Anti-Angiogenic in-Vivo Effect of Lenalidomide and Its Impact On Neoplastic and Non-Neoplastic Hematopoiesis in MDS with Del(5q) Chromosome Abnormality.
Authors: Buesche Guntram , Dieck Stephanie , Giagounidis Aristoteles , Göhring Gudrun , Schlegelberger Brigitte , Knight Robert , Aul Carlo , Kreipe Hans 
Published: October 2019

Abstract
Abstract 3800
Poster Board III-736
Proliferation and expansion of malignant tumors depend on adequate vascularization, and increased marrow vascularity is a typical feature of neoplastic disorders of bone marrow. On the other hand, the vascular system is an essential part of the micro-environment within bone marrow closely correlating with differentiation and release of hematopoietic cells. Lenalidomide, a novel immunomodulatory drug (IMiD), has significantly improved the treatment of MDS with del(5q) chromosome abnormality inducing a hematologic and cytogenetic response in the majority of patients. Besides its immunomodulatory effects, it is a multifunctional inhibitor of angiogenesis, and up to now, it is unclear whether or not its anti-angiogenic effect plays a major role in the remission or progression of disease as well as in hematotoxic side effects of treatment. - From a total of 39 patients suffering from transfusion-dependent or symptomatic erythropoietin-resistant anemia due to MDS with del(5q) and low or intermediate-1-risk (IPSS) and being treated within a prospective trial on the efficacy and toxicity of lenalidomide, biopsies and aspirates from bone marrow were taken before and at 6-month intervals after start of lenalidomide therapy. These samples were evaluated for the percentage of cells with del(5q), blast count, changes in quantity and differentiation of granulo-, erythro- and megakaryopoiesis, as well as in quantity and localization of CD34-positive immature hematopoietic precursors using cytologic, histopathologic, immunohistochemical, cytogenetic and molecular genetic methods, and the results were correlated to changes in vascularization and the course of disease.

Results
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.

Disclosures:
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.