Lenalidomide as a diseasemodifying agent in patie

Authors: Aristoteles Giagounidis Ghulam J Mufti Pierre Fenaux Ulrich Germing Alan List Kyle J MacBeth

Publish Date: 2013/09/10

Volume: 93, Issue: 1, Pages: 1-11

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Abstract

Deletion of the long arm of chromosome 5 del5q 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 del5q 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 del5q 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 eg SPARC RPS14 Cdc25C and PP2A As a result the agent specifically targets del5q 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 del5q 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 relapseMyelodysplastic syndromes MDS constitute a heterogeneous group of clonal hematopoietic disorders characterized by bone marrow BM failure dysplasia and an increased risk of developing acute myeloid leukemia AML 1 About 50  of cases of MDS are characterized by the presence of cytogenetic abnormalities in the BM 2 The most prevalent cytogenetic abnormality is a partial deletion of the long arm of chromosome 5 del5q which is present in about 15  of cases 2 It is becoming increasingly evident that del5q MDS is a highly heterogeneous disease and prognosis varies widely depending on other factors such as presence of additional chromosomal abnormalities 5  blasts in the BM and transfusion requirement 3 4 Therefore it is important that multiple risk factors are considered when deciding upon optimal management strategies for patients with del5q MDSMost patients with del5q MDS become red blood cell transfusiondependent RBCTD over the course of the disease This has a major negative impact on survival diseaserelated morbidity and quality of life 5 6 7 Therefore a major goal of the clinical management of del5q MDS is to help patients become red blood cell transfusion independent RBCTI this is complicated by the fact that patients with del5q MDS tend to respond poorly to erythropoiesisstimulating agents 8 However over the past decade clinical trials have demonstrated that patients with del5q MDS respond very well to lenalidomide an oral antineoplastic and immunomodulatory agent 9 10 11 Lenalidomide has direct effects on the del5q clone as well as pleiotropic effects on erythropoiesis and BM function though the molecular basis of these phenomena is only just beginning to be unravelled As such it is important that the mechanism of action MoA of lenalidomide is fully delineated in order to understand why some patients are refractory or become resistant to its effects Furthermore precise tools are required to predict loss of response or disease progression in patients treated with lenalidomideIn this review we discuss how the clinical activity and tolerability profile of lenalidomide are linked to its MoA at the cellular and molecular level We also discuss how emerging insights into the “natural history” of del5q MDS necessitate routine monitoring during lenalidomide therapy in order to identify early signs of disease progressionBy comparing overlapping chromosome 5 deletions among patients with del5q MDS two commonly deleted regions CDRs have been identified Horrigan et al identified a 1–15 megabase region at chromosome 5q31 that was consistently deleted in a cohort of patients with del5q MDS or AML not including patients with “5q– syndrome”—a subclass of disease characterized by 5  BM blasts and specific morphology and blood counts 12 This is known as the proximal CDR and contains tumor suppressor genes associated with advanced MDS Similarly Boultwood et al identified a 15Mb region at 5q32–33 the distal CDR that underlies the characteristic “5q– syndrome” phenotype 13 Owing to the proximity of the two CDRs many patients with del5q MDS have interstitial deletions that overlap both regions 14 and this at least partially explains why most patients with del5q MDS have a more severe disease phenotype and poorer prognosis than that associated with “5q– syndrome” Indeed in a recent study of patients with del5q MDS that utilized single nucleotide polymorphism microarrays Jerez et al demonstrated that severity of disease largely correlated with the size of the 5q deletion 15Over the past decade intensive analysis of the CDRs has been undertaken to try to identify the pathogenetic determinants of del5q MDS Boultwood et al systematically sequenced 40 genes within the distal CDR 16 Despite exhaustive efforts no mutations were detected in these genes suggesting that qualitative changes in or complete loss of gene expression are unlikely to underlie the“5q– syndrome” phenotype Conversely gene expression analysis in hematopoietic stem cells CD34+ cells indicated that most genes within the distal CDR were downregulated in patients with “5q– syndrome” suggesting that haploinsufficiency reduced expression to a level that does not support a wildtype phenotype caused by the presence of only one copy of a gene rather than two could at least partially explain the disease phenotype 16The ribosomal subunit 14 gene RPS14 located within the distal CDR is essential for the assembly of ribosomal complexes that translate mRNA into proteins Several lines of direct and indirect evidence strongly implicate RPS14 in the pathogenesis of del5q MDS 1 inactivating mutations of other ribosomal proteins have been linked with congenital BM failure syndromes such as Diamond–Blackfan anemia 18 2 systematic experimental knockdown of CDR genes in normal human CD34+ cells by RNA interference RNAi indicated that only the knockdown of RPS14 suppressed erythroblast proliferation and viability without a significant impact on thrombopoiesis 19 3 forced expression of RPS14 in CD34+ cells from patients with del5q MDS restored normal erythropoiesis 194 haploinsufficiency of the RPS14 region in a mouse model led to a “5q– syndrome” MDSlike phenotype with macrocytic anemia and monolobulated megakaryocytes 20 however these mice did not demonstrate thrombocytosis or neutropenia suggesting the involvement of distinct haploinsufficient genes in the myeloid and megakaryocyte abnormalities that are characteristic of del5q MDS Experimental evidence indicates that haploinsufficiency of RPS14 upregulates the p53 pathway a key pathway that induces cell cycle arrest and apoptosis specifically in erythroid cells leading to hypoplastic anemia 17 21 Dutt et al demonstrated that RNAi downregulation of RPS14 led to an accumulation of p53 in erythroid progenitor cells but not myeloid cells or megakaryoctes leading to apoptosis 21 Pharmacological inhibition of p53 blocked apoptosis in these cells 21 Furthermore in a series of intricate in vivo experiments involving the cross breeding of RPS14 haploinsufficient mice with p53 knockout mice Barlow et al demonstrated that absence of p53 completely blocked the development of a “5q–syndrome” MDSlike phenotype 20 There is also evidence that the p53 pathway plays a key role in the development of del5q MDS in patients gene expression analysis of CD34+ cells indicated that several genes in the p53 pathway are upregulated in patients with del5q MDS compared with healthy controls 22

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