Efficacy and safety of venetoclax-based combination therapy for previously untreated acute myeloid leukemia: a meta-analysis

Figures & data

Figure 1. Flow of studies through the review.

Figure 2. The risk of bias evaluated by the Cochrane risk of bias tool.

Table 1. Baseline characteristics of AML patients treated with venetoclax based combination therapy among the included studies.

First author (Ref.)	Country	Sample Size	Male/Female	Age (years)	Invention (time)	Prior HMAs (%)	Number of secondary AMLs (%)	ECOG (%)
DiNardo CD et al.^10	USA	45	20/25	75 (71-80)	Group A: Ven (400-1200 mg, D28) + Dec (20 mg/m^2, D5) Group B: Ven (400-1200 mg, D28) + Aza (75 mg/m^2, D7)	/	/	Group A: 0: 2 (9); 1:17 (74); 2: 4 (17) Group B: 0: 4 (18); 1:14 (64); 2:4 (18)
DiNardo CD et al.^20	USA	145	81/64	75 (65-86)	Group A: Ven (400-1200 mg, D28) + Aza (75 mg/m^2, D7) Group B: Ven (400-1200 mg, D28) + Dec (20 mg/m^2, D5)	/	Group A: 15 (21) Group B: 21 (29)	Group A: 0: 14 (19), 1: 47 (64); 2:12 (16) Group B: 0: 18 (25), 1:43 (60); 2:11 (15)
DiNardo CD et al.^19	USA	431	259/172	76 (49-91)	Group A: Ven (400 mg, D28) + Aza (75 mg/m^2, D7) Group B: Pla (400 mg, D28) + Aza (75 mg/m^2, D7)	/	Group A: 72 (25) Group B: 35 (24)	Group A: 0-1: 157 (55); 2-3: 129 (45) Group B: 0-1: 81 (56); 2-3: 64 (44)
Pollyea DA et al.^24	USA	115	66/49	73 (61-90)	Group A: Ven (400 mg, D28) + Aza (75 mg/m^2, D7) Group B: Ven (400 mg, D28) + Dec (20 mg/m^2, D5)	/	Group A: 21 (25) Group B: 9 (29)	Group A: 0-1: 58 (69); 2-3: 26 (31) Group B: 0-1: 27 (87); 2-3: 4 (13)
Yamauchi T et al.^23	Japan	37	23/14	77 (67-86)	Group A: Ven (400 mg, D28) + Aza (75 mg/m^2, D7) Group B: Pla (400 mg, D28) + Aza (75 mg/m^2, D7)	/	Group A: 4 (16.7) Group B: 3 (23.1)	Group A: 0-1: 18 (75); 2-3: 6 (25) Group B: 0-1: 8 (61.5); 2-3: 5 (38.5)
Wei AH et al.^18	Australia	211	117/94	76 (36-93)	Group A: Ven (600 mg, D28) + LDAC (25 mg/m^2, D10) Group B: Pla (600 mg, D28) + LDAC (25 mg/m^2, D10)	Group A: 28 (20) Group B: 14 (21)	Group A: 58 (41) Group B: 23 (34)	Group A: 0-1: 74 (51); 2-3: 69 (48) Group B: 0-1: 34 (50); 2-3: 34 (50)
Hu Y et al.^25	China	15	6/9	72 (61-86)	Group A: Ven (600 mg, D28) + LDAC (20 mg/m^2, D10) Group B: Pla (600 mg, D28) + LDAC (20 mg/m^2, D10)	/	Group A: 1 (11) Group B: 0 (0)	Group A: 0-1:3 (33); 2-3: 6 (66) Group B: 0-1: 1 (17); 2-3: 5 (84)
Yamamoto K et al.^21	Japan	27	16/11	79 (60-89)	Group A: Ven (600 mg, D28) + LDAC (20 mg/m^2, D10) Group B: Pla (600 mg, D28) + LDAC(20 mg/m^2, D10)	Group A: 3 (16.7) Group B: 3 (33.3)	Group A: 5 (27.8) Group B: 3 (33.3)	Group A: 0-1: 15 (83.4); 2-3: 3 (16.7) Group B: 0-1: 6 (66.6); 2-3: 3 (33.3)
Wei AH et al.^22	Australia	211	117/94	76 (36-93)	Group A: Ven (600 mg, D28) + LDAC (25 mg/m^2, D10) Group B: Pla (600 mg, D28) + LDAC (25 mg/m^2, D10)	Group A: 28 (20) Group B: 14 (21)	Group A: 58 (41) Group B: 23 (34)	Group A: 0-1:74 (51); 2-3:69 (48) Group B: 0-1:34 (50); 2-3:34 (50)

BM blast (%)	Cytogenetics risk category (%)	Somatic mutations (%)	Study design
Group A: 30%: 6 (26); 30-50%: 7 (30); 50%: 10 (43) Group B: 30%: 6 (27); 30-50%: 9 (41); 50%: 7 (32)	Group A: IR: 17 (74); PR: 6 (26) Group B: IR: 13 (59); PR: 9 (41)	Group A: FLT3: 6 (26); IDH1/2: 7 (30); TP53: 3 (13); Group B: FLT3: 1 (5); IDH1/2: 7 (33); TP53: 3 (14);	phase 1b study
Group A: 30%: 15 (21); 30-50%: 29 (40); 50%: 29 (40) Group B: 30%: 20 (28); 30-50%: 26 (36); 50%: 26 (36)	Group A: IR: 41 (56); PR: 32 (44) Group B: IR: 33 (46); PR: 39 (54)	Group A: FLT3:12 (16%); IDH1/2: 17 (23%);TP53: 16 (22%); NPM1: 15 (21%) Group B: FLT3: 6 (8); IDH1/2: 18 (25); TP53: 20 (28); NPM1: 8 (11)	Non-randonmized
Group A: 30%: 85 (30); 30-50%: 61 (21); 50%: 140 (49) Group B: 30%: 41 (28); 30-50%: 33 (23); 50%: 71 (49)	Group A: IR: 182 (64); PR: 104 (36) Group B: IR: 89 (61); PR: 56 (39)	Group A: FLT3: 29 (14); IDH1/2: 61 (25); TP53: 38 (23); NPM1: 27 (17) Group B: FLT3: 22 (20); IDH1/2: 28 (22); TP53: 14 (16); NPM1: 17 (20)	RCT
Group A: 30%: 24 (29); 30-50%: 29 (34); 50%: 31 (37) Group B: 30%: 7 (23); 30-50%: 14 (45); 50%: 10 (32%)	Group A: IR: 50 (60); PR: 33 (39) Group B: IR: 16 (52); PR: 15 (48)	Group A: FLT3: 12 (15); IDH1/2: 22 (27); TP53: 17 (21); NPM1: 14 (18) Group B: FLT3: 4 (14); IDH1/2: 8 (27); TP53: 8 (28); NPM1: 6 (21)	phase 1b study
Group A: 30%: 7 (29.2); 30-50%: 7 (29.2); 50%: 10 (41.7) Group B: 30%: 4 (30.8); 30-50%: 2 (15.4); 50%: 7 (53.8)	Group A: IR: 18 (75); PR: 6 (25) Group B: IR: 9 (69.2); PR: 4 (30.8)	Group A: FLT3: 2 (8.7); IDH1/2: 6 (28.6); TP53: 2 (14.3); NPM1: 0 Group B: FLT3: 2 (16.7); IDH1/2: 4 (30.8); TP53: 0; NPM1: 6 (66.7)	RCT
Group A: 30%: 42 (29); 30-50%: 36 (25); 50%: 65 (46) Group B: 30%: 18 (27); 30-50%: 22 (32); 50%: 28 (41)	Group A: IR: 90 (63); PR: 47 (33) Group B: IR: 43 (63); PR: 20 (29)	Group A: FLT3: 20 (18); IDH1/2: 21 (19); TP53: 22 (20); NPM1: 18 (16) Group B: FLT3: 9 (17); IDH1/2: 12 (23); TP53: 9 (17); NPM1: 7 (14)	RCT
Group A: 30%: 2 (22); 30-50%: 1 (11); 50%: 6 (67) Group B: 30%: 1 (17); 30-50%: 3 (50); 50%: 2 (33)	Group A: IR: 6 (67); PR: 3 (33) Group B: IR: 5 (83); PR: 1 (17)	/	RCT
Group A: 30%: 7 (38.9); 30-50%: 6 (33.3); 50%: 5 (27.8) Group B: 30%: 4 (44.4); 30-50%: 4 (44.4); 50%: 1 (11.1)	Group A: IR: 8 (44.4); PR: 10 (55.6) Group B: IR: 6 (66.7); PR: 3 (33.3)	Group A: FLT3: 3 (18.8); IDH1/2: 3 (18.8); TP53: 7 (43.8); NPM1: 1 (6.3) Group B: FLT3: 0; IDH1/2: 2 (22.2); TP53: 2 (22.2); NPM1: 2 (22.2)	RCT
Group A: 30%: 42 (29); 30-50%: 36 (25); 50%: 65 (46) Group B: 30%: 18 (27); 30-50%: 22 (32); 50%: 28 (41)	Group A: IR: 90 (63); PR: 47 (33) Group B: IR: 43 (63); PR: 20 (29)	Group A: FLT3: 20 (18); IDH1/2: 21 (19); TP53: 22 (20); NPM1: 18 (16) Group B: FLT3: 9 (17); IDH1/2: 12 (23); TP53: 9 (17); NPM1: 7 (14)	RCT

Note: AML: Acute myeloid leukemia; BM: Bone marrow; HMAs: Hypomethylating agents; ECOG: Eastern Cooperative Oncology Group; Ven: Venetoclax; Aza: Azacitidine; Dec: Decitabine; LDAC: Low-dose cytarabine; Pla: Placebo; IR: Intermediate Risk; PR: Poor Risk; RCT: randomized controlled trial.

Table 2. Summary of High, Moderate, Low and Very Low-Quality Evidence Meta-analysis on efficiency and AE of AML patients.

Values	RR (95% CI)	Heterogeneity (p)	No. of Studies (Participants)	Quality of the Evidence
Ven + Aza vs. Ven + Dec	0.80 (0.56, 1.15)	0.0% (0.961)	160	Very Low^a
Ven + Aza vs. Aza	2.17(1.15, 3.12)	0.0% (0.630)	464	Low
Ven + LDAC vs. LDAC	2.52 (1.45, 4.37)	0.0% (0.653)	463	High
CR + CRi
Ven + Aza vs. Ven + Dec	0.92 (0.79, 1.08)	0.0% (0.844)	305	Very Low^a
Ven + Aza vs. Aza	2.42 (1.85, 3.15)	0.0% (0.369)	675	High
Ven + LDAC vs. LDAC	2.57 (1.58, 4.17)	16.8% (0.307)	252	Moderate^a
Neutropenia
Ven + Aza vs. Ven + Dec	1.09 (0.34, 3.44)	65.2% (0.090)	160	Very Low^a,b
Ven + Aza vs. Aza	1.49 (1.12, 1.97)	0.0% (0.871)	464	Low
Ven + LDAC vs. LDAC	2.74 (1.84, 4.09)	2.8% (0.378)	462	High
Febrile neutropenia
Ven + Aza vs. Ven + Dec	0.69 (0.53, 0.90)	0.0% (0.436)	305	Very Low^a
Ven + Aza vs. Aza	2.19 (1.58, 3.03)	0.0% (0.849)	464	Low
Ven + LDAC vs. LDAC	1.09 (0.82, 1.46)	0.0% (0.995)	447	High
Nausea
Ven + Aza vs. Ven + Dec	0.97 (0.80, 1.18)	0.0% (0.416)	305	Very Low^a
Ven + Aza vs. Aza	1.26 (0.98, 1.62)	0.0% (0.946)	464	Low
Ven + LDAC vs. LDAC	1.39 (1.06, 1.82)	0.0% (0.551)	462	High
Constipation
Ven + Aza vs. Ven + Dec	1.14 (0.87, 1.48)	4.4% (0.306)	260	Very Low^a
Ven + Aza vs. Aza	1.09 (0.86, 1.36)	0.0% (0.794)	464	Low
Ven + LDAC vs. LDAC	0.61 (0.44, 0.83)	0.0% (0.784)	462	High
Diarrhea
Ven + Aza vs. Ven + Dec	0.97 (0.61, 1.55)	60.5% (0.080)	305	Very Low^a,b
Ven + Aza vs. Aza	1.21 (0.94, 1.56)	0.0% (0.575)	464	Low
Ven + LDAC vs. LDAC	1.81 (1.22, 2.67)	0.0% (0.781)	462	High
Vomiting
Ven + Aza vs. Ven + Dec	0.93 (0.65, 1.31)	0.0% (0.758)	305	Very Low^a
Ven + Aza vs. Aza	1.34 (0.96, 1.86)	0.0% (0.572)	464	Low
Ven + LDAC vs. LDAC	1.80 (1.19, 2.72)	0.0% (0.436)	462	High
Hypokalemia
Ven + Aza vs. Ven + Dec	0.77 (0.51, 1.15)	19.3% (0.266)	260	Very Low^a
Ven + Aza vs. Aza	0.99 (0.73, 1.34)	0.0% (0.709)	464	Low
Ven + LDAC vs. LDAC	1.31 (0.83, 1.53)	0.0% (0.655)	462	High
Anemia
Ven + Aza vs. Ven + Dec	1.04 (0.68, 1.59)	0.0% (0.856)	305	Very Low^a
Ven + Aza vs. Aza	1.30 (0.90, 1.88)	0.0% (0.957)	464	Low
Ven + LDAC vs. LDAC	1.20 (0.83, 1.73)	0.0% (0.872)	435	High
Thrombocytopenia
Ven + Aza vs. Ven + Dec	1.54 (0.75, 3.13)	34.0% (0.215)	160	Very Low^a
Ven + Aza vs. Aza	0.91 (0.51, 1.61)	77.1% (0.036)	464	Very Low^b
Ven + LDAC vs. LDAC	1.19 (0.93, 1.51)	0.0% (0.448)	462	High

Note: ^a Downgraded owing to imprecision: less than 400 participants included in the meta-analysis. ^b Downgraded owing to inconsistency: I² statistic was higher than 50%. Ven: Venetoclax; Aza: Azacitidine; Dec: Decitabine; LDAC: Low-dose cytarabine.

Figure 3. Meta-analysis for CR, CR/CRi and OS rates of the overall study. (a) CR rate; (b) CR/CRi rates; (c) OS rate. Note: CR: complete remission; CRi: complete remission with incomplete recovery; OS: overall survival; Ven: Venetoclax; Aza: Azacitidine; Dec: Decitabine; LDAC: Low-dose cytarabine.