Posttransplant lymphoproliferative disorder after umbilical cord blood transplantation in children

Reported are 7 cases of posttransplant lymphoproliferative disorder (PTLD) arising in children who received umbilical cord blood transplantation (UCBT). There were 4 females and 3 males with a median age of 3 years (range, 1-16 years). All 7 patients received UCBT, including 1 patient who received multiple units and 1 transplanted under nonmyeloablative condition. The time interval from UCBT to PTLD averaged 4 months (range, 2 weeks to 9 months). Patients typically presented with high-stage disease with visceral organ involvement. Histology of the PTLDs showed monomorphic morphology in 5 cases and polymorphic morphology in the remaining 2 cases. Bone marrow biopsies were performed in 3 cases and were negative for PTLD. Epstein-Barr virus (EBV) was detected in the PTLD in all 7 patients by in situ hybridization. Evidence of past EBV infection was found in the recipients, but the EBV genome was not detected in the donor cord blood samples, suggesting that donor cord blood was not the source of EBV infection. The origin of the PTLD was investigated in 5 cases. PTLD was of host origin in 2 patients who failed engraftment and of donor origin in the remaining 3 patients who had complete engraftment. Four of 5 patients with monomorphic PTLD failed to demonstrate significant responses to rituximab and/or reduction of immunosuppression and died within 1 month after diagnosis. The remaining 2 patients with polymorphic PTLD showed complete response to therapy. One patient was alive 35 months after transplant, and the other patient died of infection 6 months after transplant. It is concluded that PTLD arising after UCBT in children occurs early after transplant and represents a serious EBV-related complication. PTLD may be of donor or recipient origin depending on engraftment status. Both monomorphic and polymorphic histology may be seen, and monomorphic histology appears to predict an unfavorable prognosis.     

Long-term survival after post-transplant lymphoproliferative disease in children

Post-transplant lymphoproliferative disease (PTLD) is a well-known complication of immunosuppressive therapy. We present a series of 19 children who developed PTLD, following renal transplantation in 11 and liver transplantation in 8. The mean time between transplantation and the onset of PTLD was 19.5 months. Two patients had T-cell PTLD and died despite intensive chemotherapy. B-cell PTLD was observed in 17 patients and was associated with proven Epstein-Barr virus infection in 9. Despite immediate reduction of immunosuppressive therapy, only 8 of these 17 patients were alive at a 5.6-year mean follow-up. None of these patients had recurrence of PTLD when immunosuppression was resumed.     

Unusual manifestation of posttransplant lymphoproliferative disorder in the esophagus

Early manifestations of posttransplant lymphoproliferative disorders (PTLD) are mainly associated with a primary Epstein-Barr virus (EBV) infection. Rapid increases in peripheral blood EBV DNA load are supposed to reliably predict PTLD. We report a boy who 6 months after living-related kidney transplantation presented with an extranodal esophageal manifestation of PTLD. Despite a primary EBV infection with tonsillitis, the peripheral blood EBV DNA remained low, hiding the progression to PTLD.     

Anti-CD20 monoclonal antibody treatment of Epstein-Barr virus-induced intrahepatic lymphoproliferative disorder following liver transplantation

Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorders (PTLDs) are a common cause of death in transplant patients. Their incidence following liver transplantation is reported to be between 0.5% and 4%. Despite various therapeutic approaches, there is still no consensus on a treatment strategy. The treatment of transplant recipients with monoclonal antibodies directed against B-cell antigens is a new, therapeutic approach with which, however, little clinical experience has so far been gained. Two patients developed intrahepatic PTLD 7 and 15 months, respectively, after transplantation. In one case, this was diagnosed as polymorphic PTLD, in the other as monomorphic, monoclonal PTLD. After having their immunosuppression terminated, 4 weeks after establishment of the diagnosis, both patients were treated with anti-CD20 antibodies (rituximab) at a dose of 375 mg/m(2) on days 1, 8, 15 and 22. Treatment with rituximab was tolerated well by both patients. One of the patients in whom cholestasis parameters remained high underwent re-transplantation. In one of the cases, the histological work-up confirmed necrosis of 90% of the tumour cells, and complete remission in the other. Both patients died of secondary complications 10 weeks and 10 months, respectively, after the diagnosis of PTLD. We can conclude that treatment of PTLD with Rituximab led to remission in both of our patients. Nevertheless, progression of cholestasis persisted, and both patients ultimately died of complications unrelated to PTLD.     

Metachronous EBV-associated B-cell and T-cell posttransplant lymphoproliferative disorders in a heart transplant recipient

Posttransplant lymphoproliferative disorders (PTLDs) may occur as a complication of immunosuppression in patients who have received solid organ or bone marrow allografts. Most PTLDs are of B-cell lineage, whereas T-cell proliferations are rare. The majority of B-cell lesions are associated with Epstein-Barr virus infection. The occurrence of both B-cell and T-cell PTLDs in the same patient is extremely rare and only 6 cases have been previously published. We report a case of a 63-year-old man who developed 2 metachronous Epstein-Barr virus-related PTLDs beginning 10 years after heart transplantation. A polymorphic B-cell PTLD developed first that completely regressed after immunosuppressive therapy was partially withdrawn. Then, a monomorphic T-cell PTLD developed 31 months later. The patient died 17 months later owing to disease progression. We highlight the diagnostic challenge of this case that required numerous ancillary studies for lineage assessment and classification. Such studies are often needed in patients with a history of immunosuppression.     

Successful treatment of posttransplant lymphoproliferative disease with prolonged rituximab treatment in intestinal transplant recipients

BACKGROUND: Posttransplant Epstein-Barr virus-associated B-cell lymphoproliferative disease (PTLD) has a higher incidence after intestinal transplantation than after transplantation of other solid organs and is associated with a high mortality. A new anti-CD20 monoclonal antibody, rituximab, has shown efficiency in the treatment of B-cell lymphoma, including PTLD, but its use has not yet been reported in intestinal transplant recipients. METHODS: We retrospectively reviewed five patients who were diagnosed with PTLD from March 1999 to August 2001, after intestinal transplantation. These patients were primarily managed with rituximab, associated with reduction or interruption of immunosuppression and antiviral therapy with ganciclovir and cytomegalovirus immune globulin. Rituximab was administered at weekly doses of 375 mg/m until full remission was ascertained, and the interval between doses was then increased. No patient received chemotherapy. RESULTS: One patient had nonmalignant lymphoproliferation, and four had malignant PTLD, as assessed by histopathology and monoclonality of the tumor. Two pediatric patients had severe generalized disease. All patients had received OKT3 as treatment of rejection before developing PTLD. All tumors showed proliferation of CD20 cells and were positive for Epstein-Barr virus by in situ hybridization. All patients responded to rituximab therapy and have achieved full remission with a follow-up of 3 to 30 (median, 8) months. CONCLUSION: Prolonged rituximab treatment, in association with reduction of immunosuppression and antiviral therapy, is highly efficient as part of the first-line treatment of CD20 B-cell PTLD after intestinal transplantation.     

Rituximab in association with rapamycin for post-transplant lymphoproliferative disease treatment

Post-transplant lymphoproliferative disease (PTLD) is an uncommon but life-threatening complication of solid-organ and blood stem-cell transplants. It responds poorly to therapy, including reduction of immunosuppression, interferon, antivirals or chemotherapy. Small series of PTLD successfully treated with rituximab have been reported, and experimental studies suggest that rapamycin inhibits growth of human Epstein-Barr virus-transformed B lymphocytes. We report two cases of PTLD after renal transplantation that were successfully treated with rituximab in association with rapamycin. This report suggests that rituximab associated with rapamycin could be an effective and safe treatment for PTLD.     

Posttransplantation lymphoproliferative disorder in liver recipients: characteristics, management, and outcome.

Posttransplantation lymphoproliferative disorder (PTLD) is a well-recognized complication of organ transplantation. The aim of this study, performed over 9 years, was to examine the histopathological findings, clinical course, and outcome of patients who, having undergone orthotopic liver transplantation (OLT), developed PTLD. The sample included 7 adult liver allograft recipients (1.7%), 4 men and 3 women, with a mean age of 53 years (range, 40 to 61 years) who developed PTLD 1 to 36 months post-OLT (mean, 6 months). Four patients received either antithymocyte globulin as primary immunosuppression or OKT3 for steroid-resistant cellular rejection. Four patients had localized hepatic tumor with or without regional lymph node involvement, 2 patients had extralymphoreticular disease (head of pancreas and chest wall), and 1 patient had spleen and lymph node involvement. All tumors were B-cell lymphomas; three polymorphic and four monomorphic. Clonality was assessed by immunostaining for kappa and lambda and gene rearrangement. Monoclonality was found in 4 patients and polyclonality in 2 (1 of whom progressed to monoclonality); in 2 patients, clonality could not be determined. Immunohistochemistry findings for the presence of the Epstein-Barr virus (EBV)-determined nuclear antigen and the latent membrane protein 1 were noted in lymphoma tissue in 6 patients. Immunosuppressive therapy was decreased in all patients. Polyclonal tumors were treated with acyclovir (1 patient is in complete remission and 1 patient died), and monoclonal tumors with systemic chemotherapy (2 patients are in complete remission and 2 patients died). One patient was treated with monoclonal antibodies (CD20) but failed to respond, and 1 patient was treated with excision and is in complete remission. The mortality rate was 43%; for the remainder, median survival is 21 months (range, 10 to 42 months). We conclude that PTLD may re-present early after OLT. EBV has a special role in the pathogenesis, combined with immunosuppressive therapy. The outcome is poor, and new therapeutic approaches are needed.     

Post-transplant lymphoproliferative disorders after lung transplantation: first-line treatment with rituximab may induce complete remission

BACKGROUND: Post-transplant lymphoproliferative disorders (PTLD) are potentially lethal complications of solid organ transplantation. We, here, report on our experience with rituximab, an anti-CD20 monoclonal antibody, as first-line treatment for PTLD in six lung transplant recipients. PATIENTS AND METHODS: Two of the patients developed PTLD during the first year after transplantation, while four developed late-onset PTLD. One patient presented with PTLD localized to the graft, one had unilateral cervical lymph nodes, and the others presented with multi-organ involvement. All patients had diffuse large B-cell lymphoma. Immunosuppressive therapy was reduced and rituximab was administered at a dose of 375 mg/m(2)/wk for 4 wk. RESULTS: One patient did not respond to the first two courses of rituximab, received conventional chemotherapy, and achieved complete remission; four patients achieved complete remission after four courses with a median relapse-free survival of 34 months (range: 14-55); and one patient did not respond and died. The diagnosis of complete remission was established by conventional imaging techniques combined to whole-body positron emission tomography scan. CONCLUSIONS: We conclude that reduction in immunosuppression combined to first-line treatment with rituximab may induce long-term complete remission in lung transplant recipients presenting PTLD.     

Post-transplant lymphoproliferative disorder following cytomegalovirus reactivation in a lung recipient

Post-transplant lymphoproliferative disorder (PTLD) is a life-threatening complication after lung transplantation, for which several risk factors including pretransplant seronegativity for Epstein-Barr virus are known. However, the impact of cytomegalovirus on PTLD remains to be determined. Here, we describe a case of Epstein-Barr virus-associated polymorphic PTLD that developed shortly after treatment for cytomegalovirus reactivation in a lung transplant recipient who was preoperatively seropositive for both cytomegalovirus and Epstein-Barr virus.     

Successful Renal Retransplantation after Post-Transplant Lymphoproliferative Disease

Post-transplant lymphoproliferative disease (PTLD) is a rare but severe complication of renal transplantation. Reduction of immunosuppression is essential for controlling PTLD but may induce graft loss. Retransplantation after PTLD is considered dangerous, because immunosuppressive treatment resumption may trigger hematological relapse. We retrospectively report six patients (five adults, one child) who underwent a second renal transplantation after successfully treated PTLD. Epstein-Barr virus (EBV) serology was positive before the first transplantation in all patients except the child. Post-transplant lymphoproliferative disease was detected 6.6 months (range 4.5-9.4) after transplantation. Lymphoproliferation was always monomorphic, B-cell, and EBV-related. Post-transplant lymphoproliferative disease was confined to the renal allograft (n = 4), multilocular (n = 1) or cerebral (n = 1). Immunosuppression tapering (6/6) and transplantectomy (5/6) led to hematological remission in all patients. Retransplantation was performed 77 months (range 50-128) after PTLD diagnosis. Immunosuppression included steroids (n = 6), ATG (n = 2), anti-CD25 (n = 2), cyclosporine (n = 4), tacrolimus (n = 2), mycophenolate mofetil (n = 4) and azathioprine (n = 1). After a median follow up of 30 months (range 24-47) patient survival was 100%, with no recurrence of PTLD. In conclusion, renal retransplantation can be considered in patients with monomorphic PTLD history, without major risk of hematological recurrence.     

Post-transplant Lymphoproliferative Disorder of Appendix Mimicking Acute Appendicitis: A Case Report

Post-transplant lymphoproliferative disorder (PTLD) can be Epstein-Barr virus (EBV)-positive lymphoproliferations occurring in the first year after transplantation or EBV-negative lymphoma occurring many years after transplantation. Both B-cell and T-cell type of PTLD are described in the literature. In the gastrointestinal tract, the small and large intestine are the common sites of involvement. PTLD of the appendix is a lesser-known entity and cases described previously presented clinically as acute appendicitis. We report a case of EBV-negative B-cell PTLD of the appendix mimicking acute appendicitis in a live young renal allograft recipient 7 years after transplantation.     

A case of laryngeal posttransplantation lymphoproliferative disease

The development of posttransplant lymphoproliferative disease (PTLD) is strongly linked to infection with the Epstein-Barr virus (EBV), immunosuppression-state, the type of allograft, and EBV-seronegativity. A 18-month-old girl who had undergone living donor liver transplantation using the left lateral segment from her father was treated with tacrolimus and corticosteroid as an immunosuppressant regimen. She was readmitted 3 months after the transplant to evaluate the etiology of dyspnea and abdominal fullness as well as a decreased urine volume. She was diagnosed as an anastomotic stenosis of the hepatic vein for which she underwent balloon angioplasty. The treatment was repeated at postoperative month 5, 8, and 11. As postoperative 6 months, the result of the serological EBV-CA (IgG/IgM) was positive. In postoperative month 10, the EBV PCR serologic test become positive, and a laryngeal biopsy revealed PTLD. She was treated with acyclovir and gangyclovir as well as reduced immunosuppression. We report herein a rare case of laryngeal PTLD in a patient who had undergone living donor liver transplant with paternal allograft.     

Lung retransplantation after posttransplantation lymphoproliferative disorder (PTLD): a single-center experience and review of literature of PTLD in lung transplant recipients.

BACKGROUND: Retransplantation in adult lung transplant recipients developing progressive bronchiolitis obliterans syndrome as a consequence of posttransplantation lymphoproliferative disorder (PTLD) therapy has not been reported in the literature. Literature on PTLD after lung transplantation is limited mostly to case reports or small case series, limiting the validity of conclusions. METHODS: Retrospective chart review of patients at our center. Analysis of pooled data published on lung transplant patients developing PTLD. RESULTS: Two patients who underwent pulmonary retransplants for PTLD have functioning grafts 23 and 36 months postoperatively, with no evidence of PTLD recurrence. Review and analysis of published data and from our center revealed that incidence of PTLD, proportion of patients with thoracic involvement, and proportion of patients who were Epstein-Barr virus seronegative before transplantation decreased continuously as a function of time from transplant. Patients developing PTLD within the first 6 months after transplantation had a clinically distinct pattern of PTLD and a significantly better survival than patients developing PTLD more than 6 months after lung transplant. CONCLUSIONS: Lung retransplantation can be considered after careful selection for lung transplant recipients developing bronchiolitis obliterans syndrome as a consequence of reduced immunosuppression for PTLD. Acquisition of PTLD and pattern of organ involvement is a continuous process as a function of time. Defining "early PTLD" as occurring in the first 6 months more accurately predicts progress and prognosis of this disease than the traditional 1 year definition of early vs late onset PTLD.     

A case report: hepatic posttransplant lymphoproliferative disorder in a non-liver transplant patient

Posttransplant lymphoproliferative disorder (PTLD) is the most common malignancy in children after solid organ transplantation. We present a patient, who developed Epstein-Barr virus (EBV)-related PTLD in the liver after renal transplantation. A 10-year-old EBV-seronegative boy with cystinosis underwent a living related preemptive renal transplantation. He received antiviral prophylaxis with valacyclovir. At 5.5 months posttransplantation he displayed a primary EBV infection with an high fever, hepatosplenomegaly, monocytosis, and positive EBV DNA levels. Two months there after, a hypoechoic nodular 20-mm lesion in the left lobe of liver was detected on abdominal ultrasonography, performed because of anorexia and weight loss. EBV-DNA copy number was 7820 copies per milliliter. Liver biopsy showed a diffuse large B-cell lymphoma that was compatible with PTLD. We stopped all immunosupressive agents other than prednisolone. Chemotherapy consisting of two courses of cyclophosphamide, vincristine, prednisolone, and adriamycin was followed by rituximab. Within 2 months, the lesion resolved and within 18 months, he was free of disease.     

Immunity, Homing and Efficacy of Allogeneic Adoptive Immunotherapy for Posttransplant Lymphoproliferative Disorders

Adoptive immunotherapy using autologous Epstein-Barr virus (EBV)-specific cytotoxic T-lymphocytes (auto-CTL) can regress posttransplant lymphoproliferative disorders (PTLD). Widespread applicability of auto-CTL remains constrained. Generation is time-consuming, and auto-CTL cannot be established in patients treated with the B-cell depleting antibody rituximab. By contrast, pregenerated allogeneic CTL (allo-CTL) offers immediate accessibility. Allo-CTL has previously shown efficacy in "early" polyclonal- PTLD. We treated three patients with aggressive, advanced monoclonal-PTLD following solid-organ transplantation. All were refractory to at least three prior therapies. Despite HLA disparity, there was negligible toxicity, with early in vivo antiviral efficacy and reconstitution of EBV peptide-specific immunity. Two patients attained complete remission (CR). One remains in CR 17 months following therapy, coincident with persistence of donor-derived tumor targeted EBV-specific CTL; the other died of non-PTLD related pathology. In the third patient, autopsy demonstrated homing of allo-CTL at the tumor site. Larger prospective studies of EBV-specific allo-CTL in PTLD are warranted.     

Epstein-Barr virus-negative lymphoproliferate disorders in long-term survivors after heart, kidney, and liver transplant

BACKGROUND: Solid organ transplant patients undergoing long-term immunosuppression have high risk of developing lymphomas. The pathogenesis of the late-occurring posttransplantation lymphoproliferative disorders (PTLD) have not yet been extensively investigated. METHODS: We studied 15 patients who developed PTLD after a median of 79 months (range 22-156 months) after organ transplant. Clonality, presence of Epstein-Barr virus (EBV) genome, and genetic lesions were evaluated by Southern blot analysis or polymerase chain reaction. RESULTS: All monomorphic PTLD and two of three polymorphic PTLD showed a monoclonal pattern. Overall, 44% of samples demonstrated the presence of the EBV genome. Within monomorphic PTLD, the EBV-positive lymphomas were even lower (31%). A c-myc gene rearrangement was found in two cases (13%), whereas none of the 15 samples so far investigated showed bcl-1, bcl-2, or bcl-6 rearrangement. The modulation of immunosuppression was ineffective in all patients with monomorphic PTLD independent of the presence of the EBV genome. The clinical outcome after chemotherapy was poor because of infectious complications and resistant disease. With a median follow-up of 4 months, the median survival time of these patients was 7 months. CONCLUSIONS: Late occurring lymphomas could be considered an entity distinct from PTLD, occurring within 1 year of transplant, because they show a histological and clinical presentation similar to lymphomas of immunocompetent subjects, are frequently negative for the EBV genome, are invariably clonal, and may rearrange the c-myc oncogene. New therapeutic strategies are required to reduce the mortality rate, and new modalities of long-lasting immunosuppression are called for.     

Treatment of PTLD with Rituximab or Chemotherapy

Information regarding treatment of post-transplant lymphoproliferative disease (PTLD) beyond reduction in immunosuppression (RI) is limited. We retrospectively evaluated patients receiving rituximab and/or chemotherapy for PTLD for response, time to treatment failure (TTF) and overall survival (OS). Thirty-five patients met inclusion criteria. Twenty-two underwent rituximab treatment, with overall response rate (ORR) 68%. Median TTF was not reached at 19 months and estimated OS was 31 months. In univariable analysis, Epstein-Barr virus (EBV) positivity predicted response and TTF. LDH elevation predicted shorter OS. No patient died of rituximab toxicity and all patients who progressed underwent further treatment with chemotherapy. Twenty-three patients received chemotherapy. ORR was 74%, median TTF was 10.5 months and estimated OS was 42 months. Prognostic factors for response included stage, LDH and allograft involvement by tumor. These factors and lack of complete response (CR) predicted poor survival. Twenty-six percent of the patients receiving chemotherapy died of toxicity. Rituximab and chemotherapy are effective in patients with PTLD who fail or do not tolerate RI. While rituximab is well tolerated, toxicity of chemotherapy is marked. PTLD patients requiring therapy beyond RI should be considered for rituximab, especially with EBV-positive disease. Chemotherapy should be reserved for patients who fail rituximab, have EBV-negative tumors or need a rapid response.     

Rituximab therapy and reduction of immunosuppression to rescue graft function after renal posttransplantation lymphoproliferative disorder found by macrohematuria in a pancreas and kidney transplant recipient: a case report

Introduction

Posttransplantation lymphoproliferative disorder (PTLD) remains an uncommon complication of solid organ transplantation, with a high mortality rate reported after conventional therapies. Epstein-Barr virus (EBV) may cause PTLD, but most EBV infections after transplantation are clinically silent reactivations, so the detection of PTLD is often delayed. Recently we experienced the rare case of intrarenal graft PTLD found by macrohematuria in a simultaneous pancreas and kidney transplant recipient. The grafts were saved by treatments with rituximab, cyclophosphamide, hydroxydaunorubicin, and prednisone-based chemotherapy (R-CHOP) after reduction of immunosuppression (IR).

Methods

This 37-year-old man with insulin-dependent diabetes underwent simultaneous pancreas and kidney transplantation (SPK) with enteric drainage. Six months after transplantation, he displayed macrohematuria, which we investigated by blood tests, computer tomography (CT) scan, positron emission tomography (PET)-CT, and magnetic resonance imaging, recognizing a tumor in the transplanted renal graft. An open biopsy showed a CD20-positive PTLD. We started treatments with IR, rituximab (375 mg/m², weekly for 2 cycles) and R-CHOP therapy: rituximab (375 mg/m²) plus CHOP every 3 weeks for 6 cycles.

Results

IR and R-CHOP therapy achieved a complete remission (CR). CR has continued for 14 months at the time of writing. The maximum level of EBV DNA was 259 copies/μg DNA, but 2 months after these therapies, the level had decreased to normal. The patient had no impairment of pancreas and kidney graft functions.

Conclusions

The outcome of intragraft PTLD in the kidney of an SPK recipient suggested that the negative impact of IR on graft function may be compensated by the immunosuppressive effects of rituximab, allowing reduced immunosuppression during chemotherapy.     

A case of fulminant post-transplant lymphoproliferative disorder and septicemia

The fulminant form of post-transplant lymphoproliferative disorder (PTLD) is very uncommon and occurs in approximately 1% of PTLD patients. Approximately 85% of these lesions are of B-cell origin, and most of them are associated with Epstein-Barr virus infection. Fulminant PTLD is frequently associated with a systemic inflammatory response syndrome, and may be difficult to differentiate from septicemia. We describe the case of a 59-yr-old man who suffered from prolonged septicemia in the immediate post-transplant period, and presented again four months after cardiac transplantation with fever, painful liver edge and gastrointestinal bleeding. The diagnosis of fulminant PTLD with advanced multiorgan infiltration by a diffuse large-cell lymphoma of B-cell phenotype was made. During treatment with rituximab, the patient died from Enterococcus faecium septicemia. The sequence of septicemia, PTLD and, finally again, septicemia is an unusual challenge and urges for an aggressive diagnostic approach, where markers like procalcitonin may aid in the discrimination of fulminant PTLD from septicemia.