Meta‑analysis of the efficacy of venetoclax and azacitidine combination therapy and azacitidine monotherapy for treating acute myeloid leukemia

Xie,Yuqin; Wei,Xueqin; Wang,Weiwei; Liao,Changsheng; Han,Pengfei; Yu,Yanhui

doi:10.3892/etm.2024.12452

Meta‑analysis of the efficacy of venetoclax and azacitidine combination therapy and azacitidine monotherapy for treating acute myeloid leukemia

Authors:
- Yuqin Xie
- Xueqin Wei
- Weiwei Wang
- Changsheng Liao
- Pengfei Han
- Yanhui Yu
View Affiliations

Affiliations: Department of Hematology, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi 046000, P.R. China, Graduate School, The First Clinical College of Changzhi Medical College, Changzhi, Shanxi 046000, P.R. China, Department of Orthopedics, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi 046000, P.R. China
Published online on: February 26, 2024 https://doi.org/10.3892/etm.2024.12452
Article Number: 164
Copyright: © Xie et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The present study aimed to compare the efficacy of combination therapy with venetoclax and azacitidine with that of azacytidine monotherapy in the treatment of acute myeloid leukemia (AML). The Web of Science, PubMed, Embase, The Cochrane Library, Weipu Database, Wanfang Digital Periodicals, Sinomed, China National Knowledge Infrastructure, ProQuest Dissertations and Theses and Cumulative Index to Nursing and Allied Health Literature were searched for publications on the treatment of AML with venetoclax combined with azacitidine or with azacitidine monotherapy. A total of 5,271 relevant studies were retrieved, of which 10 were included. Literature quality was evaluated according to the Cochrane systematic review methodology, and data were extracted for meta‑analysis using Review Manager 5.4. The combination of venetoclax and azacitidine demonstrated greater overall efficacy than azacitidine monotherapy for AML treatment. Notably, combination therapy resulted in a higher frequency of complete remission. By contrast, combined treatment and monotherapy showed no significant differences in partial remission, whereas there was a statistically significant decrease in the frequency of no remission in the combination therapy group compared with in the monotherapy group. The results also revealed a significantly higher incidence of adverse reactions when venetoclax and azacitidine were combined in the treatment of AML compared with the observed rates in response to azacitidine monotherapy. Moreover, subgroup analyses showed that no statistically significant differences were observed between the two groups regarding adverse events, including hypokalemia and liver insufficiency. In conclusion, the combination of venetoclax and azacitidine was more effective than azacitidine alone, and had a good clinical application value in the treatment of AML. Although some adverse reactions occurred in response to the combination therapy, they did not significantly affect the prognosis of AML. To better evaluate the efficacy and safety of this treatment regimen, multicenter clinical studies with larger sample sizes are required.

View Figures

View References

1	Konopleva M, Pollyea DA, Potluri J, Chyla B, Hogdal L, Busman T, McKeegan E, Salem AH, Zhu M, Ricker JL, et al: Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 6:1106–1117. 2016.PubMed/NCBI View Article : Google Scholar
2	Kadia TM, Reville PK, Wang X, Rausch CR, Borthakur G, Pemmaraju N, Daver NG, DiNardo CD, Sasaki K, Issa GC, et al: Phase II study of venetoclax added to cladribine plus low-dose cytarabine alternating with 5-azacitidine in older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 40:3848–3857. 2022.PubMed/NCBI View Article : Google Scholar
3	Richard-Carpentier G and DiNardo CD: Venetoclax for the treatment of newly diagnosed acute myeloid leukemia in patients who are ineligible for intensive chemotherapy. Ther Adv Hematol. 10(2040620719882822)2019.PubMed/NCBI View Article : Google Scholar
4	Pollyea DA, Amaya M, Strati P and Konopleva MY: Venetoclax for AML: Changing the treatment paradigm. Blood Adv. 3:4326–4335. 2019.PubMed/NCBI View Article : Google Scholar
5	Wei AH, Strickland SA Jr, Hou JZ, Fiedler W, Lin TL, Walter RB, Enjeti A, Tiong IS, Savona M, Lee S, et al: Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: Results from a phase Ib/II study. J Clin Oncol. 37:1277–1284. 2019.PubMed/NCBI View Article : Google Scholar
6	DiNardo CD, Pratz KW, Letai A, Jonas BA, Wei AH, Thirman M, Arellano M, Frattini MG, Kantarjian H, Popovic R, et al: Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: A non-randomised, open-label, phase 1b study. Lancet Oncol. 19:216–228. 2018.PubMed/NCBI View Article : Google Scholar
7	Vasu S, Kohlschmidt J, Mrózek K, Eisfeld AK, Nicolet D, Sterling LJ, Becker H, Metzeler KH, Papaioannou D, Powell BL, et al: Ten-year outcome of patients with acute myeloid leukemia not treated with allogeneic transplantation in first complete remission. Blood Adv. 2:1645–1650. 2018.PubMed/NCBI View Article : Google Scholar
8	Singh R, Letai A and Sarosiek K: Regulation of apoptosis in health and disease: The balancing act of BCL-2 family proteins. Nat Rev Mol Cell Biol. 20:175–193. 2019.PubMed/NCBI View Article : Google Scholar
9	DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, Frankfurt O, Konopleva M, Wei AH, Kantarjian HM, et al: Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 133:7–17. 2019.PubMed/NCBI View Article : Google Scholar
10	Choi JH, Bogenberger JM and Tibes R: Targeting apoptosis in acute myeloid leukemia: Current status and future directions of BCL-2 inhibition with venetoclax and beyond. Target Oncol. 15:147–162. 2020.PubMed/NCBI View Article : Google Scholar
11	Pollyea DA, Stevens BM, Jones CL, Winters A, Pei S, Minhajuddin M, D'Alessandro A, Culp-Hill R, Riemondy KA, Gillen AE, et al: Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia. Nat Med. 24:1859–1866. 2018.PubMed/NCBI View Article : Google Scholar
12	Yue X, Chen Q and He J: Combination strategies to overcome resistance to the BCL2 inhibitor venetoclax in hematologic malignancies. Cancer Cell Int. 20(524)2020.PubMed/NCBI View Article : Google Scholar
13	Garciaz S, Hospital MA, Alary AS, Saillard C, Hicheri Y, Mohty B, Rey J, D'Incan E, Charbonnier A, Villetard F, et al: Azacitidine plus venetoclax for the treatment of relapsed and newly diagnosed acute myeloid leukemia patients. Cancers (Basel). 14(2025)2022.PubMed/NCBI View Article : Google Scholar
14	Cui H, Liu Z, Jin M, Wang D and Liu L: Efficacy and safety of azacytidine and BCL-2 inhibitors in the treatment of acute myeloid leukemia. Syst Med. 7:4–7. 2022.
15	Wang W, Luo Q, Chen Q, Pang A and Fang K: Analysis of the clinical efficacy of azacytidine + venetoclax in the treatment of elderly patients with relapsed refractory acute myeloid leukemia. Evid Based Complement Alternat Med. 2022(8691835)2022.PubMed/NCBI View Article : Google Scholar
16	Xia L, Tian W, Zhao Y, Jiang L, Qian W, Jiang L, Ge L, Li J, Jin F and Yang M: Venetoclax and azacitidine in Chinese patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy. Signal Transduct Target Ther. 8(176)2023.PubMed/NCBI View Article : Google Scholar
17	Yamamoto K, Shinagawa A, DiNardo CD, Pratz KW, Ishizawa K, Miyamoto T, Komatsu N, Nakashima Y, Yoshida C, Fukuhara N, et al: Venetoclax plus azacitidine in Japanese patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy. Jpn J Clin Oncol. 52:29–38. 2022.PubMed/NCBI View Article : Google Scholar
18	Stang A: Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 25:603–605. 2010.PubMed/NCBI View Article : Google Scholar
19	DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, Konopleva M, Döhner H, Letai A, Fenaux P, et al: Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 383:617–629. 2020.PubMed/NCBI View Article : Google Scholar
20	Fu L, Liao X and Xiong M: Efficacy of venetoclax combined with azacytidine in the treatment of elderly patients with acute myeloid leukemia and its effect on immune function. Gerontol Health Care. 28:125–128, 134. 2022.
21	Jonas BA, Dinardo CD, Fracchiolla N, Pristupa A, Ishizawa K, Jin J, Konopleva M, Ofran Y, Montesinos P, Kovacsovics T, et al: CYP3A inhibitors and impact of these agents on outcomes in patients with acute myeloid leukemia treated with venetoclax plus azacitidine on the VIALE-A study. Blood. 136 (Suppl 1):S50–S52. 2020.PubMed/NCBI View Article : Google Scholar
22	Pollyea DA, Dinardo CD, Arellano ML, Pigneux A, Fiedler W, Konopleva M, Rizzieri DA, Smith BD, Shinagawa A, Lemoli RM, et al: Results of venetoclax and azacitidine combination in chemotherapy ineligible untreated patients with acute myeloid leukemia with IDH 1/2 mutations. Blood. 136 (Suppl 1):S5–S7. 2020.
23	Pollyea DA, DiNardo CD, Arellano ML, Pigneux A, Fiedler W, Konopleva M, Rizzieri DA, Smith BD, Shinagawa A, Lemoli RM, et al: Impact of venetoclax and azacitidine in treatment-naïve patients with acute myeloid leukemia and IDH1/2 mutations. Clin Cancer Res. 28:2753–2761. 2022.PubMed/NCBI View Article : Google Scholar
24	Yang L, Wang S, Hu W and Zhang W: Clinical efficacy of azacytidine combined with Veneckla in the treatment of elderly patients with acute myeloid leukemia. J Clin Hematol. 35:512–516, 521. 2022.
25	Shallis RM, Wang R, Davidoff A, Ma X and Zeidan AM: Epidemiology of acute myeloid leukemia: Recent progress and enduring challenges. Blood Rev. 36:70–87. 2019.PubMed/NCBI View Article : Google Scholar
26	Shimony S, Stahl M and Stone RM: Acute myeloid leukemia: 2023 Update on diagnosis, risk-stratification, and management. Am J Hematol. 98:502–526. 2023.PubMed/NCBI View Article : Google Scholar
27	Naqvi K, Konopleva M and Ravandi F: Targeted therapies in acute myeloid leukemia: A focus on FLT-3 inhibitors and ABT199. Expert Rev Hematol. 10:863–874. 2017.PubMed/NCBI View Article : Google Scholar
28	Kwag D, Cho BS, Bang SY, Lee JH, Min GJ, Park SS, Park S, Yoon JH, Lee SE, Eom KS, et al: Venetoclax with decitabine versus decitabine monotherapy in elderly acute myeloid leukemia: A propensity score-matched analysis. Blood Cancer J. 12(169)2022.PubMed/NCBI View Article : Google Scholar
29	Lagadinou ED, Sach A, Callahan K, Rossi RM, Neering SJ, Minhajuddin M, Ashton JM, Pei S, Grose V, O'Dwyer KM, et al: BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell. 12:329–341. 2013.PubMed/NCBI View Article : Google Scholar
30	Ball S and Borthakur G: Apoptosis targeted therapies in acute myeloid leukemia: An update. Expert Rev Hematol. 13:1373–1386. 2020.PubMed/NCBI View Article : Google Scholar
31	Zhang Y and Zhou H: B-cell lymphoma/leukemia-2 inhibitor combined with azacytidine in the treatment of acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation in two cases. Chin J Transplant (Electron Ed). 15:45–48. 2021.
32	Wang WM, Wang J, Zhu MX, Wang YF, Liu YY and Jing HM: Inductive effect of 5-azacitidine on apoptosis of multiple myeloma cell lines and its mechanism. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 24:110–116. 2016.PubMed/NCBI View Article : Google Scholar : (In Chinese).
33	Zheng Y, Zheng H and Hu J: Clinical observation on reinduction of azacytidine combined with CAG regimen in the treatment of recurrent refractory acute myeloid leukemia in children. Leuk Lymphoma. 30:470–474. 2019.
34	Miu W, Sha X and Liu Y: Treatment of four cases of newly diagnosed aged acute myeloid leukemia with azactidine and review of literature. Chin J Prim Med. 28:291–293. 2019.
35	Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, et al: International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 126:291–299. 2015.PubMed/NCBI View Article : Google Scholar
36	Jin S, Cojocari D, Purkal JJ, Popovic R, Talaty NN, Xiao Y, Solomon LR, Boghaert ER, Leverson JD and Phillips DC: 5-azacitidine induces NOXA to prime AML cells for venetoclax-mediated apoptosis. Clin Cancer Res. 26:3371–3383. 2020.PubMed/NCBI View Article : Google Scholar
37	Cojocari D, Smith BN, Purkal JJ, Arrate MP, Huska JD, Xiao Y, Gorska A, Hogdal LJ, Ramsey HE, Boghaert ER, et al: Pevonedistat and azacitidine upregulate NOXA (PMAIP1) to increase sensitivity to venetoclax in preclinical models of acute myeloid leukemia. Haematologica. 107:825–835. 2022.PubMed/NCBI View Article : Google Scholar
38	Du Y, Li C and Yan J: The efficacy and safety of venetoclax and azacytidine combination treatment in patients with acute myeloid leukemia and myelodysplastic syndrome: Systematic review and meta-analysis. Hematology. 28(2198098)2023.PubMed/NCBI View Article : Google Scholar
39	Bewersdorf JP, Giri S, Wang R, Williams RT, Tallman MS, Zeidan AM and Stahl M: Venetoclax as monotherapy and in combination with hypomethylating agents or low dose cytarabine in relapsed and treatment refractory acute myeloid leukemia: A systematic review and meta-analysis. Haematologica. 105:2659–2663. 2020.PubMed/NCBI View Article : Google Scholar