Abstract
The treatment of patients with acute myeloid leukemia (AML) who are intolerable to intensive chemotherapy remains to be further explored. Recent studies have shown that venetoclax combined with hypomethylating agents (HMAs) or low-dose cytarabine (LDAC) may have a good effect on these patients. Given the lack of a comprehensive analysis of the efficacy and safety of such treatment, the aim of this review was to assess the efficacy and safety of venetoclax plus HMAs or LDAC for untreated AML patients who are ineligible for intensive chemotherapy. A systematic literature review was conducted in the PubMed, Embase, and Cochrane databases up to April 30, 2021. A total of four clinical trials including 440 patients were eligible for this meta-analysis. The pooled complete remission (CR) and complete remission plus complete remission with incomplete blood count recovery (CR/CRi) rates were 0.40 (95% CI 0.26–0.55) and 0.64 (95% CI 0.49–0.77), respectively. The median overall survival time was 11.7 (95% CI 10.15–14.18) months. The most common adverse events (AEs) of any grade were nausea (57%), diarrhea (42%), and hypokalemia (36%). The most common AEs of grade ≥ 3 were febrile neutropenia (38%) and thrombocytopenia (35%). The pooled 30-day mortality rate in our study was 5%. The improved remission rate and tolerance make venetoclax combined with HMAs or LDAC an attractive induction therapy option for untreated AML patients who are unsuitable for intensive chemotherapy.
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References
Juliusson G, Antunovic P, Derolf A, et al. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish acute leukemia registry. Blood. 2009;113(18):4179–87. https://doi.org/10.1182/blood-2008-07-172007.
Kantarjian H, O’Brien S, Cortes J, et al. Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome - predictive prognostic models for outcome. Cancer. 2006;106(5):1090–8. https://doi.org/10.1002/cncr.21723.
Buchner T, Berdel WE, Haferlach C, et al. Age-related risk profile and chemotherapy dose response in acute myeloid leukemia: a study by the German acute myeloid leukemia cooperative group. J Clin Oncol. 2009;27(1):61–9. https://doi.org/10.1200/jco.2007.15.4245.
Kantarjian H, Ravandi F, O'Brien S, et al. Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia. Blood. 2010;116(22):4422–9. doi: https://doi.org/10.1182/blood-2010-03-276485.
Pettit K, Odenike O. Defining and treating older adults with acute myeloid leukemia who are ineligible for intensive therapies. Front Oncol. 2015;5:9. https://doi.org/10.3389/fonc.2015.00280.
Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015;126(3):291–9. https://doi.org/10.1182/blood-2015-01-621664.
Kantarjian HM, Thomas XG, Dmoszynska A, et al. Multicenter, randomized, open-label, phase iii trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012;30(21):2670–7. https://doi.org/10.1200/jco.2011.38.9429.
Burnett AK, Milligan D, Prentice AG, et al. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer. 2007;109(6):1114–24. https://doi.org/10.1002/cncr.22496.
Dennis M, Hills R, Russell N, et al. An evaluation of 17 years of low dose cytarabine as therapy for AML patients not fit for intensive treatment, including patients with adverse cytogenetics, shows improving survival, potential underutilisation and highlights the need for new therapy. Blood. 2017;130:3874.
Konopleva M, Contractor R, Tsao T, et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell. 2006;10(5):375–88. https://doi.org/10.1016/j.ccr.2006.10.006.
Thanh-Trang V, Ryan J, Carrasco R, et al. Relative mitochondrial priming of myeloblasts and normal HSCs determines chemotherapeutic success in AML. Cell. 2012;151(2):344–55. https://doi.org/10.1016/j.cell.2012.08.038.
Pan RQ, Hogdal LJ, Benito JM, et al. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov. 2014;4(3):362–75. https://doi.org/10.1158/2159-8290.Cd-13-0609.
Konopleva M, Letai A. BCL-2 inhibition in AML: an unexpected bonus? Blood. 2018;132(10):1007–12. https://doi.org/10.1182/blood-2018-03-828269.
Del Poeta G, Venditti A, Del Principe MI, et al. Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in acute myeloid leukemia (AML). Blood. 2003;101(6):2125–31. https://doi.org/10.1182/blood-2002-06-1714.
Lagadinou ED, Sach A, Callahan K, et al. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell. 2013;12(3):329–41. https://doi.org/10.1016/j.stem.2012.12.013.
Fischer K, Al-Sawaf O, Fink AM, et al. Venetoclax and obinutuzumab in chronic lymphocytic leukemia. Blood. 2017;129(19):2702–5. https://doi.org/10.1182/blood-2017-01-761973.
Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311–22. https://doi.org/10.1056/NEJMoa1513257.
Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107–20. https://doi.org/10.1056/NEJMoa1713976.
Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17(6):768–78. https://doi.org/10.1016/s1470-2045(16)30019-5.
Kumar S, Kaufman JL, Gasparetto C, et al. Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood. 2017;130(22):2401–9. https://doi.org/10.1182/blood-2017-06-788786.
Moreau P, Chanan-Khan A, Roberts AW, et al. Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM. Blood. 2017;130(22):2392–400. https://doi.org/10.1182/blood-2017-06-788323.
Konopleva M, Pollyea DA, Potluri J, et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016;6(10):1106–17. https://doi.org/10.1158/2159-8290.cd-16-0313.
Bogenberger JM, Delman D, Hansen N, et al. Ex vivo activity of BCL-2 family inhibitors ABT-199 and ABT-737 combined with 5-azacytidine in myeloid malignancies. Leuk Lymphoma. 2015;56(1):226–9. https://doi.org/10.3109/10428194.2014.910657.
Niu XJ, Zhao JY, Ma J, et al. Binding of released bim to Mcl-1 is a mechanism of intrinsic resistance to ABT-199 which can be overcome by combination with daunorubicin or cytarabine in AML cells. Clin Cancer Res. 2016;22(17):4440–51. https://doi.org/10.1158/1078-0432.ccr-15-3057.
Teh TC, Nguyen NY, Moujalled DM, et al. Enhancing venetoclax activity in acute myeloid leukemia by co-targeting MCL1. Leukemia. 2018;32(2):303–12. https://doi.org/10.1038/leu.2017.243.
DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7–17. https://doi.org/10.1182/blood-2018-08-868752.
Wei AH, Strickland SA, Hou JZ, 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. 2019;37(15):1277. https://doi.org/10.1200/jco.18.01600.
Wei AH, Montesinos P, Ivanov V, et al. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood. 2020;135(24):2137–45. https://doi.org/10.1182/blood.2020004856.
Winters AC, Gutman JA, Purev E, et al. Real-world experience of venetoclax with azacitidine for untreated patients with acute myeloid leukemia. Blood Adv. 2019;3(20):2911–9. https://doi.org/10.1182/bloodadvances.2019000243.
Lachowiez CA, Loghavi S, Kadia TM, et al. Outcomes of older patients with NPM1-mutated AML: current treatments and the promise of venetoclax-based regimens. Blood Adv. 2020;4(7):1311–20. https://doi.org/10.1182/bloodadvances.2019001267.
DiNardo CD, Maiti A, Rausch CR, et al. 10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. Lancet Haematol. 2020;7(10):E724-36. https://doi.org/10.1016/s2352-3026(20)30210-6.
Moher D, Liberati A, Tetzlaff J, Altman DG, Grp P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLos Med. 2009;6(7):6. https://doi.org/10.1371/journal.pmed.1000097.
Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health. 1998;52(6):377–84. https://doi.org/10.1136/jech.52.6.377.
Combescure C, Foucher Y, Jackson D. Meta-analysis of single-arm survival studies: a distribution-free approach for estimating summary survival curves with random effects. Stat Med. 2014;33(15):2521–37. https://doi.org/10.1002/sim.6111.
Appelbaum FR, Gundacker H, Head DR, et al. Age and acute myeloid leukemia. Blood. 2006;107(9):3481–5. https://doi.org/10.1182/blood-2005-09-3724.
Mirgh S, Sharma A, Shaikh M, et al. Hypomethylating agents+venetoclax induction therapy in acute myeloid leukemia unfit for intensive chemotherapy - novel avenues for lesser venetoclax duration and patients with baseline infections from a developing country. Am J Blood Res. 2021;11(3):290–302.
Maiti A, Qiao W, Sasaki K, et al. Venetoclax with decitabine vs intensive chemotherapy in acute myeloid leukemia: a propensity score matched analysis stratified by risk of treatment-related mortality. Am J Hematol. 2021;96(3):282–91. https://doi.org/10.1002/ajh.26061.
Oran B, Weisdorf DJ. Survival for older patients with acute myeloid leukemia: a population-based study. Haematol-Hematol J. 2012;97(12):1916–24. https://doi.org/10.3324/haematol.2012.066100.
Vazquez R, Breal C, Zalmai L, et al. Venetoclax combination therapy induces deep AML remission with eradication of leukemic stem cells and remodeling of clonal haematopoiesis. Blood Cancer J. 2021;11(3):6. https://doi.org/10.1038/s41408-021-00448-w.
Gardin C, Turlure P, Fagot T, et al. Postremission treatment of elderly patients with acute myeloid leukemia in first complete remission after intensive induction chemotherapy: results of the multicenter randomized Acute Leukemia French Association (ALFA) 9803 trial. Blood. 2007;109(12):5129–35. https://doi.org/10.1182/blood-2007-02-069666.
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YQ and PK put forward the idea of the article, and YQ and PK carried out literature retrieval and data analysis. The first draft of the manuscript was written by YQ and TL strictly revised the work, and all the authors made comments on the manuscript. All the authors read and approved the final manuscript.
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Qin, Y., Kuang, P. & Liu, T. Venetoclax combined with hypomethylating agents or low-dose cytarabine as induction chemotherapy for patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy: a systematic review and meta-analysis. Clin Exp Med 23, 219–227 (2023). https://doi.org/10.1007/s10238-021-00784-y
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DOI: https://doi.org/10.1007/s10238-021-00784-y