Plasma-cell (PC) targeted therapies can reduce HLA sensitization. However, bone marrow (BM) niche resident plasma cells (BMNRPC) demonstrate resistance to proteasome inhibitor (PI) therapy. Plerixafor (PLE) inhibits CXCR4-CXCL12 interactions involved in the homing/retention of hematopoietic stem cells and PCs to bone marrow niches. Since BMNRPC undergo apoptosis after mobilization from BM, we hypothesized that PLE mobilizes BMNRPC and induces apoptosis in peripheral blood (PB) (macromobilization) and in the BM (micromobilization). We present results from patients in the first two phases of a prospective, iterative trial of PLE-based PC mobilization trial.

Methods: 4 HLA sensitized patients (cPRA >20%) in phase 1 received 4 consecutive daily doses of PLE 0.16mg/m² followed by 3 sessions of plasmapheresis. An patient in Phase 2 received the same PLE dosing followed by a bortezomib dose. Primary and secondary endpoints were safety and reduction in iAb respectively. Sequential PB and BM B- and plasma cell phenotyping was performed to assess for PB PC mobilization and evaluate markers of apoptosis and cell proliferation.

Results: Flow cytometric analysis of PB mononuclear cells showed mobilization of CD34+ckit+ stem cells (anticipated PLE effect) with a concomitant 2-4 fold increase in PB CD138+CD19-CD27+sIg- PCs. Dead PB PCs consistently increased from 1-2% to over 30% during PLE treatment. Preliminary flow cytometric analysis of the mitochondrial pro-apoptotic factor NOXA increased three fold, whereas the anti-apoptotic factor Bcl2 increased by two fold, providing further evidence of mobilization-induced apoptosis in PCs. The ability of PLE to induce apoptosis in PCs that remained in the BM was determined by analysis of BM resident CD138+CD19-CD27+sIg- PCs, that demonstrated an increase in the proportion of cells that were dead (6%-19%) following PLE treatment. PLE treatment was well tolerated. No grade 3 or 4 toxicities were observed.

Conclusions: PLE treatment demonstrated: 1)Increases in CD34+ckit+ stem cells and CD138+ CD19-CD27+sIg- PCs in PB, 2) Transient increases in apoptotic PC in PB, 3) Increased apoptosis in BM PCs, and 4) alterations in mitochondrial apoptotic regulatory factor expression. PLE has the potential to enhance PC targeted therapies with minimal added toxicity.

CITATION INFORMATION: Woodle E, Tremblay S, Castro-Rojas C, Driscoll J, Knechtle S, Shields A, Alloway R, Hildeman D. In Vivo Administration of Plerixafor in Humans Mobilizes Bone Marrow Resident Plasma Cells That Demonstrate Apoptosis in Both Bone Marrow and Peripheral Blood. Am J Transplant. 2017;17 (suppl 3).

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