EBV-Associated Post-Transplant Lymphoproliferative Disorder after Pediatric Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Yoo Keon Hee , Kim Hee-Jin , Ki Chang Seok , Sung Ki Woong , Jung Hye Lim , Ko Young Hyeh , Koo Hong-Hoe 
Published: October 2019

Abstract
Post-transplant lymphoproliferative disorder (PTLD) is a well-recognized complication arising in recipients of solid organ or hematopoietic stem cells. In most instances, it is caused by abnormal proliferation of EBV-infected B-cells under impaired cytotoxic T-cell control against B-cells. Although pediatric recipients have been known to be more prone to the development of PTLD, no data have been published on PTLD developed in Korean children who received allogeneic HSCT. We reviewed medical records of 255 pediatric allogeneic HSCT performed from March 1998 to January 2007 at Samsung Medical Center. Ten consecutive cases developed EBV-associated PTLD at a median of 94 days (range, 17–242 days) from transplantation. Fever (10/10), hepatosplenomegaly (10/10), lymphadenopathy (7/10), nausea/vomiting (7/10), malaise/lethargy (7/10), diarrhea (7/10), neurological abnormalities (6/10) and weight loss (5/10) were the most common presenting symptoms or signs of PTLD. All patients with PTLD were EBV-seropositive before transplant. EBV genome was detected in tumor cells by in situ hybridization in all cases and 3 cases were monomorphic diffuse large B-cell lymphoma by histology. Nested PCR for immunoglobulin heavy change gene rearrangement and/or kappa and lamda immunostains were done in all cases to determine the clonality of PTLD lesions, which revealed 7 cases of monoclonality, 2 cases of oligoclonality and only 1 case of polyclonality. In all of the 6 patients whose bloods were tested for quantification of EBV genome, 136 to 465800 copies of EBV DNA were detected per 106 PB lymphocytes. The estimated cumulative incidence of PTLD in all subjects was 4.5%. No PTLD occurred following 77 matched-related transplants. The incidence of PTLD was higher after unrelated cord blood transplantation (UCBT, n=61) than that after matched-unrelated marrow transplantation (MUD-BMT, n=86) without statistical significance (10.5% vs 4.9%, P=0.36). The use of ATG in conditioning regimen was a significant risk factor for the development of PTLD (9.1% vs 0.8%, Hazard ratio 11.34, P=0.0036). Eight patients received 2 to 6 weekly doses of rituximab and 5 of those (62.5%) attained complete response. One of the 5 patients who showed complete response died of pneumonia and ARDS. One patient with polymorphic polyclonal disease underwent complete resolution of PTLD with only just withdrawal of immune suppression. There were 5 deaths, 4 of which were due to PTLD progression with or without accompanied GVHD. The estimated 3-year survival from the diagnosis of PTLD was 50% with a median follow-up of 40 months (range, 8–47 mo) among surviving patients. The incidence of PTLD was relatively high in our subjects. Considering that autopsy rate is very low in Korea, the exact incidence of PTLD might be even higher. High index of suspicion and regular follow-up using EBV quantitative PCR, especially for high-risk patients, may be beneficial not to miss the potentially curable disease and to initiate early therapeutic interventions.