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Purpose: Chronic lymphocytic leukemia (CLL), a malignancy of mature B cells, is incurable with chemotherapy. Signals from the microenvironment support leukemic cell survival and proliferation and may confer chemotherapy resistance. ON 01910.Na (Rigosertib), a multikinase phosphoinositide 3-kinase (PI3K) inhibitor, is entering phase III trials for myelodysplastic syndrome. Our aim was to analyze the efficacy of ON 01910.Na against CLL cells in vitro and investigate the molecular effects of this drug on tumor biology.Experimental Design: Cytotoxicity of ON 01910.Na against CLL cells from 34 patients was determined in vitro with flow cytometry of cells stained with Annexin V and CD19. Global gene expression profiling on Affymetrix microarrays, flow cytometry, Western blotting, and cocultures with stroma cells were used to delineate ON 01910.Na mechanism of action.Results: ON 01910.Na induced apoptosis in CLL B cells without significant toxicity against T cells or normal B cells. ON 01910.Na was equally active against leukemic cells associated with a more aggressive disease course [immunoglobulin heavy-chain variable region unmutated, adverse cytogenetics] than against cells without these features. Gene expression profiling revealed two main mechanisms of action: PI3K/AKT inhibition and induction of ROS that resulted in an oxidative stress response through activating protein 1 (AP-1), c-jun-NH2-terminal kinase, and ATF3 culminating in the upregulation of NOXA. ROS scavengers and shRNA mediated knockdown of ATF3- and NOXA-protected cells from drug-induced apoptosis. ON 01910.Na also abrogated the prosurvival effect of follicular dendritic cells on CLL cells and reduced SDF-1–induced migration of leukemic cells.Conclusions: These data support the clinical development of ON 01910.Na in CLL. Clin Cancer Res; 18(7); 1979–91. ©2012 AACR.

Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a rare form of ALK-negative ALCL, usually presenting as an accumulation of seroma fluid between the implant itself and the surrounding fibrous capsule.1 It was first described in 1997.2 From 1997 to 2012, the United States Food and Drug Administration reported a total of 60 registered instances of BIA-ALCL with a mean interval to lymphoma diagnosis of 10.9 years.3-5 It is estimated that 1 of 500,000 women receiving breast implants will develop BIA-ALCL.5, 6 Recent studies have suggested that patients can be managed conservatively, by drainage of the fluid and removal of the implant and capsule, if no invasion of the capsule or breast tissue is identified. 3, 7 However, some patients manifest invasion of the capsule, and involvement of breast, lymph nodes, or more rarely distant sites. The risk factors for progression are not fully delineated.

A cytogenetic test was developed to enable the diagnostic differentiation between Fanconi anemia and the group of disorders classified as "idiopathic" aplastic anemia. The method is based on the effect of the bifunctional alkylating agent mitomycin C (MMC) on chromosomes of peripheral lymphocytes in culture 92 to 96 hours. At the highest concentration of 80 ng/ml of MMC, about a 50-fold increase of chromosomal breaks and a 200-fold increase of radial figures was observed in Fanconi anemia lymphocytes in comparison with the average values for aplastic anemia cells or cells of healthy control subjects. In addition, sister chromatid exchange analysis of cells treated with MMC demonstrated a marked inhibition of mitotic activity of lymphocytes of patients with increased sensitivity to MMC. It is advocated that the MMC-stress test should be used in each case of pancytopenia, as part of the therapy planning. The cytoreduction regimens used prior to bone marrow transplantation may produce lethal complications in patients with high clastogenic response to MMC.