HLA antibody (Ab)-secreting bone marrow (BM) plasma cell (PC) survival depends on niche occupancy via a CXCR4 (PC)-CXCL12 (BM stromal cell) interaction. Plerixafor inhibits CXCR4-CXCL12 and mobilizes PCs from the BM. We hypothesize that plerixafor may enhance PC targeting with bortezomib (BTZ).

Methods: Prospective, open-label trial (NCT 02522572). Group A (n=4) received 4 consecutive daily doses of plerixafor and 3 sessions of plasmapheresis. Group B (n=4) received a single dose of BTZ after 4 plerixafor doses. HLA Ab were tested on days 0,6,12,17,21,30 (group A) and 0,7,13,17,21,40 (group B). Precision PRA (pPRA), used to calculate number of donors required to match (#DRTM, 1/[1-pPRA]) and enabled PRA (ePRA) were computed using known haplotype frequencies. ePRA was calculated by entering HLA specificities eliminated by treatment. Time to immunodominant Ab (iAb) rebound was the number of days until iAb returned to ≥ baseline MFI.

Results: 8 patients were enrolled: 75% female, 88% Caucasian, 75% on dialysis. Sensitization by: transplantation (75%), transfusion (75%), pregnancy (62.5%). Mean cPRA was 97 ± 4%. Maximal iAb reduction was 33% in group A and 73% in group B (p=0.11). Table 1 summarizes HLA changes. 75% of patients (group A) vs 100% (group B) had an iAb nadir. Time to iAb rebound was prolonged; 50% did not return to baseline by end of study. HLA specificities were decreased in both groups (Figure 1). 4 patients were transplanted, are rejection-free with excellent graft function. Abnormal dreams and anxiety were the commonest adverse events.

Conclusions: This study provides proof of concept that BMPC mobilization may enhance PI therapy resulting in delayed HLA antibody rebound, contributing to long-term desensitization.

CITATION INFORMATION: Tremblay S., Castro-Rojas C., Driscoll J., Knechtle S., Shields A., Alloway R., Singh H., Hildeman D., Woodle E. Pilot Study of Plasma Cell Niche-Targeted Therapy for Enhancement of Proteasome Inhibitor Effectiveness Am J Transplant. 2017;17 (suppl 3).

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