Table 3.

Examples of novel HMA-based treatment regimens for AML and MDS.

Treatment regimen	Route of administration of novel HMA or combination agent	Mechanism of action of novel HMA or combination agent	Current status of development	Reference/NCT number
Novel HMA
Guadecitabine (SGI-110)	s.c.	Resistance to the DAC-degrading enzyme CDA resulting in extended exposure to DAC	Phase 3 trials	[73, 74], NCT02907359, NCT02920008
ASTX727 (cedazuridine/DAC)	oral	CDA inhibition	FDA approved	[75–77]
CC-486	oral	Oral formulation of AZA, allowing for extended lower drug exposure	FDA approved	[79, 81], NCT04173533
Combination regimens with an HMA backbone
HMA + venetoclax	oral	BCL-2 inhibition	FDA approved	[90]
DAC + ATRA	oral	Induction of differentiation	Phase 2 trial	[94]
HMA + HDAC inhibitor	oral	Gene reactivation	Phase 2 trials	[83, 94, 99, 100]
HMA + PD-1, PD-L1, or CTLA-4 inhibitor	i.v.	Immune checkpoint blockade	Phase 1/2 trials	[101]
AZA + magrolimab	i.v.	Anti-CD47 antibody inhibiting a macrophage immune checkpoint	Phase 1/3 trials	[102], NCT03248479, NCT04313881
HMA + lenalidomide	oral	Immunomodulation	Phase 2/3 trials	[103, 104]
DAC + bortezomib	s.c.	Proteasome inhibition	Phase 2 trial	[105]
DAC + ibrutinib	oral	BTK inhibition	Phase 2 trial	[106]
HMA + FLT3 inhibitor	oral	Tyrosine kinase inhibition	Phase 2/3 trials	NCT02752035, NCT04097470,
HMA + ivosidenib or enasidenib	oral	IDH1/2 inhibition	Phase 2/3 trials	NCT03173248, NCT02677922, NCT03683433, NCT03383575
AZA + APR-246	i.v.	Mutant p53 activation	Phase 2/3 trials	[110], NCT03745716
AZA + rigosertib	oral	Multikinase inhibition	Phase 1/2 trial	[113]
AZA + pevonedistat	i.v.	NEDD8-activating enzyme inhibition	Phase 2 trial	[114]

AZA azacitidine, BTK Bruton’s tyrosine kinase, DAC decitabine, i.v. intravenous, s.c. subcutaneous.