Bone marrow (BM) plasma cells (PC) secreting HLA antibody (Ab) remain a persistent reservoir of donor specific Ab and present a significant hurdle to allograft tolerance. Current therapies such as bortezomib (BTZ) do not fully eliminate BMPC possibly due to survival factors within the BM niche. Plerixafor (PLE), an inhibitor of the CXCR4-CXCL12 chemokine interaction responsible for BMPC homing to the BM, has been shown to mobilize BMPC out of their BM niche. We hypothesize that BMPC mobilization out of the BM niche with PLE may enhance PC apoptosis and potentially enhance their sensitivity to BTZ. We present results from patients in the second phase of a prospective, sequential trial of PLE-based PC desensitization trial.

Methods: 4 HLA-sensitized kidney transplant candidates (cPRA > 95%) received 4 consecutive daily doses of PLE 0.16mg/m² and 1 dose of bortezomib 1.3mg/m² followed by 3 sessions of plasmapheresis. Primary and secondary endpoints were safety and reduction in immunodominant Ab respectively. Sequential blood (PB) and BM B- and plasma cell flow cytometric phenotyping was performed to assess for PB PC mobilization and evaluate markers of apoptosis and cell proliferation.

Peripheral blood results: CD34⁺c-Kit⁺ stem cells were mobilized and a 2-4 fold increase in CD138⁺CD19^–CD27⁺sIg^– PC was observed. Increased PC death was observed following initial mobilization with a 2^nd peak of cell death 24-72h following administration of BTZ. Furthermore, CD138⁺CD38⁺IgG⁺ cells emerge following treatment with PLE and are eliminated after BTZ. Mitochondrial apoptotic factors NOXA/PUMA were increased following both PLE and BTZ. Bone marrow results: BMPC frequencies remained similar, however, a 1.5 to 2-fold increase in dead cells was observed. A CD19⁺ population significantly decreased following PLE. Similar NOXA/PUMA increases were observed.

Conclusions: In agreement with our hypothesis, PLE treatment mobilized CD34⁺ stem cells and CD138⁺ PC from BM to PB leading to an initial apoptotic wave. BTZ then induced a second PC apoptotic phase in PB. PLE increased the proportion of apoptotic PC in the BM fraction. These observations may be the results of alterations in mitochondrial apoptotic regulatory factor expression, namely NOXA/PUMA. PLE may serve as a BTZ-sensitizing PC-targeted therapy.

CITATION INFORMATION: Woodle E., Tremblay S., Castro-Rojas C., Knechtle S., Shields A., Alloway R., Singh H., Driscoll J., Hildeman D. In Vivo Administration of Plerixafor and Bortezomib Results in Bone Marrow Plasma Cell Mobilization and Death While Inducing Biphasic Plasma Cell Apoptosis in Peripheral Blood Am J Transplant. 2017;17 (suppl 3).

« Back to 2018 American Transplant Congress