The role of the microenvironment and novel therapies in Chronic lymphocytic leukemia (CLL)

Chronic lymphocytic leukemia (CLL) is a malignancy of mature B lymphocytes which grow in characteristic proliferation centers within the lymphoid tissues. CLL cell survival and growth is highly dependent on interactions with the microenvironment in secondary lymphatic tissues. Critical cellular players in the CLL microenvironment include monocyte-derived nurselike cells (NLC), mesenchymal stromal cells, and T cells, which engage CLL cells in a complex cross talk that involves chemokines (CXCL12, CXCL13), adhesion molecules, TNF family members (CD40L, BAFF, APRIL), and activation of the B-cell receptor (BCR). BCR signaling has emerged as the most prominent pathway for CLL cell survival and proliferation, and it is triggered by foreign or self-antigens, including BCR epitopes, that are present in the tissue milieu. BCR signaling in CLL cells triggers a cascade of downstream events, including cytoskeletal remodeling, downstream activation of ERK and MYC, and transcriptional activation, promoting leukemia cell survival and growth. IgM and IgD are the BCR isotypes that are characteristically expressed on the surface of CLL cells, and they have distinct non-overlapping function in BCR signaling. IgM signaling promotes CLL cell survival and transcriptional activation of CCL3, whereas IgD signaling causes upstream activation of the cytoskeleton.  Turning off BCR signaling with selective inhibitors of the BCR-associated kinases Bruton’s tyrosine kinase (BTK), and phosphoinositide 3-kinase delta (PI3Kδ), such as ibrutinib or idelalisib, induces high rates of durable responses in patients with CLL, and these novel agents currently are transforming the CLL therapeutic landscape. Characteristically, CLL patients treated with these agents experience rapid shrinkage of enlarged lymph nodes, along with a transient rise in peripheral blood CLL cell counts due to re-distribution of CLL cells from the tissues into the blood. Responsible for this phenomenon is the disruption of CLL trafficking and homing mechanism, based on the role of BTK and PI3K in signaling and function of chemokine receptor and adhesion molecules. Deuterated (heavy) water labeling of CLL cells before treatment with ibrutinib established profound effects of kinase inhibitor therapy on leukemia cell birth and death rates. Development of resistance to the new kinase inhibitors is a rare event which typically occurs in high-risk patients, with the emergence of clones carrying BTK, PLCγ2 mutations, or del(8p). Analysis of clonal evolution during ibrutinib therapy demonstrates that resistant sub-clones are already present at the beginning of therapy. These subclones then are selected and expand during ibrutinib therapy, indicating that this fundamental mechanism of drug resistance also applies to the BCR-associated kinase inhibitors. In the CLL frontline setting ibrutinib induces durable responses in the vast majority of patients, with improved progression-free and overall survival when compared to chlorambucil. So far, combination trials failed to demonstrate any major added benefit from combining kinase inhibitors with conventional chemotherapy agents, i.e. bendamustine. Collectively, discoveries related to the CLL microenvironment and BCR signaling, along with the clinical success of ibrutinib and idelalisib have fundamentally changed our understanding of CLL disease biology, and CLL patients, especially patients with high-risk disease, greatly benefit from these new therapeutic options.

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Dr Klaus Okkenhaug
The Brian Heap Seminar Room