Sandra Warnock

Somatic mutations in the HLA genes of patients with hematological malignancy

Somatic mutations and genomic alterations are frequent events in the clonal evolution of hematologic malignancies. Recent studies have reported copy neutral loss of heterozygosity (LOH) for the mismatched human leukocyte antigen (HLA) haplotype in patients relapsed after haploidentical hematopoietic cell transplantation (HCT) for a hematologic malignancy. Herein, we report 15 cases of somatic mutations in the HLA genes of patients with a variety of hematologic diseases, including acute myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, and non-Hodgkins lymphoma, encountered at our institute over the past decade. While two of the cases were identified in patient relapse specimens collected post-HCT, 13 cases were found in peripheral blood specimens submitted for HLA typing prior to transplantation. Ten patients exhibited acquired LOH for all or part of one HLA haplotype. Five other cases involved somatic mutations in the nucleotide sequences of common HLA-A or HLA-B alleles. Since they are not systematically evaluated prior to HCT, acquired mutations in HLA genes are likely under reported. Beyond the implications for accurate HLA typing and donor selection, alternations that result in the loss of HLA expression may allow escape from immune surveillance and adversely impact transplant outcome.

Prospective monitoring for alloimmunization in cord blood transplantation: "virtual crossmatch" can be used to demonstrate donor-directed antibodies.

Preformed host antibodies may contribute to graft rejection after hematopoietic stem-cell transplantation. In cord blood transplantation (CBT), donor-directed host antibodies may be particularly relevant because patients are often markedly mismatched to donors, and limited donor cells preclude cross-matching. The recent development of single human leukocyte antigen (HLA) microbead array assays allows characterization of host alloreactivity to individual HLA antigens with sufficient sensitivity and specificity to allow consideration of “virtual crossmatch” testing as a surrogate for conventional crossmatch testing in the CBT setting. We report results of prospective monitoring for alloimmunization in our recent CBT experience. Among 46 consecutive patients, four patients (9%) (5 of 88 units [6%]) had evidence of at least moderate antibodies to HLA antigens on cord units originally selected for transplantation. Virtual crossmatch can be used to screen for donor-directed antibodies in CBT. As possible, units should be changed to avoid sensitized mismatches.