), and vomiting ( 30/23% ).
Notable serious adverse effects ( grade 3 or more ) were febrile neutropenia ( 30/10% ) and pneumonia ( 16/22% ).
Laboratory tumor lysis syndrome was rare at 1% in Azacitidine + Venetoclax.
The 30-day mortality rates were 7% ( n=21 ) and 6% ( n=9 ) respectively.
In conclusion, among treatment-naïve predominantly elderly patients with acute myeloid leukemia ineligible for intensive therapy, the combination regimen of Azacitidine + Venetoclax led to statistically significant and clinically meaningful improvement in response rates and overall survival as compared to Azacitidine, with a manageable safety profile. ( Xagena )
Source: EHA25 - European Hematology Association Virtual Meeting, 2020