Mismatches in Low Expression HLA Class II Loci and MIC-A in Unrelated Donor Hematopoietic Stem Cell Transplantation (HSCT).
Authors: Patah Poliana , Fernandez-Vina Marcelo , Stastny Peter , Liu Ping , Cano Pedro , Pesoa Susana , Shpall Elizabeth J. , Giralt Sergio , Khouri Issa , Anderlini Paolo , Alousi Amin , Padua Leandro , Ramos Carlos , Rondon Gabriela , Nieto Yago , Champlin Richard , de Lima Marcos 
Published: October 2019

Little is known of the possible additive effects of mismatches in low expression class II HLA loci (DQB1, DPB1 and DRB3,4,5), and mismatches in MHC class I chain related (MIC-A) on the outcomes of unrelated donor HSCT. We investigated such hypothesis in a group of 139 consecutive patients (pts) with myeloid leukemias transplanted from 01/02 to 02/06 in our institution. All pts received a 8/8 matched graft (HLA-A, -B, -C, -DRB1). Preparative regimens were ablative [IV Busulfan-based (n=93) or Cy/TBI (n=1)], and reduced intensity [(Fludarabine (Flu)/Bu 130 mg/m2/2 doses plus Gleevec (n=7), and Flu/Melphalan 140 mg/m2 (n=38)]. Stem cell (SC) source was bone marrow (n=107) or peripheral blood (n=32). ATG was given in 134 cases. GVHD prophylaxis was tacrolimus and mini-methotrexate in all cases, with additional pentostatin in 38 pts. High-resolution typing was sequence-based for HLA-A, B, DRB1; SSP was used for DRB3/4/5, DQB1 and DPB1, SBT/SSOP for HLA-C and nucleotide-sequencing for MIC-A. A Cox proportional hazards regression model was used to study aGVHD-free and relapse-free survival (RFS). Variables with a p-value < 0.25 by univariate analysis were included in the multiple regression analysis (MV). Variables were age, gender, weight, conditioning regimen, GVHD prophylaxis, diagnosis, cytogenetics, SC source, ABO group, infused CD34 and CD3 cell dose, and HLA matching. aGVHD-free survival was calculated from transplant date to date of development of grade II-IV aGVHD or completion of 100 days of follow-up.

Results: Median age was 50 yrs (range, 14–75). Diagnoses were MDS (n=19), AML (n=95), CML (n=18) and other MPD diseases (n=6). 61 patients (44%) were in 1st or 2nd CR at transplant; all CML pts were in >1st chronic phase (CP). 133 (96%) patients engrafted neutrophils at a median of 13 days. 49 (35%) and 13 (09%) pts developed grade II-IV and III-IV aGVHD, respectively. Chronic GVHD incidence was 33%. With a median follow-up of 16 months (range, 2–64), 78 pts are alive. Median survival has not been reached. Reduced-intensity conditioning regimen was the only covariate which influenced aGVHD-free survival by MV analysis [p= 0.05; HR 0.53 (95%CI 0.28–1.0)]. Treatment-related mortality was higher among patients who had more than 3 mismatches in the low-expression loci and/or in MIC-A [p=0.01; HR 3.87 (95%CI 1.33–11.26)]. Among the 82 pts who were in CR at transplantation, 10/10 matching status reduced the incidence of grade II-IV aGVHD [p= 0.04; HR 0.35 (95%CI 1.18–0.72)], while the presence of a MIC-A mismatch determined a higher grade II-IV aGVHD incidence [p=0.02; HR 2.7 (95%CI 1.15–6.31)].

Conclusion: Multiple mismatches in low expression loci and in MIC-A increase treatment-related mortality in HLA 8/8 matched donor-recipient pairs in a cumulative manner.