Blood Spotlight How does lenalidomide target the chronic lymphocytic leukemia microenvironment?

Chronic lymphocytic leukemia (CLL) is one of the most common B-cell malignancies in adults, characterized by an accumulation of monoclonal CD5 mature B cells in lymphoid tissues and the peripheral blood. Clonal expansion and invasive migration typically causes the lymph nodes, spleen, and the bone marrow to become infiltrated with tumor. Current standard therapy combines chemotherapy with an anti-CD20 monoclonal antibody (mAb) (chemoimmunotherapy [CIT]). Although highly potent, CIT induces substantial toxicity and is not curative, with nearly all patients eventually relapsing. Recent advances using kinase inhibitors (eg, ibrutinib and idelalisib) that targetB-cell receptor (BCR) signaling indicate anexciting shift toward a nonchemotherapy treatment era (reviewed by Jones and Byrd). Present indications suggest these drugs are not producing many complete responses and should be taken continuously to avoid relapse. Unanswered questions include whether long-term persistent disease and prolonged therapy promote drug-resistant variants through clonal evolution and/or activation of compensatory oncogenic signaling in CLL. Ibrutinib resistance has already been detected in genetically high-risk patients, highlighting the necessity to identify combinatorial therapy using agents with distinct mechanism of action (MOA). In addition to genome alterations, CLL exhibits another dimension of complexity: leukemic cells are nurtured and protected from anticancer therapies by a variety of resident and recruited ostensibly normal cells that constitute the tumor microenvironment (TME) in lymphoid organs. Nonmalignant components of the TME include: mesenchymal stromal/stem cells (MSCs), endothelial cells, tumorassociated macrophages (TAMs or “nurse-like cells” [NLCs]), dendritic cells (DCs) and T cells. A recent breakthrough in cancer therapeutics hasbeen theuseof immunotherapies (immunecheckpoint blockade) that target mechanisms of T-cell evasion by tumors. In this review, we focus on the immunomodulatory drug (IMiD) lenalidomide which activates antitumor T-cell activity and is showing clinical activity in ongoing CLL clinical trials. Lenalidomide (Revlimid) is a derivative of thalidomide that is US Food and Drug Administration (FDA) approved for the treatment of multiple myeloma, myelodysplastic syndromes, and mantle cell lymphoma. Remarkably, in contrast to the BCR inhibitor drugs, IMiDs exemplify successful bedside-to-bench research, in that their clinical effectiveness was known before recent MOA data emerged that help explain their pleotropic effects in the TME.