The efficacy and safety of venetoclax and azacytidine combination treatment in patients with acute myeloid leukemia and myelodysplastic syndrome: systematic review and meta-analysis

Figures & data

Figure 1. PRISMA flow chart of study selection process.

Table 1. Clinical characteristics of patients included in the studies.

Study	Disease	Patients (numbers)	Median Age (years)	median follow up time(months)	Efficacy			Adverse effects (Grade 3/4)				Early death ≤60days (%)
					CR/CRi	ORR	Median os months	Anemia (%)	Thrombocytopenia (%)	Neutropenia (%)	Febrile neutropenia (%)
Pollyea DA et al. [23]	ND AML	84	75 (61-90)	29(0.4-42)	71%	N	16.4(11.3-24.5)	30%	25%	20%	39%	N
DiNardo CD et al. [24]	ND AML	29	74(65-86)	15.1(9.8-31.7)	76%	83%	NR (9.0-NR)	31%	N	N	38%	2(8%)
DiNardo CD et al. [25]	ND AML	431	76 (49–91)	20.5(0.1-30.7)	64.7%	66.4%	14.1(10.7-19.3)	26%	45%	42%	42%	N
Cherry EM et al. [26]	ND AML	143	69.5 (22-91)	N	71.3%	76.9%	16.1(11.2-21.3)	N	N	N	N	N
Byrne M et al. [27]	R/R AML	12	64(34-73)	N	42%	58%	4.5(0.4-12.5)	N	N	N	N	N
Labrador J et al. [28]	R/R AML	30	67 (41–76)	5.5(0.7-10.4)	17.9%	32.1%	4(2.6-5.8)	N	N	N	N	N
Garcia JS et al. [29]	High-Risk MDS	57	71(26-85)	13(11.3-15.6)	77%	77%	NR (16.2-NR)	N	30%	51%	46%	N
DiNardo CD et al. [30]	ND AML	22	75(71-80)	12.7(9.0-15.8)	59%	82%	14.2(9.3-NR)	5%	59%	36%	45%	14%
Matthews AH et al. [31]	ND AML	439	75(36-88)	8.8(N)	65%	N	11(N)	N	N	N	N	13%
Ucar MA et al. [32]	R/R AML	35	65(19-85)	N	20%	51.4%	9.13(7.65-10.62)	N	N	N	N	N
Zeidan AM et al. [33]	R/R MDS	24	76(44-91)	N	50%	50%	N	0	43%	57%	N	N
Mirgh S et al. [34]	ND AML R/R AML	ND:16 R/R:8	60(30-69)	8(N)	ND:75% R/R:12.5%	ND81.2% R/R: 12.5%	8 (2-26)	49.2%	38%	70%	33%	8%
Taniguchi S et al. [35]	ND AML R/R AML	ND:5 R/R:1	75 (66–80)	11.4(1.9–29.7)	ND:100% R/R:0	ND:100% R/R:0	15.7 (6.2-NR)	N	50%	50%	67%	N
Pollyea DA et al. [36]	ND AML	33	75(65-89)	11.7(4.9–15.6)	85%	91%	NR	N	N	N	N	N
Winters AC et al. [37]	ND AML	30	72(33-85)	21.9(1.2-37.7)	63.3%	73.3%	29.3 (12.8-NR)	63.3%	16.7%	53.3%	N	13%
Wei AH et al. [38]	High-Risk MDS	59	71(26-85)	N	70.2%	70.2%	NR	20%	39%	61%	34%	N
Aktimur SH et al. [39]	R/R AML	30	67(33-84)	8(1-12)	50%	63.3%	7(7.8-10.1)	N	N	83.3%	70%	N
Lou Y et al. [40]	R/R AML	48	61(19-73)	5.1(1.7-15.8)	47.9%	47.9%	9.6(N)	N	N	N	N	18.8%
Labrador J et al. [41]	ND AML R/R AML	ND:38 R/R:39	69(22-86)	N	ND:45% R/R:21%	ND:58% R/R:37%	ND:9.4(N) R/R 5.9(N)	N	N	N	N	15%

Abbreviations: ND, newly diagnosed; R/R, relapsed/refractory; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; CR: Complete remission; CRi: complete remission with incomplete hematological recovery; OS: overall survival; N: not mentioned; NR: not reached.

Table 2. The treatment regimen of Included Studies in the meta-analysis.

First author	Year	Country	Diagnose	Treatment regimen
Pollyea DA et al. [19,23]	2021	American	Newly diagnosed AML: De novo AML Secondary AML	AZA: 75 mg/m^2; days 1-7; Ven: 100 mg day 1→200 mg day 2→400 mg day 3-28; Or Ven: 50 mg day 1→100 mg day 2→200 mg day 3-28(coadministered with moderate CYP3Ai or PgPi); Or Ven: 10 mg day 1→20 mg day 2→50 mg day 3-28(coadministered with moderate CYP3Ai or PgPi).
DiNardo CD et al. [20,24]	2019	American	Newly diagnosed AML: De novo AML Secondary AML	AZA: 75 mg/m^2/d, days 1-7; Ven was administered with a short ramp-up from 20 mg on day 2 or 100 mg on day 2 to a target dose of 400 mg during the first cycle.
DiNardo CD et al. [21,25]	2020	American	Newly diagnosed AML: De novo AML Secondary AML (History of myelodysplastic syndrome or CMML; Therapy-related AML)	AZA: 75 mg/m^2; days 1-7; S.C. or I.V. Ven: 100 mg day 1→200 mg day 2→400 mg day 3-28; Or Ven: 50 mg day 1→100 mg day 2→200 mg day 3–28 (coadministered with moderate CYP3Ai or PgPi); Or Ven: 10 mg day 1→20 mg day 2→50 mg day 3–28 (coadministered with moderate CYP3Ai or PgPi).
Cherry EM et al. [22,26	2021	American	Secondary AML Treatment-related AML Prior therapy for MDS or MPN Allogeneic stem cell transplantation	Not mentioned.
Byrne M et al. [23,27]	2020	American	Post-hematopoietic cell transplantation relapse of AML	AZA: 75 mg/m^2; days 1-7; Ven was started at 100 mg daily and escalated to 400 mg daily, which was reduced by 75% when used in combination with strong inhibitors of CYP3A4.
Labrador J et al. [24,28	2022	Spanish	R/R-AML	AZA: 75 mg/m^2; days 1-7; S.C. Ven was administrated at 400 mg/d which was reduced when in combination with inhibitors of CYP3A4.
Garcia JS et al. [25,29	2020	American	High-risk MDS	AZA: 75 mg/m^2; days 1-7; S.C. or I.V. Ven was initially given at a dose of 400 mg for 28 days in a 28-day or 14-day cycle.
DiNardo CD et al. [26,30	2018	American	Newly diagnosed AML	AZA: 75 mg/m^2; days 1-7; S.C. or I.V. Ven was administered with a short ramp-up from 20 mg day 2 or 100 mg day 2 to a target dose of 800 mg during the first cycle.
Matthews AH et al. [27,31	2022	American	Newly diagnosed AML: De novo AML Secondary AML Therapy-Related	Not mentioned.
Ucar MA et al. [28,32	2021	Turkey	R/R-AML	Not mentioned.
Zeidan AM et al. [29,33	2019	American	High-risk MDS	AZA: 75 mg/m^2; days 1-7; Ven: 100 mg day 1→200 mg day 2→400 mg day 3-14.
Mirgh S et al. [30,34	2021	India	Newly diagnosed AML R/R-AML	AZA: 75 mg/m^2; days 1-7; S.C. Ven: 50 mg × 2 days→100 mg × 2 days→200 mg × 2 days→400 mg for 14–21 days.
Taniguchi S et al. [31,35]	2021	Japan	Newly diagnosed AML R/R-AML	AZA: 75 mg/m^2; days 1-7; subcutaneously or intravenously Ven: 100 mg day 2→200 mg day 3→400 mg day 4-28. From cycle 2 onward, patients received ven 400 mg orally once daily on days 1–28 of each 28-day cycle.
Pollyea DA et al. [32,36]	2017	American	newly-diagnosed AML	Not mentioned.
Winters AC et al. [33,37]	2019	American	newly-diagnosed AML	AZA: 75 mg/m^2; days 1-7; S.C. or I.V. Ven: 100 mg day 1→200 mg day 2→400 mg day 3-28.
Wei AH et al. [34,38]	2019	American	High-risk MDS	AZA: 75 mg/m^2; days 1-7; S.C. or I.V. Ven was administered with a ramp-up of 100 mg on day 2 to a target dose of 400 mg or 800 mg during the first cycle.
Aktimur SH et al. [35,39]	2020	Turkey	R/R AML: Primary AML Secondary AML	Not mentioned.
Lou Y et al. [36,40]	2020	China	R/R AML	AZA: 75 mg/m^2; days 1-7; S.C. Ven was started at a daily dose of 100 mg with a 3-day ramp to the target dose of 400 mg for 28 days.
Labrador J, et al. [37,41]	2022	Spain	newly-diagnosed AML R/R AML	AZA: 75 mg/m^2; days 1-7; S.C. Ven: 100 mg day 1→200 mg day 2→400 mg day 3-28.

Abbreviations: AZA, azacytidine; Ven, venetoclax; AML, acute myeloid leukemia; R/R, relapsed/refractory; CYP3Ai, CYP3A inhibitor; PgPi, PgP inhibitor; S.C., Subcutaneous; IV, Intravenous.

Note: The treatment regimen in the table is usually a 28-day cycle, with some studies of 14 or 21 days.

Figure 2. Forest plots of overall CR/CRi rate with AML/MDS.

Figure 3. Forest plots of overall ORR rate with AML/MDS.

Figure 4. Forest plots of CR/CRi rate in subgroups of AML/MDS.

Figure 5. Forest plots of pooled rate with grade 3–4 adverse events.

Figure 6. Forest plots of the pooled mortality within 60 days.

Pollyea DA, Pratz K, Letai A, et al. Venetoclax with azacitidine or decitabine in patients with newly diagnosed acute myeloid leukemia: Long term follow-up from a phase 1b study. Am J Hematol 2021;96(2):208–217.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617–629.

 PubMed Web of Science ®Google Scholar

Cherry EM, Abbott D, Amaya M, et al. Venetoclax and azacitidine compared with induction chemotherapy for newly diagnosed patients with acute myeloid leukemia. Blood Adv 2021; 5(24): 5565–5573.

 PubMed Web of Science ®Google Scholar

Byrne M, Danielson N, Sengsayadeth S, et al. The use of venetoclax-based salvage therapy for post-hematopoietic cell transplantation relapse of acute myeloid leukemia. Am J Hematol 2020;95(9):1006–1014.

 PubMed Web of Science ®Google Scholar

Labrador J, Saiz-Rodriguez M, de Miguel D, et al. Use of venetoclax in patients with relapsed or refractory acute myeloid leukemia: The PETHEMA registry experience. Cancers (Basel). 2022;14(7):1734.

 PubMed Web of Science ®Google Scholar

Jacqueline S, Safety GM. Efficacy, and patient-reported outcomes of venetoclax in combination With azacitidine for the treatment of patients With higher-risk myelodysplastic syndrome: A phase 1b study. Clin Adv Hematol Oncol. 2020;19(1):14–16.

 Web of Science ®Google Scholar

DiNardo CL, Pratz KW, Letai A, 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. 2018;19(2):216–228.

 PubMed Web of Science ®Google Scholar

Matthews AH, Perl AE, Luger SM, et al. Real-world effectiveness of CPX-351 vs venetoclax and azacitidine in acute myeloid leukemia. Blood Adv. 2022;Jul 12;6(13):3997–4005.

 Web of Science ®Google Scholar

Ucar MA, Ozet G, Koyuncu MB, et al. Real world results of venetoclax combined with hypomethylating agents in relapsed/refractory AML. Eur Rev Med Pharmacol Sci. 2021;25(21):6557–6565.

 PubMed Web of Science ®Google Scholar

Zeidan AM, Pollyea DA, Garcia JS, et al. A phase 1b study evaluating the safety and efficacy of venetoclax As monotherapy or in combination with azacitidine for the treatment of relapsed/refractory myelodysplastic syndrome. Blood. 2019;134:565.

 Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

Taniguchi S, Yamauchi T, Choi I, et al. Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. Jpn J Clin Oncol 2021;51(6):857–864.

 PubMed Web of Science ®Google Scholar

Pollyea DA, Stevens BM, Winters A, et al. Venetoclax (Ven) with azacitidine (Aza) for untreated elderly acute myeloid leukemia (AML) patients (Pts) unfit for induction chemotherapy: single center clinical experience and mechanistic insights from correlative studies. Blood. 2017;130:181.

 PubMed Web of Science ®Google Scholar

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): 2911–2919.

 PubMed Web of Science ®Google Scholar

Wei AH, Garcia JS, Borate U, et al. A phase 1b study evaluating the safety and efficacy of venetoclax in combination with azacitidine in treatment-naive patients with higher-risk myelodysplastic syndrome. Blood. 2019;134:568.

 PubMed Web of Science ®Google Scholar

Aktimur SH, Gunes AK, Akidan O, et al. Efficacy of the Combination of Venetoclax and Azacitidine in Elderly of Frail Relapsed/Refractory Patients with Acute Myeloid Leukemia, First Multi-Institutional Real World Experience from Turkey. UHOD - Uluslar Hematol-Onkol Derg. 2020;30(4):213–221.

 Web of Science ®Google Scholar

Lou YJ, Shao L, Mao LP, et al. Efficacy and predictive factors of venetoclax combined with azacitidine as salvage therapy in advanced acute myeloid leukemia patients: A multicenter retrospective study. Leuk Res 2020 Apr;91:106317.

 PubMed Web of Science ®Google Scholar

Labrador J, Saiz-Rodríguez M, de Miguel D, et al. Use of Venetoclax in Patients with Relapsed or Refractory Acute Myeloid Leukemia: The PETHEMA Registry Experience. Cancers (Basel). 2022;14(7):1734.

 Google Scholar

Common Terminology Criteria for Adverse Events (CTCAE). Version 4.03 (2010) Us Department of Health and Human Services. National Institutes of Health National Cancer Institute. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5 ( 7.pdf.

 Google Scholar

Higgins JP, Altman DG, Gøtzsche PC, et al. Cochrane bias methods group; cochrane statistical methods group. The cochrane collaboration's tool for assessing risk of bias in randomised trials. Br Med J. 2011;343:d5928.

 PubMed Web of Science ®Google Scholar

Slim K, Nini E, Forestier D, et al. Methodological index for non-randomized studies (minors): development and validation of a new instrument. ANZ J Surg. 2003;73(9):712–6.

 PubMed Web of Science ®Google Scholar

Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. Br Med J. 2003;327(7414):557–60.

 PubMed Web of Science ®Google Scholar