Adding Venetoclax to Cladribine and Cytarabine Backbone Improves Response Rates, Outcomes in Older Patients With AML

The addition of the BCL2 inhibitor venetoclax (alternating with the hypomethylating agent azacitidine) to a low-intensity backbone combination of cladribine with low-dose cytarabine (CLAD/LDAC) led to high rates of durable remissions and measurable residual disease (MRD) negativity in older patients with newly diagnosed acute myeloid leukemia (AML). Tapan Kadia, MD, from the University of Texas MD Anderson Cancer Center in Houston, presented these findings at the 2020 ASH Annual Meeting.

The trial included 55 patients with newly diagnosed AML between the ages of 57 and 84 years (median age= 68). Approximately 40% of patients were aged 70 years or older, and one patient was younger than 60 but was considered unfit for intensive chemotherapy. One-quarter of patients had secondary AML, and another one-quarter had adverse karyotype.

Treatment in the induction phase included one cycle of cladribine 5 mg/m2 on days 1-5, cytarabine 20 mg on days 1-10, and venetoclax 400 mg on days 1-21. Consolidation treatment consisted of two cycles of cladribine 5 mg/m2 on days 1-3 plus cytarabine 20 mg on days 1-10, alternating with 2 cycles of azacitidine 75 mg/m2 on days 1-7 for up to 18 cycles, with venetoclax on days 1-14.

During a median follow-up of more than 14 months, 42 of the 54 evaluable patients (78%) experienced a complete remission (CR) and 8 (15%) experienced a CR with incomplete count recovery (CRi), for a CR/CRi rate of 93%. Response was achieved early, Dr. Kadia and researchers reported, with responding patients requiring a median of one treatment cycle (range = 1-3). At the time of CR/CRi, 42 patients (84%) were negative for measurable residual disease (MRD); the MRD-negative rate was higher in those who had CR with complete count recovery (n=39/42; 93%).

The investigators also noted that the CR/CRi rates were high among patients with secondary AML or adverse karyotype.

The median overall survival (OS) had not been reached during study follow-up. At 6 and 12 months, the OS rates were 86% and 70%. Median relapse-free survival (RFS) also was not reached, and the respective 6- and 12-month rates of RFS were 79% and 64%.

Fifteen of the 50 responding patients (30%) proceeded to allogeneic hematopoietic cell transplant, suggesting that this combination could serve as a bridging therapy. Receiving a transplant was associated with long OS, Dr. Kadia added (TABLE).

The 8-week mortality rate in the study population was 4%, and the authors reported that this lower-intensity regimen appeared to be well-tolerated. The most common adverse events included infection (n=17; 14 of which were grade 3/4), arthralgia (n=16), rash (n=15), and edema (n=15). Myelosuppression could be limited with adjustment of venetoclax schedule, Dr. Kadia noted.

While these results suggest that the alternating venetoclax plus azacitidine combination leads to durable remissions and high survival rates, the study is limited by its small study population and lack of a comparator arm. Dr. Kadia said that the study will be expanded to explore further molecular subgroups and younger patients.

Study authors report relationships with Genentech and AbbVie.


Kadia TM, Borthakur G, Pemmaraju N, 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). Abstract #25. Presented at the 2020 American Society of Hematology Annual Meeting, December 5, 2020.

TABLE. Overall Survival According to Different Subgroups

Subgroup Median Overall Survival (Months) 6-Month Overall Survival 12-Month Overall Survival p Value
Diploid karyotype Not reached 90% 80% Not applicable
Adverse karyotype 7.8 83% 33%
Intermediate karyotype Not reached 71% 63%
MRD-negative Not reached 92% 83% 0.003
MRD-positive 11.8 82% 48%
Secondary AML Not reached 83% 63% 0.642
De novo AML Not reached 85% 74%
HCT in CR1 Not reached 100% 91% 0.059
No HCT in CR1 Not reached 86% 69%
MRD = measurable residual disease; AML = acute myeloid leukemia; HCT = hematopoietic cell transplantation; CR1 = first complete remission