Pre-Emptive Therapy with Modified Donor Lymphocyte Infusion Could Reduce Relapse and Improve Survival in Standard-Risk Acute Leukemia Patients After Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Yan Chenhua , Liu Daihong , Xu Lanping , Liu Kaiyan , Chen Huan , Han Wei , Wang Yu , Huang Xiaojun 
Published: October 2019

Abstract
Abstract 659
Objects To evaluate the role of pre-emptive therapy with modified DLI on the prevention of relapse and improvement of survival after allo-HSCT. Methods The prospective study was performed to monitor MRD including WT1 and leukemia-associated aberrant immunophenotypes (LAIPs) in consecutive 814 standard-risk acute leukemia and MDS-RAEB patients after allo-HSCT, and then to initiate pre-emptive therapy with IL-2 (group B) or modified DLI (group C). Results The 3-year cumulative incidence of relapse, OS, DFS, and TRM were 18.1%, 66.0%, 61.6% and 19.7% for group A (without MRD); 68.0%, 23.9%, 20.8% and 11.2% for group B; as well as 29.8% (P=0.000), 55.4% (P=0.003), 52.5% (P=0.000), and 15.6% (P=0.208) for group C (Figure 1). In addition, the cumulative incidence of acute GVHD, grade 2 to 4 acute GVHD and grade 3 to 4 acute GVHD after MRD were 10.2%, 8.2% and 4.1% for group B; but 30.8% (P=0.017), 27.9% (P=0.017), and 8.4% (P=0.471) for group C. As well as, the 2-year cumulative incidence of chronic GVHD and chronic extensive GVHD after MRD were 37.3% and 30.5% for group B; as well as 42.9% (P=0.982) and 34.2% (P=0.858) for group C. Multivariate analysis identified pre-emptive therapy with modified DLI for the intervention of MRD (P=0.029, OR=2.016) as the only significant influence factor of superior survival. Furthermore, for the patients receiving modified DLI, multivariate analysis identified DLI-associated chronic GVHD (P=0.037, OR=6.158) and MRD conversion to negative within 3 months after DLI (P=0.042, OR=4.929) as the significant influence factors of lower relapse. Among the patients receiving modified DLI, the patients who had DLI-associated chronic GVHD and had MRD conversion to negative within 3 months after DLI, obtained the most superior survival (3-y relapse 0.0%, TRM 7.7%, OS 92.3%, and DFS 92.3%); however, the patients who had no DLI-associated chronic GVHD and had persistent MRD within 3 months after DLI, obtained the most inferior survival (3-y relapse 51.0% (P=0.045), TRM 20.4% (P=0.484), OS 28.6% (P=0.035), and DFS 27.4% (P=0.041)) (Figure 3). Moreover, apart from the patients who had MRD conversion to negative within 3 months after DLI and had DLI-associated chronic GVHD, repeated DLI possibly made other patients get better survival (P>0.05) (Figure 4). Conclusions This study for the first time confirmed that as compared with the use of IL-2, pre-emptive with modified DLI was more an effective method to prevent relapse and probably a superior method to improve DFS in standard-risk acute leukemia and MDS-RAEB patients after HSCT. Furthermore, for the patients without DLI-associated chronic GVHD, repeated DLI should be performed in order to induce chronic GVHD, so as to possibly make the patients get better survival. In addition, this study confirmed again that MRD monitoring with WT1 and LAIPs was a reliable measure to detect relapse of acute leukemia after HSCT, because of its high specificity and sensitivity.Figure 1.The relapse, TRM, OS and DFS among the patients in all patients. (A) Cumulative incidence of relapse. (B) Cumulative incidence of transplant-related mortality (TRM). (C) Overall survival (OS). (D) Disease-free survival (DFS). The patients without MRD post-HSCT were assigned to group A (n=709); the patients with MRD post-HSCT and receiving IL-2 treatment were assigned to group B (n=49); the patients with MRD post-HSCT and receiving DLI were assigned to group C (n=56). 1* represents the P value of comparison between group B and C; 2* represents the P value of comparison between group A and C; and 3* represents the P value of comparison among three group.Figure 1. The relapse, TRM, OS and DFS among the patients in all patients. (A) Cumulative incidence of relapse. (B) Cumulative incidence of transplant-related mortality (TRM). (C) Overall survival (OS). (D) Disease-free survival (DFS). The patients without MRD post-HSCT were assigned to group A (n=709); the patients with MRD post-HSCT and receiving IL-2 treatment were assigned to group B (n=49); the patients with MRD post-HSCT and receiving DLI were assigned to group C (n=56). 1* represents the P value of comparison between group B and C; 2* represents the P value of comparison between group A and C; and 3* represents the P value of comparison among three group.Figure 2.The relapse, TRM, OS and DFS among the patients receiving DLI (n=56). (A) Cumulative incidence of relapse. (B) Cumulative incidence of transplant-related mortality (TRM). (C) Overall survival (OS). (D) Disease-free survival (DFS). The patients were divided into four groups according to the results of MRD and chronic GVHD after DLI.Figure 2. The relapse, TRM, OS and DFS among the patients receiving DLI (n=56). (A) Cumulative incidence of relapse. (B) Cumulative incidence of transplant-related mortality (TRM). (C) Overall survival (OS). (D) Disease-free survival (DFS). The patients were divided into four groups according to the results of MRD and chronic GVHD after DLI.Figure 3.The effects of repeated DLI on the disease-free survival (DFS). (A) Patients had MRD conversion to negative within 3 months after DLI and had no DLI-associated chronic GVHD (n=15). (B) Patients had persistent MRD within 3 months after DLI, but had no DLI-associated chronic GVHD (n=19). (C) Patients had persistent MRD within 3 months after DLI and had DLI-associated chronic GVHD (n=9). The patients were divided into two groups according to the numbers of DLI that patients received.Figure 3. The effects of repeated DLI on the disease-free survival (DFS). (A) Patients had MRD conversion to negative within 3 months after DLI and had no DLI-associated chronic GVHD (n=15). (B) Patients had persistent MRD within 3 months after DLI, but had no DLI-associated chronic GVHD (n=19). (C) Patients had persistent MRD within 3 months after DLI and had DLI-associated chronic GVHD (n=9). The patients were divided into two groups according to the numbers of DLI that patients received.

Disclosures:
No relevant conflicts of interest to declare.