Impact of Minor Histocompatibility Antigens (mHAg) Mismatches On Gvhd Incidence in Non-Myeloablative or Reduced Intensity Allogeneic Stem Cell Transplantation.

Mismatches of minor Histocompatibility antigens (mHAg) have been considered as an important immunogenetic factor influencing outcomes and immune responses following allogeneic stem-cell transplantation (alloSCT) despite fully matched HLA of donor and recipient.

Aim of this study was to assess whether mHAg incompatibilities may affect overall survival (OS), progression free survival (PFS) and GVHD incidence (acute and chronic, aGVHD and cGVHD) in patients receiving alloSCT for lymphoid malignancies.

Sixty-four consecutive patients with B-cell lymphomas who underwent alloSCT were studied. Ten patients had chronic lymphocytic leukemia (CLL, 15.8%), 3 had follicular lymphoma (FCL, 4.7%), 1 had diffuse large B cell lymphoma (DLBCL, 1,5%), 17 had Hodgkin's lymphoma (26.5%) and 33 had multiple myeloma (51.5%). All underwent peripheral blood stem-cells allograft with non-myeloablative (13 patients, 20%) or reduced intensity (51 pts, 80%) Fludarabine-based conditioning; GVHD prophylaxis included methotrexate and oral cyclosporine +/- micomofetil fenolate in case of matched unrelated donors. Median age was 51 years (range 18-66); 35 patients were male (55%), median number of previous chemotherapies was 3 (0-7), 49 patients had a previous autologous transplant (76%). Twenty-five patients were in complete remission (CR, 39%), 30 and 9 were in partial response and progression (PR 47% and PD 14%). Karnofsky performance status (PS) was >80% in 50 patients (78%). Forty-four patients allografted from HLA-matched siblings (69%), 20 from matched unrelated donor (31%): all were matched at allelic level for HLA-A, -B, -Cw, -DRB1 and -DQB1 loci. Allelic mHAs typing was performed by PCR with sequence-specific primers for 14 autosomic mHAg and H-Y. Host versus Graft or Graft versus Host direction of immune responses in donor/recipient pairs was analyzed with use of the minor Histocompatibility Database of Leiden University Medical Center. OS and PFS were analyzed with Kaplan-Meier method and log-rank test. aGVHD and cGVHD were analyzed with a multivariate logistic regression including as covariates age, sex, previous lines of chemotherapy, disease, pre-transplant status, PS and mHAs mismatches; grade >=2 aGVHD and extensive cGVHD were considered events.

Median follow-up was 34 months (2-83). One-year OS was 85%, 2- and 3-years OS were 82% and 77%. One-year PFS was 61%, 2- and 3-years PFS were 49% and 41%.

The univariate analysis which considered transplant characteristics showed that OS and PFS were significantly affected by disease status at transplant (p<0.001 for both OS and PFS) and PS (<=80 vs >80, p<0.001 for both OS and PFS). Donor-vs-recipient (DR) mHAs mismatches did not significantly impact OS and PFS. The multivariate analysis which considered aGVHD as the outcome of interest, showed that the presence of at least one DR mHAg mismatch, and the presence of DR hematopoietic-restricted mHA mismatches significantly increased aGVHD incidence (p=0.02 for both). On the other hand, broad DR mHA and H-Y disparities did not affect aGVHD. DR disparities at the LB-ADIR, HA-1, HA-2 and HA-8 mHAgs did not increase the incidence of aGVHD. Recipient-vs-donor (RD) mHAg mismatches did not significantly affect aGVHD as none of the other factors considered in the multivariate associated with increased risk of cGVHD of any grade.

This study showed that in the non-myeloablative and RIC setting, mHAg mismatches may have a significant role in determining aGVHD. Assessing mHAg mismatches may be a useful tool to choose patient-specific GVHD prophylaxis in conditioning regimens and in post transplant follow-up. Larger prospective data are needed in order to confirm these results.

No relevant conflicts of interest to declare.