Anti-Angiogenic in-Vivo Effect of Lenalidomide and Its Impact On Neoplastic and Non-Neoplastic Hematopoiesis in MDS with Del(5q) Chromosome Abnormality.

Before start of treatment, vascularity of bone marrow, measured as the total length density of vessels within the marrow volume, was markedly increased in 85 % of patients (33/39) exceeding that from normal marrow by a factor of 4 – 5 (P < 0.00005). During therapy with lenalidomide, vascularity markedly decreased to normal or reduced values in 76 % of them (25 / 33; P < 0.00005). The anti-angiogenic effect of lenalidomide depended on the dose applied (P < 0.00005), and it was an independent significant predictor of the probability and the degree of a cytogenetic response achieved during the course of disease (P < 0.00005; multivariate analysis). In mixed effect multiple-regression analysis however, a cytogenetic response did not allow prediction of anti-angiogenic efficacy of treatment. The lenalidomide dose was the only independent significant predictor. - Reduction of marrow vascularity was accompanied by a significant reduction of perivascular and perisinusoidal proliferation zones of granulo- and megakaryopoiesis resulting in an absolute reduction of CD34-positive immature hematopoietic precursors within bone marrow followed by a decrease of mature cells within both cell lines (P < 0.0005). This effect was independent of the cytogenetic remission of disease as well as of the promotion of erythroid differentiation by lenalidomide and resulted in a varying degree of neutro- and / or thrombopenia, requiring a dose reduction or an interruption of treatment in the majority of patients. Nevertheless, during periods with normal or reduced vascularity within bone marrow, the probability of progression of disease (occurrence of >= 5 % blasts within bone marrow) was markedly reduced by a factor of 9 (P < 0.0005) whereas a loss of the anti-angiogenic efficacy of lenalidomide turned out to be an independent significant predictor of progressive disease (P < 0.0005), correlating with a > 50 % risk of leukemic transformation of disease. We conclude that, in MDS with del(5q) chromosome abnormality, the anti-angiogenic effect of lenalidomide plays a central role in both its anti-neoplastic efficacy and hematotoxic side effects. Reduction of the vascular system within bone marrow markedly influences the micro-environment of neoplastic and non-neoplastic hematopoiesis due to an absolute reduction of such (perivascular and perisinusoidal) zones required for adequate proliferation of hematopoiesis. The anti-angiogenic effect of lenalidomide appears to be antagonized by the evolution of a more malignant (pro-angiogenic) subclone of MDS in a relevant proportion of patients. A loss of the anti-angiogenic efficacy of lenalidomide restores the proliferative capacity of marrow, thus supporting re-expansion of disease.

Buesche:Celgene Corp.: histology reference lab for MDS-004 study. Giagounidis:Novartis Pharma: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Glaxo SmithKline: Consultancy; Johnson&Johnson: Consultancy; Celgene Corp.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Göhring:Celgene Corp.: cytogenetic reference lab for Celgene MDS-004 study. Schlegelberger:Celgene Corp.: cytogenetic reference lab for Celgene MDS-004 study. Knight:Celgene: Employment, Equity Ownership. Kreipe:Celgene: Research Funding.