Post-transplant Lymphoproliferative Disorder In Children Research Articles

The IPTA Nashville consensus conference on post-transplant lymphoproliferative disorders after solid organ transplantation in children: IV-consensus guidelines for the management of post-transplant lymphoproliferative disorders in children and adolescents.

The International Pediatric Transplant Association convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post-transplant lymphoproliferative disorders (PTLD) after pediatric solid organ transplantation. This report addresses the outcomes of deliberations by the PTLD Management Working Group. A strong recommendation was made for reduction in immunosuppression as the first step in management. Similarly, strong recommendations were made for the use of the anti-CD20 monoclonal antibody (rituximab) as was the case for chemotherapy in selected scenarios. In some scenarios, there is uncoupling of the strength of the recommendations from the available evidence in situations where such evidence is lacking but collective clinical experiences drive decision-making. Of note, there are no large, randomized phase III trials of any treatment for PTLD in the pediatric age group. Current gaps and future research priorities are highlighted.

Mutations in latent membrane protein 1 of Epstein-Barr virus are associated with increased risk of posttransplant lymphoproliferative disorder in children

Epstein-Barr virus (EBV)–positive posttransplant lymphoproliferative disorder (PTLD) results in significant morbidity and mortality in pediatric transplant recipients. Identifying individuals at an increased risk of EBV-positive PTLD could influence clinical management of immunosuppression and other therapies, improving posttransplant outcomes. A 7-center prospective, observational clinical trial of 872 pediatric transplant recipients evaluated the presence of mutations at positions 212 and 366 of EBV latent membrane protein 1 (LMP1) as an indicator of risk of EBV-positive PTLD (clinical trials: NCT02182986). DNA was isolated from peripheral blood of EBV-positive PTLD case patients and matched controls (1:2 nested case:control), and the cytoplasmic tail of LMP1 was sequenced. Thirty-four participants reached the primary endpoint of biopsy-proven EBV-positive PTLD. DNA was sequenced from 32 PTLD case patients and 62 matched controls. Both LMP1 mutations were present in 31 of 32 PTLD cases (96.9%) and in 45 of 62 matched controls (72.6%) (P = .005; OR = 11.7; 95% confidence interval, 1.5, 92.6). The presence of both G212S and S366T carries a nearly 12-fold increased risk of development of EBV-positive PTLD. Conversely, transplant recipients without both LMP1 mutations carry a very low risk of PTLD. Analysis of mutations at positions 212 and 366 of LMP1 can be informative in stratifying patients for risk of EBV-positive PTLD.

Distinctive Clinicopathologic Features of Monomorphic B-cell Post-transplant Lymphoproliferative Disorders in Children.

Post-transplant lymphoproliferative disorders (PTLDs) comprise a heterogeneous group of Epstein-Barr virus (EBV)-positive or negative lymphoid or plasmacytic lesions in solid organ or hematopoietic stem cell (HSC) transplant recipients. Although PTLDs in adults have been extensively studied, the clinicopathologic features of monomorphic B-cell PTLD in children, particularly EBV-negative forms, are still poorly understood. We retrospectively reviewed all our pediatric cases of monomorphic B-cell PTLDs diagnosed in the past 10 years. Clinical data were reviewed. Pathologic data including histologic types and EBV status were analyzed. Additional immunohistochemical stains, FISH studies, and TP53 gene mutational status were performed. 4 of 18 cases were EBV-negative. All 4 EBV-negative cases were strikingly confined to the gastrointestinal (GI) tract or abdominal lymph nodes, while tumors in EBV-positive cases were found at various anatomic sites; 2 of 4 EBV-negative cases carried mutations in TP53 gene. Our cohort also included 2 rare types of PTLD, one plasmablastic lymphoma and one high-grade B-cell lymphoma, not otherwise specified (HGBL, NOS). We report that monomorphic B-cell PTLDs in children have distinctive clinical and pathological features. More studies are needed to clarify whether and how much these pediatric PTLDs differ from their adult counterparts.

A 9-Year-Old Male with Barth Syndrome and a Cardiac Transplant Presenting with Hyperviscosity Syndrome Caused By EBV-Negative Plasmacytic PTLD

Posttransplant lymphoproliferative disorders (PTLD) are a spectrum of disorders characterized by lymphoid or plasmacytic proliferation secondary to extrinsic immunosuppression in solid organ transplant (SOT) or hematopoietic transplant recipients. According the 2016 revision of World Health Organization (WHO) classification, PTLD ranges from early lesion (mononucleosis-like) lymphoid hyperplasia or plasmacytic hyperplasia, polymorphic, monomorphic to classical Hodgkin lymphoma PTLD (Swerdlow et. al. Blood 2016). The incidence of PTLD in the pediatric population is closely associated with the type of transplanted organ, with the highest incidence in lung and small bowel transplant recipients due to chronic, iatrogenic immunosuppression. While Epstein-Barr Virus (EBV) is the key driver of abnormal lymphocytic proliferation in the majority of PTLDs, EBV-negative PTLD is a distinct subtype. We hereby report a 9-year-old boy with Barth syndrome, a rare genetic syndrome caused by a TAZ mutation, characterized by dilated cardiomyopathy, skeletal myopathy, neutropenia, and short stature. He required a heart transplant for left ventricular non-compaction cardiomyopathy at 11 months of age and presented with lower GI bleeding, acute-onset anemia, somnolence, retinal hemorrhages, and increased serum viscosity eight years post transplant. Workup was significant for hyperimmunoglobulinemia with elevated IgA and IgG, and serum protein electrophoresis (SPEP) showed two monoclonal bands (IgA Lambda and IgG Kappa) and an M spike. He was treated with plasmapheresis, and his symptoms improved significantly. Further workup with PET/CT scan showed diffuse lymphadenopathy of cervical, mediastinal, axillary, abdominal, and inguinal lymph nodes. Axillary lymph node biopsy was done, demonstrating a nondestructive morphology with an increase in plasma cells expressing excess lambda light chain and IgA; these abnormal cells were CD20 negative and CD138 positive, suggesting a clonal process. Cytogenetic fluorescence in situ hybridization (FISH) showed loss of TP53. Serum EBV detection by PCR and EBER staining by immunohistochemistry (IHC) on lymph node pathology were negative. Bone marrow biopsy showed a hypocellular marrow with trilineage hematopoiesis and 5-10% CD138 positive plasma cells. Combined, these studies were consistent with the diagnosis of early onset, nondestructive, plasmacytic PTLD. The patient was treated with a multiple myeloma-type therapy with dexamethasone and bortezomib (Short et. al. J Pediatr Hematol Oncol 2016), in addition to reduced immunosuppression consisting of low dose tacrolimus. Repeat PET/CT scan after 2 cycles of therapy showed resolution of previous PET-avid lesions. Stem cell collection was performed after 3 cycles in case of relapsed or recurrent disease. He completed 5 cycles of therapy with no complications. Unfortunately, the patient's end of treatment PET/CT scan was significant for a new mediastinal mass and multiple intraabdominal lymph nodes. Lymph node biopsy showed a lymphoplasmacytic infiltrate, which was IgA and lambda positive. The cells showed plasmacytoid features, but in contrast to the initial biopsy at diagnosis, there was marked CD20 positivity (image attached). This recurrence was most suggestive of a marginal zone lymphoma like PTLD (Galera et. al. Am J Surg Pathol 2020). He was initiated on therapy with rituximab and bendamustine. He is currently status post 2 treatment cycles and doing well. We continue to discuss the utility of autologous bone marrow transplant in this case, although the risks and benefits will have to be weighed carefully in a child who is prone to develop infections and complications from Barth Syndrome. We would like to share this case of EBV negative, plasmacytic PTLD with relapsed marginal zone lymphoma type PTLD to highlight the heterozygous pathologies of PTLD in children, and to share our experience of treating in the absence of standard protocol due to the rarity of this diagnosis. Figure Disclosures No relevant conflicts of interest to declare.

Transplantation for congenital heart disease is associated with an increased risk of Epstein-Barr virus–related post-transplant lymphoproliferative disorder in children

Children undergoing heart transplant are at higher risk of developing post-transplant lymphoproliferative disorder (PTLD) than other solid organ recipients. The factors driving that risk are unclear. This study investigated risk factors for PTLD in children transplanted at 1 of 2 United Kingdom pediatric cardiac transplantation centers. All children (<18 years, n = 200) transplanted at our institution over a 16-year period were analyzed. Freedom from PTLD was assessed using the Kaplan-Meier method and Cox proportional regression. PTLD occurred in 17 of 71 children transplanted for congenital heart disease (CHD) and 18 of 129 transplanted for acquired cardiomyopathy (ACM). The cumulative incidence of all PTLD was 21.1% at 5 years after transplant. Median time from transplant to PTLD was 2.9 years (interquartile range: 0.9-4.6). Negative Epstein-Barr virus (EBV) serostatus pre-transplant (adjusted hazard ratio [HR]: 2.7, 95% CI: 1.3-5.6, p = 0.01) and underlying CHD (adjusted HR: 3.2, 95% CI: 1.4-7.4, p = 0.007) were independently associated with higher risk of PTLD. Age at thymectomy was significantly different between children with CHD and ACM (0.4 vs 5.5 years, p < 0.01). Median CD4+ and CD8+ T lymphocyte counts at 2years after transplant were significantly lower in children transplanted for CHD vs ACM (CD4+: 391/µl vs 644/µl, p = 0.01; CD8+: 382/µl vs 500/µl, p = 0.01). At 5years after transplant, those differences persisted among patients who developed PTLD (CD4+, 430/µl vs 963/µl, p < 0.01 and CD8+, 367/µl vs 765/µl, p < 0.01). Underlying CHD is an independent risk factor for PTLD and is associated with a younger age at thymectomy. A persistent association with altered T lymphocyte subsets may contribute to the impaired response to primary EBV infection and increase the risk of PTLD.

Epidemiology of Post-Transplant Lymphoproliferative Disorders in Children with Solid Organ Transplant over 34 Years of a Single Center Experience

Background Post-Transplant lymphoproliferative disorders (PTLD) are a heterogeneous group of lymphoid neoplasms following solid organ transplantation (SOT) caused by uncontrolled lymphoproliferation often induced by Epstein Barr Virus (EBV) due to the lack of cytotoxic T cell response resulting from immunosuppression. A pre-emptive intervention strategy for PTLD prevention was implemented in our center in 2002 for all EBV-mismatched SOT recipients consisting in close monitoring of the viral load and consideration for early intervention (Ex; reduction of immunosuppression) in addition to universal antiviral prophylaxis (implemented in 1990). We aim to describe the incidence and risk factors for PTLD in children with SOT, including all transplant types, at a single center over 34 years. We also aim to analyze the impact of a pre-emptive PTLD prevention program. Material and methods All patients younger than 18 years of age who received SOT at the University of Alberta Hospital/Stollery Children's Hospital from January 1st, 1984 to December 31st, 2018 were included. Donor and recipient baseline data (age, sex, donor living status, date and type of transplant, EBV and cytomegalovirus serostatus) were extracted from a prospective database. Retrospective chart review was performed for PTLD cases along with expert pathology review (when tissue available). Local Ethics Board was obtained. Statistical analyses were performed using SPSS software version 25 and R version 3.3.3. Results Characteristics of the study population, immunosuppression regimen used by transplant program and specific immunosuppression for PTLD cases are summarized in table 1, 2 and 3 respectively. PTLD characteristics were compared based on the time of presentation of PTLD ≤1 year, 1 to 5 years and &amp;gt;5 years (table 4). Most of the cases with PTLD presented with primary involvement in multiple sites followed by lymph nodes, gastro-intestinal tract, allograft, tonsils/adenoids and other sites. Advance staging (III-IV) was present in 71% of cases. The incidence rate of PTLD for the whole group was 0.82/100 Person-year (Figure 1 A). The incidence rate peaked at 1-year post-transplant and had a decreasing trend in the following years post-transplant, with no cases beyond 12 years post-transplant (Figure 1 B). The cumulative incidence was the highest for the multi-visceral transplants followed by thoracic, liver and kidney transplants (Figure 1C). Univariate analysis showed children younger than 5 years at transplant had 5-fold higher risk of PTLD compared to children ≥ 10 years of age at transplant. Donors ≤ 5 years of age at transplant, showed 3-fold higher risk PTLD comparing to older donors. Liver transplant had 2.8-fold and thoracic transplants had 5-fold higher risk of PTLD comparing to kidney transplants, no significant risk was associated with multi-visceral group (only 1 case in the cohort). EBV seronegative recipient was associated with 2.6-fold higher risk of PTLD comparing to EBV seropositive recipient. Era prior to implementation of pre-emptive intervention had 3-fold risk of PTLD comparing to era post implementation. Patients transplanted at 1.1 - 5 years of age was an independent risk factor associated with PTLD in multivariate analysis (table 3) SOT recipients showed EBV seroconversion with age (Figure 3A). PTLD based on EBV Donor Recipient (DR) serostatus showed more cases D positive R negative (D+R-) in the first-year comparing to D negative Recipient negative (D-R-), D-R- cases increased between 1-5 years equivalent to D+R-, beyond 5 years D+R- decreased with no D-R- cases (Figure 3B). D-R- serostatus had the highest probability of PTLD followed by D+R- (Figure 3 C). Eleven (24%) out of 45 patients with PTLD presented with PTLD relapse. Seven (5.6%) out of 125 deaths of SOT were secondary to PTLD. PTLD was the most common cause of death in the PTLD group (50%) followed by graft failure/rejection. Conclusions Incidence of PTLD peaked in the first-year post-transplant and decreased overtime with increase incidence in thoracic and multi-visceral transplants. Risk factors for PTLD included patients transplanted at younger age, younger donors, thoracic and liver transplants and EBV seronegativity in the recipient. A pre-emptive intervention strategy for PTLD prevention implemented in 2002 decreased the risk of PTLD. Disclosures No relevant conflicts of interest to declare.

Editorial introductions

Editorial introductions

Post-Transplant Lymphoproliferative Disorders (PTLDs) After Heart Transplantation

Objective Post-transplant lymphoproliferative disorders (PTLDs) are one of most important cause of morbidity and mortality after heart transplantation (HTx), especially in children. Although Rituximab therapy combined with chemotherapy and reduced immunosuppression has been reported to be effective to suppress B cell type PTLD (B-PTLD), PTLDs relapse frequently and the outcome is still poor. Everolimus (EVL) has been reported to inhibit growth of human EBV-transformed B lymphocytes in vitro and in vivo. In this report, we described 4 adults and 4 children of PTLD after HTx. Material and Methods All 8 cases were suffered from B-PTLD and one concomitantly had leiomyoma. Duration between HTx and onset of PTLD in children was shorter than that in adults [a mean 20.0 (6 to 38) months vs 65.5 (18 to 104) months]. In all patients, final diagnosis was made by histological examination (lymph nodes in 4, tumors in 3 and ulcer in 1). All patients received calcineurin inhibitor (CNI) (cyclosporine in 3 and tacrolimus in 5) and 7 received mycophenolate mofetil and one received EVL prior to PTLD. Results All 4 children and 3 adult showed elevation of Epstein Barr virus (EBV) DNA. In children, chief complaints were fever and/or abdominal pain, but no adults showed abdominal pain. All patients were given Rituximab and chemotherapy with reduced. EVL was started to be given after chemotherapy to keep a trough level within 3-8 ng/ml. A girl showed relapse of PTLD in the trachea, but she was cured after Rituximab treatment and withdrawal of CNI. One adult showed relapse of T-PTLD 7 years after the onset of B-PTLD. One adult shoed relapse of PTLD in the chest and died 15 months after the onset of PTLD. One boy showed complete remission of B-PTLD but still had multiple leiomyoma in the intestine. Other 4 patients showed no relapse. Conclusion All patients had B-PTLD but showed different histology and clinical findings. Most patients were associated with EBV and combination therapy with Rituximab may be useful. However, to manage PTLD, individual strategy might be required, and histological examination is essential to decide treatment strategy. the Practical Research Project for Allergic Diseases and Immunology (Research on Technology of Medical Transplantation) from the Japan Agency for Medical Research and Development, AMED (Grant No. 17ek0510017h0002).

A Review of Induction with Rabbit Antithymocyte Globulin in Pediatric Heart Transplant Recipients.

Pediatric heart transplantation (pHTx) represents only a small proportion of cardiac transplants. Due to these low numbers, clinical data relating to induction therapy in this special population are far less extensive than for adults. Induction is used more widely in pHTx than in adults, mainly because of early steroid withdrawal or complete steroid avoidance. Antithymocyte globulin (ATG) is the most frequent choice for induction in pHTx, and rabbit antithymocyte globulin (rATG, Thymoglobulin®) (Sanofi Genzyme) is the most widely-used ATG preparation. In the absence of large, prospective, blinded trials, we aimed to review the current literature and databases for evidence regarding the use, complications, and dosages of rATG. Analyses from registry databases suggest that, overall, ATG preparations are associated with improved graft survival compared to interleukin-2 receptor antagonists. Advantages for the use of rATG have been shown in low-risk patients given tacrolimus and mycophenolate mofetil in a steroid-free regimen, in sensitized patients with pre-formed alloantibodies and/or a positive donor-specific crossmatch, and in ABO-incompatible pHTx. Registry and clinical data have indicated no increased risk of infection or post-transplant lymphoproliferative disorder in children given rATG after pHTx. A total rATG dose in the range 3.5–7.5 mg/kg is advisable.

Посттрансплантационное лимфопролиферативное заболевание у детей после аллогенной транспланта- ции гемопоэтических стволовых клеток: опыт центра и обзор литературы

Посттрансплантационное лимфопролиферативное заболевание у детей после аллогенной транспланта- ции гемопоэтических стволовых клеток: опыт центра и обзор литературы

Epstein-Barr Virus-related Posttransplant Lymphoproliferative Disorder in Children: A Single-institution Experience.

We report 4 pediatric cases of biopsy-proven posttransplant lymphoproliferative disorder (PTLD) in the context of allogeneic hematopoietic stem cell transplantation (HSCT). All cases showed diffuse staining with latent membrane protein-1 in immunohistochemistry. The median age at transplant of 4 patients with PTLD was 10.1 years (range, 2.2 to 13.2 y). The median interval between HSCT and the diagnosis of PTLD was 5.5 months (range, 4 to 8 mo). All patients were treated with rituximab at dosage of 375 mg/m at weekly intervals. Reduction of immunosuppression was warranted in all cases. All patients survived with median follow-up duration of 27 months. Although PTLD has been rare following allogeneic HSCT, reduction of immunosuppression combined with rituximab yielded significant response rates in patients with this infrequent but potentially lethal complication. The preliminary finding of this study demonstrated that severe aplastic anemia is closely associated with the development of PTLD in children.

Pathology of Central Nervous System Posttransplant Lymphoproliferative Disorders: Lessons from Pediatric Autopsies

Posttransplant lymphoproliferative disorders (PTLD) involving the central nervous system (CNS) in children are uncommon and can prove diagnostically challenging. The clinical and imaging characteristics of CNS PTLD can overlap with those of infection, hemorrhage, and primary CNS tumors. Some cases of CNS PTLD remain clinically unsuspected and are diagnosed postmortem. We report 6 instances of CNS PTLD in children, 2 of which were limited to the CNS and were unsuspected before autopsy. In our autopsy series, PTLD was found outside the CNS in 4 out of 6 cases. Since CNS PTLD has a poor prognosis and the presentation can be subtle, unsuspected, and high grade, it is important to maintain a high index of suspicion and to perform imaging and brain biopsy whenever clinically appropriate. In the presence of leptomeningeal involvement, the diagnosis could be made by cerebral spinal fluid examination.

Epstein-Barr Virus-Related Post-Transplant Lymphoproliferative Disorder in Children Treated with Rituximab: The Impact of Viral Load and Non-Lymphoid Tissue Involvement

Epstein-Barr Virus-Related Post-Transplant Lymphoproliferative Disorder in Children Treated with Rituximab: The Impact of Viral Load and Non-Lymphoid Tissue Involvement

Post-transplant lymphoproliferative disorders in children: The role of chemotherapy in the era of rituximab

PTLD are the most frequent neoplasms in children postorgan transplantation. We describe our experience in the treatment of 14 children (three with early and 11 with late-onset disease) treated with a step-wise protocol developed at our institution. Treatment consisted of reducing immunosuppressants, followed by rituximab and chemotherapy if required. Rituximab, incorporated into the protocol in 2001, has been determinant for the total chemotherapy burden patients need to achieve remission. In seven patients who did not receive rituximab, anthracycline total dose ranged from 160 to 240 mg/m(2), while only one of the patients receiving rituximab required DOXO (range: 0-120 mg/m(2)) (p = 0.003). The use of alkylating agents was also notably lower in patients receiving rituximab (median dose = 1200 mg/m(2)) compared with those who did not receive rituximab (median dose = 5800 mg/m(2)) (p = 0.006). Twelve patients are in remission and two died, one from refractory disease and the other from septic shock. Two-year OS and EFS were 85.7% and 57%, respectively. In conclusion, our experience with the use of rituximab in children with PTLD after solid organ transplantation appeared to be associated with a lesser requirement for alkylating agents and anthracyclines compared with historical subjects, suggesting a reduction in the side effects of these agents.

Central nervous system lymphoproliferative disorder in pediatric kidney transplant recipients

Post-transplant lymphoproliferative disorder (PTLD) is a complication of transplantation resulting from impaired immune surveillance because of pharmacologic immunosuppression. We present two cases of central nervous system (CNS) PTLD in children on calcineurin-inhibitor free immunosuppression with dramatically different presentations and outcomes. One patient had brain and spinal cord lymphoma with a rapid and fatal course. The other patient had brain and ocular PTLD that responded to multimodal therapy with reduction of immunosuppression, high-dose steroids, and rituximab given in a dose-escalation protocol. This protocol may have enhanced the penetration of rituximab into the CNS. We review the literature on CNS and ocular PTLD and elaborate on the treatments available for both diseases.

Post‐transplant lymphoproliferative disorder following pediatric heart transplantation

Immunosuppression after heart transplantation is implicated in development of post-transplant lymphoproliferative disorder (PTLD). Despite a higher prevalence of PTLD in children, there is scarce knowledge about incidence, pathophysiologic mechanisms and risk factors for PTLD in pediatric recipients of cardiac allografts. We examined retrospectively the medical records of all 143 pediatric patients (mean age 9.2 +/- 6.1 yr) who received donor allografts between 1984 and 2002 and survived over 30 days. Five children (3.5%) developed PTLD over a mean follow-up period of 41.1 +/- 46.0 months. Time from transplant to diagnosis of PTLD ranged from 3.9 to 112 months (mean 48.0 +/- 41.9 months). Excluding PTLD, no other malignancies were found in this population. Actuarial freedom from PTLD was 99.2%, 99.2% and 96.2% at 1, 2, and 5 yr, respectively. Children who developed PTLD were more likely (by univariate analysis) to have been Rh negative (p = 0.01), Rh mismatched (p = 0.003), Epstein-Barr virus (EBV) seronegative (p = 0.001) and transplanted for congenital heart disease (p < 0.02). PTLD was associated with significant morbidity and mortality with a mean survival following diagnosis of 21.2 months. PTLD is a serious complicating outcome of cardiac transplantation that occurs in approximately 3.5% of children. Aside of immunosuppression, risk factors in this series for developing PTLD include EBV seronegativity and Rh negative status and mismatch. Non-hematogenous malignancies are rare in light of short allograft half-life.

Post-Transplant Lymphoproliferative Disorder in Children

Post-transplant lymphoproliferative disorder (PTLD) after solid organ or hematopoietic stem cell transplantation in children is a serious complication that has been responsible for high mortality rates over recent years. PTLDs are part of a clinically and histologically heterogeneous group of B-lymphocyte proliferations mostly induced by Epstein-Barr virus (EBV) in a context of immunosuppression. Major risk factors for PTLDs in solid organ transplantation are the EBV serostatus mismatch and the intensity, duration, and type of immunosuppression. T-cell depletion and the HLA-mismatched donor and recipient are the main risk factors following hematopoietic stem cell transplantation. For a long time, the only safe and effective therapeutic approach to PTLD was reduction of immunosuppression, with a risk of graft rejection. Based on a better knowledge of the pathophysiology and risk factors for PTLD, preventive and pre-emptive strategies have been recently proposed to control PTLD. New treatment modalities, such as anti-B-cell antibodies, cytokine inhibitor therapy, or anti-EBV cytotoxic T lymphocytes are promising and may improve the outcome of PTLD. These therapeutic approaches need to be further evaluated, especially in the context of pre-emptive strategies adapted to predictive markers of EBV-induced PTLD.

Anti-CD20 Monoclonal Antibody (rituximab) for Refractory PTLD after Pediatric Solid Organ Transplantation: Multicenter Experience from a Registry and from a Prospective Clinical Trial.

Background: Anti B cell antibodies have been proposed as a treatment for post-transplant lymphoproliferative disorders (PTLD). Experience in children is limited.Methods and Results: We report experience (n=40) with use of the chimeric mouse/human antiCD20 monoclonal antibody (rituximab) in pediatric PTLD patients with refractory disease (no response to reduced immunosuppression, progressive or relapsed disease, or concomitant allograft rejection). Initial experience was through a voluntary registry (n=26), and most recent experience is from an onging prospective, non-randomized clinical trial (n=14). Use of chemotherapy or other experimental therapies were an exclusion criteria for both studies. All PTLD were of B cell origin and expressed CD20 and all but 2 (both in registry cohort) were EBV positive. The first cohort (registry) comprised 26 solid organ recipients from 12 centers (heart 11, kidney 6, lung 4, other 5) with mean age of 12.5 years, 29 months (range 2–132) from transplant. Histology revealed these lesions: polymorphic 17, monomorphic 7 (including 1 Burkitts-like), Hodgkins-like 1, unspecified 1. 21/26 received 375mg/m2 x 4 doses. There were no SAE's. 18 pts (69%) showed CR, and 4 (16%) showed PR. The 4 non-responders comprised the 2 EBV negative cases, the Burkitts-like disease and the earliest onset case (fulminant disease at 2 months post-transplant). At latest follow-up (mean 41 months), 73% survive with one graft loss (kidney). In the prospective clinical trial, 14 patients (to date) with refractory disease were enrolled. The protocol comprises 4 doses of 375mg/m2 (weeks 1–4) with no further treatment for patients with CR or for those with no response. Patients with PR receive 4 further doses (weeks 5–8). The 14 patients were from 5 centers (lung 5, kidney 5, heart 4) with mean age of 6.5 years, 41 months (range 4–120) from transplant. Histology revealed the following: polymorphic 10, monomorphic 3, Hodgkin-like 1. There were no SAE's. Two are still recieving therapy. Of the other 12, 9 (75%) acheived CR and 10 pts (83%) are alive with one graft loss (kidney) at mean follow-up of 1.5 years. The two deaths were due to fungal pneumonia and complications of elective surgery in a patient in CR (both lung recipients).Conclusions: These results suggest that rituximab may have an important role to play in management of refractory PTLD in solid organ recipients (CR rate approx. 70–75% with low incidence of graft loss). This group of patients traditionally has high mortality and has been treated with chemotherapy. Rituximab should be considered as first line treatment for refractory polymorphic PTLD in children after solid organ transplantation. Role in monomorphic disease requires further investigation. Use of rituximab as first line therapy is under investigation.

Hodgkin-like posttransplant lymphoproliferative disorder in children: does it differ from posttransplant Hodgkin lymphoma?

Epstein-Barr virus (EBV)-mediated lymphoid proliferations occur in patients who are immunocompromised and are reported following bone marrow or solid organ transplantation. Most post-transplant lymphoproliferative disorders (PTLD) are polymorphic in appearance; some are monomorphic and can resemble conventional malignant lymphomas. PTLD that resembles Hodgkin lymphoma has been reported infrequently. We herein report seven cases of PTLD that have large numbers of Reed-Sternberg-like (RS-like) cells and highlight differences in the phenotype of these cases that may distinguish Hodgkin-like PTLD (HL-PTLD) from true Hodgkin lymphoma/disease (HD). All patients were in the second decade of life and were 8 months to 13 years following transplant. HL-PTLD involves lymph nodes that contain a mixed population of small to intermediate-sized lymphocytes with large mononuclear and occasionally binucleate RS-like cells. The large cells of HL-PTLD are pleomorphic B cells that react strongly for CD20 and/or CD79a, express CD30, but are usually negative for CD15 and have few mitoses. They are positive for EBV early RNA (EBER) using an EBER-1 probe, as are some of the background small lymphocytes. A single case of true Hodgkin lymphoma has highly atypical RS-like cells that contain numerous mitoses, does not have CD20 or CD79a reactivity, has CD15 and CD30 staining, and the EBER-1 probe is confined to the large cells only. All patients were managed by withdrawal of immunosuppression and variably treated with either antiviral or anti-CD20 monoclonal antibody, or with chemotherapy. A unique instance of evolution from a HL-PTLD to true HD is also illustrated. In conclusion, HL-PTLD and HD appear to be two related but immunophenotypically and biologically distinct forms of lymphoproliferation in post-transplant patients and may require different protocols for their management.

Risk factors for posttransplant lymphoproliferative disorder (PTLD) in pediatric kidney transplantation: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS).

Posttransplant lymphoproliferative disorder (PTLD) is an important complication of transplantation. The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database has documented 56 cases of PTLD, the largest such series to date. We analyzed the available longitudinal and multicenter data in the NAPRTCS database to evaluate the demographic and therapeutic risk factors and the temporal trends for PTLD in children after renal transplantation. The overall incidence of PTLD was 1.2% of all patients or 298/100,000 posttransplantation years of follow-up. However, this incidence increased from 254/100,000 years between 1987 and 1991 to 395/100,000 years from 1992 onwards. In the same periods, the time to PTLD decreased from a median of 356 days (range 843048) to a median of 190 days (range 42-944). PTLD occurred with greater frequency in white children (P=0.003) and in cadaver donor transplants (P=0.019), but there was no significant predilection for gender, younger children (0-5 years), or primary diagnosis. No significant difference was found in the use of anti-T-cell antibodies or in doses of CsA, azathioprine, or prednisone at 1 month, 6 months, and 1 year. Between 1996 and 1997, 69 patients were initiated with tacrolimus. Eight cases of PTLD were identified in these recipients to date (prevalence rate 11.5%), compared with 46/4084 (1.1%) where cyclosporine was used (P<0.0001). There is a trend towards increasing incidence and earlier occurrence of PTLD in the pediatric renal transplant population. White race and cadaver donor sources are risk factors not reported before. Continued monitoring of tacrolimus immunosuppression is important.