Evaluation of the Impact of Non-Inherited Maternal Antigens on the Outcome of HLA Mismatched Unrelated Donor Hematopoietic Stem Cell Transplantation for Hematological Malignancies on Behalf of the ALWP of the EBMT and the CIBMTR

Allogeneic hematopoietic stem cell transplantation (HSCT) offers a potential cure for a variety of hematological malignancies.  Patients without an HLA matched sibling donor can turn to unrelated donor registries to identify a suitably HLA matched donor.  In the case where a fully HLA-A, -B, -C, -DRB1 and -DQB1 (10/10) matched donor is unavailable, there are often multiple 9/10 matched donors to select from.  However, the prioritization and identification of permissive HLA mismatches in the 9/10 matched setting have proven elusive. Fetal exposure to non-inherited maternal antigens (NIMA) imparts lifelong immune modulating effects leading to tolerance to these antigens.  Prior studies have found that matching for non-inherited maternal antigens (NIMA) can lead to lower rates of acute graft versus host disease (aGVHD) and lower treatment-related mortality (TRM) in cord blood HSCT (J.J. van Rood et al., Blood 2002; J. J. van Rood et al., PNAS, 2009; V. Rocha et al., BBMT, 2012). Patients undergoing mismatched HSCT with adult unrelated donors could benefit from NIMA matching by introducing maternal HLA testing during confirmatory typing of the donor and using NIMA matching as a criterion for mismatched donor selection.

This joint EBMT-CIBMTR retrospective analysis was designed to evaluate the influence of NIMA matching in HSCT with mismatched adult unrelated donors. Matching criteria were based on HLA-A, -B, -C, -DRB1, -DQB1 at high resolution. Included donor-recipient pairs had 5 loci HLA typing and a minimum of one year follow-up recorded at EBMT or CIBMTR and donors were registered with DKMS German Bone Marrow Donor Center. To obtain maternal HLA typing information, DKMS contacted the respective donors by mail to inform about the study and to provide detailed information, a buccal swab kit and an informed consent form to the donor’s mother that the donor could send on. SBT-based HLA typing was performed at the DKMS Life Science Lab, Dresden, Germany once signed informed consent and samples were received. A total of 1735 donors were contacted and maternal samples could be retrieved for 803 cases (46%). A total of 50 NIMA matches (6%) were found reflecting the rate expected from previous studies.

Multivariate analyses were performed using Cox proportional hazards models adjusting for significant co-variates for overall survival (OS), disease free survival (DFS), relapse, TRM and acute and chronic GVHD comparing NIMA matched to NIMA mismatched cases.

The final analysis population was restricted to 9/10 matched cases (N=452) transplanted for acute myeloid leukemia (N=307) and acute lymphoblastic leukemia (N=145) using myeloablative (N=307) or reduced intensity (N=145) conditioning from 1999-2013.  The NIMA matched (N=32) and mismatched (N=420) groups were well balanced for all disease, patient, transplant and donor characteristics.  The groups differed by mismatched HLA locus with the NIMA matched group skewed towards more HLA-C mismatches (66% vs. 35%).  Univariate analyses did not find any significant differences between the NIMA matched and mismatched groups for any outcomes. TRM rates were similar between the groups at 1 year with 23% (95% CI: 10-40%) and 23% (95% CI: 19-28%) in the NIMA matched and mismatched groups, respectively. No significant associations were observed in multivariate analyses of the NIMA matched versus mismatched groups (Table). 

In contrast to prior studies of NIMA matched HSCT, no significant associations were found between NIMA matching and any outcomes. However, our findings may be due to the fact that the current study was underpowered to detect the expected difference in TRM observed in prior studies. Investigation on a larger cohort or a prospective trial would be needed.

We thank Carlheinz Müller from the German unrelated donor registry ZKRD for providing additional HLA information and the donors and their mothers for their cooperation in this study.

Table. Multivariate analysis results of NIMA matched versus mismatched (used as reference) HSCT

Outcome	HR	95%   CI	p-value
OS	0.89	0.54-1.48	0.653
DFS	0.88	0.53-1.43	0.598
TRM	0.74	0.35-1.60	0.447
Relapse	0.89	0.45-1.75	0.737
aGVHD II-IV	0.97	0.53-1.80	0.935
aGVHD III-IV	0.59	0.19-1.91	0.382
cGVHD	1.77	0.99-3.16	0.053