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Epstein-Barr virus (EBV) infection may result in a spectrum of diseases in recipients of transplant. The aim of this study is to investigate the incidence, clinical characteristics, and prognosis of the spectrum of EBV-associated diseases in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Background:Relapsed/refractory Peripheral T-cell lymphomas (PTCL) is an aggressive and heterogeneous Non-Hodgkin's T cell lymphoma, which is resistant to conventional chemotherapy with poor prognosis. Therefore, there is an urgent need to exploit potential therapeutics and novel treatment for R/R PTCL. Targeting PI3K/AKT/mTOR pathway is an effective therapy for PTCL. However, recent research demonstrated that the mTOR inhibitor everolimus monotherapy has low response rate and short duration time in treating with R/R PTCL.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Background:Primary mediastinal B-cell lymphoma (PMBCL) is a rare subtype of aggressive B-cell lymphoma. The majority of relapses occur within the first few months resulting in a dismal prognosis, thus we need to identify the risk of early relapse. Circulating tumor DNA (ctDNA)-based response assessment may enable response adapted therapy and early prognostication. In this study, we aim to clarify the role of ctDNA-monitoring in early prediction of relapse.

Li: Guangdong Province Hospital: Employment.

Li: Guangdong Province Hospital: Employment.

Li: Guangdong Province Hospital: Employment.

Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group comprising about 10-15% of non-Hodgkin lymphomas in Western populations. Only a minority (~30%) of patients with the most common PTCL subtypes achieve a durable remission and long-term survival. Data on the clinical features of PTCL in a Chinese population are limited.

Background:Relapsed/refractory anaplastic lymphoma kinase (ALK) positive anaplastic large cell lymphomas (ALCLs) respond to ALK inhibitors, but resistance, which bear a poor prognosis. No biomarkers were found to predict long duration of response to ALK inhibitors. The ALK gene was first identified as the fusion partner of the nucleophosmin (NPM1) gene in the recurrent t(2;5)(p23;q35) found in a subset of ALCL. However, several distinct ALK fusions which result in highly different characteristics have also been described in lymphomas.

Background:

About 10-15% DLBCL are primary refractory, the underlying biology aggressiveness contributed to refractoriness remain to be defined. To date, whole-exome (WES) or whole-genome sequences (WGS) obtained from primary or refractory/relapse DLBCL tumors have been published, while the biology study conduct on patients of mixed prognosis failed to characterizing the 10-15% primary refractory cases, and WES or WGS are not applicable in clinical routine practice. To address this issue, we performed target next generation sequencing in 11 primary refractory DLBCL cases. Through pathway enrichment analysis, as expected, the cell cycle/apoptosis and P53 signaling (FDR 10-11~10-9), NF-kB (FDR ~10-9), BCR signaling(FDR ~10-9), PI3K/Akt (FDR ~10-8), MAPK(FDR ~10-10), Wnt (FDR ~10-12), Jak/STAT (FDR ~10-14) signaling were significant mutated. Furthermore, some pathogen infection pathways were also significantly affected, which was not identified as significantly mutated in previous DLBCL WGS studies, including hepatitis B virus infection(HBV) signaling pathway involving BCL-2, MYC, MYD88, CREBBP, FAS, STAT3, TP53, and 4 of the 11 (36.4%) patients were HBsAg-positive. Overall, somatic mutations or copy number aberrations of CD79B (5/11, 45.5%), TP53(4/11, 36.3%), PIM1 (4/11, 36.3%) , MYD88 (3/11, 27.2%), KMT2D (3/11, 27.2%), CREBBP(3/11, 27.2%) and IRF4 (3/11, 27.2%) were the most prevalent aberrations. We separately compared the prevalence of target gene variants in our refractory (ref)-DLBCLs to published cohorts of responsive or de novo or relapse(rel) or relapse/refractory(r/r)-DLBCLs, the profile and frequency was highly concordant to those of relapse ones, while CD79B and cell cycle regulation or apoptosis related genes were more prevalent affected in our refractory cohort than those of responsive or de novo ones(table 2).

ABSTRACTTo improve prognosis of post-transplant lymphoproliferative disease (PTLD), a sequential therapeutic strategy that rituximab-based treatments followed by donor lymphocyte infusion (DLI) or autologous EBV-specific cytotoxic T lymphocytes (EBV-CTL) for biopsy-proven EBV-associated PTLD in recipients of allogeneic hematopoietic stem cell transplantation was designed. 84 patients with EBV-PTLD were enrolled in this prospective study. After two cycles of the rituximab-based treatments, 68 of 84 patients (81% [95% CI 71–88]) responded and 52 (62% [51–72]) had CRs. This increased to 73 of 77 patients (95% [87–98]) with completion of sequential cell infusions, and 70 of 77 (91% [82–96]) achieved CRs after DLI or autologous EBV-CTL infusion. 22 patients experienced acute GVHD (aGVHD) (grade I in 5 and grade II in 13, grade III in 4) and 13 chronic GVHD (limited cGVHD in 7 and extensive cGVHD in 6) in 62 patients undergoing a median of three doses of DLI. The incidences of GVHD were similar between DLI and EBV-CTL group (aGVHD 35% vs. 33%, p= 0.876; cGVHD 21% vs. 13%; p= 0.503). EBV-CTL activity after the rituximab-based treatments did not change, while increased after cell infusions and reached its maximum in the 3rd or 6th month after EBV-CTL or DLI treatment, respectively. The 5-y cumulative incidence of PTLD relapse was 4.5% ± 3.3%. The 5-y overall survival (OS) and progression-free survival (PFS) after PTLD were 70.7% ± 5.2% and 68.9% ± 5.3%, respectively. Rituximab-based treatments combined with adoptive cellular immunotherapy might elevate CR rates and reduce relapse of PTLD after allo-HSCT.

Epstein-Barr virus (EBV) infection is a common complication in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT), leading to fatal post-transplant lymphoproliferative disorders (PTLD) and other EBV-associated diseases. A few studies suggested that cytomegalovirus (CMV) might play a role in PTLD. In this study, the effect of CMV on EBV DNA-emia and EBV-associated diseases was evaluated in the recipients of allo-HSCT.Three hundred and fifty-two patients undergoing allo-HSCT were enrolled in this prospective study between July 2008 and June 2013. The EBV-DNA and CMV-DNA levels in blood and secretion were monitored by quantitative real-time polymerase chain reaction (RQ-PCR) before and in different time points after transplantation. EBV and CMV DNA-emia were diagnosed when EBV-DNA or CMV-DNA in the blood was positive twice consecutively.During the follow-up period, 99 patients (28.1%) developed EBV DNA-emia and 41 (11.6%) developed EBV-associated diseases including 27 EBV-associated PTLD and 14 other EBV-associated diseases. One hundred and fifty-nine patients (45.2%) developed CMV DNA-emia and 10 (2.8%) developed CMV-associated diseases. Of the 99 patients who developed EBV DNA-emia, 56 had CMV DNA-emia before EBV DNA-emia, and the median time from occurrence of CMV DNA-emia to EBV DNA-emia and EBV-associated diseases were 15 (range, 0-269) days and 26 (range, 0-255) days, respectively. Six patients developed co-existing CMV DNA-emia at the time of EBV-associated diseases diagnosed. DNA-emia before EBV infection had positive correlation with EBV DNA-emia (r=0.14, p=0.007) and EBV-associated diseases (r=0.15, p=0.005), but both correlation coefficients were weak. There was a strong positive correlation between EBV DNA-emia and EBV-associated diseases (r=0.56, p<0.001). The patients with CMV DNA-emia had a higher risk for developing EBV infection than those without (OR 2.279, 95% confidence interval [CI] 1.420-3.657, p=0.001). After EBV infection occurred, 15 patients developed CMV DNA-emia, including 4 developed CMV-associated diseases, at a median time of 33 days (range, 12-50 days). EBV infection was not related to CMV DNA-emia (p=0.87) or CMV associated diseases (p=0.27) occurring after EBV infection.The results suggest that CMV may play a contributory role in the development of EBV DNA-emia and EBV-associated diseases.Liu: This work was supported by the National High Technology Research and Development Program of China (863 Program) (No. 2011AA020105), the National Public Health Grand Research Foundation (Grant No. 201202017).: Research Funding; This work was also supported by National Natural Science Foundation of China (Grant No.81000231, No.30971300, No.81270647), the Science and Technology Project of Guangdong Province of China (Grant No.2009A030200007).: Research Funding; This work was also supported by the Science and Technology Program of Guangzhou of China (11A72121174).: Research Funding.

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.

Epstein-Barr virus (EBV) infection is a common complication in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT), leading to fatal post-transplant lymphoproliferative disorders (PTLD) and other EBV-associated diseases. A few studies suggested that cytomegalovirus (CMV) might play a role in PTLD. In this study, the effect of CMV on EBV DNA-emia and EBV-associated diseases was evaluated in the recipients of allo-HSCT.

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