A Prospective, Multi Center Phase II Study Evaluating Predictive Factors for Lenalidomide Treatment in Relapse or Refractory Chronic Lymphocytic Leukemia Patients (LE.P.RE.): Preliminary Results about the First 20 Enrolled Patients

Abstract

Abstract 1782 The aims of LE.P.RE. study include the identification of clinical and biological factors associated with clinical response and toxicity of lenalidomide monotherapy in relapsed/refractory CLL patients enrolled from 9 Italian centers. Lenalidomide treatment schedule starts with 5 mg daily and increases of 5 mg daily every two weeks, up to 25 mg daily or maximum tolerated dose. Therapy is scheduled to be administered for 12 courses (1 course = 4 weeks) unless disease progression or excessive toxicity are observed. Here we show preliminary results about the first 20 enrolled patients up to the 4th treatment course. Patients received a mean daily lenalidomide dose of 8 mg in the 1st course, 10 mg in the 2nd, 14 mg in the 3rd and 4th. Four patients left the study at the 1st course (1 acute renal failure ARF, 1 infection, 1 second neoplasia likely related to CLL, 1 consent withdrawal) and 3 patients at the 3rd (1 Tumor Flare Reaction TFR, 1 infection, 1 thrombocytopenia). The observed toxicities are listed in Table 1. After the 4th course, 13 patients were evaluable for response: 9 partial response (PR), 3 progressive disease (PD) and 1 stable disease (SD) [ORR 69%]. We compared the levels of several cytokines measured by ELISA in plasma of the 20 patients at baseline and day+8 of therapy. We observed a significant increase of IL2 Receptor (mean 55,31 vs 112,14 ng/ml; p We also studied peripheral blood cell subsets (T, B, NK, monocyte, dendritic and endothelial cells) in the 20 patients by flow cytometry. From baseline to day+8 we observed a significant increase of the Thelper1/Thelper2 ratio (p In conclusion: (i) the increase of inflammatory cytokines IL2R, IL2, CCL3, CCL4, IL10, IL1b and TNFa observed from baseline to day+8 suggests that lenalidomide can induce immune activation; (ii) the augmentation of IL2, IL2R and memory T cells and the decrease of naive T cells noticed from baseline to day+8 indicate that lenalidomide can promote T cell activation; (iii) the shift toward Thelper1 and Tcytotoxic1 phenotypes and the increased expression of co-stimulatory molecules on B-CLL cells observed from baseline to day+8 suggest that lenalidomide can promote an active T cell response against leukemic cells; (iv) the alterations in EPC and CEC noticed from baseline to day+8 suggest that lenalidomide may also have an anti angiogenic action. Moreover, our preliminary data seem to show interesting biological differences among CLL patients that respond or do not respond to lenalidomide treatment, which if replicated in additional patients and with increasing time on therapy could give important information for predicting which patients may best respond to therapy or may experience TFR or TLS. Disclosures: Maffei: CELGENE CORPORATION: Research Funding. Off Label Use: Lenalidomide, a thalidomide analogue, is an immunomodulatory drug (IMiD) with antitumoural activity reported in various malignant disorders including multiple myeloma and myelodysplastic syndrome. At preclinical level, lenalidomide has shown to decrease the production of several prosurvival cytokines. This drug is also reported to modulate an effector cell immune response through the activation of T and natural killer cells, inducing apoptosis directly on tumour cells. Currently available data indicate that lenalidomide is active also in heavily pre-treated CLL patients. However, in order to reduce toxicity and to optimize the therapeutic index of lenalidomide treatment in CLL patients, it is necessary to identify features of tumour cells that differ between responder and non responder patients. Hence, we propose a multicenter, phase II study designed in order to identify potential predictive factors correlating with response and toxicity to Lenalidomide treatment in relapsed/refractory CLL patients. Martinelli: CELGENE CORPORATION: Research Funding. Debbia: CELGENE CORPORATION: Research Funding. Rigolin: CELGENE CORPORATION: Research Funding. Rizzotto: CELGENE CORPORATION: Research Funding. Castelli: CELGENE CORPORATION: Research Funding. Bonacorsi: CELGENE CORPORATION: Research Funding. Bulgarelli: CELGENE CORPORATION: Research Funding. Fiorcari: CELGENE CORPORATION: Research Funding. Zucchini: CELGENE CORPORATION: Research Funding. Santachiara: CELGENE CORPORATION: Research Funding. Forconi: CELGENE CORPORATION: Research Funding. Rossi: CELGENE CORPORATION: Research Funding. Laurenti: CELGENE CORPORATION: Research Funding. Palumbo: CELGENE CORPORATION: Research Funding. Vallisa: CELGENE CORPORATION: Research Funding. Cuneo: CELGENE CORPORATION: Research Funding. Gaidano: CELGENE CORPORATION: Research Funding. Luppi: CELGENE CORPORATION: Research Funding. Marasca: CELGENE CORPORATION: Research Funding.