Assessment of Patient-Specific Human Leukocyte Antigen Genomic Loss at Relapse After Antithymocyte Globulin-Based T-Cell-Replete Haploidentical Hematopoietic Stem Cell Transplant

Abstract

Importance: Patient-specific human leukocyte antigen (HLA) genomic loss (HLA loss) is one of the reputed mechanisms of leukemia immune escape and relapse after haploidentical hematopoietic stem cell transplant (HSCT). However, clinical characteristics and prognosis of this distinct relapse type in the setting of haploidentical HSCT based on antithymocyte globulin (ATG) T-cell-replete conditioning are still unknown, especially for patients with lymphoid leukemia.

Objective: To identify the incidence of and patient characteristics associated with HLA loss at hematologic cancer relapse after ATG-based haploidentical HSCT and to assess overall survival after HLA loss at relapse.

Design, setting, and participants: This retrospective and multicenter case series study used data from medical records to identify patients who experienced relapse of hematologic cancer after receipt of ATG-based haploidentical HSCT. The study included 788 consecutive patients aged 8 to 70 years with lymphoid or myeloid leukemia who received ATG T-cell-replete haploidentical HSCT at the Zhejiang Cooperative Group for Blood and Marrow Transplantation between May 1, 2012, and May 31, 2021.

Exposures: Relapse after ATG-based haploidentical HSCT.

Main outcomes and measures: Incidence, risk factors, and postrelapse overall survival among patients with HLA loss at hematologic cancer relapse after receipt of haploidentical HSCT. Logistic regression analysis was used to identify characteristics associated with the likelihood of HLA loss, and Kaplan-Meier and Cox regression analyses were performed to evaluate postrelapse survival.

Results: A total of 788 patients who received haploidentical HSCT for hematologic cancer were identified, 180 of whom experienced relapse after HSCT. Of those, 106 evaluable patients (median age, 30.9 years [range, 8.3-64.6 years]; 54 female [50.9%] and 52 male [49.1%]) were screened for HLA loss, which was detected in 54 patients (50.9%). Patients with HLA loss experienced relapse later than those without HLA loss (lymphoid group: median, 323 days [range, 98-2056 days] vs 151 days [range, 57-2544 days]; P = .01; myeloid group: median, 321 days [range, 55-1574 days] vs 223 days [range, 68-546 days]; P = .03). Among patients with lymphoid leukemia, those with minimal residual disease positivity before hematologic relapse (odds ratio [OR], 28.47; 95% CI, 1.99-407.98; P = .01), those with chronic graft-vs-host disease (OR, 27.68; 95% CI, 1.40-546.88; P = .03), and those with more than 180 days between HSCT and relapse (OR, 6.91; 95% CI, 1.32-36.22; P = .02) were more likely to lose unshared HLA at relapse, whereas male patients (OR, 0.03; 95% CI, 0.003-0.32; P = .04) were more likely to preserve their HLA genome at relapse. Patients with myeloid leukemia had different factors associated with HLA loss, including underweight status (OR, 0.10; 95% CI, 0.02-0.60; P = .01) and acute graft-vs-host disease (OR, 4.84; 95% CI, 1.14-20.53; P = .03). The receipt of preemptive donor lymphocyte infusion among patients with minimal residual disease recurrence did not postpone hematologic cancer relapse in those with HLA loss (median, 322 days [range, 204-1030 days]) compared with no receipt of donor lymphocyte infusion (median, 340 days [range, 215 days to not available]; P > .99).

Conclusions and relevance: In this study, HLA loss at leukemia relapse occurred frequently after receipt of ATG-based haploidentical HSCT. The identification of risk factors associated with HLA loss would help to prompt screening, avoid potentially harmful infusions of donor T cells, and develop alternative therapeutic strategies.

Conflict of interest statement

Conflict of Interest Disclosures: None reported.

Figures

Figure 1.. Study Flow Diagram

Initial records search was performed for patients who had (1) hematologic cancer, (2) age between 8 and 70 years, (3) a low-dose antithymocyte globulin–based haploidentical hematopoietic stem cell transplant (HSCT), and (4) a transplant date between May 2012 and May 2021. A total of 788 records were identified and screened for patients with (1) minimal residual disease–negative during complete remission after haploidentical HSCT, (2) engraftment with 100% donor chimerism after haploidentical HSCT, (3) bone marrow hematologic relapse of minimal residual disease–positive, and (4) donor chimerism less than 97%. HLA indicates human leukocyte antigen.

Figure 2.. Independent Risk Factors Associated With Human Leukocyte Antigen Loss at Relapse

AUROC indicates area under the receiver operating characteristic curve; GVHD, graft-vs-host disease; HLA, human leukocyte antigen; HSCT, hematopoietic stem cell transplant; and MRD, minimal residual disease.

Figure 3.. Postrelapse Overall Survival

Plus signs indicate deaths occurring at specific time points. Boxes outlined by dashes indicate patients who were alive in each group at different time points. HLA indicates human leukocyte antigen; and OS, overall survival.