The efficacy and adverse events of venetoclax in combination with hypomethylating agents treatment for patients with acute myeloid leukemia and myelodysplastic syndrome: a systematic review and meta-analysis

Figures & data

Figure 1. Flow diagram of study selection.

Table 1. Baseline characteristics of included studies.

Study	Disease	Patients	Age(median range)	Risk stratification by genetics				Efficiacy			toxicity(Gr3/4)
				favorable	intermediate	unfavourable	not available	CR (%)	ORR (%)	median OS	Febrile neutropenia(%)	Decreased WBC count(%)	Anemia (%)	thrombocytopenia(%)
Aldoss et al.[8]	R/R-AML	90	59 (18-81)	8%	26%	66%	0%	41 (46%)	N	7.8 months	N	N	N	N
Asghari et al.[9]	De novo-AML	41	75 (47-86)	24%	59%	17%	22 (56%)	27 (69%)	13.8 months	N	N	N	N
	R/R-AML	31	63 (25-77)	26%	45%	29%	8 (28%)	11 (38%)	4.9 months
Ball et al.[10]	MDS	42	68 (31-88)	40%	12%	45%	2%	22 (55%)	22 (55%)	N	N	N	N	N
DiNardo et al.[4]	AML	145	74 (65-86)	0%	51%	49%	0%	97 (67%)	120 (83%)	17.5 months	63 (43%)	45 (31%)	36 (25%)	35 (24%)
Lou et al.[11]	R/R-AML	48	61 (19-73)	15%	44%	42%	0%	23 (48%)	N	9.6 months	40 (83%)	N	N	43 (90%)
Maiti et al.[12]	AML	101	N (34-75)	18%	15%	67%	0%	60 (59%)	76 (75%)	N	35 (35%)	61 (61%)	N	2 (2%)
Mittal et al.[13]	R/R-AML	11	66 (25-75)	N	N	N	N	4 (36%)	N	11 months	N	N	N	N
Rausch et al.[14]	AML	121	72 (48-86)	N	N	N	N	69 (57%)	81 (67%)	N	66 (55%)	N	N	44 (36%)
Wei et al.[15]	HR-MDS	59	72 (26-85)	N	19%	41%	N	40 (70%)	40 (70%)	N	20 (34%)	18 (31%)	12 (20%)	23 (39%)
Winters et al[16]	AML	30	71 (60-88)	17%	10%	73%	N	19 (63%)	21 (70%)	N	11 (37%)	16 (53%)	N	13 (44%)
Winters et al.[17]	AML	30	72 (33-85)	23%	10%	67%	0%	19 (63%)	22 (73%)	12.7 months	14 (47%)	N	19 (63%)	5 (17%)
Zeidan et al.[18]	R/R-MDS	24	N	N	N	N	N	12 (50%)	12 (50%)	N	9 (38%)	8 (33%)	3 (13%)	11 (46%)
DiNardo et al.[19]	AML	286	76 (49-91)	0%	64%	36%	0%	190 (66.4%)	N	14.7 months	118 (42%)	58 (20%)	74 (26%)	126 (45%)

Table 2. The study design and treatment regimen used in the included studies.

Study	Diseases	Regimen
Aldoss, et al. [8]	De novo AML: 58 Therapy-related AML: 10 Secondary AML: 22	AZA + VEN: 9; DEC + VEN: 81 5-day DEC: 33; 10-day DEC: 48
Asghari et al. [9]	AML-MRC: 38 Therapy-related AML: 10	AZA + VEN: 40; DEC + VEN: 31
Ball et al. [10]	MDS-EB1: 14 MDS-EB2: 25 MDS-RS MLD: 2 MDS-U: 1	VEN starting dose: 400 200 mg, ≤100 mg, AZA + VEN: 23; DEC + VEN: 19
DiNardo et al. [4]	De novo AML: 109 Secondary AML: 36	-Dose escalation phase(AZA/ DEC: 22/23): VEN: from 20 mg to a target dose of 400, 800, 1200 mg/d orally. AZA: 75 mg/m^2 day1-7, IV; DEC: 20 mg/m^2 day1-5 IV. -Dose-expansion phase(AZA/DEC: 50/50): VEN: from 100 mg to a target dose of 400, 800 mg/d orally. AZA: 75 mg/m^2 day1-7, IV; DEC: 20 mg/m^2 day1-5 IV.
Lou, et al. [11]	Primary refractory AML: 16 Relapsed AML: 32	VEN: from 100 mg with a 3-day ramp to target dose of 400 mg/d orally. AZA: 75 mg/m^2 day1-7, H.
Maiti et al. [12]	New diagnosed AML: 40 Secondary AML: 28 Relapsed/refractory AML: 33	VEN: 400 mg/d orally on day1-28 in cycle 1. DEC: 20 mg/m^2 day1-10 IV(until CR/CRi), followed by 5-day cycles.
Mittal et al. [13]	Relapsed/refractory AML: 11	AZA + VEN: 8; DEC + VEN: 3
Rausch et al. [14]	De novo AML: 69 Secondary AML: 40 Therapy-related AML: 12	-DEC 20 mg/m^2 d1-5/d1-10: 110 -AZA 75 mg/m^2 d1-7: 11 -VEN 400 mg/d or >400 mg/d orally × 7-30d
Wei et al. [15]	Treatment-Naive Higher-Risk MDS: 59	-randomized cohort: VEN 400/800 mg daily + AZA 75 mg/m^2 d1-7 -dose escalation cohort: VEN 100/200/400 mg daily + AZA 75 mg/m^2 d1-7 -safety expansion cohort: VEN 400 mg daily + AZA 75 mg/m^2 d1-7
Winters et al. [16]	Older Newly Diagnosed AML: 30	VEN from 100 mg with a 4-day ramp to target dose of 600 mg/d orally + AZA 75 mg/m^2 d1-7
Winters, et al. [17]	Older Newly Diagnosed AML: 30	VEN: from 100 mg with a 3-day ramp to a target dose of 400 mg/d orally, for 28-day cycles. AZA: 75 mg/m^2 day1-7, IV/H
Zeidanet al. [18]	Relapsed/refractory MDS: 46	-C1 group(22): VEN monotherapy 400 and 800 mg/d for 28-day cycles -C2 group(24): VEN + AZA 100, 200 and 400 mg daily for 14 of 28-day cycles + AZA 75 mg/m^2 d1-7
DiNardo et al, [4]	-AML(C1 group) De novo: 214; Secondary: 72 -AML(C2 group) De novo: 110; Secondary: 35	-C1 group(286): VEN: from 100 mg with a 3-day ramp to a target dose of 400 mg/d orally, for 28-day cycles. AZA: 75 mg/m2 day1-7, IV/H -C2 group(145): VEN placebo. AZA: 75 mg/m2 day1-7, IV/H

Table 3. The quality of the included studies assessed by NOS.

Study	Selection				Comparability	Outcome			Scores
	Representativeness of the exposed cohort	Selection of the non exposed cohort	Ascertainment of exposure	Demonstration that outcome of interest was not present at start of study	Comparability of cohorts on the basis of the design or analysis	Ascertainment of exposure	Was follow-up long enough for outcomes to occur	Non-response rate
Aldoss, et al.[8]	⋆	⋆	⋆	–	⋆⋆	⋆	⋆	⋆	8
Asghari et al.[9]	⋆	⋆	⋆	–	⋆⋆	⋆	⋆	⋆	8
Ball et al.[10]	⋆	⋆	⋆	–	⋆⋆	⋆	⋆	⋆	8
DiNardo et al.[4]	⋆	⋆	⋆	⋆	⋆⋆	⋆	⋆	⋆	9
Lou et al.[11]	⋆	⋆	⋆	–	⋆⋆	⋆	⋆	⋆	8
Maiti et al.[12]	⋆	⋆	⋆	⋆	⋆⋆	⋆	⋆	⋆	9
Mittal et al.[13]	⋆	⋆	⋆	–	⋆	⋆	⋆	⋆	7
Rausch et al.[14]	⋆	⋆	⋆	–	⋆⋆	⋆	⋆	⋆	8
Wei et al.[15]	⋆	⋆	⋆	⋆	⋆⋆	⋆	⋆	⋆	9
Winters et al[16]	⋆	⋆	⋆	⋆	⋆⋆	⋆	⋆	⋆	9
Winters et al.[17]	⋆	⋆	⋆	–	⋆⋆	⋆	⋆	⋆	8
Zeidan et al.[18]	⋆	⋆	⋆	–	⋆⋆	⋆	⋆	⋆	8

Figure 2 ,#Forest plots of pooled overall CR rate (A) and ORR (B) after treatment.

Figure 3. Forest plots of the most common grade 3–4 adverse events (A): pooled febrile neutropenia rate (B): rate of grade 3–4 decreased WBC count (C): rate of grade 3–4 anemia (D): rate of grade 3–4 thrombocytopenia.

Figure 4. Forest plots of the pooled CR rate for different disease types.

Figure 5. Forest plots of the pooled CR rate for different genetic risk stratification.

Aldoss I, Yang D, Pillai R, et al. Association of leukemia genetics with response to venetoclax and hypomethylating agents in relapsed/refractory acute myeloid leukemia. Am J Hematol. 2019;94(10):E253–e255.

 PubMed Web of Science ®Google Scholar

Asghari H, Lee D, Deutsch YE, et al. Outcomes of patients with Relapsed or refractory acute myeloid leukemia Receiving hypomethylating agent and venetoclax. Blood. 2019;134(Suppl 1):1357–1357.

 Google Scholar

Ball BJ, Famulare C, Stein EM, et al. Combined venetoclax and hypomethylating agent (HMA) therapy Induces high response rates in patients with myelodysplastic syndrome including patients Previously Failing HMA. Blood. 2019;134(Suppl 1):4241–4241.

 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

Lou Y, Shao L, Mao L, 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;91:106317.

 PubMed Web of Science ®Google Scholar

Maiti A, DiNardo CD, Rausch CR, et al. Ten-Day decitabine with venetoclax (DEC10-VEN) in acute myeloid leukemia: Updated results of a phase II trial. Blood. 2019;134(Suppl 1):2637–2637.

 Google Scholar

Mittal V, Lo M, Damon LE, et al. Efficacy of venetoclax combination therapy with hypomethylating agents in patients with Relapsed acute myeloid leukemia after allogeneic hematopoietic cell transplantation. Blood. 2019;134(Suppl 1):5089–5089.

 Google Scholar

Rausch CR, DiNardo CD, Maiti A, et al. Venetoclax Dosing in combination with Antifungal agents: Real World Experience in patients with acute myeloid leukemia. Blood. 2019;134(Suppl 1):2640–2640.

 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-Naïve patients with higher-risk myelodysplastic syndrome. Blood. 2019;134(Suppl 1):568–568.

 PubMedGoogle Scholar

Winters A, Gutman JA, Purev E, et al. Venetoclax and azacitidine for older Newly diagnosed patients with acute myeloid leukemia: A Single-Institution Pilot study using Measurable Residual disease to Guide therapy. Blood. 2019;134(Suppl 1):2638–2638.

 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 Advances. 2019;3(20):2911–2919.

 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(Suppl 1):565–565.

 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