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Amsterdam-Zuidoost, Netherlands

Kater A.P.,Lymphoma and Myeloma Center Amsterdam | Tonino S.H.,Lymphoma and Myeloma Center Amsterdam | Egle A.,Paracelsus Medical University | Ramsay A.G.,Kings College London
Blood | Year: 2014

Immunotherapy has emerged as a viable clinical strategy to harness endogenous antitumor T-cell immunity. Lenalidomide is anoralimmunomodulatorydrugthat repairs antitumor T-cell function and is showing efficacy in ongoing chronic lymphocytic leukemia (CLL) and lymphoma clinical trials. This article focuses on advances in our understanding of its mechanism of action in the tumor microenvironment and provides a clinical update in CLL. Challenges associated with this drug and its potential use in the targeted drug treatment era are discussed. (Blood. 2014; 124(14):2184-2189). © 2014 by The American Society of Hematology. Source


Thijssen R.,University of Amsterdam | Thijssen R.,Lymphoma and Myeloma Center Amsterdam | Ter Burg J.,University of Amsterdam | Ter Burg J.,Lymphoma and Myeloma Center Amsterdam | And 18 more authors.
Leukemia | Year: 2016

The phosphoinositide 3-kinases (PI3Ks) are critical components of the B-cell receptor (BCR) pathway and have an important role in the pathobiology of chronic lymphocytic leukemia (CLL). Inhibitors of PI3Kδ block BCR-mediated cross-talk between CLL cells and the lymph node microenvironment and provide significant clinical benefit to CLL patients. However, the PI3Kδ inhibitors applied thus far have limited direct impact on leukemia cell survival and thus are unlikely to eradicate the disease. The use of inhibitors of multiple isoforms of PI3K might lead to deeper remissions. Here we demonstrate that the pan-PI3K/mammalian target of rapamycin inhibitor SAR245409 (voxtalisib/XL765) was more pro-apoptotic to CLL cells - irrespective of their ATM/p53 status - than PI3Kα or PI3Kδ isoform selective inhibitors. Furthermore, SAR245409 blocked CLL survival, adhesion and proliferation. Moreover, SAR245409 was a more potent inhibitor of T-cell-mediated production of cytokines, which support CLL survival. Taken together, our in vitro data provide a rationale for the evaluation of a pan-PI3K inhibitor in CLL patients. © 2016 Macmillan Publishers Limited. Source


Eldering E.,Lymphoma and Myeloma Center Amsterdam | van Oers M.H.,Lymphoma and Myeloma Center Amsterdam | Kater A.P.,Lymphoma and Myeloma Center Amsterdam
Leukemia Research | Year: 2013

Chronic lymphocytic leukemia (CLL) is still incurable, with considerable resistance to the standard therapy. CLL cells receive anti-apoptotic and pro-proliferation stimuli in lymph nodes and bone marrow, mainly through B cell receptor activation and TNF-receptor family ligation. In recent years, the focus for finding new drugs has shifted to blocking signals from the microenvironment. Novel therapeutical agents interfere with these microenvironmental interactions, and include inhibitors of kinases Syk, Btk and PI3Kδ. In this review we will focus on the microenvironmental interactions of CLL and the role of tyrosine kinases. Furthermore, early results from clinical trials with kinase inhibitors are discussed. © 2013 Elsevier Ltd. Source


Kater A.P.,Lymphoma and Myeloma Center Amsterdam | Tonino S.H.,Lymphoma and Myeloma Center Amsterdam | Beckers M.M.,University of Groningen | Daenen S.,University of Groningen | And 4 more authors.
Leukemia Research | Year: 2014

Resistance to chemotherapy-induced apoptosis in CLL is associated with overexpression of antiapoptotic proteins induced by signals from the microenvironment. In vitro, dasatinib effectively inhibits expression of anti-apoptotic regulators and restores fludarabine sensitivity in activated CLL. The aim of this study was to evaluate efficacy of one cycle of dasatinib monotherapy (100mg/day, days 1-28) followed by combination of dasatinib with fludarabine (40mg/m2/day, days 1-3 every 28 day) for a total of 6 cycles in fludarabine-refractory CLL. The primary endpoint was overall response rate according to the IWCLL'08 criteria.20 patients were enrolled: 18 completed at least one cycle of treatment of which 67% finished at least 2 cycles of combination treatment. 3 of these 18 patients reached a formal PR (16.7%). Majority of patients obtained some reduction in lymph node (LN) size. Most frequent toxicity was related to myelosuppression. NF-κB RNA expression levels of circulating CLL cells decreased whereas the levels of pro-apoptotic NOXA increased during treatment. In conclusion, dasatinib/fludarabine combination has modest clinical efficacy in fludarabine-refractory patients. © 2013 Elsevier Ltd. Source


Tonino S.H.,Lymphoma and Myeloma Center Amsterdam | Suo G.,University of California at San Diego | Croon-De Boer F.,Ikazia Hospital | Van Oers M.H.J.,Lymphoma and Myeloma Center Amsterdam | And 3 more authors.
Leukemia and Lymphoma | Year: 2015

In chronic lymphocytic leukemia (CLL), strategies to overcome drug resistance due to p53 dysfunction are highly needed. Platinum-based compounds such as cisplatinum (CDDP) are active in fludarabine-refractory CLL through a largely unknown mechanism. We analyzed the mechanism of action of CDDP in the context of p53 dysfunctionality. In vitro treatment with CDDP did not induce death in quiescent CLL cells, but did induce apoptosis in CD40-ligand (and CpG) stimulated and proliferating cells, irrespective of p53 function. In the p53 dysfunctional prolymphocytic cell-line MEC1, CDDP treatment resulted in apoptosis, cell cycle arrest and ABL1-dependent expression of TAp73, CDKN1A, PUMA and BID. TAp73 RNA-interference decreased sensitivity to CDDP. Finally, both in vitro stimulated CLL cells and lymph node (LN) derived CLL cells showed increased TAp73 expression in comparison with quiescent peripheral blood derived cells. Activity of CDDP may therefore be mediated by TAp73, especially in the context of activation such as occurs in the LN microenvironment. © 2015 © 2015 Informa UK, Ltd. Source

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