Imatinib Mesylate Treatment Increases Lymphoplasmocytoid Cells through SDF-1 and BMP4/7 Production in the Bone Marrow of Patients with Chronic Myelogenous Leukaemia: Relationship with Clinical/Haematological Response.

Abstract 3263

Poster Board III-1

In the last years, tyrosine kinase inhibitors, as imatinib mesylate (Gleevec, Novartis, formerly known as STI571) are confirmed the first line treatment of Chronic Myelogenous Leukemia (CML) and of a rare form of gastroenteric stromal cancer. In the latter case, the response to the drug in vivo is mainly due to immunocompetent cells, able to produce cytokines with antineoplastic activity. In this study, 30 CML patients, prior and during treatment with imatinib mesylate, underwent bone marrow (BM) aspirates every 6 months to assess morphologic phenotypic, cytogenetic and biomolecular patterns, compared to peripheral blood. Plasma from BM and peripheral blood (PB) was also tested for cytokines able to induce B lymphocytes differentiation, such as interleukin IL-4, IL-6 (whose receptor is CD126), IL-3, IL-10 or IL-21 (by ELISPOT and real time polymerase chain reaction) togheter with the expression of MCP-1, SDF-1, BMP4, BMP7, IP-10 and IL-8 . We report that in 24 out of 30 CML patients a significant increase in the percentage of BM lymphoplasmocytoid cells was observed upon treatment with imatinib mesylate, with >10% (range 8–12%) of CD20+CD126+cells. Among this population, two third of cells coexpressed IgM and one third was IgD+, whereas a lower fraction of IgM+CD126+CD20- (3–4%) or IgD+CD126+CD20- (2–3%) cells was detected , too. In all these patients SDF1 increased in the BM plasma after imatinib (from 10–80pg/ml to 150–450pg/ml) and its receptor CXCR4 was up-regulated on CD20+CD126+cells. In some cases also IP-10 and its receptor CXCR3 were up-.regulated. No significant increase in transcription and secretion of IL-3, IL-4, IL-6, IL-10, IL-21, IL-8 or MCP1 were observed. The lasting 6 patients had<5% of CD20 +CD126+ lymphocytes (range2-4%), 2/3 coexpressing IgM and 1/3 coexpressing IgD. Every patients with increased number of CD126+ B lymphocytes achieved hematologic remission, most of them complete cytogenetic and molecular remission. On the other hand, among the patients with low or undetectable CD20+CD126+cells, only 4 obtained hemathological remission and none of them stable cytogenetyc and molecular remission. In 4 patients relapsed after six months of treatment, the fraction of BM CD20+CD126+ lymphocytes decreased from 11% and 8% to 7 and 5%, respectively, with undetectable IgM+ CD126+CD20- or IgD+ CD126+CD20- cells. The increased production of SDF-1,(partially mediated by production of BMP4 and BMP7), following imatinib administration might increase BM lymphoplasmocitoid cells, thanks to the double proliferative/chemotactic effect of the cytokine on B cells, with redistribution and in situ differentiation of CD20+ CD126+ lymphocytes. These findings shed some light on the possibility that, even in CML,immunological events may play a role in disease control ; moreover they could be useful in monitoring disease outcome .