Table 5.

Preclinical and clinical studies regarding the efficacy of HHT and OM in CML: mechanisms and synergistic interactions

Types of studies
Preclinical studies using cell lines (in vitro) or animal model (in vivo)
Experimental model	Mechanisms	Results	References
CP CML cells (In vitro)	Cytotoxicity comparison with normal bone marrow	↑ Cytotoxicity against CP CML cells compared to normal bone marrow	[95]
Ponatinib-resistant BCR–ABL + cell lines (In vitro)	Activity against Y253H, E255K, and T315I mutations	OM demonstrated efficacy in ponatinib-resistant BCR–ABL + cell lines	[96]
CD34 + CD38–LICs from CML patients (In vitro)	Targeting leukemia initiating cells	OM effectively killed BCR−ABL + LICs	[55]
BCR–ABL + cell line with E255K mutation and CML BP cells (In vitro)	Synergistic/additive effect with imatinib	HHT showed synergistic effects with imatinib in resistant CML cell lines	[98, 99]
DLBCL and mantle cell lymphoma cells (In vitro)	Combination with bortezomib: ↓ MCL-1, ↑ NOXA, ↑ BAK	↑ Apoptosis anti-proliferative activity against K562 cells	[100, 101]
Ph + CML animal models (In vivo)	Targeting BCR–ABL + LICs; ↓ BCR–ABL; ↑ HSP-90 and MCL-1 levels	Substantial survival benefit in leukemic mice	[97]

Clinical studies
Cancer Type	Study design	Primary outcomes	References
CML	Phase II: Continuous infusion of HHT for remission induction and maintenance	72% CHR, 31% CG response rate, 15% complete CG response	[102]
	Phase II: Six courses of HHT followed by IFN-α maintenance in 90 early CP CML patients	Higher CHR and CG rates compared to IFN-α alone	[103]
	Phase II: HHT with IFN-α in 47 CP CML patients	66% CG responses	[104]
	Phase II: HHT and ara-C combination in 100 CML patients failing IFN-α therapy	Similar response rates with HHT and ara-C vs. HHT alone; longer survival with combination	[105]
	Phase II: HHT plus cytarabine in 44 untreated Ph chromosome positive CP CML patients	82% achieved hematologic remission; 17% MCyR	[8]
	Phase II: HHT with ongoing imatinib therapy in 13 patients with suboptimal response to imatinib	50% decrease in BCR–ABL transcript levels	[106]
	Phase II: HHT after imatinib failure in 5 evaluable CML patients	CG response in 60%; undetectable BCR−ABL mutations in 40%	[107]
	Phase II: Triple therapy with HHT, INF-α, and cytarabine, followed by imatinib	Estimated 5-year survival rate of 88%	[69]
	Phase II: OM in 46 CML patients failing two or more prior TKIs	67% hematologic responses; 22% MCyR	[91]
	Phase II: OM in 62 CML patients with T315I mutation	CHR in 48 patients; MCyR in 14 patients	[89]
	Phase II: Triple combination of IFN-α, ara-C, and HHT, followed by imatinib	Improved prognosis with an estimated 5-year survival rate of 88%	[108]

BAK: Bcl-2 homologous antagonist/killer; BCR–ABL: Breakpoint Cluster Region–Abelson; CML: Chronic Myeloid Leukemia; CP: Chronic Phase; DLBCL: Diffuse Large B-cell Lymphoma; HHT: Homoharringtonine; HSP-90: Heat Shock Protein-90; LICs: Leukemia Initiating Cells; MCL-1: Myeloid cell leukemia 1; NOXA: Phorbol-12-myristate-13-acetate-induced protein 1; OM: Omacetaxine Mepesuccinate; Ph + : Philadelphia chromosome positive; BAK: Bcl-2 homologous antagonist/killer; BCR–ABL: Breakpoint Cluster Region–Abelson; BP: Blastic Phase; CHR: Complete Hematologic Response; CG: Cytogenetic; CML: Chronic Myeloid Leukemia; CP: Chronic Phase; DLBCL: Diffuse Large B-cell Lymphoma; HHT: Homoharringtonine; HSP-90: Heat Shock Protein-90; IFN-α: Interferon Alpha; LICs: Leukemia Initiating Cells; MCL-1: Myeloid cell leukemia 1; MCyR: Major Cytogenetic Response; NOXA: Phorbol-12-myristate-13-acetate-induced protein 1; OM: Omacetaxine Mepesuccinate; Ph + : Philadelphia chromosome positive