Donor-specific anti-human leukocyte antigen antibodies were associated with primary graft failure after unmanipulated haploidentical blood and marrow transplantation: a prospective study with randomly assigned training and validation sets

Abstract

Background: Small studies suggest an association of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) with primary graft failure (GF) following haploidentical stem cell transplantation, but primary graft rejection (GR) was not discriminated from primary poor graft function (PGF). In this study, we aimed to determine the association of DSAs with primary GF, including GR and PGF, in patients who underwent unmanipulated haploidentical blood and marrow transplantation.

Methods: A total of 345 subjects were prospectively recruited and randomly selected as training group (n = 173) and validation group (n = 172). Patient plasma/serum was screened. For HLA antibody positive samples with a median fluorescent intensity (MFI) >500, DSAs were further tested using a LABScreen Single Antigen Kit (One Lambda).

Results: A total of 342 patients (99.1%) achieved sustained myeloid engraftment. The median times to neutrophil engraftment and platelet engraftment were 13 days (range, 8-28 days) and 18 days (range, 6-330 days), respectively. The cumulative incidence of primary GF was 6.4 ± 1.3% and included GR (0.9 ± 0.5%) and PGF (5.5 ± .2%). Of the 345 cases tested, 39 (11.3%) were DSA positive. Multivariate models showed that DSAs (MFI ≥ 10,000) were correlated to primary GR (P < 0.001) and that DSAs (MFI ≥ 2000) were strongly associated with primary PGF (P = 0.005). All patients were classified into three groups for analysis. Group A included cases that were DSA negative and those with a DSA MFI <2000 (n = 316), group B included cases with a 2000 ≤ MFI < 10,000 (n = 19), and group C included cases with a MFI ≥ 10,000 (n = 10). The DSAs were associated with an increased incidence of the primary GF (3.2 vs. 31.6 vs. 60%, for groups A, B, and C, respectively, P < 0.001), transplant-related mortality (TRM) rate (17.2 vs. 14.7 vs. 33.3%, for groups A, B, and C, respectively, P = 0.022), and inferior overall survival (OS, 77.3 vs. 85.3 vs. 44.4%, for groups A, B, and C, respectively, P = 0.015). The primary GF was independently associated with a higher incidence of TRM (P < 0.001), inferior disease-free survival (P < 0.001), and OS (P < 0.001).

Conclusions: The findings confirmed the effect of DSAs on primary GF, including GR and PGF, and survival. Our results suggest incorporating DSAs in the algorithm for haploidentical donor selection.

Fig. 1

Pretransplant DSA and cumulative incidence of neutrophil (a) and platelet (b) engraftment. All patients were classified into three groups, group A includes cases with DSA negative and those with a DSA MFI <2000 (n = 316, solid line), group B includes cases with 2000 ≤ MFI < 10,000 (n = 19, dotted line), and group C includes those with a MFI ≥ 10,000 (n = 10, dashed line)

Fig. 2

Transplant-related mortality (a) and overall survival (b). All patients were classified into three groups, group A includes cases with DSA negative and those with a DSA MFI <2000 (n = 316, solid line), group B includes cases with 2000 ≤ MFI < 10,000 (n = 19, dotted line), and group C includes those with a MFI ≥10,000 (n = 10, dashed line)

Fig. 3

Transplant-related mortality (a) and overall survival (b). The solid line, dotted line, and dashed line represents patients without primary graft failure, with graft rejection, and with poor graft function, respectively