Are myelodysplastic syndromes ready for venetoclax? Exploring future potential and considerations

Figures & data

Figure 1. Targeting BCL-2 in MDS. (a) Anti- and pro-apoptotic members of the BCL-2 family proteins as regulators of the mitochondrial pathway of apoptosis. (b) Cancer cell survival: BCL-2 overexpression sequestering high levels of pro-apoptotic proteins prevents cells from initiating apoptosis. (c) Induction of apoptosis: displacing BIM and BAK by venetoclax allows pro-apoptotic proteins to initiate apoptosis. (d) Suggested synergy between hypomethylating agents and venetoclax. (e) Decreasing basal apoptosis rate with increasing BCL-2 dependency and suggested higher venetoclax sensitivity upon disease progression in MDS

VEN: venetoclax, AZA: azacitidine, HMA: hypomethylating agents, MDS: myelodysplastic syndrome.

Table 1. Selection of current clinical trials with venetoclax in MDS

Study		Phase	Estimated Enrollment	Regimen	Disease	Criteria	Status
1	M15-531 (NCT02942290)	1	137	Venetoclax, Azacitidine	HR-MDS	Treatment naive	Recruitment completed, final results pending
2	M15-522 (NCT02966782)	1	70	Venetoclax, Azacitidine	MDS	r/r	Recruitment completed, final results pending
3	2019–0368 (NCT04160052)	1/2	116	Venetoclax, Azacitidine	MDS	Treatment naive, r/r	Recruiting
4	M15-954 (NCT04401748)	3	500	Venetoclax or Placebo + Azacitidine	HR-MDS	Treatment naive	Recruiting
5	STIMULUS-MDS3 (NCT04812548)	2	76	Sabatolimab (TIM-3 Monoclonal Antibody), Venetoclax, Azacitidine	HR-MDS	Treatment naive or nHSCT/niCTX	Not yet recruiting

Table 2. Selection of clinical trials with venetoclax in myeloid malignancies including MDS

Study		Phase	Estimated Enrollment	Regimen	Disease	Criteria	Status
1	CYC065-03 (NCT04017546)	1	25	CYC065 (CDK Inhibitor), Venetoclax	AML, MDS	r/r	Recruiting
2	CHDM201H12101 C (NCT03940352)	1	80	HDM201, MBG453, Venetoclax	AML, HR-MDS	r/r, nHSCT/ niCTX	Recruiting
3	CA-4948-102 (NCT04278768)	1/2	178	CA-4948 (IRAK4 Kinase Inhibitor), Azacitidine, Venetoclax	AML, MDS	r/r	Recruiting
4	2020–0129 (NCT04655755)	1/2	52	ASTX727 (Cedazuridine/ Decitabine), Venetoclax	MDS, CMML	Treatment naive	Not yet recruiting
5	2020–0128 (NCT04550442)	1/2	58	Azacitidine, Venetoclax	MDS, CMML	r/r	Recruiting
6	AMLSG31-19/HO501/ AbbVieB18-982 (NCT04628026)	3	650	Venetoclax, Placebo, standard CTX, auto SCT, allo SCT	AML, MDS-EB2	Treatment naive	Not yet recruiting
7	2012–0648 (NCT02115295A)	2	408	Cladribine, Cytarabine, Gilteritinib, Idarubicin, Midostaurin, Venetoclax	AML, MDS, CML	r/r	Recruiting
8	ONO-7475-01 (NCT03176277)	1/2	67	ONO-7475 (AXL-Inhibitor), Venetoclax	AML, MDS	r/r	Recruiting
9	2018–0394 (NCT03661307)	1/2	52	Decitabine, Quizartinib, Venetoclax	AML, MDS, FLT3-ITD mutation	r/r	Recruiting
10	2018–0724 (NCT03862157)	1/2	40	Azacitidine, Pevonedistat, Venetoclax	AML, MDS, CMML	therapy-related	Recruiting
11	2016–0979 (NCT03214562)	1/2	116	Cytarabine, Fludarabine, Idarubicin, Venetoclax	AML, MDS	r/r	Recruiting
12	2017–0490 (NCT03471260)	1/2	48	Azacitidine, Ivosidenib, Venetoclax	MDS, MPN, AML, IDH1 mutation	r/r	Recruiting
13	2019–0366 (NCT04140487)	1/2	42	Azacitidine, Gilteritinib, Venetoclax	AML, CMML, MDS, MPN, FLT3-ITD mutation	r/r	Recruiting

HR-MDS, higher risk-myelodysplastic syndrome; r/r, relapsed or refractory; HSCT, hematopoietic stem-cell transplantation; pHSCT, prior to HSCT; nHSCT/niCTX, not immediately eligible for HSCT or intensive chemotherapy at the time of screening.