According to the results of a phase 3 study published in Blood Advances, the antisense oligonucleotide (ASO) oblimersen can be added safely to conventional chemotherapy for older patients with acute myeloid leukemia (AML), and although adding the ASO did not improve complete remission (CR) rates, it appeared to improve disease-free survival (DFS) in patients with secondary AML.
The Cancer and Leukemia Group B (CALGB) 10201 study (ClinicalTrials.gov Identifier: NCT00085124) aimed to determine whether the addition of oblimersen (G3139), a phosphorothioate ASO directed to BCL2 mRNA, to cytarabine/daunorubicin induction chemotherapy and high-dose cytarabine consolidation therapy improves outcomes in previously untreated AML patients who are ≥60 years of age.
Patients were randomized to receive cytarabine (100 mg/m2 per day on days 4-10) and daunorubicin (60 mg/m2 per day on days 4-6) followed by cytarabine consolidation (2000 mg/m2 per day on days 4-8) with or without G3139 (7 mg/m2 per day on days 1-10 [induction] and days 1-8 [consolidation]). The primary endpoint was overall survival (OS), and key secondary outcomes were DFS, event-free survival (EFS), and CR rates.
Between October 2004 and October 2006, total of 506 patients (chemo + G3139 arm: n=254; chemo-only arm: n=252) enrolled at 75 CALGB member institutions and their affiliated hospitals. The median age was 69 years (range, 48.5-88.3 years). Patient characteristics were well balanced between the arms. The patients were 60.7% male and 89.5% White. Disease types were classified as 19.2% post-myelodysplastic syndrome AML, 74.9% de novo AML, and 5.9% therapy-related AML.
Estimated 1-year OS was 43% in the chemo + G3139 arm and 40% in the chemo-only arm (1-sided log-rank P =.13); no differences were observed in CR rate (P =.53), DFS (P =.26), or EFS (P =.80). Subgroup analyses revealed that OS among patients <70 years of age in the chemo + G3139 arm was prolonged by 1 month compared with those in the chemo-only arm (P =.04), and patients with secondary AML in the chemo + G3139 arm had better DFS than those in the chemo-only arm (P =.04).
No differences in toxicity were observed between the arms, suggesting G3139 did not increase or prolong adverse events normally seen during cytarabine/daunorubicin induction chemotherapy and high-dose cytarabine consolidation.
“The approval of venetoclax in combination with hypomethylating agents or low-intensity chemotherapy has already changed the therapeutic landscape for older patients with AML,” wrote the authors. “Whether using an antisense molecule such as G3139 to lower the intracellular levels of BCL2 would provide any synergistic benefit beyond the use of venetoclax plus chemotherapy is uncertain. Although there has been no further development of G3139, the concept of attacking antiapoptotic proteins, as attempted in the current trial, may represent a new paradigm in AML therapy.”
Disclosure: The study author(s) declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Walker A, 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. doi:10.1182/BLOODADVANCES.2021004233