The addition of BCL-2 antisense oligonucleotide oblimersen to standard induction chemotherapy did not improve remission rates in older patients with newly diagnosed acute myeloid leukemia (AML), according to findings from a phase III trial published in Blood Advances.
"Antisense molecules are known to have issues with delivery and off-target effects, and whether this played a role in the results that were observed is uncertain," said lead study author Alison Walker, MD, of The Ohio State University in Columbus. "Given the availability of more potent molecules that target BCL2, such as venetoclax, it is unlikely that oblimersen will undergo further development."
Dr. Walker and colleagues examined whether the addition of oblimersen to induction chemotherapy with cytarabine/daunorubicin and high-dose cytarabine consolidation therapy was effective for improving outcomes in older patients with AML.
Patients were randomly assigned to the following groups:
- arm A (n=254): cytarabine (100 mg/m2/day on days 4-10) and daunorubicin (60 mg/m2/day on days 4-6) followed by cytarabine consolidation (2,000 mg/m2/day on days 4-8) with oblimersen (7 mg/m2/day on days 1-10 [induction] or days 1-8 [consolidation])
- arm B (n=252): cytarabine (100 mg/m2/day on days 4-10) and daunorubicin (60 mg/m2/day on days 4-6) followed by cytarabine consolidation (2,000 mg/m2/day on days 4-8) without oblimersen
The mean age of the overall population was 69.7 years. Over half of patients were under 70 years of age (54.9%), and most of the cohort consisted of men (60.7%) and patients who were white (89.5%).
Approximately 74.9% of patients had de novo AML, 19.2% of patients had AML after prior myelodysplastic syndromes, and 5.9% of patients had therapy-related AML. There were no significant differences between treatment arms in terms of the proportions of patients with either disease type.
A total of 277 patients in the overall cohort achieved remission. There was no statistically significant difference in complete remission rate between arms A or B (53% vs. 56%, respectively; p=0.53).
Each group had a median overall survival (OS) of nine months. The estimated one-year OS was 43% for the combination arm and 40% for arm B, with no significant difference between either group (p=0.13). In both groups, disease-free survival (DFS) was eight months (p=0.26) and event-free survival was three months (p=0.80).
"Given the availability of more potent molecules that target BCL2, such as venetoclax, it is unlikely that oblimersen will undergo further development."
—Alison Walker, MD
While there was no overall difference in OS between the groups, the median OS for patients under age 70 in arm A was longer than the OS for patients under age 70 in arm B (10 months vs. 9 months, respectively; p=0.04). Additionally, the DFS for patients with secondary AML in group A was greater than the DFS for patients with secondary AML in group B (median = 10 vs. 6 months; p=0.04).
According to the researchers, the small number of pretreatment and follow-up samples for the BCL2 expression analysis challenged their ability to identify whether the lack of benefit between the treatment arms was a result of lacking target inhibition or other underlying mechanisms responsible for preventing chemotherapy response.
This study raises the question of whether antisense molecules that target BCL2 might be synergistic with venetoclax plus chemotherapy, concluded Dr. Walker.
The researchers wrote that while there has been no further development of oblimersen, the current "concept of attacking antiapoptotic proteins, as attempted in the current trial, may represent a new paradigm in AML therapy."
The authors report no relevant conflicts of interest.
Reference
Walker AR, Marcucci G, Yin J, et al. Phase 3 randomized trial of chemotherapy with or without oblimersen in older AML patients: CALGB 10201 (Alliance). Blood Adv. 2021;5(13):2775-2787.
