TY - JOUR
T1 - Phase 3 randomized trial of chemotherapy with or without oblimersen in older AML patients
T2 - CALGB 10201 (Alliance)
AU - Walker, Alison R.
AU - Marcucci, Guido
AU - Yin, Jun
AU - Blum, William
AU - Stock, Wendy
AU - Kohlschmidt, Jessica
AU - Mrózek, Krzysztof
AU - Carroll, Andrew J.
AU - Eisfeld, Ann Kathrin
AU - Wang, Eunice S.
AU - Jacobson, Sawyer
AU - Kolitz, Jonathan E.
AU - Thakuri, Mohan
AU - Sutamtewagul, Grerk
AU - Vij, Ravi
AU - Stuart, Robert K.
AU - Byrd, John C.
AU - Bloomfield, Clara D.
AU - Stone, Richard M.
AU - Larson, Richard A.
N1 - Funding Information:
Roche, Stemline Therapeutics, Takeda, and Trovagene; and has received institutional research support from AbbVie, Agios, AROG, and Novartis. A.-K.E. has received a research grant from Novartis and has ownership interest in Karyopharm Therapeutics. A.R.W. has received clinical research support from Gilead, Novartis, Geron, and Newave. The remaining authors declare no competing financial interests.
Funding Information:
This work was supported by the National Cancer Institute, National Institutes of Health, under awards U10CA180821, U10CA180882, and U24CA196171 (Alliance for Clinical Trials in Oncology) and P30CA033572, UG1CA189848, UG1CA-189850, UG1CA189858, UG1CA233180, UG1CA233191, UG1CA233327, UG1CA233331, UG1CA233338, and UG1CA-233339. Support to Alliance for Clinical Trials in Oncology and Alliance Foundation Trials programs is listed at https:// acknowledgments.alliancefound.org. This work was also supported in part by Deltec, Inc.
Publisher Copyright:
© 2021 by The American Society of Hematology.
PY - 2021/7/13
Y1 - 2021/7/13
N2 - Overexpression of B-cell leukemia/lymphoma 2 (BCL2) renders acute myeloid leukemia (AML) cells resistant to chemotherapy and has been associated with unfavorable outcomes. Oblimersen (G3139) is a phosphorothioate 18-mer antisense oligonucleotide directed against the first 6 BCL2 codons. In a phase 1 study of AML patients treated with G3139, cytarabine, and daunorubicin induction with cytarabine consolidation, no antisense-related toxicity was reported, and BCL2 downregulation occurred in patients achieving complete remission. In this phase 3 trial, untreated older AML patients were randomized to 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 (arm A) or without (arm B) G3139 (7 mg/m2 per day on days 1-10 [induction] or days 1-8 [consolidation]). A total of 506 patients were enrolled. No differences in toxicity were observed between arms. Estimated overall survival (OS) at 1 year was 43% for arm A and 40% for arm B (1-sided log rank P = .13), with no differences in disease-free (DFS; P = .26) or event-free survival (P = .80). Subgroup analyses showed patients age ,70 years in arm A had improved OS by 1 month vs those in arm B (P = .04), and patients with secondary AML in arm A had better DFS vs those in arm B (P = .04). We conclude that addition of G3139 to chemotherapy failed to improve outcomes of older AML patients. However, more effective means of inhibiting BCL2 are showing promising results in combination with chemotherapy in AML.
AB - Overexpression of B-cell leukemia/lymphoma 2 (BCL2) renders acute myeloid leukemia (AML) cells resistant to chemotherapy and has been associated with unfavorable outcomes. Oblimersen (G3139) is a phosphorothioate 18-mer antisense oligonucleotide directed against the first 6 BCL2 codons. In a phase 1 study of AML patients treated with G3139, cytarabine, and daunorubicin induction with cytarabine consolidation, no antisense-related toxicity was reported, and BCL2 downregulation occurred in patients achieving complete remission. In this phase 3 trial, untreated older AML patients were randomized to 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 (arm A) or without (arm B) G3139 (7 mg/m2 per day on days 1-10 [induction] or days 1-8 [consolidation]). A total of 506 patients were enrolled. No differences in toxicity were observed between arms. Estimated overall survival (OS) at 1 year was 43% for arm A and 40% for arm B (1-sided log rank P = .13), with no differences in disease-free (DFS; P = .26) or event-free survival (P = .80). Subgroup analyses showed patients age ,70 years in arm A had improved OS by 1 month vs those in arm B (P = .04), and patients with secondary AML in arm A had better DFS vs those in arm B (P = .04). We conclude that addition of G3139 to chemotherapy failed to improve outcomes of older AML patients. However, more effective means of inhibiting BCL2 are showing promising results in combination with chemotherapy in AML.
UR - http://www.scopus.com/inward/record.url?scp=85110101931&partnerID=8YFLogxK
U2 - 10.1182/bloodadvances.2021004233
DO - 10.1182/bloodadvances.2021004233
M3 - Article
C2 - 34251414
AN - SCOPUS:85110101931
SN - 2473-9529
VL - 5
SP - 2775
EP - 2787
JO - Blood Advances
JF - Blood Advances
IS - 13
ER -