Hodgkin’s Disease / Hodgkin-PTLD after Solid Organ Transplantation in Children: A Report on 16 Patients Treated According to Subsequent Gpoh-HD Treatment Schedules
Authors: Kampers Johanna , Beier Rita , Orjuela-Grimm Manuela A. , Schober Tilmann , Schulz Thomas , Stiefel Martina , Klein Christoph , Mauz-Koerholz Christine , Kreipe Hans H. , Maecker-Kolhoff Britta 
Published: October 2019

Abstract
Post-transplant lymphoproliferative diseases (PTLD) are severe complications of immunosuppressive therapy after solid organ transplantation (SOT) in children. Among those, Hodgkin’s disease (HD) or Hodgkin(-like) PTLD is a rare entity, and systematic data on pathogenesis, treatment, and prognosis are lacking. Here, we report on 16 children and adolescents who were treated according to standard treatment guidelines from the German HD (GPOH-HD) study cente.
All patients with HD after SOT reported to the German pediatric PTLD (Ped-PTLD) registry between 1999 and 2013 were included in this analysis (14 of 182 patients = 7.7% of pediatric PTLDs). Data were supplemented by information recorded in the GPOH-HD registry. In addition, 2 U.S. patients treated according to the respective GPOH-HD guidelines were included. Central pathology review was performed in 12/16 cases. Epstein-Barr virus (EBV) in tumor tissue was evaluated by EBER in situ hybridization, immunohistochemistry for LMP-1 or EBNA-2, and/or EBV-PCR. All patients were treated with chemotherapy according to the respective GPOH-HD recommendations (treatment group (TG)-1: 2xOEPA; TG-2: 2xOEPA+2xCOPP/COPDAC; TG-3: 2xOEPA+4xCOPP/COPDAC) tailored according to stage and LDH. Indication for involved field radiotherapy was based on the current study recommendations. Six patients had additional rituximab treatment, two as upfront monotherapy and four as addition to chemotherapy. Events recorded included disease progression, relapse, second malignancy, and death of any cause. Overall and event-free survival was calculated using log-rank test.
16 predominantly male (13/16) patients developed HD after SOT, among them 7 renal, 4 liver, and 5 heart transplant recipients. Median age at diagnosis of HD was 13.9 [range 4.3 – 19.4] years with a median duration from SOT to HD of 7.4 [0.75 – 14.3] years. Histopathology review was classified as classical Hodgkin’s disease in 10 patients (nodular sclerosis =1, mixed type =5, epitheloid-cell predominant =2, not further specified =2) and Hodgkin-PTLD in 6 patients. 8 of 10 patients with data evaluable had a negative EBV-serology at transplantation, while antibodies against EBV were detected in 15/15 patients at the time of HD diagnosis. Fifteen of sixteen tumors proved positive for EBV and/or EBV-gene products. As expected, all tumors expressed CD30 and 7 of 16 tumors demonstrated moderate to strong expression of CD20.
Staging revealed 1 patient with stage I disease, 8 with stage II, 5 with stage III, and 2 patients with stage IV disease. Four patients presented with extranodal involvement, among them one with graft organ involvement, and three patients with involvement of the gastrointestinal tract. None of the patients had CNS disease. Patients were treated in TG-1 (6 patients), TG-2 (5 patients), TG-3 (4 patients), respectively. One patient received an individualized treatment scheme, and 2 of 16 patients (both TG-2) were assigned to consolidating involved field radiotherapy. Median follow up was 4.1 [0.3 – 9.2] years. One patient in TG-3 died of infection during COPDAC treatment; all others are alive at the time of abstract preparation. Overall survival (OS) at 2 and 5 years was 93%. In addition to the treatment-related death two patients experienced events, 1 relapse after 9 months and 1 secondary malignancy (polymorphic PTLD) after 1.2 years. Event-free survival after HD chemotherapy at 2 and 5 years was 79%. Rituximab monotherapy did not result in long-term remission, both patients relapsed after 0.4 and 2.7 years, respectively. None of the parameters examined (organ graft, stage, treatment group) was significantly associated with overall or event-free survival.
In conclusion, HD is a rare type of PTLD in children arising late after SOT, which may lead to underrepresentation in the pediatric patient population. The analysis of 16 patients treated according to a uniform concept represents the largest series reported to date. Almost all cases were EBV-associated. Although tumors often express CD20 rituximab monotherapy does not seem to establish long-lasting remissions. In contrast, the chemotherapy regimens based on the German protocols for de novo Hodgkin’s disease present well tolerated and effective treatment strategies for HD after SOT in children. International efforts are warranted to improve understanding and treatment for this rare disease.

Disclosures
No relevant conflicts of interest to declare.