Mantle Cell Lymphoma
Role of Bruton Tyrosine Kinase in B-Cell Tumorigenesis
Bruton tyrosine kinase (BTK) plays an important role in oncogenic signaling that is essential to the proliferation and survival of leukemic cells in many B-cell malignancies. BTK activity is also crucial in the retention of mantle cell lymphoma (MCL) cells in lymphoid tissues and their interactions with other cells in the tumor microenvironment.
Distinguished Professor of Medicine
“Upon inhibition of BTK, neoplastic B cells may become vagabonds that lack the ability to find their way back to the lymphoma microenvironment, where they receive sustenance. This can result in exhaustion or death of the lymphoma B cells over time. Some tumor cells, however, are still able to ‘limp along’ in the context of BTK inhibitor monotherapy.”
BTK interacts with the B-cell receptor CD19 to trigger the kinase cascade that is very important for B-cell tumor proliferation and survival. BTK also is involved in signaling pathways of important chemokine receptors, such as CXCR4, which binds to chemokines excreted by bone marrow stromal cells or cells within lymph nodes. These chemokines are important in lymphocyte trafficking. As such, inhibition of BTK inhibits not only B-cell receptor signaling, but also chemokine receptor signaling. Inhibition of BTK may then affect the retention of lymphocytes in lymphoid tissues, where these cells are exposed to accessory cells and other factors within the lymphoma microenvironment that promote lymphoma cell survival and/or proliferation.
Upon inhibition of BTK, neoplastic B cells may become vagabonds that lack the ability to find their way back to the lymphoma microenvironment, where they receive sustenance. This can result in exhaustion or death of the lymphoma B cells over time. Some tumor cells, however, are still able to “limp along” in the context of BTK inhibitor monotherapy. This has fueled interest in the investigation of multi-agent targeted therapy in conjunction with agents that block BTK.
Patients can respond favorably to BTK inhibitors, alone or in combination with multi-agent therapy, and subsequently be found to lack detectable minimal residual disease (MRD) in the blood or bone marrow. However, some caution must be used in interpreting the significance of finding no detectable MRD, as this also may represent a sampling bias due to the fact that MCL may not be widely distributed throughout the bone marrow. This may account for the observation that patients with MCL who achieve complete responses to therapy often relapse, even if they have no detectable MRD and remain on therapy, particularly if they had aggressive disease going into therapy. Relapse in the setting of BTK inhibitor therapy indicates that the neoplastic cells may have developed mutations allowing for drug resistance or have adapted to alternate signaling pathways, which allow them to resist BTK inhibitor therapy.
Testing is ongoing using BTK inhibitors in conjunction with chimeric antigen receptor (CAR) T-cell therapy. There are some data indicating that BTK inhibition actually may improve a patient’s tolerance and/or response to therapy because it may mitigate some of the problems associated with CAR T-cell therapy, such as cytokine release syndrome or the lack of persistence of CAR T cells required to reject neoplastic B cells.
Chang BY, Francesco M, De Rooij MF, et al. Egress of CD19(+)CD5(+) cells into peripheral blood following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients. Blood. 2013;122(14):2412-2424.
Cheah CY, Seymour JF, Wang ML. Mantle cell lymphoma. J Clin Oncol. 2016;34(11):1256-1269.
Pal Singh S, Dammeijer F, Hendriks RW. Role of Bruton's tyrosine kinase in B cells and malignancies. Mol Cancer. 2018;17(1):57.
Ruella M, Kenderian SS, Shestova O, et al. Kinase inhibitor ibrutinib to prevent cytokine-release syndrome after anti-CD19 chimeric antigen receptor T cells for B-cell neoplasms. Leukemia. 2017;31(1):246-248.
Wang M, Rule S, Zinzani PL, et al. Long-term follow-up of acalabrutinib monotherapy in patients with relapsed/refractory mantle cell lymphoma. Abstract presented at: 60th American Society of Hematology Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 2876.