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Deleterious Effect of High-Expression HLA-DPB1 Allele Mismatch in Patients (pts) Undergoing 10/10 Match Unrelated Donor (MUD) Hematopoietic Cell Transplant (HCT) for Hematological Malignancies

Year: 2016

Type: article

Abstract: HLA mismatch at DP locus (mmDP) has been associated with significant increase in the incidence of acute graft versus host disease (aGvHD) and decrease in relapse rate (RR) in myeloablative HCT using 10/10 MUD. Lately, DP mismatch with high protein expression (based on SNP rs9277534G vs. A) in pts was described to be an independent predictor of increased risk of aGVHD but no impact on overall survival (OS). We evaluate the impact of DP mismatch and the expression of HLA-DPB1 allele on the outcome of 10/10 MUD in patients with hematological malignancies undergoing myeloablative (MAC) or reduced conditioning regimen (RIC). 264 pts who underwent (10/10 HLA-A, B, C, DR, and DQ) MUD HCT at City of Hope from 2006 to 2012 were included. HLA DPB1 alleles were grouped based on linkage disequilibrium reported between rs9277534 and HLA-DPB1 alleles (Petersdorf et al. 2015). 23% (n=61) of pts were 12/12 matched DP (mDP), 77% (n=203) were mmDP (at single or double alleles), 21% (n=57) pts had high expression mismatched allele (HmmDP), and 30% (n=80) low expression mismatched allele (LmmDP). Median age was 54.5 years (range: 18-73). Seventy-eight percent received Tacrolimus/Sirolimus-based GVHD prophylaxis; Mini-methotrexate or ATG was added in 22% (n=60). Conditioning regimen used was MAC (39%, n=103) and RIC (61%, n=161). Diseases included acute leukemia (n=166), MDS/MPN (n=44), NHL (n=32), HL (n=2), CLL (n=7), CML (n=10), and multiple myeloma (n=3). Disease risk was low in 40% (n=106), intermediate in 11% (n=30) and high in 44% pts (n=115). With the exception of disease risk (p=0.04), patient/disease characteristics were similar in all groups. With median follow-up of 3.8 years (range: 1.4 to 8.2 years) for surviving pts 51% were alive and 31% had relapsed. In univariate analysis, mmDP had lower RR compared to mDP (HR=0.62, [95% CI: 0.39-1.00] p=0.05), which translates to better EFS (HR=0.68, [95% CI: 0.47-0.98] p=0.04). This was confirmed in a multivariable analysis after adjusting for age, disease risk, and conditioning regimen used. However, no significant effect was found on the incidence of aGvHD, NRM or OS. In multivariable analysis, pts with HmmDP had increased incidence of II-IV aGvHD (HR=1.74, [95% CI: 1.04-2.9] p=0.03) as well as III-IV aGVHD (HR=2.96, [95% CI: 1.2-7.3] p=0.02) when compared to pts with LmmDP. This was adjusted for age, disease risk and intensity of conditioning (p=0.03). This has led to a trend in increased overall mortality (HR=1.62, [95% CI: 0.96-2.76] p=0.07). No significant effect was found on RR or NRM. In pts undergoing 10/10 MUD HCT, mmDP improved RR when compared to mDP. Among patients with mismatch, those with HmmDP had higher risk of II-IV and III-IV aGVHD. Selecting donor with DP mismatch may result in a better outcome, however donor-patient mismatched for high-expression DPB1 allele should be avoided.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2015.11.364