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.     

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.     

Treatment of posttransplant lymphoproliferative disease with rituximab: the remission, the relapse, and the complication.

BACKGROUND: Rituximab, a humanized anti-CD20 monoclonal antibody, is a promising new tool for the treatment of posttransplant lymphoproliferative disease (PTLD), especially for patients transplanted with rejection prone transplants of vital organs, such as patients after lung transplantation. Thus far, no major complications have been described. We treated three lung transplant recipients with Rituximab because of PTLD. METHODS: Patients were treated with four weekly doses of 375 mg/m2 of Rituximab. Epstein-Barr virus (EBV) DNA was monitored with quantitative-competitive polymerase chain reaction and circulating B cells with flow cytometry. RESULTS: Treatment with Rituximab resulted in a complete remission in all patients without signs of or progression of bronchiolitis obliterans syndrome. Patient 1 relapsed after 2 months with a partly CD20-negative PTLD but is in stable remission after radiotherapy. Patient 2 is in complete remission 16 months after treatment, but patient 3 developed a hypogammaglobulinemia and died of invasive aspergillosis after 6 months. EBV DNA was detectable in the blood samples of patients 2 and 3 before treatment with Rituximab and became negative instantly after Rituximab. In all three patients, B cells are absent in the peripheral blood 7 months (at death), 16 months, and 16 months after treatment with Rituximab. Antiproliferating agents, such as mycophenolate mofetil (MMF), might prolong B-cell depletion. CONCLUSIONS: Rituximab was effective for the treatment of PTLD without progression of transplant dysfunction in our patients. Complications were a partly CD20-negative relapse of PTLD and a hypogammaglobulinemia. Attention should be paid to immunoglobulin G (IgG) levels, especially in patients treated with antiproliferating agents such as MMF.     

Posttransplant lymphoproliferative disorders after liver transplantation: analysis of early and late cases in a 255 patient series

We reviewed the incidence and the impact of posttransplant lymphoproliferative disorders (PTLDs) on patient survival among a consecutive series of 255 patients. Five cases of PTLD were observed in adults: two cases were early (less than 1 year) and three cases, late lymphomas. The EBV positivity and the degree of immunosuppression were the main risk factors. We labeled cases as early or late according to whether the time elapsed from the transplant to the first clinical evidence of PTLD was less than 12 months. The median time from transplant to diagnosis of PTLD was 8 (early) and 108 (late) months. All cases were treated by reduction in immunosuppressive therapy with conventional chemotherapy and rituximab. The early cases with lymphoma located at the hepatic hilum died due to local complications (biliary sepsis and hemobilia), after an initial partial response to chemotherapy. The three patients with late cases are in remission after a mean follow-up of 23 months.     

Salvage chemotherapy for refractory and relapsed posttransplant lymphoproliferative disorders (PTLD) after treatment with single-agent rituximab

BACKGROUND: Single-agent rituximab has demonstrated encouraging efficacy and tolerability in posttransplant lymphoproliferative disorders (PTLDs) failing to respond to immunosuppression reduction (IR). This retrospective analysis was undertaken to determine the efficacy and safety of salvage therapy in recipients of solid organ transplants with progression of PTLD after rituximab first-line therapy. METHODS: Eleven patients who had received IR and single-agent rituximab were analyzed. Of these, 10 had received CHOP salvage chemotherapy. One patient with limited disease received tumor irradiation and further IR. Most patients (73%) had late PTLD (median onset of disease 145 months posttransplant), and most (83%) had monomorphic histology; 36% had EBV-association. RESULTS: IR and irradiation therapy re-induced complete remission (CR) and allowed long-term disease control in a patient with polymorphic PTLD relapse. CHOP therapy achieved CR in five (50%) and partial remission (PR) in two (20%) patients. Four of five (80%) patients achieving CR remained in CR at a median follow-up of 44.2 months. Of the patients achieving PR, one is currently alive, and the second died from transplant rejection after converting to CR after consolidative chemotherapy. Patients with stable disease (two) and progressive disease (one) have died from PTLD. There was one possible CHOP-associated death (acute cardiac event) and two patients had to be switched to less-toxic monotherapies. Median overall survival was 46.5 months (95% confidence interval: 23.6-49.1 months). CONCLUSIONS: CHOP salvage therapy achieved a favorable overall response rate of 70% in this setting, indicating that PTLD generally remains chemotherapy-sensitive after progression following first-line rituximab.     

Treatment of EBV-Related Post-Renal Transplant Lymphoproliferative Disease with a Tailored Regimen Including EBV-Specific T Cells

The treatment of EBV-associated post-transplant lymphoproliferative disease (PTLD) poses a considerable challenge. Efforts have been made to define regimens based on combination of the available therapeutic agents, chosen and tailored on a patient-by-patient basis, with the aim of augmenting event-free patient and graft survival. Recently, autologous EBV-specific cytotoxic T-lymphocytes (CTL) have proved effective in enhancing EBV-specific immune responses and reducing viral load in organ transplant recipients with active infection. We investigated the use of a tailored combined approach including autologous EBV-specific CTL for the treatment of EBV-related PTLD developing after pediatric kidney transplantation. Five patients with disseminated monoclonal (n = 3) or localized polyclonal (n = 2) PTLD unresponsive to reduction of immunosuppression were enrolled. The patients with disseminated PTLD received 4-5 courses of reduced-dosage polychemotherapy, accompanied by rituximab on the first day of each course, while localized disease was removed surgically. At treatment completion, autologous EBV-specific CTL were infused. All patients showed a complete response to treatment, without therapy-related toxicity or rejection, and persist in remission with good renal function at a median follow-up of 31 months. These preliminary results suggest that a combined chemoimmunotherapy regimen including virus-specific T-cells is well tolerated and potentially effective as first-line treatment of EBV-related PTLD.     

Posttransplant lymphoproliferative disorders of the central nervous system after kidney transplantation: single center experience over 40 years. Two case reports

Posttransplant lymphoproliferative disorder (PTLD) is one of the life-threatening complications of organ transplantation. PTLD sometimes involves the central nervous system (CNS), but the clinical characteristics are not well recognized. A total of 631 patients received kidney transplantation at Osaka University Hospital between March 1965 and December 2008. Two of the 631 patients (0.32%) developed CNS PTLD. A 40-year-old Japanese woman suffered onset of CNS PTLD 5 years after renal transplantation. After diagnosis based on histological examination by open biopsy, she obtained remission with dose increase of steroid and dose reduction of mycophenolate mofetil. She experienced relapse 20 months after first remission. She underwent second biopsy and the diagnosis was recurrent CNS PTLD. Further reduction of mycophenolate mofetil and increase of steroid led to second remission. The disease remained in complete remission at 60 months after first onset. A 61-year-old woman suffered onset of CNS PTLD 19 years after renal transplantation. After tumor removal, whole brain irradiation was performed. The disease remained in remission at 54 months after onset. Histological examination showed polymorphic-type PTLD in both cases. The first case of polymorphic CNS PTLD was successfully treated by modulation of immunosuppressants without radiation therapy even at recurrence. PTLD should be included in the differential diagnosis of brain tumors in recipients of solid organ transplantation, and histological subtype should be carefully identified to establish the correct treatment strategy.     

Successful outcome with a "quintuple approach" of posttransplant lymphoproliferative disorder

BACKGROUND: The treatment of posttransplant lymphoproliferative disorder (PTLD) remains empirical. We review our treatment of seven cases of PTLD consisting of five interventions: 1) reduction of immunosuppression; 2) antiviral drugs; 3) interferon-alpha; 4) gamma-globulins; and 5) anti-CD19 monoclonal antibodies. METHODS AND RESULTS; Seven consecutive patients who had undergone a simultaneous pancreas-kidney, liver, heart, or kidney transplantation were treated. One patient acquired a primary EBV infection with an oligoclonal immunoblastic lymphoma early after pancreas-kidney transplantation; all others developed a monoclonal polymorphic or immunoblastic lymphoma 2 to 123 months after transplantation. In all patients extranodal sites were involved, in three the graft was also involved. Five patients received the full quintuple approach and all rapidly obtained a complete remission (CR) with a median follow-up of 31 months (7-74 months). Of the two patients who did not receive interferon-alpha for fear of graft rejection one responded slowly with a CR after 7 months, and the other obtained a rapid CR followed by a relapse at 4 months. All three patients with a liver or heart transplant could keep their graft. All patients are still alive with a median follow-up of 31 months (7-74 months). CONCLUSION: This combined approach resulted in a favorable outcome in patients with high risk monoclonal PTLD after solid organ transplantation.     

Effect of Anti-CD 20 Antibody Rituximab in Patients with Post-Transplant Lymphoproliferative Disorder (PTLD)

Post-transplant lymphoproliferative disorders (PTLD) are a life-threatening complication following solid organ transplantation. Treatment with rituximab, a humanized anti-CD20 monoclonal antibody, has proved to be a promising approach and shown a low toxicity profile. Between February 1999 and April 2002, we conducted a multicentre phase II trial investigating rituximab as single agent in 17 patients with PTLD. Transplanted organs were heart (n = 5), kidney (n = 4), lung (n = 4) and liver (n = 4). Patients were treated with four weekly doses of 375 mg/m² of rituximab. The mean follow-up time is 24.2 months. Histology was distributed in 10 diffuse large cell-, 2 marginal zone-, 1 Burkitt-like lymphoma, 1 Hodgkin-like PTLD and 3 polymorphic lymphoproliferations. Therapy was well tolerated and no severe adverse events were observed. The mean overall survival period is 37.0 months with 11 patients still living. In total, 9 patients (52.9%) achieved a complete remission, with a mean duration of 17.8 months. Partial remission was observed in 1 patient, minor remission in 2 patients, no change in 3 patients and 1 patient experienced progressive disease. Two patients relapsed, at intervals 3 and 5 months after obtaining complete remission. Rituximab proved to be well tolerated and effective in the treatment of PTLD.     

Analysis of risk factors for the development of posttransplant lymphoprolipherative disorder among 119 children who received primary intestinal transplants at a single center

Posttransplant lymphoproliferative disorder (PTLD) is a well-known complication after pediatric transplantation. We analyzed all potential risk factors to assess patient and graft outcomes of 119 children who received intestinal transplantations. MATERIALS AND METHODS: Between August 1994 and March 2005, 119 patients underwent cadaveric intestinal transplantation. Their median age at transplant was 1.4 years (range: 0.6-17), median weight was 9.5 kg (range: 4.7-67), and 57% were boys. The median follow-up among 49 ongoing survivors was 41 months (range: 4-121). All PTLD cases were biopsy proven. In the past 5 years, treatment included antiviral therapy, immunosuppression withdrawal, and use of rituximab. RESULTS: The incidence of PTLD was 11.8% (14/119). No patient experienced graft failure secondary to PTLD, while two patients died from PTLD (14.2%). The PTLD group was divided into an early onset group (<4 months, 6 of 14; 42.8%) and a late onset group (>2 years, 8 of 14; 57.2%). No patient experienced PTLD between 4 months and 2 years after transplantation. The use of OKT3 was the only significant risk factor for the development of PTLD. No factor was specifically associated with the early versus late development of PTLD. CONCLUSIONS: The only factor associated with a significantly higher risk of PTLD was the use of OKT3 to treat a rejection episode. Finally, since the the introduction of anti-CD20 antibodies as part of the treatment protocol for PTLD, the risk of death due to PTLD appears to have become manageably low.     

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.     

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.     

Post-transplant lymphoproliferative disorders in lung transplant recipients: 20-yr experience at the University of Minnesota

Post-transplant lymphoproliferative disorders (PTLD) are potentially fatal complications of solid organ transplantation. The natural history of PTLD varies considerably among the different types of organs transplanted. While lung transplant recipients are highly susceptible to PTLD, there are only a few small studies that detail PTLD in this setting. We undertook this study to better describe the characteristics and treatment response in PTLD after lung transplantation. We conducted a retrospective chart review of lung and heart/lung-transplant recipients between 1985 and 2008. A total of 32 cases (5%) of PTLD were identified in 639 patients. The median interval after transplantation to the diagnosis was 40 (3-242) months. Eight patients (25%) were diagnosed within one yr of transplantation and had PTLD predominantly within the thorax and allograft. Twenty-four patients (75%) were diagnosed more than one yr after transplantation and their tumors mainly affected the gastrointestinal tract. Monomorphic PTLD, diffuse large B-cell lymphoma, was diagnosed in 91%. Treatment of PTLD varied according to stage and clinical circumstances. Twenty-four patients (75%) have died. The median overall survival was 10 (0-108) months. PTLD after lung transplantation remains a challenge as a result of its frequency, complexity and disappointing outcome.     

Posttransplant Lymphoproliferative Disorder After Clinical Islet Transplantation: Report of the First Two Cases

We report the first two cases of posttransplant lymphoproliferative disorder (PTLD) in recipients of islet transplants worldwide. First, a 44‐year‐old recipient of three islet infusions developed PTLD 80 months after his initial transplantation, presenting with abdominal pain and diffuse terminal ileum thickening on imaging. He was treated with surgical excision, reduction of immunosuppression, and rituximab. Seven months later, he developed central nervous system PTLD, presenting with vertigo and diplopia; immunosuppression was discontinued, resulting in graft loss, and he was given high‐dose methotrexate and underwent consolidative autologous stem cell transplantation. He remains in remission 37 months after the initial diagnosis. Second, a 58‐year‐old female recipient of two islet infusions developed PTLD 24 months after initial islet infusion, presenting with pancytopenia secondary to extensive bone marrow involvement. Immunosuppression was discontinued, resulting in graft loss, and she received rituximab and chemotherapy, achieving complete remission. Both patients were monomorphic B cell PTLD subtype by histology and negative for Epstein–Barr virus in tissue or blood. These cases document the first occurrences of this rare complication in islet transplantation, likely secondary to prolonged, intensive immunosuppression, and highlight the varying clinical manifestations of PTLD. Further studies are needed to determine incidence rate and risk factors in islet transplantation.     

常规方案联合利妥昔单抗治疗单倍体相合HSCT后淋巴细胞增生性疾病三例

目的 观察含利妥昔单抗的方案治疗单倍体相合造血干细胞移植(HSCT)后淋巴细胞增生性疾病(PTLD)的疗效.方法 回顾性分析3例单倍体相合HSCT后PTLD患者的临床资料.3例分别于移植后57～164 d发生PTLD,临床表现为发热、浅表淋巴结肿大.经淋巴结组织病理检查确诊为PTLD,均为B淋巴细胞来源,EB病毒DNA阳性.采用减量或者停用免疫抑制剂,抗病毒治疗,应用利妥昔单抗(1例联合化疗)治疗.利妥昔单抗的剂量为375 mg/m2,每周1次,共用4次.结果 治疗后3例的淋巴结均明显缩小,患者的体温恢复正常,病情缓解.结论 PTLD是HSCT尤其是单倍体相合HSCT后的严重并发症,含利妥昔单抗的治疗方案对于PTLD的治疗效果较好.

Abstract：

Objective To evaluate the efficacy of rituximab-containing regimens on post-transplantation lymphoproliferative disorder (PTLD) following haploidentical hematopoietic stem cell transplantation (HSCT). Methods The clinical data of 3 cases of PTLD after haploidentical HSCT were analyzed retrospectively. Time to development of PTLD ranged from 57 to 164 days after HSCT.The main symptoms included fever, superficial lymph node enlargement. Epstein-Bart virus (EBV)-positive B-cell PTLD was diagnosed by biopsy of lymph node. Management of 3 patients consisted of withdraw of immunosuppressive treatment, anti-viral therapy, rituximab (375 rng/m2 , per week for four weeks) monotherapy or chemotherapy plus rituximab. Results All the patients had complete remission after treatment. Conclusion PTLD is a serious complication of HSCT especially haploidentical HSCT. Rituximab-containing regimens are potentially effective, well-tolerated with mild toxicity and improve the prognosis of PTLD following haploidentical HSCT.     

Graft outcomes following diagnosis of post‐transplant lymphoproliferative disease in pediatric kidney recipients: a retrospective study

Data related to graft outcomes following post‐transplant lymphoproliferative disease (PTLD) in pediatric kidney transplantation are scarce. Data were analyzed retrospectively from 12 children (eight boys) for 3 years after diagnosis of PTLD, with a loss of follow‐up after 2 years in two of 12. In all cases, intensity of immunosuppressive therapy was reduced, which switched from calcineurin inhibitor to a mammalian target of rapamycin (mTOR) inhibitor in ten cases. Nine children were treated with six doses of rituximab according to the PED‐PTLD‐2005 protocol, with additional treatment in one child as per protocol. One patient received EuroNet‐PHL C1. In four patients, donor‐specific antibodies were detected after PTLD diagnosis at 3, 4, 5 and 7 years, respectively. One patient developed chronic antibody‐mediated rejection (cAMR) 12 years after diagnosis, losing the graft 1 year later. Three patients with recurrence of the original disease also lost their grafts, one at the time of diagnosis of PTLD, and two after 4 years. Range‐based analysis of variance showed that there was no decrease in estimated GFR at 1, 2, or 3 years after diagnosis of PTLD (P = 0.978). In conclusion, treatment of PTLD with reduced immunosuppression is safe and efficient. This may be due to B‐cell‐depleting therapy of PTLD with rituximab.     

Humanized anti-CD20 monoclonal antibody (Rituximab) treatment for post-transplant lymphoproliferative disorder

INTRODUCTION: Post-transplant lymphoproliferative disorders (PTLD) is a consequence of Epstein-Barr virus (EBV) infection and is a B-cell hyperplasia with CD-20 positive lymphocytes. The treatment of PTLD includes reduction/withdrawal of immunosuppression and chemotherapy. This study reports our center experience with humanized monoclonal antibody against CD-20 (Rituximab) for the treatment of PTLD. MATERIAL AND METHODS: Eight cases of PTLD after solid organ transplantation [six kidney, one kidney/pancreas (KP) and one liver] occurred between September 1998 and October 2001. The mean time between transplant and the diagnosis of PTLD was 57.3 months (range 3 months to 10 yr). Five patients underwent cadaveric transplant, five males and six were Caucasians with mean age of 48 yr (range 20-67 yr). RESULTS: The clinical presentation was as follows: lymphadenopathy--5, gastrointestinal bleeding--2 and tonsillar enlargement--1. The diagnosis was made by a lymph node biopsy in five, a gastric ulcer biopsy in two and a tonsillar biopsy in one case. Six of them had polymorphous, two had monoclonal B-cell lymphoma, and all were positive for CD-20. Six were related to EBV, documented by latent membrane protein (LMP) or Epstein-Barr encoded RNA (EBER) staining. Immunosuppression at the time of PTLD diagnosis consisted of tacrolimus in six cases and cyclosporine A (CsA) in two with mycophenolate mofetil (MMF) and azathioprine--3 each and sirolimus--1. Rituximab was administered at a dose of 375 mg/m2 once a week for 4 wk. There were no side effects seen with this therapy. Immunosuppression was reduced in all patients. Complete remission was observed in seven cases (one required two courses). One patient who did not respond received chemotherapy. Patients were followed for a mean period of 22.5 months (range 10-45 months post-PTLD diagnosis. At the last follow-up all eight patients were alive, seven with a functioning graft and one on maintenance dialysis. Three of these patients had been in remission for more than 2.5 yr. CONCLUSION: Rituximab is an effective agent in the treatment of PTLD without the morbidity characteristic of chemotherapy. Chemotherapy should be reserved only for those refractory to Rituximab therapy.     

Preemptive Therapy of EBV-Related Lymphoproliferative Disease after Pediatric Haploidentical Stem Cell Transplantation

The treatment of Epstein-Barr virus (EBV)-related post-transplant lymphoproliferative disease (PTLD) after hematopoietic stem cell transplantation (HSCT) is still unsatisfactory. We conducted a prospective trial to evaluate the impact of routine EBV surveillance and preemptive treatment with the anti-CD20 monoclonal antibody rituximab on the development of PTLD in pediatric recipients of extensively T-cell depleted HSCT from an HLA-haploidentical relative. Twenty-seven patients were included in the surveillance program, 12 developed EBV DNA positivity, with 8 of 12 presenting with sustained viral DNA levels requiring treatment with rituximab. Treatment was well tolerated, and induced clearance of EBV DNA in all patients. However, 4/8 patients showed a new increase in EBV load, coincident with the emergence of CD20(-)/CD19(+) B cells in peripheral blood, accompanied by overt PTLD in 3 patients. The latter cleared PTLD after receiving donor EBV-specific cytotoxic T-lymphocytes (CTLs), and persist in remission at a median 30-month follow-up. EBV-specific T-cell frequency, undetectable at time of EBV DNA positivity, was restored by T-cell therapy to levels comparable with controls. We conclude that preemptive therapy with rituximab is safe, but only partly effective in haplo-HSCT recipients. Patients who progress to PTLD under rituximab treatment can be rescued permanently by infusion of EBV-specific CTLs.     

Outcomes of kidney retransplantation in recipients with prior post‐transplant lymphoproliferative disorder

Post‐transplant lymphoproliferative disease (PTLD) is an uncommon but serious complication of solid organ transplantation. Reduction in immunosuppression is the mainstay of PTLD treatment, but it may precipitate graft loss. Retransplantation remains controversial, as immunosuppression resumption may trigger PTLD relapse. Herein, we describe the experience of eight patients who underwent kidney retransplantation after successful PTLD treatment. Epstein–Barr virus (EBV) serology was not known before the first transplantation. PTLD was diagnosed 62.5 months (range 5–323 months) after transplantation and was confined to the renal allograft (n = 1), lymph nodes (n = 2), gastrointestinal tract (n = 4), or central nervous system (n = 1). Immunosuppression tapering (8/8), chemotherapy (6/8), oral cavity lymphoma excision (1/8), and allograft nephrectomy (1/8) led to hematological remission in all patients. Retransplantation was performed at a median of 55.5 months (range 29–95   months) after PTLD diagnosis. After a median follow‐up of 62.5 months (range 2–125 months) allograft survival was 87.5% (seven functioning grafts, one failed graft from chronic rejection), with no recurrence of PTLD. In all, five patients remain alive; the other three died from causes other than PTLD. In conclusion, kidney retransplantation appears to be safe in patients with prior PTLD and without major risk of hematological recurrence provided that PTLD has remitted.     

Posttransplant lymphoproliferative disorders in renal allograft recipients: report of 53 cases of a French multicenter study

Abstract New immunosuppressive therapies are currently being developed in renal transplantation and their relative risk in terms of post‐transplant lymphoproliferative disorders (PTLD) must be carefully evaluated. For this purpose, a French registry of PTLD occurring after renal transplantation was set up. Among 10000 patients presently followed up in 30 French renal transplantation centers, we prospectively identified 53 new PTLD (0.5 %) since January 1998. Patients (34 male, 19 female) ranged from 3 to 72 years (mean age: 46 years), and the median time between grafting and diagnosis of PTLD was 63 months (2 months to 14 years). Ninety percent of recipients were Epstein‐Barr virus (EBV) positive before transplantation. Most patients received a quadruple sequential therapy with polyclonal anti‐lymphocyte globulin. Sites involved in PTLD were isolated lymph nodes in 13 cases, stomach or bowel in 10 cases, allograft in 14 cases, central nervous system in 6 cases, oropharynx in 4 cases, and skin or mucosa in 4 cases. Only three PTLD expressed markers of T lineage. Out of 40 studied tumors, 31 (78%) were EBV positive. Tumors were classified as polymorph in 26 cases and monomorph in 23 cases. Genotype studies in 18 PTLD showed a monoclonal pattern in 13 cases. In most patients, treatment consisted of reduction of immune suppression, 21 patients were given additional anti‐viral therapy, 13 patients had anti‐CD20, 23 patients underwent chemotherapy, and 4 patients were given cerebral radiotherapy. Five patients underwent transplantectomy. Sixteen patients (30 %) died within the 1st year and 7 patients returned to dialysis (13 %). The outcome of patients with PTLD remains poor, and the optimal approach to therapy is largely unknown. This ongoing registry is not only a national observatory but also a task force designed to improve the treatment strategy of PTLD.