43 A PREDICTIVE MODEL OF RESPONSE TO ERYTHROPOIETIC STIMULATING AGENTS IN PATIENTS WITH MYELODYSPLASTIC SYNDROME

Abstract

Downregulation of cereblon (CRBN) gene expression is associated with resistance to the immunomodulatory drug (IMiD) lenalidomide and poor survival outcomes in multiple myeloma patients. However, the importance of CRBN gene expression in patients with myelodysplastic syndrome (MDS) and its impact on lenalidomide therapy are not clear. In this study we are following up our earlier investigation (results were published in EJH). We are presenting data from larger sample of patients and in addition bringing the results from lower risk MDS patients without del(5q), marked as non-5q-, treated with lenalidomide. We evaluate cereblon expression in mononuclear cells isolated from peripheral blood (PB) [43 lower risk MDS with isolated 5q deletion (5q-), 53 non-5qand 32 healthy controls] and from bone marrow (BM) [27 lower risk MDS with 5q-, 38 non-5qlower risk MDS and 25 healthy controls] to gain insight into, firstly, the role of cereblon in lower risk MDS patients with or without 5q deletion, and secondly, into the mechanism of lenalidomide action. Patients with 5qlower risk MDS have the highest levels of CRBN mRNA in comparison with both lower risk MDS patients without del(5q) and healthy controls. Five non-5qanemic patients who were treated with lenalidomide showed all lower levels of CRBN mRNA. All these patients did not respond to the treatment. CRBN gene expression level was analyzed by using the reverse transcriptase quantitative “best coverage” TaqMan PCR assay with primers in exon 9 and 10 and probe on exon 9. This assay allowed the detection of the full-length CRBN transcript but not alternative splicing forms without exon 10 (binding site of IMiDs on CRBN). We found that a high level of full-length CRBN mRNA in both bone marrow and peripheral blood mononuclear cells of lower risk MDS with isolated 5q deletion corresponds to the efficacy of lenalidomide in these patients. Moreover, we found that patients who stopped responding to lenalidomide and whose disease progressed showed a sudden decrease of CRBN gene expression. Supported by the research grant NT/13836 from the IGA, Ministry of Health, Czech Republic.