Blood
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Chimeric antigen receptor T cells demonstrate efficacy in B-cell malignancies, leading to US Food and Drug Administration approval of axicabtagene ciloleucel (October 2017) and tisagenlecleucel (May 2018) for large B-cell lymphomas after 2 prior lines of therapy. Durable remissions are seen in 30% to 40% of study-treated patients, but toxicities of cytokine release syndrome and neurotoxicity require administration in specialized centers. This article reviews data of current diffuse large B-cell lymphoma management, focusing on axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel.
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Primary effusion lymphoma (PEL) is an aggressive cancer with few treatment options. The immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide have recently been shown to kill PEL cell lines, and lenalidomide is in clinical trials against PEL. IMiDs bind to the CRL4CRBN E3 ubiquitin ligase complex, leading to the acquisition of the Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3), casein kinase 1 α (CK1α), and zinc finger protein 91 (ZFP91) as neosubstrates. ⋯ IRF4 was critical in all 8 PEL cell lines tested, and surprisingly, IMiDs triggered downregulation of IRF4 expression independently of both IKZF1 and IKZF3. Reexpression of CK1α and/or IRF4 partially rescued PEL cell lines from IMiD-mediated toxicity. In conclusion, IMiD toxicity in PEL cell lines is independent of IKZF1 and IKZF3 but proceeds through degradation of the neosubstrate CK1α and downregulation of IRF4.