Immunoadoptive effect of donor lymphocyte infusion-induced acute graft-versus-host disease in children with acute leukemia

Donor lymphocyte infusion (DLI) for prophylactic purposes enhances the immunoadoptive antitumor effect, thereby reducing the risk of relapse after allogeneic hematopoietic stem cell transplantation (HSCT) in patients with acute leukemia. One of the main limiting factors for the use of DLI is the risk of developing graft-versus-host disease (GVHD). According to studies, the incidence of this complication of DLI ranges from 15% to 45% for acute GVHD (aGVHD) and from 10% to 50% for the chronic form. The development of GVHD after DLI also leads to enhancement of the antitumor effect and reduces the risk of relapse. At the same time, an increased risk of relapse is associated with the loss of HLA heterozygosity after haploidentical HSCT, and the role of GVHD in this process has not been investigated yet. In this single-center retrospective study, we performed a comparative analysis of the risk of bone marrow and extramedullary relapses in pediatric patients with acute lymphoblastic leukemia and acute myeloid leukemia who had received prophylactic DLI after allogeneic HSCT. We also assessed the severity of DLI-induced aGVHD and the incidence and severity of chronic GVHD, and investigated the relationship between aGVHD and the loss of HLA heterozygosity. We identified two groups of patients: those who had received prophylactic DLI (an intervention group; n = 41) and those who had not (a comparison group; n = 46). Informed consent to the inclusion in the study was obtained from all the patients/legal representatives. Protocol (No. 249 dated 31.05.2021) was registered in the Ethics Committee of the I.P. Pavlov First Saint Petersburg State Medical University of Ministry of Healthcare of the Russian Federation. All the patients were divided into four subgroups according the use of IDL and the development of aGVHD: +DLI – patients with DLI and without aGVHD (n = 34); +DLIGVHD – patients with DLI-induced aGVHD (n = 7); –DLI – patients without DLI and aGVHD (n = 34); –DLIGVHD – patients without DLI and with a history of aGVHD (n = 12). A total of 7 (17%) cases of DLI-induced aGVHD were recorded. There were no statistically significant differences in the incidence and severity of gastrointestinal tract involvement (p = 1) and liver involvement (p = 0.75) between the 2 groups. The incidence of grade III–IV skin GVHD (p = 0.06) was higher in the non-DLI group. No deaths associated with DLI-induced GVHD were recorded. The median number of aGVHD treatment lines (2 (1–4) and 1 (1–2); p = 0.2) and the duration of treatment (63 (23–1455) days and 70 (44–111) days; p = 0.72) were similar in the 2 groups. The incidence of chronic GVHD in the DLI group (n = 7; 17%) and in the comparison group (n = 12; 26%) did not differ significantly (p = 0.45). The cumulative incidence of bone marrow relapses was significantly lower in those patients who developed aGVHD, after DLI or without DLI (–DLI 63% (95% confidence interval (CI) 43–77), +DLI 41% (95% CI 24–57), –DLIGVHD 21% (95% CI 5–46), +DLIGVHD 14% (1–50%) (p = 0.003)). There were no significant differences between the study groups in terms of the cumulative incidence of extramedullary relapses that ranged from 16% to 29% (p = 0.8). The overall survival of the patients with aGVHD (from the –DLIGVHD and +DLIGVHD groups) was 86% (95% CI 33–98) and 84% (95% CI 50–96), respectively, and it was statistically significantly different from the overall survival of the patients without aGVHD: 54% (95% CI 35–70) and 38% (95% CI 20–56) in the +DLI and –DLI subgroups, respectively (p = 0.012). The loss of HLA heterozygosity was evaluated in 22 (40%) out of 55 patients with a post-transplant relapse. In total, HLA haplotype loss was detected in 7 (32%) patients, 3 of whom were from the +DLI group (42.9%), 2 from the –DLI group (28.6%), and another 2 from the –DLIGVHD group (28.6%). Out of 15 individuals without HLA loss, one patient (6.7%) had a history aGVHD and did not receive DLI (p = 0.57). Thus, prophylactic DLI in children with acute lymphoblastic leukemia and acute myeloid leukemia is shown to be effective in preventing bone marrow relapses after allogeneic HSCT. The development of aGVHD has a potentiating effect resulting in increased immunoadoptive activity of donor lymphocytes. The severity and clinical manifestations of DLI-induced aGVHD in pediatric patients do not differ significantly from those patients who develop classical aGVHD early after transplantation.