Changes in HLA Antigens Is Not a Major Mechanism of Acute Myeloid Leukemia Relapse After Matched Allogeneic Stem Cell Transplantation

Disease relapse after allogeneic hematopoietic stem cell transplantation (HSCT) is the most important cause of treatment failure. The mechanisms of leukemia relapse after allogeneic stem cell transplantation remain elusive. Loss of HLA class I antigens has been associated with disease relapse, tumor progression and metastasis in solid tumors and has been shown to be the direct consequence of selective pressure mediated by T cells. We aimed to detect if changes in HLA antigens occurs and is responsible for leukemia relapse.

We reviewed patients who relapsed post allogeneic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML) or myelodysplastic syndrome and conducted post-transplantation studies that included morphologic examination of bone marrow and HLA typing. Donor and recipient blood specimens, which were collected pre-transplant and post-relapse, were typed at intermediate- and high-resolution for HLA-A, -B, -C, -DRB1, and -DQB1 loci.  A leukemia-enriched population was isolated from peripheral blood using a CD3+/CD19+ depletion technique using MACs (Miltenyi, Auburns CA). HLA typing was performed for all samples either prospectively prior to transplantation and on archived samples at the time of relapse by polymerase chain reaction (PCR) amplification and oligonucleotide hybridization using molecular methods. We compared pre-transplant and post-relapse specimens with the specimen at diagnosis to evaluate the loss of heterozygosity (LOH) in blasts.

We identified 71 patients (median age: 51, 18-67; 48% male) who relapsed after allo-HSCT and had samples stored at the time of relapse. Sixty one (86%) transplantations were matched for 10/10 HLA alleles and 10 (14%) for 9/10 alleles. Eleven patients (15%) underwent transplantation in first remission (CR1), 15 (21%) in CR2, and 45 (63%) patients had relapsed AML or primary induction failure. Conditioning regimen consisted of a myeloablative regimen in 46 patients (65%) and reduce intensity regimen in 25 patients (35%). The source of stem-cells was peripheral blood in 47 (66%) and bone marrow in 24 (34%).  LOH in relapsed blasts was presented in only one case after HSCT; in this patient LOH was also observed in the blasts collected in a pre-transplant specimen.

In conclusion, contrasting with the frequent finding of LOH in relapse blasts after HSCT in haploidentical transplantation followed by donor T-cell infusion, LOH in relapse blasts is not common in T cell-replete matched HSCT. LOH does not appear to be a dominant escape mechanism for relapse in allogeneic HSCT with a closely HLA matched donor.