Acute myeloid leukaemia (AML) frequently affects older adults who are unsuitable for intensive therapies and is often associated with a poor prognosis and short survival. Azacitidine and venetoclax is a potent combination therapy that offers an opportunity to improve the previously dismal prognosis of these patients.
The evidence supporting this protocol comes from the VIALE-A studyr, a phase 3, multicentre, double blind, randomised controlled trial, involving 431 patients with AML, ineligible for standard induction therapy who had not received prior treatment. Patients with favourable cytogenetics and myelofibrosis associated AML were excluded. Patients of median age 76 years from 134 sites in 27 countries participated from February 2017 to May 2019 and were randomised in a 2:1 ratio to receive azacitidine 75 mg/m2 subcutaneously or intravenously, and either venetoclax 400 mg target dose (286 patients) or placebo (145 patents) in 28-day cycles. Daily dose escalation of venetoclax was done in cycle 1, following the dosing schedule established in earlier phase 1 trialsrr (100 mg day 1, 200 mg day 2, then the 400 mg target dose from day 3). All patients were hospitalised for tumour lysis prophylaxis consisting of an oral uric acid reducing agent and oral hydration 72 hours prior to venetoclax, intravenous hydration 24 hours before venetoclax commencement.
The primary end point was overall survival (OS). Secondary end points included complete remission (CR), event-free survival (EFS) and composite complete remission(CRc)/complete remission with incomplete haematological recovery(CRi).
Clinical experience among patients with myelofibrosis associated AML remains minimal. Severe hypoplasia and prolonged pancytopenia has been noted in such patients. Therefore, it is recommended that patients with extensive myelofibrosis are excluded from treatment until more data is published.
Azacitidine and venetoclax therapy is an effective and well-tolerated combination therapy for upfront treatment of elderly AML and has been found to be effective in AML with a variety of mutations. Following preclinical data suggesting synergistic activity between hypomethylating agents and venetoclax, a phase 1b study looked at the safety and preliminary efficacy of azacitidine/decitabine and venetoclax combination in elderly patients over age 65, with previously untreated AML, featuring intermediate or poor risk cytogenetics, unsuitable for standard induction therapy.r
DiNardo et al.r confirmed the superiority of the venetoclax/azacitidine combination over azacitidine alone. The median duration of follow up was 20.5 months, OS 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 statistically significant (p<0.001) better remission rate for the combination (hazard ratio 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 (hazard ratio for 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.
Fig 1: Overall survivalr
Overall, this study and its predecessors provided evidence for an effective treatment for elderly AML patients.rrr
Gastrointestinal toxicity, particularly nausea (in 44% of the patients in the azacitidine–venetoclax group and 35% of those in the control group), constipation (in 43% and 39%, respectively), diarrhoea (in 41% and 33%), and vomiting (in 30% and 23%), cytopenias (grade 3 or higher thrombocytopenia in 45% vs 38%; neutropenia in 42% vs 28%) and febrile neutropenia (42% vs 19%) were more prevalent with the combination treatment group and, as such, transfusion dependence was more common in the azacitidine/venetoclax combination group. Treatment delays between cycles and reduction in treatment duration from 28 to 21 days happened in 53% in the azacitidine-venetoclax group and 28% of the control group. Tumour lysis presenting as transient biochemical changes requiring simple measures and not interrupting dosing, occurred in 1% of patients during venetoclax dose escalation phase. Treatment interruption due to adverse events occurred in 72% patients with combination treatment compared to 57% in the control group. 30-day mortality was similar at 7% in the azacitidine venetoclax group and 6% in the control group.
Fig 2: Adverse Eventsr