Results from the Phase III VIALE-A trial, published in the August 13, 2020 issue of the New England Journal of Medicine (NEJM), demonstrated that venetoclax (Venclexta®; Abbvie/Genentech), a drug used to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), in combination with azacitidine (Vidaza®; Celgene/Bristol Meyer Squibb) extended overall survival (OS) in newly-diagnosed, treatment-naïve Acute Myeloid Leukemia (AML) patients that were ineligible or were unable to tolerate traditional, intensive, chemotherapy therapy, compared to azacitidine plus placebo.
The published findings were earlier this year presented as late-breaking data during the virtual 25th European Hematology Association (EHA) Annual Congress.
Acute Myeloid Leukemia is the most common acute leukemia in the world  and not all patients can tolerate the current standard intensive chemotherapy,  making it among the most difficult blood cancers to treat.  Despite advances in available therapies and care, the five-year survival rate for patients diagnosed with AML remains approximately 28%. 
A total of 433 treatment-naïve, intensive chemotherapy ineligible AML patients were randomized in the double-blind, placebo-controlled Phase III VIALE-A trial. The trial was designed to evaluate the efficacy and safety of venetoclax in combination with azacitidine (n=286) compared with azacitidine in combination with placebo (n=145).
The results of the VIALE-A trial and additional data have been submitted to the FDA and global health authorities to convert the accelerated approval to full approval for venetoclax in combination with azacitidine, or decitabine, or low-dose cytarabine (LDAC) for the treatment of newly-diagnosed AML in adults who are age 75 years or older, or who have comorbidities that preclude the use of intensive induction chemotherapy.
“The ability of venetoclax plus azacitidine to improve outcomes of newly-diagnosed AML patients unable to tolerate intensive chemotherapy represents a potentially practice-changing advance in AML treatment,” noted Courtney D. DiNardo, M.D., MSCE, Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center and the lead study investigator.
In the VIALE-A study, overall survival was the sole primary study endpoint in the U.S. Overall survival and composite complete remission rate (CR+CRi) were co-primary endpoints in China, Japan, the European Union (EU) and EU reference countries.
CR+CRi is a composite score reflecting the complete remission (CR) and CR with incomplete hematologic recovery (CRi), which is an incomplete CR with blood counts not fully recovered.  Treatment with venetoclax plus azacitidine reduced the risk of death by 34% compared to azacitidine in combination with placebo (Hazard Ratio [HR]=0.66 [95% CI: 0.52-0.85], p<0.001). 
Patients in the venetoclax combination arm had a median OS of 14.7 months (95% CI: 11.9-18.7) versus 9.6 months for patients in the placebo arm (95% CI: 7.4-12.7). Additionally, 66.4% (95% CI: 60.6-71.9) of patients treated with venetoclax plus azacitidine achieved CR+CRi versus 28.3% (95% CI: 21.1-36.3) of patients treated with azacitidine plus placebo (p<0.001). Other secondary endpoints that were published in NEJM include CR and CR with partial hematologic recovery (CR+CRh).
The observed safety profile in the VIALE-A trial is generally consistent with the known safety profiles of venetoclax combined with azacitidine. The most common adverse events (AEs [occurring in ≥40% of patients]) in patients receiving venetoclax plus azacitidine were mostly hematologic and gastrointestinal in nature and consisted of thrombocytopenia (46%), nausea (44%), constipation (43%), neutropenia (42%), febrile neutropenia (42%) and diarrhea (41%). The most frequent serious adverse reactions (ARs [occurring in >10% of patients]) in patients receiving venetoclax plus azacitidine were febrile neutropenia (30%) and pneumonia (17%).
Tumor lysis syndrome (TLS) was reported during ramp-up in three patients in the venetoclax arm and none in the placebo arm. All were transient biochemical changes that resolved with uricosuric agents – medications that increase excretion of uric acid in the urine and decrease the concentration of uric acid in blood plasma – and calcium supplements without treatment interruption.
The VIALE-A trial results were presented as late-breaking data during the virtual 25th European Hematology Association (EHA) Annual Congress in June 2020 (abstract #LB2601).
AbbVie, in collaboration with Genentech, submitted the results of the VIALE-A (M15-656) trial, along with data from the VIALE-C (M16-043) trial and updated data from the Phase I/II studies M14-358 (NCT02203773) and M14-387, to the U.S. Food and Drug Administration (FDA) to convert the accelerated approval for venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine (LDAC) for the treatment of newly-diagnosed AML in adults who are age 75 years or older, or who have comorbidities that preclude the use of intensive induction chemotherapy, to full approval. AbbVie also submitted these data to additional health authorities around the world.
This practice-changing multicenter randomized Phase III trial establishes venetoclax and azacitidine as a new standard of care for older patients with AML.
* Venetoclax is a first-in-class medicine that selectively binds and inhibits the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers, BCL-2 prevents cancer cells from undergoing their natural death or self-destruction process, called apoptosis. VENCLEXTA targets the BCL-2 protein and works to help restore the process of apoptosis.
Study of ABT-199 (GDC-0199) in Combination With Azacitidine or Decitabine (Chemo Combo) in Subjects With Acute Myelogenous Leukemia (AML) – NCT02203773
A Study Evaluating Venetoclax in Combination With Low-Dose Cytarabine in Treatment-Naïve Participants With Acute Myelogenous Leukemia – NCT02287233
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Featured image: AbbVie scientist looks at experimental results through a microscope. Photo courtesy: © 2020 AbbVie. Used with permission.