The Search for a Biomarker in cGVHD Focuses on HLA-DR+CD3+ T Cells

Low counts of activated HLA-DR+CD3+ T cells in peripheral blood may serve as a novel predictive biomarker for increased transplant-related mortality (TRM) and severe chronic graft-versus-host disease (cGVHD) following allogeneic hematopoietic stem cell transplantation (HSCT), according to a new study. The findings, published in the Journal of Leukocyte Biology, are particularly relevant for patients who undergo reduced intensity conditioning (RIC).¹ cGVHD remains a major cause of late morbidity and mortality post-HSCT and predictive tools are limited.

Investigators from the University of Innsbruck in Austria reported on transplant-related mortality (TRM) that measured counts and percentages of HLA-DR+CD3+ T cells 3 months after patients underwent HSCT.

The study found that an absolute count of 140 cells/μL or less was significantly correlated with increased TRM. Furthermore, a count of 100 cells/μL or less was associated with a higher rate of moderate-to-severe cGVHD (grade 2 to 3). The ideal predictive cutoff was defined as 140 cells/μL for absolute counts and 28.75 percent for relative values.

In this retrospective study, adults who underwent HSCT and had an overall survival (OS) of 3 months or more were screened between 2008 and 2022. Data on HLA-DR+CD3+ T cells from a total of 107 patients were collected. The primary end points were TRM and the incidence of moderate-to-severe cGVHD grade 2 to 3.

The median age was 56 years old (range, 23-74), 55% of patients were female, and the most common diagnoses were acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS; both at 72%). Peripheral blood stem cells were used in all patients and counts were determined by flow cytometry.

Causes of TRM were bacterial infection (50%), viral infection (14.3%), fungal infection (7.1%) and cGVHD (28.6%). Acute GVHD of any grade was observed in 45.8% of patients. cGVHD of grade 0 to 1 occurred in 72% of patients and cGVHD grade 2 to 3 was observed in 28% of patients.

Ideal cutoff points were defined as 140 cells/μL for absolute cell counts and 28.75% for relative values, with a significant result for absolute HLA-DR+CD3+ T cell counts regarding TRM (AUC 0.658, P = 0.044, sensitivity 59.3%, specificity 81.2%). No significant differences in OS and relapse-free survival (RFS) were found between patients with high and low HLA-DR+CD3+ T cell counts. The 3-year TRM was 26% for patients with low-activated T cell counts and 5.5% for patients with high-activated T cell counts 3 months after HSCT.

Subgroup Analysis

Subgroup analysis was performed regarding the TRM and higher-grade cGvHD 2 to 3-free survival for myoablative conditioning (MAC) vs RIC.

The subgroup analysis revealed that these results were significant primarily for patients who received RIC, not for those who received myeloablative conditioning (MAC). For the RIC group, a T-cell count of 140 cells/μL or less was associated with a significantly reduced TRM-free survival. The 3-year TRM was 26% for patients with low-activated T-cell counts compared with 5.5% for those with high counts. The incidence of higher-grade cGVHD was also significantly increased in patients who underwent RIC with T-cell counts of 100 cells/μL or less.

No significant differences were observed in overall survival or relapse-free survival based on T-cell counts.

Although this is the first study to show a correlation between reduced cell counts of activated HLA-DR+CD3+ T cells and higher-grade cGvHD, Koeck S et al, were nonetheless cautious because of the trial’s inherent limitations, including its retrospective nature, the single-center design, and the relatively small patient cohort.

“Our preliminary data suggest that reduced numbers of activated HLA-DR+CD3+ T lymphocytes 3 months after HSCT might serve as a potential biomarker to identify patients with an increased risk for TRM and higher-grade cGvHD,” the authors concluded.

REFERENCE:

Koeck S, Hetzenauer G, Peschel-Schaar I, Wolf D, Steiner N, Nachbaur D. Decreased HLA-DR+CD3+ T cells three months after allogeneic stem cell transplantation predict severe chronic GvHD and transplant-related mortality. J Leukoc Biol. 2025;117(8):qiaf106. doi:10.1093/jleuko/qiaf106