In human visualization of ibrutinib-induced CLL compartment shift.

Bruton's tyrosine kinase inhibitor ibrutinib is effective in treating chronic lymphocytic leukemia (CLL). However, after ibrutinib treatment initiation, patients frequently experience an increase of CLL blood cell count. This phenomenon in clinical practice is thought to reflect a "compartment shift" of CLL cells from lymph nodes to the peripheral blood, but the actual shifting has not yet been demonstrated. Using [68Ga]Pentixafor-PET/MRI (positron emission tomography/magnetic resonance imaging) for in vivo CXCR4 visualization, we here provide images of topical changes of CLL cells upon ibrutinib treatment. Within the first month of ibrutinib treatment, mean standardized [68Ga]Pentixafor uptake decreased in the bone marrow and lymph nodes, whereas [68Ga]Pentixafor uptake increased in the spleen. Leukocytosis rose, as did numbers of CXCR4high (tissue-resident) CLL cells. Volumes of lymph nodes and spleen decreased. Upon longer ibrutinib treatment, leukocytosis decreased followed by a decrease of [68Ga]Pentixafor uptake in the spleen. These results support the pre-existing clinical hypothesis of a "compartment shift" of CLL cells from the lymph nodes to the peripheral blood, but also refine the mechanistic model by describing early clearing of the bone marrow and re-distribution of CLL cells to the orthotopic splenic cavernous system in response to ibrutinib treatment.