Diagnosis Of Post-transplant Lymphoproliferative Disorder Research Articles

Post-Transplant Lymphoproliferative Disorder after Autologous Hematopoietic Cell Transplantation for Hodgkin's Lymphoma

Post-transplant lymphoproliferative disorder is a very rare complication post autologous bone marrow transplant with few cases reported so far. We report a case of a child with history of classic Hodgkin's lymphoma, nodular sclerosis type, who was treated with autologous stem cell transplantation. Three months after the transplant, he developed bilateral cervical lymphadenopathy, splenomegaly, neutropenia and thrombocytopenia. Excisional biopsy of a left cervical lymph node revealed a post-transplant lymphoproliferative disorder. The morphological pattern of this post-transplant lymphoproliferative disorder was combined monomorphic and polymorphic, with plasmacytoid/plasmablastic differentiation expressing CD20 and CD79A. Kappa and lambda light chain immunohistochemistry stains showed a clear evidence of lambda light chain restriction. Immunohistochemistry stain and in situ hybridization for Latent membrane protein-1 were positive for Epstein-Barr virus. Polymerase chain reaction study revealed monoclonal B-cell proliferation with immunoglobulin heavy chain gene rearrangement. The patient was treated with prednisolone as 2 mg/kg/day over 2 weeks with tapering over the following 3 months. The white cell count recovered with regression of splenomegaly and cervical lymphadenopathy. On his last visit to the outpatient clinic, two years after the diagnosis of post-transplant lymphoproliferative disorder, he was in good health with normal laboratory parameters.

A case of Epstein‐Barr virus associated post‐transplant lymphoproliferative disorder with CNS involvement: pathological findings at both biopsy and autopsy

Post-transplant lymphoproliferative disorder (PTLD) with CNS involvement is an uncommon and fatal side effect of immunosuppressants. A 55-year-old man presented with non-fluent aphasia, fever, neck stiffness and disturbance of consciousness. Twenty-one years previously, the patient had undergone kidney transplantation for chronic renal failure. Brain MRI revealed multiple lesions in the bilateral cerebrum, right cerebellum and medulla oblongata. The brain biopsy showed EBV-positive lymphocytes infiltrating into the subarachnoid and Virchow-Robins space. The diagnosis of PTLD was made and the patient received a reduction in immunosuppressants. However, the patient died of massive bleeding from a rectal ulcer 3 months after the onset. An autopsy conducted 1 month after the biopsy revealed a diffuse large B-cell lymphoma at the biopsy site and extracranial PTLD lesions. Moreover, a human cytomegalovirus infection involving the rectum, pancreas, trachea and bladder was confirmed. Comparisons with past cases clarified the characteristics of this case, in particular, the clinicopathological involvement of leptomeninges. In addition, there have so far been only a limited number of such reports demonstrating detailed pathological findings, including both biopsy and autopsy findings. We herein describe the relationship between clinical and pathological findings and demonstrate the way CNS PTLD lesion progresses.

Outcomes In the Pre-Rituximab and Post-Rituximab Eras In Post-Transplantation Lymphoproliferative Disorders (PTLD) In Adult Solid Organ Transplant Recipients

AbstractAbstract 2859 Background:PTLD is the most common malignancy, other than melanomatous skin cancer complicating solid organ transplantation and has been one of the most commonly observed fatal consequences. The histologies are diverse and include B-cell, T-cell and Hodgkin lymphomas. Rituximab has affected the outcome in CD20+ patients with PTLD. This single institution study sought to identity the outcomes in patients of all histologies and presentations managed in the post-rituximab era. Methods:Patients with solid organ transplantation who were diagnosed with PTLD at Mayo Clinic (Rochester, MN) between December 1970 and October 2009 were identified through the Mayo Clinic Lymphoma Data Base. The rituximab era was defined as patients diagnosed after December 26, 2000, the date of diagnosis for the first patient treated with rituximab in our series. Cox proportional hazards models were used to assess the association of clinical factors and overall survival (OS). Results:143 patients diagnosed with PTLD between December 1970 and October 2009 were identified. The median age at the time of diagnosis of PTLD was 50 years (range 15–84) with 41 patients (29%) over the age of 60. 93 were male (65%). At a median follow-up of 84 months (range 1–295), 95 patients (65%) have died. The types of organ transplant included renal (39%), liver (31%), cardiac (11%), lung (6%), renal/pancreas (6%), pancreas (4%), and multiorgan (4%). 83% of patients presented with extranodal disease. 28% had involvement of the engrafted organ. 76% of the patients developed PTLD that was EBV+ by in situ hybridization. 62% were stage 3–4. The IPI was intermediate-high in 39% of patients. Initial approaches to management included reduction in immunosuppression (45%), chemotherapy (12%), reduction in immunosuppression with rituximab (12%), rituximab (8%), and radiation therapy (6%). The overall response to therapeutic approaches was 46% in the pre-rituximab era and 56% in the post-rituximab era (chi-squared p=0.25). Patients treated with rituximab had an improved overall survival (HR = 1.66, 95% CI: 0.99–2.79). Patients treated in the rituximab era had improved 1 year survival (76%) compared to patients in the pre-rituximab era (59%) (chi-squared p=0.03). However, the survival advantage in the rituximab era was not maintained in longer follow-up. The median overall survival in the pre-rituximab era was 31 months compared to 56 months in the post-rituximab era (logrank p=0.63). Conclusion:The overall response rates and overall survival are improved with rituximab treatment in CD20+ PTLD, however, the natural history of all PTLD has not improved significantly in the post-rituximab era. New approaches are needed for the prevention and management of all the histologies of PTLD. Disclosures:No relevant conflicts of interest to declare.

Sirolimus addition to tacrolimus-based immunosuppression induces complete remission of post-transplant lymphoproliferative disorder in a liver transplant recipient

Sirolimus addition to tacrolimus-based immunosuppression induces complete remission of post-transplant lymphoproliferative disorder in a liver transplant recipient

Multiple Clinical Presentations of Lymphoproliferative Disorders in Pediatric Liver Transplant Recipients: A Single-Center Experience

Posttransplantation lymphoproliferative disorder (PTLD) is a serious complication following solid organ transplantation that has been linked to Epstein-Barr virus (EBV) infection. The aim of this article was to describe a single-center experience with the multiplicity of clinical presentations of PTLD. Among 350 liver transplantations performed in 303 children, 13 survivor children displayed a histological diagnosis of PTLD (13/242 survivors; 5.4%). The age at diagnosis ranged from 12 to 258 months (median, 47), and the time from transplantation ranged from 1 to 84 months (median, 13). Ten of these children (76.9%) were EBV-naïve prior to transplantation. Fever was present in all cases. The clinical signs at presentation were anemia (92.3%), diarrhea and vomiting (69.2%), recurrent upper airway infections (38.4%), Waldeyer ring lymphoid tissue hypertrophy (23.0%), abdominal mass lesions (30.7%), massive cervical and mediastinal adenopathy (15.3%), or gastrointestinal and respiratory symptoms (30.7%). One child developed fulminant hepatic allograft failure secondary to graft involvement by PTLD. Polymorphic PTLD was diagnosed in 6 patients; 7 had the diagnosis of lymphoma. Treatment consisted of stopping immunosuppression as well as starting intravenous gancyclovir and anti-CD20 monoclonal antibody therapy. The mortality rate was 53.8%. The clinical presentation of PTLD varied from fever of unknown origin to fulminant hepatic failure. The other symptoms that may be linked to the diagnosis of PTLD are pancytopenia, tonsil and adenoid hypertrophy, cervical or mediastinal lymph node enlargement, as well as abdominal masses. Despite numerous advances, the optimal treatment approach for PTLD is not completely known and the mortality rate is still high.

Clinical Characteristics of Monomorphic Post-transplant Lymphoproliferative Disorders

Post-transplant lymphoproliferative disorders (PTLD) are a heterogeneous group of lymphoproliferative disorders associated with immunosuppression and Epstein-Barr virus infection. PTLD is classified into three major categories: early lesions, polymorphic PTLD, and monomorphic PTLD. The majority of monomorphic PTLD cases are non-Hodgkin's lymphoma of B-cell origin. This retrospective study was conducted to investigate the incidence, clinical manifestation, treatment, and outcomes of monomorphic PTLD among 5,817 recipients of solid organ or allogeneic hematopoietic stem cell transplantation from five institutions. Fourteen patients with monomorphic PTLD were identified (male:female 11:3; median age 42.6 yr, range 24-60). The overall incidence rate was 0.24%. The most common disease type was diffuse large B cell lymphoma (n=7). The median time between the transplant and diagnosis of PTLD was 85.8 months. However, all cases of PTLD after allogeneic hematopoietic stem cell transplantation occurred within 1 yr after transplantation. Ten of the 14 patients had EBV-positive tumor. Fourteen patients received combination systemic chemotherapy and four patients were treated with radiation therapy. Ten patients achieved a complete response (CR) and two patients a partial response (PR). The median follow-up period for surviving patients was 36.6 months. Nine patients remain alive (eight CR, one PR). Nine of 11 solid organ transplantations preserved graft function. The present study indicates a lower incidence rate and a longer median time before the development of PTLD than those of previous reports. Careful monitoring was needed after allogeneic hematopoietic stem cell transplantation for PTLD.

Posttransplant Lymphoproliferative Disorder Following Kidney Transplant

Posttransplant Lymphoproliferative Disorder Following Kidney Transplant

Post‐transplant lymphoproliferative disorder after pediatric liver transplantation: Characteristics and outcome

Post-Transplant Lymphoproliferative Disorder (PTLD) is a life threatening complication in organ transplant recipients. Risk factors include primary Epstein-Barr virus infection, intensity of immunosupression and cytomegalovirus infection. To evaluate the incidence, clinical presentation, risk factors, histopathologic appearance and outcome of pediatric liver recipients with PTLD at our institution. Retrospective, descriptive and observational analysis. Between November 1992 and December 2005, 383 liver transplants were performed. The diagnosis of PTLD was based on clinical history and physical examination and confirmed by histologic appearance and immunohistologic staining. Knowles' classification was used for histopathologic diagnosis. The incidence of PTLD was 5.7% (n: 22p). The average onset after tansplantation (OLT) was 24.9 months. Clinical manifestations were malaise, anorexia, fever of more than 3 days, peripheral adenopathy, tonsillar hypertrophy, abdominal mass, hepatosplenomegaly, snoring, interstitial pulmonary infiltrate, G.T.-tract bleeding, rash, submaxilar mass. Histopathologic diagnosis were Plasmocytic Hyperplasia (n: 10), Polymorphic Lymphoproliferative Disorder (n: 8), Non-Hodgkin Lymphoma (n: 4). Mortality was 18%. The clinical presentations were protean and not specific. A high index of suspicion is important for early diagnosis as it correlates with more benign lesions and more favorable outcume. The lower mortality rate in our series is concordant with that reported in more recent articles.

Timing of Epstein-Barr Virus Acquisition and the Course of Posttransplantation Lymphoproliferative Disorder in Children

To investigate the clinical course and risk factors of Epstein-Barr virus (EBV)-associated posttransplantation lymphoproliferative disorder (PTLD) after liver transplantation (LT) among children in Taiwan where children acquired EBV infection in early childhood. In the retrospective study, 67 children underwent LT in our hospital and survived for more than 3 months were recruited. Various predisposing risk factors, including viral status, nutritional status, age at transplantation, and medications, were assessed. The diagnosis of EBV-associated PTLD in these liver transplanted patients was confirmed by histologic examination. Eight children developed EBV-associated PTLD after LT, and all (100%) had gastrointestinal tract mucosa-associated lymphoid tissue involvement with the initial presentation as bloody stool. The incidence of PTLD is 11.9% (8/67) in the liver transplanted children in our hospital. Children who received LT before 1 year of age had a higher risk of EBV-associated PTLD than others (relative risk [RR]=10.37, P=0.006). The absence of EBV nuclear antigen antibody in recipients before LT also increased the risk (RR=8.63, P=0.018). The RR of EBV-associated PTLD increased to 13.3 (P=0.002) in EBV naïve children who received LT before 1 year of age. Additional risk of EBV naivity and transplantation age below 1 year was evident in our series to the development of EBV-associated PTLD. Acquired EBV infection in early infancy after the LT may increase the risk of gastrointestinal tract involvement of EBV-associated PTLD in Taiwan.

Pediatric post-transplant diffuse large B cell lymphoma after cardiac transplantation

Post-transplant lymphoproliferative disorders (PTLDs) occur in 3.5-9% of patients after pediatric cardiac transplantation. Caution is needed when treating patients with PTLD because of the risk of allograft rejection frequently caused by withdrawal of immunosuppression. In this report, we describe a 47-month-old boy who developed PTLD as an ileocecal mass 29 months after cardiac transplantation. Immunosuppressive therapy with cyclosporine A (CyA) had been reduced due to an elevation of Epstein-Barr virus (EBV) titer for 8 months before development of PTLD. Histology of the tumor was diffuse large B cell lymphoma. EBV was detected by in situ hybridization assay. Cytogenetic analysis revealed t(8;14)(q24;q32) and Southern blot analysis detected a c-Myc rearrangement. He was treated with rituximab and combination chemotherapy with excellent response. CyA dose was maintained at reduced levels during chemotherapy and later minimized with introduction of everolimus. The child is free of both PTLD and allograft rejection 41 months after the diagnosis of PTLD.

Reduction of Immunosuppression and Subsequent Rituximab Monotherapy or CHOP-Based Chemotherapy +/− Rituximab as a Treatment for PTLD Does No Impair the Renal Graft Function: A Matched Pair Control Analysis in 55 Renal Transplant Recipients with PTLD and 1075 Renal Transplant Controls

Purpose: Post transplant lymphoproliferative disorder (PTLD) is a serious and often devastating complication after solid organ transplantation. The initial therapeutic action is reduction of immunosuppression (IR). Patients not responding to IR usually are treated with rituximab monotherapy and/or CHOP-based chemotherapy. The impact of treatment on the renal graft function is to be analyzed.Methods: A retrospective data analysis was performed on adult renal transplant recipients with PTLD requiring further therapy after failing to respond to IR. All patients gave their informed consent to this study and all had been treated within one of the prospective German PTLD Study Group protocols: PT-LPD-1 (rituximab monotherapy), PTLD-1 (sequential treatment with rituximab and CHOP chemotherapy) or PTLD D2006–2012 (different treatment protocols). Renal graft function was analyzed 6 months (6m) before, during and up to 2 years after treatment of PTLD. From our renal transplant database altogether 1075 transplant recipients that had transplantation between January 1998 and June 2008 served as a control. Controls were matched for sex, patient age, transplant age and transplant function at time of diagnosis of PTLD.Results: Median age at diagnosis of PTLD was 49 years. 38/55 pts. were male, 43/55 had late onset PTLD. 53/55 had B-cell PTLD: 2 polymorphic, 37 aggressive B-cell, 3 Hodgkin or Hodgkin-like PTLD and 11 others. 2/55 had T-cell PTLD. 34/55 had an advanced stage of disease and 26/51 had elevated LDH levels. 1 patient had renal graft involvement. Renal transplantation for endstage renal disease was either due to autoimmune disorders (26/55), to diabetes (4/55), to cystic renal degeneration (5/55) or to metabolic dysfunction (1/55, 19 others). At diagnosis of PTLD 10 patients were on calcineurin-inhibitor (CNI) therapy only, 16 were on CNI plus mycophenolate mofetil (MMF), 13 were on CNI plus azathioprin (AZA), 4 were on CNI plus mTor-inhibitor, 4 were on mTor-inhibitor plus MMF or AZA and 7 were on single agent immunosuppression with MMF, AZA or prednisone. Immunosuppression was reduced in all patients immediately after diagnosis of PTLD. 15/55 patients received further therapy with single agent rituximab, 40/55 patients received CHOP or CHOP-like chemotherapy +/− rituximab. 36/53 (68%) patients reached a complete remission (CR). At a median follow up of >2 years 4 patients relapsed and 17 died: 5 from PTLD, 7 from infections, 1 from myocardial infarction and 3 of unknown reason. Matching criteria were equally distributed in the patient and control group. After successful treatment of PTLD 4 of 38 PTLD survivors (10%) had failed renal allografts and recommenced hemodialysis: 1 due to a haemolytic uremic syndrom, 1 due to acute renal failure after a septic complication, 2 due to chronic transplant dysfunction. With a mean transplant age of 6.2 years transplant survival at 1 year after diagnosis of PTLD is 92% in the stable CR group. In a longitudinal analysis in 27 and 44 patient pairs evaluable not requiring hemodialysis we found a drop in eGFR values from 50.9 ml/min 6m before diagnosis of PTLD to 46.8 ml/min at time of diagnosis of PTLD that was statistically significant (p=0.04) suggesting a negative impact of the lymphoma (and/or of IR) to the graft function. With treatment of PTLD the graft function improved up to a mean eGFR of 56.3 ml/min 4 weeks after completing therapy (p=0.014). In subsequent subgroup analyses we found this effect to be restricted to and more durable in patients that had been treated with chemotherapy resulting in an eGFR of 57.6 ml/min, 55.7 ml/min and 58.6 ml/min 4 weeks, 6 months and 12 months after therapy, respectively. The graft function in this subgroup of patients was even superior to controls (p=0.012 at 6m, p=0.004 at 12m), which may result from the immunosuppressive effect of chemotherapy.Conclusion: PTLD may be associated with a worsening of graft function in renal transplant recipients but the graft often ameliorates during therapy. Beside rare acute complications like acute renal failure during septic complications there is no evident negative impact of therapy on renal graft function with rituximab and chemotherapy based 1st-line protocols in PTLD. Transplant survival in the disease free survival group is excellent.

Outcomes and a New Prognostic Model in Posttransplantation Lymphoproliferative Disorders (PTLD): Intent-to-Treat (ITT) Analysis of 81 Patients in the Post-Rituximab Era.

The outcome of PTLD has a reported approximate 3-year (yr) overall survival (OS) rate of 35%–40% in the pre-RTX era (JCO 2001; 19:772). The impact, if any, of RTX on the prognosis or outcome of PTLD is not known. We retrospectively studied the clinical features, treatment, outcomes (ITT), and prognostic factors among a large multi-center cohort of solid organ transplantation (SOT)-related PTLD cases over a 10-yr period in the post-RTX era (1/98–2/08) at 4 Chicago academic institutions. Prognostic factors were evaluated in Cox proportional hazards regression for indicators of progression-free survival (PFS) and OS. 81 pts were identified with a median age at PTLD diagnosis (dx) 48 yrs (range, 20–72) and median time from SOT to PTLD dx 42 months (mo) (range, 1-216 mo). EBV+ PTLD pts more commonly were treated by concurrent reduction of immune suppression (median reduction 75%) with single agent RTX whereas EBV-neg pts more frequently received RTX/chemotherapy with median immune suppression reduction of 90%. On ITT (median follow-up 36 mo), the 3-yr PFS for all pts was 58% and 3-yr OS was 62%. Of note, 13/81 (16%) pts died ≤6 weeks from PTLD dx, primarily due to progressive disease. Univariate analysis found several factors highly predictive of outcome (Table 1):performance status (PS),serum albumin,>1 extranodal (EN) site,bone marrow (BM) involvement,CNS disease, andRTX as part of initial therapy (alone or combined with chemotherapy).Neither EBV status nor time to PTLD predicted outcome.Table 1. PTLD characteristics and univariate predictors of EFS and OS (n=81).Variable (at dx)Pt characteristicsPFSOSNo.%HR*PHR*PKidney3746Kidney-pancreas1012SOTPancreas450.740.380.710.36Liver1721Heart810Lung56Time to PTLDEarly (<1 yr)30371.020.950.910.81Late (> 1 yr)5163Monomorphic5568Histology**Polymorphic22271.610.272.180.11Plasmacytic/reactive45EBV + (tumor)Yes3948No30371.090.820.820.64n/a1215PS2–425312.870.0023.310.0010–15669CNS involvementYes10122.570.032.470.050No7188BM involvementYes1215No58723.300.0033.480.003n/a1113EN > 1Yes2936No50622.010.042.190.03n/a22High LDHYes4960No27331.640.212.000.11n/a57Yes5669Low serum albuminNo24303.020.024.720.01n/a11IPI2–447580–233412.040.0531.760.16n/a11Immune suppression alone79Treatment***Radiation or surgery alone22Chemotherapy alone12150.280.0030.300.001Rituximab alone2632Rituximab/chemotherapy3442*Prognostic factors were tested for association with survival by proportional hazards analysis. Hazard ratios (HRs) >1 indicate a poor prognosis, while HRs <1 indicate a good prognosis.**Analysis was monomorphic PTLD (n=55) vs polymorphic and reactive (n=26).***Analysis combined rituximab alone and rituximab/chemotherapy-treated pts (n=60) vs all other therapy (n=21).n/a = not available.Table 2 shows 3-yr survival rates based on these variables. On multivariate analysis, 4 factors remained significant:1) RTX (EFS HR 0.26 (CI 0.11–0.60), p=0.002; OS HR 0.23 (CI 0.090.56), p=0.001),2) >1 EN site (EFS HR 2.15 (CI 1.04–4.42), p=0.04; OS HR 2.14 (CI 1.01–4.54), p=0.047),3) low albumin (EFS HR 3.19 (CI 1.17–8.72), p=0.02; OS HR 4.73 (CI 1.39–16.16), p=0.01), and4) CNS (EFS HR 4.48 (CI 1.80–11.17), p=0.01; OS HR 3.90 (CI 1.54–9.88), p=0.004).A prognostic model based on 3 factors: >1 EN site, albumin, and CNS disease was constructed (EFS p=0.008, OS=p=0.006), suggesting that pts with differential outcomes can be identified. In summary, we show that the introduction of RTX appears to have improved the outcome of PTLD compared to published data. However, a significant minority of pts still experience short survival. Clinical features at PTLD dx can predict outcome and should be incorporated into future therapeutic strategies.Table 2. Three-year survival (Kaplan-Meier) based on prognostic variables (univariate).Variable3-year EFS*3-year OS*PSp < 0.0001p < 0.00010–165% (50%, 77%)72% (57%, 82%)2–436% (18%, 54%)35% (15%, 56%)Albuminp = 0.002p = 0.0004Normal75% (49%, 89%)85% (59%, 95%)Low49% (34%, 61%)51% (37%, 64%)CNSp = 0.001p = 0.004No60% (47%, 71%)64% (51%, 74%)Yes30% (7%, 58%)40% (12%, 67%)Received rituximabp = 0.0002p = 0.001No21% (7%, 42%)32% (14%, 79%)Yes69% (55%, 79%)71% (57%, 81%)BM involvementp = 0.005p = 0.005No64% (49%, 75%)70% (56%, 80%)Yes18% (3%, 44%)18% (3%, 44%)> 1 EN sitep = 0.01p = 0.008No64% (48%, 76%)72% (57%, 82%)Yes39% (22%, 58%)40% (20%, 58%)*3-year PFS and OS by Kaplan-Meier analysis are reported (and their 95% CIs).

Post-Transplant Lymphoproliferative Disorder: Evaluation of Effectiveness of Reduction of Immunosuppression or Systemic Chemotherapy

BACKGROUND: Post transplant lymphoproliferative disorder (PTLD) is the commonest malignancy associated with pharmacologic immunosuppression after organ transplantation. Reduction in immunosuppression (RI) is a common initial strategy, but many pts require systemic therapy (ST) because of rapid disease progression. We evaluated the treatment and outcome of PTLD at a large multi-organ transplant programme to examine prognostic factors and predictors of outcome with RI and ST.METHODS: Patients (pts) were identified from the UHN Multi Organ Transplant Database and the Cancer Registry at Princess Margaret Hospital. Pts were included if they had a pathologic diagnosis of PTLD and adequate information to assess response to treatment. Variables evaluated for their influence on response to treatment and survival included age, organ transplanted, pathology, CD20+, time to PTLD from transplant, organ dysfunction, EBV+ lymphoma, stage, extranodal disease, B symptoms, CMV infection prior to PTLD, and LDH. RI was defined as a trial of „□10 days of reduction or discontinuation of calcineurin inhibitor (CNI), reduction or discontuation of mycophenolate mofitel or azathioprine and maintenance prednisone, with or without surgical resection of all known disease with repeat imaging to assess response. (Paya, Transplantation 68(10):1517, 1999). Chemotherapy consisted of CHOP or equivalent regimens. Rituximab was given as a single agent 375 mg/m2 weekly ×4 doses.RESULTS: 80 pts were identified; 3 pts were excluded from the current analysis for a diagnosis of marginal zone lymphoma (2) or primary body cavity lymphoma (1). Of the 77 pts included 53 (69%) were males. 66% (51) of pts had monomorphic PTLD (44 diffuse large B cell lymphoma, DLBCL), 31% (24) had polymorphic PTLD, 3 (2%) pts had Hodgkin lymphoma-like PTLD; 79% were EBV positive by in-situ hybridization. Organ transplanted: liver 34 (44%), kidney 22 (29%), lung 16 (21%), heart 5 (7%). Fifty percent of pts presented with stage III/IV disease, 81% with extranodal disease, 52% with B symptoms and 69% with an elevated LDH. Initial therapy: RI 43 pts, chemotherapy 31 pts, RI + rituximab 1 pt, surgical resection and re-transplantation 1 pt. For those treated with RI, extent of reduction of CNI did not influence response rate, overall survival (OS) or rate of organ rejection. Overall response rate to RI was 74%; only CD20 expression on the lymphoma was associated with a higher rate of response (p=0.026). Inclusion of antiviral therapy (generally gancyclovir) reduced the risk of relapse in those responding to RI (p=0.026). Response to RI did not vary by time to PTLD diagnosis from transplantation (p=.355), however, the rate of relapse following RI was significantly higher in pts developing PTLD >1 year from transplantation (p=.017). OS in pts undergoing RI as initial treatment was 73% at 3 yrs and 66% at 5 yrs. Nine pts received single agent rituximab, either with RI or because of progression after RI; 4 of the 9 pts responded, and 3 are progression-free. Of the 31 pts treated with primary chemotherapy, 24 had a CR or PR (78%); 4 pts died of toxicity (13%). OS of pts undergoing chemotherapy as initial treatment was 62% at 3 yrs and 58% at 5 yrs. Pts who received RI +/− rituximab followed by chemotherapy for lack of response or relapse had no significant difference in OS compared to those who received frontline chemotherapy (p=0.36). Evidence of graft rejection during treatment was seen in 13 pts (30%) treated with first line RI, compared to 6 (19%) in pts treated initially with chemotherapy. The rate of graft loss was low in both groups at 7% (3) in the RI group and 3% (1) in the chemotherapy group. Median follow up of survivors is 92 months. Overall survival (OS) for the entire cohort was 110 months (95% CI: 67.6, 152.7). Investigation of independent variables affecting OS revealed that organ dysfunction at diagnosis was significantly associated with shorter survival (p=.028).CONCLUSIONs: The outcome of pts with PTLD managed with initial RI is similar to those receiving ST; however the latter is toxic and there are no reproducible variables predicting response to RI as primary treatment. OS is similar in pts receiving RI followed by ST, versus those that received first line chemotherapy, suggesting that a delay in ST for a trial of RI may be justified. Prospective controlled trials of antiviral therapy and the timing and addition of rituximab and chemotherapy are still needed to improve patient outcome and guide future therapy.

Lymphoma after living donor kidney transplantation: an Iranian multicenter experience

Post-transplant lymphoproliferative disorders (PTLD) are well-recognized complications in solid organ recipients. Limited data exist about the development of PTLDs in living kidney recipients. This study deals with a multicenter nationwide experience with kidney recipients from living donors. We reviewed data of PTLD patients from a total population of 6,500 patients transplanted at three different transplant centers in Iran from 1984 to 2006. We also compared their data with 2,250 normal kidney recipients of Baqiyatallah Transplant Center. Data were analyzed to determine potential correlates with the occurrence of PTLD and patient outcome. Overall, 31 patients were diagnosed as having post-transplant lymphomas. The incidence of PTLD in our kidney transplant population comprised 0.47%. Sixteen (53%) PTLD patients were females, whereas 15 (47%) were males. The mean ages at transplantation and diagnosis were 37.1 and 41.9, respectively. Twelve (63%) patients died, and seven are alive. All deaths occurred within the 1st year after PTLD diagnosis. The mean time period from transplantation to diagnosis of PTLD was 64 (0.7-173) months. Localization of PTLD in the brain associated the worst outcome. Compared to non-PTLD patients, PTLD patients were significantly female predominated (51.6% vs. 32.2%; P = 0.03) and had lower age at transplantation (36.9 years vs. 42.9 years, respectively; P = 0.01). Patients under immunosuppressive regimens containing azathioprine were at higher risk for acquiring PTLDs compared to those with a MMF-containing regimen. PTLD is a major threat to kidney transplant recipients. Immunosuppressive agents have a significant role in developing the disease. Early detection of the disease and using more safe immunosuppresants may have beneficial effects on patient outcomes and incidence of the disease.

Case Report: Successful Treatment of Posttransplant Lymphoproliferative Disorder and Quiescence of Dermatomyositis With Rituximab and Sirolimus

Posttransplant lymphoproliferative disorder (PTLD) remains one of the most important complications of intensive immunosuppressive therapy. A 65-year-old Caucasian woman received a primary en bloc kidney transplant from a deceased 2-year-old donor. After antithymocyte globulin induction she was treated with a maintenance regimen including cyclosporine and mycophenylate mofetil (MMF). She had a history of recurrent dermatomyositis, suggesting a flawed immune system. After a benign course for 9 months and after an increase in MMF from 2 to 3 g daily, she presented with pneumonia owing to Candida albicans, which was responsive to antibiotics, as was the PTLD. Persistent fever led to a diagnosis of PTLD. The immunosuppressive regimen was converted to sirolimus (SRL) and rituximab, with over 90% necrosis of the neoplasm at 1 month. However, owing to concern at exploration, the allografts were extirpated. This case documented the benefit of the rituximab–SRL combination to treat PTLD while maintaining dermatomyositis in remission.

A new prognosticator for post‐transplant lymphoproliferative disorders after renal transplantation

A new prognosticator for post‐transplant lymphoproliferative disorders after renal transplantation

EBV-Associated Post-Transplant Lymphoproliferative Disorder after Pediatric Allogeneic Hematopoietic Stem Cell Transplantation.

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

A Single-Centre Experience of Clinico-Pathological Features, Risk Factors and Treatment Outcome of Posttransplant Lymphoproliferative Disorders (PTLD) after Renal Transplantation.

Background: PTLD is a lymphoid proliferation that develops as a consequence of immunosuppression and represents monoclonal B-cell, or rarely T-cell proliferations, occurring in a setting of decreased T-cell immune surveillance. PTLD is a major complication after solid organ transplantation. The disease is often unpredictable and devastating of nature resulting in a high rate of morbidity and patient mortality.Methods: Between 1990 and 2005 872 renal transplantations in 793 patients were performed at Skejby University Hospital in Aarhus and 11 cases of PTLD were identified retrospectively. PTLD Patients were investigated according to transplantation procedure, patient characteristics, type of lymphoma, treatment and outcome.Results: 11 of 793 renal transplant recipients (1,4%) developed PTLD. Patients (7 male, 4 female) ranged from 19 to 73 years of age at the time of diagnosis (mean age: 42 years). 8 had a cadaveric renal transplant while 3 received a transplant from related donor. Lymphomas were classified as diffuse large B-cell lymphoma in 10 cases and as Burkitt lymphoma in 1 case. No cases were of T-cell origin or Hodgkins lymphomas. Six cases were EBV positive (54%). Out of 11 cases, 5 were diagnosed within 1 year after transplantation, among which 4 were EBV positive, whereas 6 had a latency period of more than 1 year, among which only 2 were EBV positive. The mean latency time between grafting and diagnosis of PTLD among the early lesions was 7 months and among late lesions 6 years and 2 months (ranging from 1 month to 10 years and 8 months). Sites involved in PTLD were renal graft in 2 cases (both early lesions), lungs in 1 case, bowel system in 4 cases, CNS in 1 case, isolated lymph nodes in 1 case, widespread disease in 1 case and uncertain location in 1 case. All patients were treated by tapering of the immunosuppressive regimen. Two were treated with additional surgery and 3 with chemotherapy - all 5 of them are alive and in complete remission. Among those 5 patients 3 have preserved graft function (60%) and 2 returned to dialysis. One patient was treated with anti-CD20 monoclonal antibody, 3 had both conventional chemotherapy and anti-CD20 immunotherapy and 2 did not receive additional treatment. All 6 were dead at the end of the study period. With a median follow-up period of 5 years and 2 months (ranging from 6 months to 11½ years) 5 patients of 11 PTLD cases (45%) were alive with no sign of lymphoma relapse.Conclusions: PTLD is a severe complication, usually running an aggressive course and the outcome remains poor. The incidence in our population-based regional study material is 1,4%. Overall survival after a median follow-up of 62 months was 45%, with 60% of survivors maintaining graft function.

Posttransplant Lymphoproliferative Disorder in Adult Lung Transplant Recipients: A Report on Twenty-Seven Patients.

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication of organ transplantation. We report a case series on the diagnosis, treatment and outcome of PTLD in lung transplant recipients. From 1991 to 2006, 27 (5%) of the 502 lung transplant recipients at our institution developed PTLD. The median age at transplant was 51.5 years (range 21–65 years) and the median time from transplant to PTLD diagnosis was 33.7 months (range 1–174 months). Most cases had an elevated LDH (86%) and were EBV-positive (85%). Of the cases tested (n=14), 64% were monoclonal. PTLD was most commonly diagnosed in the lung (56%) and gastrointestinal tract (26%). Three patients were diagnosed at autopsy, while the remaining 24 received therapy. Eight patients were initially treated with reduced immunosuppression (RI) alone, but only 3 (38%) obtained a complete response (CR). Rituxan (R) was used alone (n=3) or in combination with RI (n=3) as initial therapy in six patients, four of whom obtained a CR. Five patients utilized RI +/− surgical resection as a primary treatment modality, all of whom achieved a CR. However, all of them relapsed and required further treatment. Of these five patients initially treated with RI +/− surgical resection, a CR was reestablished in 3 using rituxan alone (1/3), combined rituxan and reduced immunosuppression (1/3) and radiation treatment alone (1/3). The remaining five patients from the 24 patients receiving induction therapy for PTLD were given other treatments. With an average follow-up of 28 months (range 1-130 months), 81% of patients have died. However, only 18% of deaths were directly related to progressive PTLD. The remaining 17 deaths were due to: infection unrelated to PTLD treatment (15%), multi-organ failure (7%), graft failure not due to RI (30%), stroke (4%), and renal failure (4%). Most deaths can be attributed to disease specific and posttransplant complications rather than PTLD. Although an unfortunate diagnosis, PTLD is responsive to therapy, particularly reduced immunosuppression and rituximab.

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.