Levels of ANTI-HLA DONOR Specific Antibodies (DSA) and GRAFT Outcome in Allogeneic Hematopoietic STEM CELL Transplant

Studies have shown that anti-HLA donor specific antibodies are detrimental in solid organ transplantations. However, their roles in hematopoietic stem cell transplantation (HSCT) have not been fully studied. The aim of our study was to investigate the levels of anti-HLA donor specific antibodies (DSA) and their impact on graft outcome in HSCT.

Patients and methods: 49 recipients of allogeneic HSCT with anti-HLA DSA pre-transplant were included in the study between July, 2006 and July, 2012. All patients (pts) were screened for anti-HLA antibodies using LABScreen® PRA and/or LABScreen® Mixed kits. And antibody specificity analysis was conducted for screening positive patients using LABScreen® Single Antigen beads on Luminex platform method (One Lambda Inc., Canoga Park, CA). Results were expressed as mean fluorescence intensity (MFI) with MFI >= 500 considered positive. Sera from initial testing and the time of transplant (Tx) for each patient were included in the analysis. Pretransplant specimens with the highest MFI were used in the analysis.

Results: Majority of pts who had anti-HLA DSA were females (91.8%). The transplant donors included in three categories: 16 haplo-identical, 12 double umbilical cord blood units (DCBU), and 21 unrelated donors. More class II DSAs (67%) were observed than class I (33%). HLA-DPB1 only DSA accounted for 48.8%. Forty-three of the 49 patients had DSA at the time of Txt. Of the 43 pts, 27 had DSA <5,000 MFI, 10 had DSA >5,000 MFI, and 6 had DSA >10,000 MFI. Early death occurred in 4 pts (3 had DSA <5,000 MFI, 1 had DSA >5,000 MFI). Seven pts developed rejection/primary GF, 6 pts had secondary GF within 100 days of transplantation and 9 pts had mixed chimerism. Of the 7 pts with rejection/primary GF, 3 were haplo-identical Tx (all DSA >5,000 MFI) and 4 were unrelated (2 with DSA <5,000 MFI and 2 with DSA >5,000 MFI). The rate of rejection/primary GF was higher in pts who had DSA >5,000 MFI (5/15) compared to those DSA <5,000 MFI (2/24) (p = 0.0846). While in contrast, more pts with secondary GF within 100 days (5/6) or mixed chimerism (8/9) had DSA <5,000 MFI (p = 0.3461, p = 0.21, respectively). Of the 6 pts with secondary GF, 1 had haplo-identical Tx (DSA <5,000 MFI), 2 unrelated (DSA <5,000 MFI), and 3 DCBU (1 DSA >5,000 MFI, 2 DSA <5,000 MFI).  

In conclusion, at least moderate DSA (MFI >5,000) seemed more frequently to result in rejection/primary graft failure while secondary GF/mixed chimerism could be associated more with lower DSA levels (MFI <5,000) suggesting that DSA could be a predisposing factor for these to develop in the appropriate setting (e.g. reduced-intensity conditioning). Over half of the pts with rejection/primary or secondary GF had DSA to HLA-DPB1 only (7/13). This suggested that matching at DPB1 locus could be as important as matching in other HLA loci.  These results suggest that avoidance of DSA even with low MFI levels could be essential for improving graft outcome in HSCT pts.