Clinical Management of Anemia in Patients with Myelodysplastic Syndromes: An Update on Emerging Therapeutic Options

Figures & data

Table 1 Currently Available Agents for the Treatment of Anemia in LR-MDS

Treatment Agent	Relevant Trial	Trial Population	Efficacy Data	Reference
Epoetin alfa	NCT01381809	LR-MDS, anemic, no or moderate transfusion burden	HI-E: 49.6% vs 4.4% (placebo), p<0.0001	^Citation56
Darbepoetin	NCT01362140	LR-MDS, anemic, low transfusion burden	HI-E: 14.7% (q3 week dosing) vs 0% (placebo), p<0.0.016; HI-E 34.7% with q2 week dosing	^Citation55
Luspatercept	NCT02631070 (MEDALIST Trial)	LR-MDS with ring sideroblasts, transfusion dependent	TI-8w: 38% vs 13% (placebo), p<0.001	^Citation68
Lenalidomide	NCT00179621 (MDS-004)	LR-MDS with del (5q), transfusion dependent	TI-182d: 57.4% (10mg, p<0.0001 vs placebo), 37.2% (5mg, p=0.0001 vs placebo), 2.2% (placebo)	^Citation80
ATG + CSA	NCT00004208	MDS, transfusion dependent	HR: 29% vs 9% (placebo), p=0.0156	^Citation90
Azacitidine	NCT01720225	LR-MDS or MDS/MPN	TI: 32% (decitabine) vs 16% (azacitidine), p=0.20	^Citation96
Decitabine	NCT01720225	LR-MDS or MDS/MPN	TI: 32% (decitabine) vs 16% (azacitidine), p=0.20	^Citation96

Note: Azacitidine and decitabine are not currently licensed for use in LR-MDS in Europe.

Abbreviations: ATG, antithymocyte globulin; CSA, cyclosporin; ER, erythroid response (IWG-2006); TI, transfusion independence; TI-8w, transfusion independence for 8 weeks or longer; TI-182, transfusion independence for 182 days; LR-MDS, lower risk myelodysplastic syndrome; MDS-RS, myelodysplastic syndrome with ring sideroblasts; MDS/MPN-RS-T, myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis; HR, hematologic response (normalized blood counts or TI for greater than 60 days).

Table 2 Investigational Agents for the Management of Anemia in LR-MDS

Name	Mechanism of Action	NCT	Phase	Patient Population	Intervention Arms
Lenalidomide	Immunomodulatory agent (IMiD)	NCT01243476	III	LR-MDS with del (5q), not transfusion dependent	Lenalidomide vs placebo
Luspatercept	TGF-beta pathway inhibitor	NCT03682536	III	LR-MDS (with or without ring sideroblasts), transfusion dependent	Luspatercept vs epoetin alfa
		NCT03900715	II	LR-MDS (with or without ring sideroblasts), not transfusion dependent	Luspatercept
Galunisertib	TGF-beta pathway inhibitor	NCT02008318	II/III	LR-MDS, transfusion dependent	Galunisertib vs placebo
KER 050	TGF-beta pathway inhibitor	NCT04419649	II	LR-MDS with anemia	KER 050
CC-486	Oral HMA	NCT01566695	III	LR-MDS, transfusion dependent	CC-486 vs placebo
ASTX727	Decitabine + Cedazuridine (cytidine deaminase inhibitor)	NCT03502668	I/II	LR-MDS	ASTX727
Imetelstat	Telomerase Inhibitor	NCT02598661	II/III	LR-MDS, transfusion dependent, ESA refractory	Imetelstat vs placebo
Roxadustat	HIF-prolyl hydroxylase inhibitor	NCT03263091	II/III	LR-MDS, low transfusion burden	Roxadustat vs placebo

Figure 1 Mechanism of action for select agents used or under investigation for the management of LR-MDS, Imetelstat directly inhibits telomerase, thus preventing telomerase from adding telomere repeat sequences to the 3ʹ-end of telomeres. Roxadustat inhibits HIF-PH, thus leading to decreased HIF-alpha degradation and increased HIF-alpha signaling. Luspatercept and similar erythropoiesis maturation agents (EMAs) act as a ligand trap which prevents TGF-beta activation and leads to decreased downstream SMAD2 and SMAD3 signaling. Lenalidomide has a complex mechanism of action; it has a direct antiproliferative effect via inhibition of CDC25C phosphatase which leads to cell cycle arrest; it also leads to ubiquitination of CK1a and IKZF1 which leads to apoptosis. Hypomethylating agents (HMA) lead to increased DNA methylation by causing degradation of DNA methyltransferase (DNMT). This leads to decreased inactivation of tumor suppressor genes.

Abbreviations: Hypomethylating agents, (HMA); lead to increased DNA methylation by causing degradation of DNA methyltransferase, (DNMT); this leads to decreased inactivation of tumor suppressor genes.

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