Clinical Data
Preclinical data demonstrated that AZA could reduce MCL-1 levels, mediating resistance to BCL-2 inhibitors. AZA primed AML cells for venetoclax-induced apoptosis via NOXA induction. Thus, AZA and venetoclax synergistically activated BAX and thus stimulated mitochondrial apoptosis in AML cells
[29][30].
In , a large, multicenter, phase Ib dose-escalation and expansion study reported on the safety and efficacy of venetoclax with HMA in AML patients older than 65 years with treatment-naive AML who were ineligible for intensive chemotherapy
[28]. During dose escalation, oral venetoclax was administered at 400, 800, or 1200 mg daily in combination with either decitabine (DEC) (20 mg/m
2, days 1–5, intravenously [IV]) or azacytidine (AZA) (75 mg/m
2, days 1–7, IV or subcutaneously [SC]). In the expansion, 400 or 800 mg venetoclax was given with either DEC or AZA. The median patient age was 74 years, and poor-risk cytogenetics was present in 49% of patients. In a median follow-up time of 8.9 months, the CR/CRi rates were 67% and did not differ between the AZA and DEC groups. Patients with poor-risk cytogenetics and those older than 75 years had CR/CRi rates of 60% and 65%, respectively. The median time to response was 1.2 cycles (months) and the MRD negativity rate among responders was 29%. With a median follow-up time of 15 months, the median duration of response (DOR) and OS were 13.1 and 17.5 months, respectively. Among patients with CR/CRi, median DOR was 11.3 months, and median OS was not reached. Although benefits were seen in all patients, outcomes differed between the molecular and cytogenetic subgroups. Accordingly, CR/CRi rates were higher in patients with NPM1 and IDH1/2 mutations (91 and 71%, respectively) and lower in patients with TP53 mutations and poor cytogenetics (47 and 60%, respectively). Median DOR was also longer in patients with NPM1 and IDH1/2 mutations (24.4 months) and shorter in those with FLT3 and TP53 mutations (7.2 months).
Another phase III, multicenter, randomized, double-blind, placebo-controlled trial was conducted to evaluate the efficacy and safety of AZA plus venetoclax, compared to AZA plus placebo in 431 newly diagnosed AML patients who were unfit for standard induction therapy due to coexisting comorbidities and age greater than 75 years old
[31]. The patients were treated with AZA (75 mg/m
2 SC or IV on day 1–7, 28-day cycle) plus venetoclax (target dose, 400 mg) or matching placebo administered orally in 28-day cycles. The intention-to-treat population included 431 patients (286 in the AZA-venetoclax group and 145 in the AZA–placebo control group). The median age was 76 years in both groups (range, 49–91 years old). At a median follow-up of 20.5 months, the median OS was 14.7 months in the AZA–venetoclax group versus 9.6 months in the control group (hazard ratio for death, 0.66; 95% CI, 0.52–0.85;
p < 0.001). The incidence of CR was also higher in the AZA–venetoclax group than in the control group (36.7% vs. 17.9%;
p < 0.001). Moreover, the composite CR and DOR were higher in the AZA-venetoclax group than in the control group (composite CR, 66.4 vs. 28.3%,
p < 0.001; DOR, 17.8 vs. 13.9 months). The incidence of any-grade important adverse events (44% in the AZA-venetoclax group vs. 35% in the control group) and >grade 3 thrombocytopenia (45 vs. 38%, respectively), neutropenia (42 vs. 28%), febrile neutropenia (42 vs. 19%) and any-grade infections (84 vs. 67%) were also investigated.
A recent phase Ib/II study also investigated the safety and preliminary efficacy of venetoclax combined with LDAC in AML patients older than 60 years old and unfit for intensive chemotherapy. In the data, venetoclax (600 mg/day) was orally administrated in 28-day cycles, and LDAC (20 mg/m
2 per day, SC) was given on days 1 to 10
[27]. The median age was 74 years (range, 63–90 years). Overall, 29% of the patients had previously received HMA, 49% had secondary AML, and 32% had poor-risk cytogenetic features. The early mortality rate was 6%. Moreover, 54% of the patients achieved CR/CRi. The median OS was 10.1 months (95% CI, 5.7 to 14.2), and the median DOR was 8.1 months (95% CI, 5.3 to 14.9 months). Among patients without prior HMA exposure, CR/CRi was achieved in 62% of cases, median DOR was 14.8 months, and median OS was 13.5 months (95% CI, 7.0 to 18.4 months). The most common grade 3 or greater adverse events were febrile neutropenia (42%), thrombocytopenia (38%), and neutropenia (34%). In addition, patients with NPM1 or IDH1/2 mutations had better outcomes (CR/CRi rate, 89 and 72%, respectively), compared to those with TP53 or FLT3 mutations (30 and 44%, respectively). The data showed that venetoclax plus LDAC showed a significantly improved safety profile, producing rapid and durable remission in older adults with AML ineligible for intensive chemotherapy.
In another international phase III randomized double-blind placebo-controlled trial, patients older than 18 years old with newly diagnosed AML ineligible for intensive chemotherapy were randomized 2:1 to receive venetoclax (
n = 143) or placebo (
n = 68) in 28-day cycles, plus LDAC on days 1 to 10
[32]. The median age was 76 years old (range, 36–93 years), 38% of patients had secondary AML and 20% had received prior HMA treatment. The planned data analysis showed that venetoclax plus LDAC led to a 25% reduction in the risk of death, compared to LDAC alone, but the difference was not statistically significant (HR, 0.75; 95% CI, 0.52–1.07;
p = 0.11), although median OS was 7.2 vs. 4.1 months, respectively. The unplanned analysis showed that the venetoclax arm had significantly greater OS (8.4 months; HR, 0.70; 95% CI, 0.50–0.98;
p = 0.04). The CR/CRi rates were 48 and 13% in the venetoclax plus LDAC group and LDAC alone group, respectively (
p < 0.001). The reported adverse events greater than grade 3 (venetoclax vs. LDAC alone) were febrile neutropenia (32 vs. 29%), neutropenia (47 vs. 16%), and thrombocytopenia (45 vs. 37%). Venetoclax plus LDAC treatment was associated with significant improvements in response and OS, compared to LDAC alone, with a favorable safety profile.
In the abovementioned data, the efficacy of venetoclax-based chemotherapy was associated with prognosis in patients with specific cytogenetic abnormalities. In particular, patients with NPM1 and IDH 1/2 mutations treated with venetoclax-based chemotherapy had favorable median survival duration. The data suggest the utility of harnessing molecular strategies for patient selection to optimize response to venetoclax-based chemotherapy, particularly for AML patients with treatment-naïve NPM1 or IDH1/2 mutations unfit for intensive chemotherapy.