Graft-Specific HLA-Antibodies Do Not Influence Unit Dominance and Do Not Prevent High Rates of Sustained Donor Engraftment in Recipients of Double-Unit Cord Blood (CB) Transplantation

Background: While HLA-antibodies (Ab) have an established role in failed engraftment after single-unit CB transplantation (CBT), their role in double-unit CBT (DCBT) engraftment is more controversial. 

Methods: We evaluated the influence of pre-transplant HLA-Ab on sustained donor neutrophil engraftment & unit dominance in 82 recipients (median age 48, range 2-69) of 4-6/6 HLA-A,B antigen, DRB1 allele matched double-unit CB grafts, & transplanted for hematologic malignancies from 7/2008-7/2012. HLA-Ab were measured by the American Red Cross Blood Service using Single Antigen Luminex beads & analyzed by HLA Fusion software. The cut-off for positive results was a normalized mean fluorescence intensity value > 1000.

Results: 28/82 (34%) patients were positive for HLA-Ab [16 (19.5%) had Ab without graft specificity, & 12 (14.5%) had Ab with graft specificity]. These patients were more likely to be female with acute leukemia & CMV seropositive. All patients with graft-specific Ab received myeloablative conditioning; 5 had Ab against class I HLA, 6 against class II, & one patient had Ab to both Class I/II. Moreover, of these 12 patients, 6 had Ab against one unit & 6 had Ab against both units. Neutrophil engraftment according to Ab is summarized in the Table. 64/66 (97%) evaluable myeloablative DCBT recipients (Table 1A) engrafted at a median of 24 days (range 12-40); one patient without Ab & one with Ab against both units had primary graft failure, both in the setting of early onset multi-organ failure. Both patients were 100% donor in the marrow with one unit but did not recover counts. Of the 6 patients with Ab to one unit, 3 engrafted with that unit & 3 with the opposite unit. Of the 6 patients with Ab against both units, one had clinical graft failure as described above, & the 5 others had sustained donor engraftment (4 with one unit & one with both). In engrafting myeloablative recipients, the median time to neutrophil recovery was 8 days slower in patients with graft-specific Ab, but the engrafting unit in these patients also had the lowest infused dose: median CD34+ cell dose/kg if no Ab 0.83 x 10⁵/kg, non-specific Ab 1.09 x 10⁵/kg, & Ab specific to graft 0.65 x 10⁵/kg. In non-myeloablative recipients, 15/16 (94%) engrafted (Table 1B). The single patient with rejection/ autologous recovery had Ab that were not graft specific.

Conclusions: 11/12 double-unit CBT recipients with graft-specific Ab engrafted successfully. While myeloablative recipients with graft-specific Ab engrafted more slowly, this may be explained by their lower infused CD34+ cell dose. While multivariate analysis of larger series will be required to further evaluate the effect of graft-specific Ab on engraftment speed, currently the presence of graft-specific Ab should not preclude DCBT, & whether their presence should influence graft selection is unclear. Moreover, there is no suggestion that HLA-Ab influence unit dominance after DCBT.