Human leukocyte antigen (HLA) DR4 is associated with inferior progression free survival (PFS) following allogeneic hematopoietic stem cell transplantation (allo HSCT) for lymphoid malignancies

Abstract

6543 Background: HLA DR4 is associated with autoimmune disorders and response to cyclosporine immunosuppression in T-cell Large Granular Lymphoproliferative Disorder (BJH 2003;123(3)). We investigated the HLA DR4 role on graft-versus-host disease (GVHD) and graft-versus-leukemia effect in HLA-matched HSCT performed for lymphoid malignancies. Methods: We retrospectively reviewed 77 related and 22 unrelated consecutive allo HSCT patients (pts) treated between 1992 and 2003 at RPCI to investigate the influence of HLA DR4 on overall survival (OS), PFS and grade 2–4 acute and chronic GVHD (cGVHD) incidence. HLA DR B1 typing was determined by molecular (n=69) or serologic (n=30) methods. The pt proportion with one or two HLA DR4 antigens was 18% (18/99), similar to the general Caucasian population. Pt characteristics included: ALL (n=41), CLL (n=4), HD (n=7) and NHL (n=47); median age 36 y (range 6–64); Male (n=65), Female (n=34); Caucasian (>95%); Total Body Irradiation (TBI) conditioning regimens (n=79); Busulfan/Cyclophosphamide (BuCy) (n=6), Thiotepa/TBI (n=23), Cy/TBI (n=9), Etoposide/Cy/TBI (n=9), Fludarabine/Melphalan (n=8), Thiotepa/Carboplatin (n=8) or other combinations (n=6). Results: There was no difference in OS between the HLA DR4 positive vs negative pts in any disease or donor subgroups (p=0.25). Nine of 18 DR4 positive pts (50%) and 20 of the 81 DR4 negative pts (25%) had disease progression (p=0.033). PFS at 33 months was 70% in the DR4 negative group and 30% in the DR4 positive group (p=0.004). In a univariate analysis, DR4 positivity, conditioning regimen and disease stage at HSCT were significant factors for PFS. However in the multivariate analysis, DR4 positivity was the only significant factor for PFS (RR=3.2, p=0.007). By preliminary analysis, 0/18 of the HLA DR4 positive pts and 13/81 HLA DR4 negative pts developed cGVHD (p=0.06). Conclusions: These results suggest that HLA DR4 positive pts have reduced cGVHD leading to increased relapse and decreased PFS with no effect on OS. Increased sensitivity of HLA DR4 lymphocytes to GVHD prophylaxis agents or reduced binding affinity for the CD4 coreceptor are possible reasons for these observations. No significant financial relationships to disclose.