Rituximab-Based Treatments Followed By Adoptive Cellular Therapies For EBV-Associated Post-Transplant Lymphoproliferative Disease In Recipients Of Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Jiang Xinmiao , Xu Lanping , Zhang Yu , Huang Fen , Liu Daihong , Sun Jing , Song Chaoyang , Liang Xinquan , Fang Zhiping , Zhou Hongsheng , Dai Min , Liu Can , Jiang Qianli , Xu Na , Xuan Li , Wu Meiqing , Huang Xiaojun , Liu Qifa 
Published: October 2019

Background
The introduction of rituximab has improved the complete remission(CR) rate of EBV-associated posttransplant lymphoproliferative disease(PTLD), thus the recurrence of PTLD becomes the main cause affecting long-term survival, which is closely related with the reestablishment of immune functions. Unfortunately, PTLD happens generally at the early stage of transplants and the reconstitution of immunocompetence needs for 3-5 years in the recipients of allo-HSCT. In this study, a sequential therapeutic strategy that based on rituximab followed by adoptive cellular therapies (G-CSF mobilized donor lymphocyte infusion (DLI) or EBV-specific cytotoxic T lymphocyte infusion (EBV-CTL)) was evaluated for decreasing relapse of PTLD.

Methods
Fifty-two patients with EBV-PTLD were enrolled in this prospective study. Once PTLD was diagnosed,immunosuppressants would be withdrawn in a stepwise fashion (ie, total dose reduced by 20%/week)if the condition of the patient was acceptable. The rituximab-based treatments (rituximab alone or combined with chemotherapy) were administrated based on PTLD histopathology and the blood cells counts. After CR or 2 cycles of rithuximab-based treatments, DLI or EBV-CTL therapy would be performed in this cohort. The rituximab-based treatments would be discontinued once patient obtained CR, and DLI would be performed once Monthly till GVHD occurred or for a total of 4 doses and EBV-CTL infusion would be performed every two weeks till GVHD occurred or for a total of 8 doses .

Results
After 2 cycles of the rituximab-based treatments, 37 patients obtained complete remission (CR), 8 obtained partial remission (PR), and 7 no remission (NR), including 4 died of PTLD progression. The CR rate of 2 cycles of rituximab-based treatments was 71.2%. After rituximab-based treatments combined with the adoptive cellular therapies, 9 obtained CR and 2 died of PTLD progression in 11 patients who did not achieve CR within 2cycles of rituximab-based treatments. The CR rate of 2 cycles of rituximab-based treatments combined with cellular therapies was 88.5%. Seven patients experience acute GVHD (aGVHD) (grade I in 1 and grade II in 6) and 8 chronic (cGVHD) (limited cGVHD in 5 and extensive cGVHD in 3) in 39 patients underwent a median 4 doses of DLI. One patient experienced grade II aGVHD and 2 limited cGVHD in 8 patients underwent a median of 7 doses of EBV-CTL. There were no differences in incidence of aGVHD(P=1.000) and cGVHD(P=1.000) between the patients received DLI and CTL. Within a median follow-up of 632 (range, 21 to 1651) days, one patient experienced PTLD relapse, and the 4 year cumulative incidence of PTLD relapse and primary malignancy relapse was 5.3%±5.1% and 6.2±4.3%, respectively. The 4 year cumulative overall survival (OS) after PTLD and disease(PTLD)-free survival were 66.2%±7.1% and 65.9±7.3%, respectively.

Conclusions
Rituximab-based treatments combined with the adoptive cellular therapies might elevate PTLD CR rate, and decrease the relapse in the recipients of allo-HSCT.

Disclosures:
Liu: It was supported by 863 Program (No. 2011AA020105), National Public Health Grand Research Foundation (Grant No. 201202017): Research Funding; It was supported by National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China(11A72121174): Research Funding.