Lenalidomide as a disease-modifying agent in patients with del(5q) myelodysplastic syndromes: linking mechanism of action to clinical outcomes

TY - JOUR

T1 - Lenalidomide as a disease-modifying agent in patients with del(5q) myelodysplastic syndromes

T2 - linking mechanism of action to clinical outcomes

AU - Giagounidis, Aristoteles

AU - Mufti, Ghulam J.

AU - Fenaux, Pierre

AU - Germing, Ulrich

AU - List, Alan

AU - MacBeth, Kyle J.

PY - 2014/1

Y1 - 2014/1

N2 - Deletion of the long arm of chromosome 5, del(5q), is the most prevalent cytogenetic abnormality in patients with myelodysplastic syndromes (MDS). In isolation, it is traditionally associated with favorable prognosis compared with other subtypes of MDS. However, owing to the inherent heterogeneity of the disease, prognosis for patients with del(5q) MDS is highly variable depending on the presence of factors such as additional chromosomal abnormalities, > 5 % blasts in the bone marrow (BM), or transfusion dependence. Over recent years, the immunomodulatory drug lenalidomide has demonstrated remarkable efficacy in patients with del(5q) MDS. Advances in the understanding of the pathogenesis of the disease have suggested that lenalidomide targets aberrant signaling pathways caused by haplosufficiency of specific genes in a commonly deleted region on chromosome 5 (e.g., SPARC, RPS14, Cdc25C, and PP2A). As a result, the agent specifically targets del(5q) clones while also promoting erythropoiesis and repopulation of the bone marrow in normal cells. This review discusses recent developments in the understanding of the mechanism of action of lenalidomide, and how this underlies favorable outcomes in patients with del(5q) MDS. In addition, we discuss how improved understanding of the mechanism of disease will facilitate clinicians' ability to predict/monitor response and identify patients at risk of relapse.

AB - Deletion of the long arm of chromosome 5, del(5q), is the most prevalent cytogenetic abnormality in patients with myelodysplastic syndromes (MDS). In isolation, it is traditionally associated with favorable prognosis compared with other subtypes of MDS. However, owing to the inherent heterogeneity of the disease, prognosis for patients with del(5q) MDS is highly variable depending on the presence of factors such as additional chromosomal abnormalities, > 5 % blasts in the bone marrow (BM), or transfusion dependence. Over recent years, the immunomodulatory drug lenalidomide has demonstrated remarkable efficacy in patients with del(5q) MDS. Advances in the understanding of the pathogenesis of the disease have suggested that lenalidomide targets aberrant signaling pathways caused by haplosufficiency of specific genes in a commonly deleted region on chromosome 5 (e.g., SPARC, RPS14, Cdc25C, and PP2A). As a result, the agent specifically targets del(5q) clones while also promoting erythropoiesis and repopulation of the bone marrow in normal cells. This review discusses recent developments in the understanding of the mechanism of action of lenalidomide, and how this underlies favorable outcomes in patients with del(5q) MDS. In addition, we discuss how improved understanding of the mechanism of disease will facilitate clinicians' ability to predict/monitor response and identify patients at risk of relapse.

KW - Erythropoiesis

KW - Immunomodulatory

KW - Lenalidomide

KW - Myelodysplastic syndromes

KW - CHROMOSOME 5Q DELETION

KW - TRANSFUSION-DEPENDENT PATIENTS

KW - ACUTE MYELOID-LEUKEMIA

KW - TP53 MUTATIONS

KW - THALIDOMIDE ANALOGS

KW - PROGNOSTIC-FACTORS

KW - HUMAN 5Q-SYNDROME

KW - AML PROGRESSION

KW - CD34(+) CELLS

KW - FORMIN MDIA1

U2 - 10.1007/s00277-013-1863-5

DO - 10.1007/s00277-013-1863-5

M3 - Literature review

SN - 0939-5555

VL - 93

SP - 1

EP - 11

JO - Annals of Hematology

JF - Annals of Hematology

IS - 1

ER -