Addition of venetoclax provides an effective, lower-intensity regimen

The addition of venetoclax to cladribine plus low-dose cytarabine is an effective, lower-intensity regimen that is well tolerated among older patients with newly diagnosed acute myeloid leukaemia (AML). This regimen produced high rates of durable measurable residual disease (MRD)-negative remission and meaningful blood count recovery. With a follow-up of approximately 1 year, the rates of overall and relapse-free survival were encouraging in this cohort of older AML patients.

“For many years, safe and effective treatment of older and unfit patients with newly diagnosed AML has been challenging, trying to attain the balance between modest response rates with low-intensity therapy and higher levels of toxicity with intensive therapy,” Dr Tapan Kadia (MD Anderson Cancer Center, Texas, USA) mentioned at the beginning of his lecture. Until recently, the standard of care for these patients has been a hypomethylating agent as a single agent, with complete remission (CR) rates around 19% and median overall survival (OS) ranging from 7.7 to 10.4 months. Dr Kadia previously demonstrated that a low-intensity backbone of cladribine plus low-dose cytarabine alternating with a hypomethylating agent for older patients with AML yielded higher rates of CR and improved outcomes compared with hypomethylating agents alone [1]. A recent randomised study showed that addition of the BCL-2 inhibitor venetoclax to hypomethylating agents improved survival over hypomethylating agents alone [2]. The current phase 2 trial evaluated if the addition of venetoclax to the low-intensity backbone with cladribine plus low-dose cytarabine would further improve response rates and outcomes in elderly patients (n=48; median age 68 years, range 57–84) with newly diagnosed AML [3].

The addition of venetoclax to cladribine plus low-dose cytarabine was found to be effective, with a composite complete remission (CRc) rate of 93%, and 93% of patients who achieved a CR were MRD-negative. In total, 30% of responding patients were able to move forward to allogeneic stem cell transplantation. For the entire population, the median overall survival (OS) was not reached, and 1-year OS was 70%. OS benefit was observed across genomically defined subgroups, with more modest activity among those with adverse karyotype.

In this older patient population, the treatment regimen was well tolerated with 4- and 8-week mortality rates of 2% and 4%, respectively. Myelosuppression could be limited by adjusting venetoclax and concomitant 5-azacytidine schedule.

The study is ongoing and expansion is planned to further explore molecular subgroups and younger age groups.

1. Kadia TM, et al. Lancet Haematol. 2018 Sep;5(9):e411-e421.
2. DiNardo CD, et al. N Engl J Med. 2020;383:617-629.
3. Kadia TM, et al. Phase II Study of Venetoclax Added to Cladribine + Low Dose AraC (LDAC) Alternating with 5-Azacytidine Demonstrates High Rates of Minimal Residual Disease (MRD) Negative Complete Remissions (CR) and Excellent Tolerability in Older Patients with Newly Diagnosed Acute Myeloid Leukemia (AML). 62^nd ASH Annual Meeting, 5-8 December 2020. Abstract 25.

Posted on 18 February 202122 February 2021