mycophenolic-acid and Lymphoproliferative-Disorders

Oral manifestations of side effects of medications, such as methotrexate (MTX) for management of rheumatoid arthritis (RA) and mycophenolate mofetil (MMF) for solid organ transplant (SOT), are very rare. The known side effects include entities called other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPD) due to immunosuppression caused by these medications. While there has been an increased incidence of oral cavity LPD reported in the literature associated with MTX, oral presentations that involve MMF are rare. This case report will detail a 74-year-old man with scleroderma treated with MMF who developed Epstein-Barr virus + polymorphic B-cell lymphoproliferative disorder in the right maxillary gingiva presenting as osteonecrosis of the jaw (ONJ). His oral presentation was successfully treated with a combination of surgery and MMF dosage reduction with an oral presentation free of disease at 6 months follow-up. This is the first known case report of an oral manifestation of MMF-related OIIA-LPD.

Topics: Aged; Arthritis, Rheumatoid; Humans; Iatrogenic Disease; Lymphoproliferative Disorders; Male; Methotrexate; Mycophenolic Acid

Most people who receive a kidney transplant die from either cardiovascular disease or cancer before their transplant fails. The most common reason for someone with a kidney transplant to lose the function of their transplanted kidney necessitating return to dialysis is chronic kidney transplant scarring. Immunosuppressant drugs have side effects that increase risks of cardiovascular disease, cancer and chronic kidney transplant scarring. Belatacept may provide sufficient immunosuppression while avoiding unwanted side effects of other immunosuppressant drugs. However, high rates of post-transplant lymphoproliferative disease (PTLD) have been reported when belatacept is used in particular kidney transplant recipients at high dosage.. 1) Compare the relative efficacy of belatacept versus any other primary immunosuppression regimen for preventing acute rejection, maintaining kidney transplant function, and preventing death. 2) Compare the incidence of several adverse events: PTLD; other malignancies; chronic transplant kidney scarring (IF/TA); infections; change in blood pressure, lipid and blood sugar control. 3) Assess any variation in effects by study, intervention and recipient characteristics, including: differences in pre-transplant Epstein Barr virus serostatus; belatacept dosage; and donor-category (living, standard criteria deceased, or extended criteria deceased).. We searched the Cochrane Renal Group's Specialised Register to 1 September 2014 through contact with the Trials' Search Co-ordinator using search terms relevant to this review.. Randomised controlled trials (RCT) that compared belatacept versus any other immunosuppression regimen in kidney transplant recipients were eligible for inclusion.. Two authors independently extracted data for study quality and transplant outcomes and synthesized results using random effects meta-analysis, expressed as risk ratios (RR) and mean differences (MD), both with 95% confidence intervals (CI).  Subgroup analyses and univariate meta-regression were used to investigate potential heterogeneity.. We included five studies that compared belatacept and calcineurin inhibitors (CNI) that reported data from a total of 1535 kidney transplant recipients. Of the five studies, three (478 participants) compared belatacept and cyclosporin and two (43 recipients) compared belatacept and tacrolimus. Co-interventions included basiliximab (4 studies, 1434 recipients); anti-thymocyte globulin (1 study, 89 recipients); alemtuzumab (1 study, 12 recipients); mycophenolate mofetil (MMF, 5 studies, 1509 recipients); sirolimus (1 study, 26 recipients) and prednisone (5 studies, 1535 recipients).Up to three years following transplant, belatacept and CNI-treated recipients were at similar risk of dying (4 studies, 1516 recipients: RR 0.75, 95% CI 0.39 to 1.44), losing their kidney transplant and returning to dialysis (4 studies, 1516 recipients: RR 0.91, 95% CI 0.61 to 1.38), and having an episode of acute rejection (4 studies, 1516 recipients: RR 1.56, 95% CI 0.85 to 2.86). Belatacept-treated kidney transplant recipients were 28% less likely to have chronic kidney scarring (3 studies, 1360 recipients: RR 0.72, 95% CI 0.55 to 0.94) and also had better graft function (measured glomerular filtration rate (GFR) (3 studies 1083 recipients): 10.89 mL/min/1.73 m², 95% CI 4.01 to 17.77; estimated GFR (4 studies, 1083 recipients): MD 9.96 mL/min/1.73 m², 95% CI 3.28 to 16.64) than CNI-treated recipients. Blood pressure was lower (systolic (2 studies, 658 recipients): MD -7.51 mm Hg, 95% CI -10.57 to -4.46; diastolic (2 studies, 658 recipients): MD -3.07 mm Hg, 95% CI -4.83 to -1.31, lipid profile was better (non-HDL (3 studies 1101 recipients): MD -12.25 mg/dL, 95% CI -17.93 to -6.57; triglycerides (3 studies 1101 recipients): MD -24.09 mg/dL, 95% CI -44.55 to -3.64), and incidence of new-onset diabetes after transplant was reduced by 39% (4 studies (1049 recipients): RR 0.61, 95% CI 0.40 to 0.93) among belatacept-treated versus CNI-treated recipients.Risk of PTLD was similar in belatacept and CNI-treated recipients (4 studies, 1516 recipients: RR 2.79, 95% CI 0.61 to 12.66) and was no different among recipients who received different belatacept dosages (high versus low dosage: ratio of risk ratios (RRR) 1.06, 95% CI 0.11 to 9.80, test of difference = 0.96) or among those who were Epstein Barr virus seronegative compared with those who were seropositive before their kidney transplant (seronegative versus seropositive; RRR 1.49, 95% CI 0.15 to 14.76, test for difference = 0.73).Th. There is no evidence of any difference in the effectiveness of belatacept and CNI in preventing acute rejection, graft loss and death, but treatment with belatacept is associated with less chronic kidney scarring and better kidney transplant function. Treatment with belatacept is also associated with better blood pressure and lipid profile and a lower incidence of diabetes versus treatment with a CNI. Important side effects (particularly PTLD) remain poorly reported and so the relative benefits and harms of using belatacept remain unclear. Whether short-term advantages of treatment with belatacept are maintained over the medium- to long-term or translate into better cardiovascular outcomes or longer kidney transplant survival with function remains unclear. Longer-term, fully reported and published studies comparing belatacept versus tacrolimus are needed to help clinicians decide which patients might benefit most from using belatacept.

Topics: Abatacept; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Basiliximab; Calcineurin Inhibitors; Cyclosporine; Graft Rejection; Graft Survival; Humans; Immunoconjugates; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Mycophenolic Acid; Prednisone; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Sirolimus; Tacrolimus

A 43-year-old male renal transplant recipient, who received a living related renal transplant 7 years ago and had been maintained with tacrolimus, mycophenolate mofetil (MMF), and prednisolone, was admitted to our hospital complaining of headache and nausea. MRI showed a large mass in the right hemisphere with ring-enhancement indicating brain abscess, tumor or lymphoma. Open biopsy was performed and pathological examination demonstrated diffuse proliferation of polymorphic cells, positive for CD20, bcl-2, EBER, and LMP-1. Based on these findings, primary central nervous system post-transplant lymphoproliferative disorder (PCNS-PTLD) was diagnosed. MMF was discontinued and tacrolimus was tapered. After 2 weeks, MRI showed regression of the tumor size and after 9 months, the tumor had disappeared. Though many reports have shown the severity of PCNS-PTLD, and recommend aggressive treatments such as chemotherapy and/or radiotherapy, our case shows that reduction of immunosuppressant alone with close observation could be a choice of treatment.

Topics: Adult; Brain Diseases; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Male; Mycophenolic Acid; Prednisolone; Remission Induction; Tacrolimus

Knowledge of the significance of post-transplant lymphoproliferative disorders (PTLD) that occur "very late" or more 10 years after renal transplantation is limited. thus, we analysed and compared characteristics and prognosis of the disease in renal transplant patients with very late onset PTLD vs. early- and late-onset PTLD.. Retrospective study of data obtained from comprehensive search of medical literature. We searched for available data using the Pubmed and Google scholar search engines for reports of lymphoproliferative disorders occurring in renal transplant patients by disease presentation time.. We analyzed data from 27 studies that included 303 patients with lymphoproliferative disorders after renal transplantation. Renal graft recipients with very late onset PTLD were significantly less likely to be under mycophenolate mofetil (MMF)- and/or tacrolimus (FK-506) (vs. azathioprine) -based immunosuppression (P=.035) and less likely to have a history of antibody induction immunosuppression (P<.001). Compared to "early onset" disease, "very late" onset PTLD is more likely to develop in older patients (P=.032). Survival analysis did not show any difference in outcome (P=.5). no organ involvement priority was found for this patient group (P>.1 for all).. Older renal transplant patients are at increased risk for development of very late onset PTLD, and should be strictly followed. further multi-institutional prospective studies are needed to confirm our results.

Topics: Graft vs Host Disease; Health Surveys; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Mycophenolic Acid; Retrospective Studies; Survival Analysis; Tacrolimus; Time Factors

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Diabetic Nephropathies; Disease Progression; Epstein-Barr Virus Infections; Fatal Outcome; Ganciclovir; Humans; Immunosuppressive Agents; Kidney Transplantation; Lumbar Vertebrae; Lymphoproliferative Disorders; Male; Middle Aged; Multiple Myeloma; Mycophenolic Acid; Pancreas Transplantation; Plasmacytoma; Postoperative Complications; Prednisone; Reoperation; Rituximab; Spinal Neoplasms; Tacrolimus; Thalidomide

As newer immunosuppressive regimens have steadily reduced the incidence of acute rejection and have extended the life expectancy of allograft recipients, posttransplant malignancy has become an important cause of mortality. In fact, it is expected that cancer will surpass cardiovascular complications as the leading cause of death in transplant patients within the next 2 decades. An understanding of the underlying pathobiology and how to minimize cancer risks in transplant recipients are essential. The etiology of posttransplant malignancy is believed to be multifactorial and likely involves impaired immunosurveillance of neoplastic cells as well as depressed antiviral immune activity with a number of common posttransplant malignancies being viral-related. Although calcineurin inhibitors and azathioprine have been linked with posttransplant malignancies, newer agents such as mycophenolate mofetil and sirolimus have not and indeed may have antitumor properties. Long-term data are needed to determine if the use of these agents will ultimately lower the mortality due to malignancy for transplant recipients.

Topics: Azathioprine; Calcineurin Inhibitors; Carcinoma, Hepatocellular; Cyclosporine; Hepatitis, Viral, Human; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Lymphoproliferative Disorders; Mycophenolic Acid; Neoplasms; Sirolimus; Skin Neoplasms; Tacrolimus; Transplantation Immunology; Transplantation, Homologous

This review covers the new immunosuppressive drugs that have appeared in the past 5 years. It begins with the newest formulation (Neoral, Sandoz Pharmaceuticals, East Hanover, NJ, USA) of the clinically "mature" drug cyclosporin A and then reviews the literature on tacrolimus, sirolimus, and mycophenolate mofetil. In each case, the emphasis is on the evolution of experience with the drug and on the questions that the drug poses for pediatricians considering the risk-benefit ratio of the drug in children.

Topics: Child; Cyclosporine; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Mycophenolic Acid; Sirolimus; Tacrolimus

This exploratory phase II study evaluated the safety and efficacy of belatacept in de novo adult liver transplant recipients. Patients were randomized (N = 260) to one of the following immunosuppressive regimens: (i) basiliximab + belatacept high dose [HD] + mycophenolate mofetil (MMF), (ii) belatacept HD + MMF, (iii) belatacept low dose [LD] + MMF, (iv) tacrolimus + MMF, or (v) tacrolimus alone. All received corticosteroids. Demographic characteristics were similar among groups. The proportion of patients who met the primary end point (composite of acute rejection, graft loss, death by month 6) was higher in the belatacept groups (42–48%) versus tacrolimus groups (15–38%), with the highest number of deaths and grafts losses in the belatacept LD group. By month 12, the proportion surviving with a functioning graft was higher with tacrolimus + MMF (93%) and lower with belatacept LD (67%) versus other groups (90%: basiliximab + belatacept HD; 83%: belatacept HD; 88%: tacrolimus). Mean calculated GFR was 15–34 mL/min higher in belatacept-treated patients at 1 year. Two cases of posttransplant lymphoproliferative disease and one case of progressive multifocal leukoencephalopathy occurred in belatacept-treated patients. Follow-up beyond month 12 revealed an increase in death and graft loss in another belatacept group (belatacept HD), after which the study was terminated.

Topics: Abatacept; Adult; Aged; Drug Administration Schedule; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Hepatitis C; Humans; Immunoconjugates; Immunosuppression Therapy; Immunosuppressive Agents; Leukoencephalopathies; Liver Failure; Liver Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Mycophenolic Acid; Recurrence; Tacrolimus; Treatment Outcome

We enrolled 11 patients with refractory graft-versus-host disease (GVHD) in a prospective trial evaluating the efficacy of mycophenolate mofetil (MMF). Four (67%) of the 6 patients with acute GVHD and all 5 patients with chronic GVHD responded to MMF. Ten (91%) of the 11 patients were able to decrease steroid use (median decrease, 86%; range, 25%-100%). After a median follow-up of 18 months (range, 1-65 months), 7 patients (64%) remained alive. The adverse events were infectious complications (36%), diarrhea (27%), and neutropenia (18%); the only patient discontinuing MMF did so because of grade 4 neutropenia. This preliminary study suggests that MMF is a well-tolerated agent and has a beneficial effect in the treatment of refractory acute and chronic GVHD.

Topics: Acute Disease; Adult; Aged; Chronic Disease; Female; Follow-Up Studies; Graft vs Host Disease; Humans; Immunosuppressive Agents; Lymphoproliferative Disorders; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Stem Cell Transplantation; Transplantation, Homologous

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of apoptosis associated most often with heritable FAS mutations leading to lymphadenopathy, hypersplenism and chronic refractory autoimmune cytopenias. Mycophenolate mofetil (MMF) was used to treat cytopenias in 13 ALPS patients aged 9 months to 17 years from a cohort of 118 children (aged < 18 years) and 82 adults. Twelve responded for a median follow-up of 49 weeks (range 38-240 weeks), defined by maintenance of adequate blood counts and reduction in dosage or cessation of other immunosuppressive agents. This preliminary experience suggests that MMF may spare steroid usage in patients with ALPS-associated cytopenias.

Topics: Adolescent; Anemia, Hemolytic, Autoimmune; Autoimmune Diseases; Child; Child, Preschool; Follow-Up Studies; Humans; Immunosuppressive Agents; Infant; Leukocyte Count; Lymphoproliferative Disorders; Male; Mycophenolic Acid; Neutropenia; Pain; Prodrugs; Thrombocytopenia

A widely held view is that any increase in the potency of an immunosuppressive agent will lead to an increase in infection and malignancy, such as life-threatening Epstein-Barr virus (EBV) induced posttransplant lymphoproliferative disorders (PTLD). We tested this paradigm by studying the effect of adding mofetil to a steroid-free protocol under cover of high-dose aciclovir prophylaxis on the number of acute rejections, EBV infections and PTLDs after kidney transplantation.. EBV serology was performed in 267 consecutive renal transplantations (1990-1997). All were treated with cyclosporine with an initial 10-day antilymphocyte globulin course, supplemented from September 1995 with MMF. In 208 consecutive transplantations after June 1992 aciclovir 3200 mg/day was given for 3 months posttransplantation.. After an observation period of up to 7 years we found that: (1) primary or reactivated EBV infection (PREBV) was correlated to acute rejection (treated with OKT3; P<0.00005) and to the incidence of PTLD (P=0.03; P=0.01, if Hodgkin's disease is included); (2) aciclovir protected against PREBV (P<0.00005) and (3) adding mofetil to the immunosuppressive protocol reduced PREBV further (P=0.0001), (4) in 78 transplantations treated with cyclosporine/antilymphocyte globulin/mofetil we observed only 10 acute rejections (P=0.0001), 10 PREBVs (P<0.00005), and no PTLDs compared with the cyclosporine/antilymphocyte globulin group (P=0.04).. Supplemental immunosuppression with mofetil protects against acute rejection. In combination with aciclovir, there is also a reduction in the number of PREBVs, apparently as a result of both direct viral prophylaxis and better rejection control, and in the incidence of EBV-induced PTLD.

Topics: Acute Disease; Acyclovir; Adolescent; Adult; Antilymphocyte Serum; Antiviral Agents; Child; Female; Graft Rejection; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Muromonab-CD3; Mycophenolic Acid; Prospective Studies; Retrospective Studies

Posttransplant lymphoproliferative diseases are a rare but important cause of morbidity and mortality secondary to immunosuppression after solid-organ or bone marrow transplant. Generally, posttransplant lymphoproliferative diseases develop in the first 2 years after transplant, when immunosuppressive therapy is the most intense. Change or reduction in immunosup - pressive treatment is an option for treatment of posttransplant lymphoproliferative diseases. We evaluated the treatment of a patient with posttransplant lymphoproliferative disease after liver transplant. A 64-year-old man underwent liver transplant from a living donor (the patient's son) in 2011 to treat hepatocellular cancer secondary to chronic hepatitis B. Tacrolimus and mycophenolate mofetil were used for immunosuppression through 9 years after liver transplant. In the abdominal computed tomography performed in response to abdominal pain during follow-up in March 2019, multiple solid lesions were observed. A liver biopsy revealed posttransplant lymphoproliferative disease with diffuse large B-cell lymphoma. Fluorine-18 positron emission tomography/computed tomography imaging of the patient showed no pathology in favor of primary lymphoproliferative disease. Mycophenolate mofetil and tacrolimus treatment was changed to everolimus. In the follow-up dynamic magnetic resonance imaging examination that was performed at 3 months after treatment change, we observed that the lesion at liver segment 6 had regressed to 30 mm and several lesions with similar features were observed in the right lobe of the liver. Additional liver biopsy results were compatible with complete remission. The patient's clinical symptoms had fully regressed at 18 months after the diagnosis of PTLD, at the time of this writing. Ongoing radiological and clinical follow-up has shown complete remission. Change from calcineurin treatment to treatment with an inhibitor of the mechanistic target of rapamycin may be an essential and new option for treatment of posttransplant lymphoproliferative disease after liver transplant.

Topics: Humans; Immunosuppressive Agents; Liver Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Mycophenolic Acid; Tacrolimus

There is a scarcity of long-term data on steroid-free immunosuppression using alemtuzumab in pediatric kidney transplantation (KTx). This study examines long-term outcomes with alemtuzumab without steroid maintenance therapy in pediatric KTx.. From July 2005 to June 2015, 71 pediatric KTx recipients received alemtuzumab without steroid maintenance. They were followed from 4.1 to 14.1 years post KTx.. Patient survival: One child expired with a functioning graft from post-transplant lymphoproliferative disorder (PTLD). Patient survival was 98.6%. Graft survival: Eighteen grafts were lost (16 from chronic rejection). Graft survival at 5 and 10 years was 92.3% and 61.3%, respectively. Rejection: Twenty-three (32.4%) patients were free from T-cell-mediated rejection (TCMR), 16 (22.5%) had >3 episodes. Sixteen (22.5%) were treated for antibody-mediated rejection (AMR). Infection: Twenty-three children developed Epstein-Barr virus (EBV), 5 developed cytomegalovirus (CMV), and 20 developed BK virus infection. Four (5.6%) developed PTLD. Twenty-two (31.0%) required treatment for neutropenia. Growth parameters: Mean height and weight increased by 0.56 and 0.69 SDS (standard deviation score), respectively. Body mass index increased by 5.1 kg/m. Alemtuzumab, without corticosteroid maintenance, offers 98.6% patient survival at 14 years with five and 10-year graft survival of 92.3% and 61.3%, respectively. TCMR and AMR requiring treatment were 67.4% and 22.5%, respectively. CMV, EBV, and BK viremia rates were 7.0%, 32.4%, and 28.2%, respectively. Thirty-one percent were treated for neutropenia; 5.6% developed PTLD. There were improvements in growth parameters and blood pressure.

Topics: Adolescent; Alemtuzumab; Child; Child, Preschool; Cytomegalovirus Infections; Epstein-Barr Virus Infections; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infant; Kidney Transplantation; Lymphoproliferative Disorders; Male; Mycophenolic Acid; Tacrolimus

Topics: Humans; Iatrogenic Disease; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Lymphoproliferative Disorders; Myasthenia Gravis; Mycophenolic Acid

CBT with ATG use is a well-known PTLD risk factor. However, little is known regarding the clinical features of PTLD after ATG-free CBT.. We analyzed the incidence, risk factors and prognosis of PTLD in 183 adults undergoing ATG-free CBT.. Fifteen patients (diffuse large B-cell lymphoma, n = 9, mucosa-associated lymphoid tissue lymphoma, n = 2 nondestructive PTLD, n = 1, T-cell lymphoma, n = 3) developed PTLD. The 2-year CuI of PTLD was 8.0% (95% CI: 4.6-12.7). Pathologically, all 12 B-cell PTLD patients had Epstein-Barr virus (EBV), compared with 1 of 3 T-cell PTLD patients. All patients, excluding one with nondestructive PTLD, showed extranodal involvement. In the univariate analysis, the 2-year CuI of PTLD was significantly higher in patients who received mycophenolate mofetil to prevent graft-versus-host disease than in nonrecipients (11.2%/2.9%, P = .0457). However, multivariate analysis revealed no independent PTLD risk factors. All 11 PTLD patients who received specific therapy achieved complete remission. The 1-year overall survival of PTLD patients was 70.9%.. Although we found a higher CuI of PTLD than previously reported, the prognosis was generally good. In CBT recipients, many factors, including MMF use, may be associated with the clinical features of PTLD.

Topics: Adult; Antilymphocyte Serum; Cord Blood Stem Cell Transplantation; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Lymphoproliferative Disorders; Mycophenolic Acid; Retrospective Studies

Post-transplant lymphoproliferative disorder is a life-threatening complication of immunosuppression following transplantation mediated by failure of T cells to control Epstein-Barr virus (EBV)-infected and transformed B cells. Typically, a modification or reduction of immunosuppression is recommended, but insufficiently defined thus far. In order to help delineate this, we characterized EBV-antigen-specific T cells and lymphoblastoid cell lines from healthy donors and in patients with a kidney transplant in the absence or presence of the standard immunosuppressants tacrolimus, cyclosporin A, prednisolone, rapamycin, and mycophenolic acid. Phenotypes of lymphoblastoid cell-lines and T cells, T cell-receptor-repertoire diversity, and T-cell reactivity upon co-culture with autologous lymphoblastoid cell lines were analyzed. Rapamycin and mycophenolic acid inhibited lymphoblastoid cell-line proliferation. T cells treated with prednisolone and rapamycin showed nearly normal cytokine production. Proliferation and the viability of T cells were decreased by mycophenolic acid, while tacrolimus and cyclosporin A were strong suppressors of T-cell function including their killing activity. Overall, our study provides a basis for the clinical decision for the modification and reduction of immunosuppression and adds information to the complex balance of maintaining anti-viral immunity while preventing acute rejection. Thus, an immunosuppressive regime based on mTOR inhibition and reduced or withdrawn calcineurin inhibitors could be a promising strategy for patients with increased risk of or manifested EBV-associated post-transplant lymphoproliferative disorder.

Topics: Calcineurin; Cyclosporine; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Lymphoproliferative Disorders; MTOR Inhibitors; Mycophenolic Acid; Prednisolone; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases

Posttransplant lymphoproliferative disorder (PTLD) occurs in 1% to 3% of adult renal transplant recipients (RTRs). PTLD has a heterogeneous presentation and is often associated with Epstein-Barr virus (EBV) and immunosuppression. We present a descriptive case series of 16 RTRs who demonstrate a variety of PTLD manifestations. Fifty-six percent received rabbit antithymocyte globulin induction, and 37.5% received basiliximab. Maintenance immunosuppression included glucocorticoids, tacrolimus, and mycophenolate mofetil. Median time from transplantation to PTLD diagnosis was 96.5 months. PTLD involved a single site in 44% of RTRs and multiple sites in 56%. PTLD was localized to the gastrointestinal tract in 9 RTRs, in lymph nodes in 9, central nervous system in 4, bone marrow in 3, skin in 3, lungs in 2, perinephric space in 2, mediastinum in 1, and native kidney in 1. PTLD was EBV positive in 8 RTRs, monomorphic/monoclonal in 14, and of B-cell lineage in 13. Three RTRs had T-cell PTLD. Immunosuppressive agents, except glucocorticoids, were discontinued at diagnosis. Treatment was chemotherapy either alone (in 14 RTRs) or in combination with radiation. Complete remission was achieved in 62.5% of RTRs. Renal dysfunction developed in 62.5% of RTRs, and 4 received dialysis. The overall mortality rate was 62.5%, with median time of death 6.5 months after diagnosis. PTLD that was EBV negative and had T-cell involvement presented with aggressive disease and a higher mortality. Clinicians should be aware of the various PTLD manifestations. Early diagnosis and a multidisciplinary approach to treatment is crucial for improved patient outcomes.

Topics: Adult; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Lymphoma; Lymphoproliferative Disorders; Male; Mycophenolic Acid; Postoperative Complications; Renal Dialysis; Tacrolimus; Treatment Outcome

The incidence of Epstein-Barr virus (EBV)associated lymphoproliferative disorders has increased with greater use of immunomodulatory therapies. We present a woman who developed subacute cognitive decline and unilateral weakness while taking long-term mycophenolate mofetil for granulomatosis with polyangiitis; her postmortem brain histopathology confirmed an EBV-driven lymphoproliferative disorder. Clinicians must have a high index of suspicion for EBV-driven lymphoma in people taking long-term immunosuppression who develop new neurological problems. We review the role of mycophenolate mofetil in EBV-driven lymphoproliferative disorders, and discuss checking EBV status in all patients starting immunosuppression and in older people already taking immunosuppression.

Topics: Aged; Cerebral Hemorrhage; Cognitive Dysfunction; Epstein-Barr Virus Infections; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Lymphoproliferative Disorders; Mycophenolic Acid

Post-transplant lymphoproliferative disorders (PTLD) represent a severe complication in transplanted patients and Epstein-Barr Virus (EBV) is the main driver. Besides immunodepression, immune activation/chronic inflammation play an important role in both virus reactivation and expansion of EBV-positive B cells. The aim of this study was to assess the impact of immunosuppressive strategies on factors involved in the PTLD's pathogenesis. 124 kidney transplanted patients were enrolled in this study: 71 were treated with mycophenolic acid (MPA) and 53 treated with mTOR inhibitor (mTORi), both in combination with different doses of calcineurin inhibitor. At the time of the transplant (T0), profile of inflammation/immune activation and immune senescence didn't differ between the two groups, but after one year of treatment (T1) markers were significantly higher in MPA-treated patients; their immunosenescence process was supported by the greater erosion of telomeres despite their younger age. Percentages of activated B cells and levels of EBV-DNA significantly increased in MPA-treated patients, and at T1 were significantly higher in MPA- than in mTORi-treated patients. Overall, these findings indicate that mTOR inhibitors constrain the inflammation/immune activation and senescence status, thus reducing the expansion of EBV-infected B cells and the risk of virus-associated PTLD in kidney transplant recipients.

Topics: Adult; B-Lymphocytes; Calcineurin; Calcineurin Inhibitors; Cellular Senescence; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Mycophenolic Acid; TOR Serine-Threonine Kinases; Viral Load

A case of primary cutaneous post liver transplant lymphoproliferative disorder (PTLD) mimicking squamous cell carcinoma-in-situ is presented.. Lesions mimicking SCC-in-situ were confirmed to be PTLD on histopathology and immunohistochemistry. Immunosuppression was gradually reduced and the lesions were successfully treated with 50 gray (Gy) in 25 fractions of radiotherapy.. There was no recurrence of lesions at 3 months follow-up.. Radiotherapy is an effective form of cutaneous directed treatment for localized PTLD.

Topics: Aged; Antibiotics, Antineoplastic; B-Lymphocytes; Carcinoma, Squamous Cell; Follow-Up Studies; Gamma Rays; Humans; Immunohistochemistry; Liver Cirrhosis, Biliary; Liver Transplantation; Lymphoproliferative Disorders; Male; Mycophenolic Acid; Tacrolimus; Tomography, X-Ray Computed; Treatment Outcome

Post-transplant lymphoproliferative disorder (PTLD) is a well-recognized and potentially fatal complication of cardiac transplantation that commonly involves the gastrointestinal tract. Herein, we report a case of life-threatening gastrointestinal bleeding from recurrent terminal ileac ulcers mimicking PTLD in a heart recipient treated with everolimus (EVL). A 40-year-old man underwent heart transplantation for dilated cardiomyopathy 3 years prior to the current admission and was treated with tacrolimus and EVL. He was admitted to a local hospital because of fever, abdominal pain, and diarrhea. His symptoms persisted and, 3 weeks later, hematochezia occurred; thus, he was transferred to our hospital. As computed tomography and

Topics: Adult; Diagnosis, Differential; Everolimus; Graft Rejection; Heart Transplantation; Humans; Ileal Diseases; Immunosuppressive Agents; Lymphoproliferative Disorders; Male; Mycophenolic Acid; Tacrolimus; Ulcer

Topics: Aged; Eosinophils; Female; Humans; Hypereosinophilic Syndrome; Immunoglobulin E; Leukocyte Count; Lymphoproliferative Disorders; Mycophenolic Acid; T-Lymphocytes

Immunosuppression for solid organ transplantation increases lymphoproliferative disease risk. While central nervous system (CNS) involvement is more rare, we noticed an increase in primary CNS (PCNS) disease. To investigate a potential association with the immunosuppressive regimen we identified all post-transplant lymphoproliferative disease (PTLD) cases diagnosed over a 28-year period at our institution (174 total, 29 PCNS) and all similar cases recorded in a United Network for Organ Sharing-Organ Procurement and Transplant Network (UNOS-OPTN) datafile. While no PCNS cases were diagnosed at our institution between 1986 and 1997, they comprised 37% of PTLD cases diagnosed from 2011-2014. PCNS disease was more often associated with renal vs. other organ transplant, Epstein-Barr virus, large B-cell morphology and mycophenolate mofetil (MMF) as compared to PTLD that did not involve the CNS. Calcineurin inhibitors were protective against PCNS disease when given alone or in combination with MMF. A multivariate analysis of a larger UNOS-OPTN dataset confirmed these findings, where both MMF and lack of calcineurin inhibitor usage were independently associated with risk for development of PCNS PTLD. These findings have significant implications for the transplant community, particularly given the introduction of new regimens lacking calcineurin inhibitors. Further investigation into these associations is warranted.

Topics: Adult; Aged; B-Lymphocytes; Calcineurin Inhibitors; Central Nervous System; Databases, Factual; Female; Herpesvirus 4, Human; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Lymphoma; Lymphoproliferative Disorders; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Odds Ratio; Organ Transplantation; Postoperative Complications; Regression Analysis; Retrospective Studies

Posttransplant lymphoproliferative disease (PTLD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation. We describe here the case of a boy with history of induction failure of a T-cell acute lymphoblastic leukemia, who presented a life-threatening situation of nonengraftment and rituximab-refractory PTLD after the first hematopoietic stem cell transplantation. We decided to use an unusual strategy of combining a nonmyeloablative conditioning (fludarabine and cyclophosphamide) with a calcineurin inhibitor-free GvHD prophylaxis (sirolimus and mycophenolate mofetil). This strategy had permitted the control of an Epstein-Barr virus PLTD in umbilical cord blood transplantation without further reactivation.

Topics: Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Calcineurin; Child; Combined Modality Therapy; Drug Resistance, Neoplasm; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Lymphoproliferative Disorders; Male; Mycophenolic Acid; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Rituximab; Sirolimus; Transplantation Conditioning; Transplantation, Homologous; Vidarabine

The association of immunosuppressive regimens (ISRs) with posttransplant lymphoproliferative disorder (PTLD) may be related with the Epstein-Barr virus (EBV) recipient serostatus.. We selected primary kidney transplant recipients from Organ Procurement Transplant Network/United Network for Organ Sharing database (2000-2009) who were discharged with a functioning graft and were receiving an ISR including an antiproliferative drug and a calcineurin inhibitor as follows: mycophenolate mofetil (MMF)/mycophenolate sodium+tacrolimus (TAC), MMF+cyclosporine A (CsA); mammalian target of rapamycin inhibitor (mTORi)+TAC; and mTORi+CsA. Adjusted risks of PTLD, rejection, death, and graft failure were examined in all recipients and compared between EBV+ and EBV- recipients.. Of 114,025 recipients, 754 developed PTLD (5-year incidence of 0.84%). Adjusted hazard ratio for PTLD was 4.39 (95% CI: 3.60-5.37) for EBV- versus EBV+ recipients; and 1.40 (95% CI: 1.03-1.90) for mTORi+TAC, 0.80 (95% CI: 0.65-0.99) for MMF+CsA, and 0.90 (95% CI: 0.57-1.42) for mTORi+CsA, versus MMF+TAC users. In EBV- recipients, hazard ratio for PTLD was 1.98 (95% CI: 1.28-3.07) for mTORi+TAC, 0.45 (95% CI: 0.28-0.72) for MMF+CsA, and 0.84 (95% CI: 0.39-1.80) for mTORi+CsA users versus MMF+TAC. No difference was seen in EBV+ recipient groups. Rejection rates were higher among MMF+CsA recipients in both EBV groups. Death and graft failure risk were increased in all EBV+ISR groups, while in EBV- these risks were only increased in mTORi+TAC group versus MMF+TAC.. In EBV- recipients, immunosuppression with mTORi+TAC was associated with increased risk of PTLD, death, and graft failure, while MMF+CsA use was associated with a trend to increased risk of rejection, lower PTLD risk, and similar risk for graft failure when compared with MMF+TAC.

Topics: Adolescent; Adult; Comorbidity; Cyclosporine; Drug Therapy, Combination; Epstein-Barr Virus Infections; Female; Graft Rejection; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Incidence; Kaplan-Meier Estimate; Kidney Transplantation; Longitudinal Studies; Lymphoproliferative Disorders; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Risk Factors; Tacrolimus; TOR Serine-Threonine Kinases; Transplantation; Young Adult

The aim of this study is to clarify the association between hepatitis C virus (HCV) infection and post-transplant lymphoproliferative disease (PTLD) in the liver allograft.. Of the 933 adults who underwent liver transplantation (LT) between 1990 and 2005, 10 patients developed PTLD. Seven of the 10 patients that were HCV(+) (group 1) were compared with three HCV-negative recipients (group 2).. The mean time between LT and PTLD was 24.5 months. There were no differences between in Epstein-Barr virus antibody status or tumor lymphocyte subsets. In five of the seven HCV-positive recipients who developed PTLD, PTLD recurred preferentially in the liver allograft, whereas none of the three HCV-negative patients who developed PTLD did so in the liver (71.4 vs. 0%, respectively, P=0.038). In all five patients with graft PTLD, HCV recurred within 12 months followed by PTLD. There were significant differences between groups 1 and 2 in mean lymphocyte infiltrate scores (6.0±2.1 vs. 2.0±0.7, P=0.037), fibrosis stage (2.4±0.5 vs. 0.7±0.5, P=0.029), and frequency of lymphoid follicles in portal areas (33.6±14.8% vs. 1.1±2.3%, P=0.0002).. When PTLD occurs in patients with HCV recurrence after LT, it does so preferentially in the liver allograft.

Topics: Adolescent; Aged; Antibodies, Viral; Azathioprine; Cohort Studies; Cyclosporine; Drug Therapy, Combination; Female; Graft Rejection; Hepatitis C; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Steroids; Tacrolimus

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Azathioprine; Diagnosis, Differential; Drug Therapy, Combination; Epstein-Barr Virus Infections; Female; Gingival Diseases; Hepatitis, Autoimmune; Herpesvirus 4, Human; Hodgkin Disease; Humans; Iatrogenic Disease; Immunocompromised Host; Immunosuppressive Agents; Lymphoproliferative Disorders; Mandibular Diseases; Mycophenolic Acid; Oral Ulcer; Prednisone; Remission Induction; Rituximab; Virus Activation

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.

Topics: Adult; B-Lymphocytes; Central Nervous System Diseases; Dose-Response Relationship, Drug; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Middle Aged; Mycophenolic Acid; Steroids; T-Lymphocytes; Treatment Outcome

Immunosuppressive therapies are critical in the management of numerous conditions including myasthenia gravis. Mycophenolate mofetil is a widely used, oral immunosuppressive agent that is considered to have few adverse effects compared with similar drugs. We report the case of a patient who developed T-cell lymphoproliferative lesions following long-term treatment with mycophenolate mofetil and prednisone for myasthenia gravis. The lesions resolved following cessation of the treatment. This case highlights a serious complication of a commonly used drug.

Topics: Aged; Biomarkers; Epstein-Barr Virus Infections; Female; Genitalia, Female; Gingiva; Gingivitis; Humans; Immunosuppressive Agents; Lymphoproliferative Disorders; Mouth; Myasthenia Gravis; Mycophenolic Acid; Positron-Emission Tomography; Prednisone; T-Lymphocytes

Mycophenolate mofetil (MMF) has been used to rescue liver allografts with steroid-resistant rejection (SRR). However, the long-term outcome of these patients is not known. This study evaluates the long-term outcome of MMF rescue therapy for SRR in pediatric liver allograft recipients. Twenty-six children (who received 28 liver transplants), including 16 girls, were given MMF for SRR. The median age at transplant was 1.7 (range 0.4-13.6) years. Primary immunosuppression was cyclosporine-based in 22 and tacrolimus-based in 6. All patients except one had been converted to tacrolimus prior to MMF, having already received a median of 2 (1-5) courses of high-dose intravenous methylprednisolone. The median time to MMF rescue therapy was 1.8 (0.4-35.8) months. Twenty-one of 28 episodes of SRR responded to MMF therapy. The median follow-up was 8.8 (7.7-11.5) years. In responders, there was 1 death from posttransplant lymphoproliferative disease, and no grafts were lost to chronic rejection. In the 7 nonresponders, 3 grafts were lost to chronic rejection with 2 patient deaths. Surviving children are clinically well with good liver function, and 17 remain on MMF. Three children have glomerular filtration < 80 mL/minute/1.73 m(2). Side effects of MMF were seen in 12 patients; diarrhea (n = 5) and leukopenia (n = 5) being the most common. MMF was found to be effective in treating SRR in pediatric allograft recipients, with good long-term graft function and an acceptable side-effect profile.

Topics: Adolescent; Child; Child, Preschool; Female; Graft Rejection; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Lymphoproliferative Disorders; Male; Methylprednisolone; Mycophenolic Acid; Retrospective Studies; Treatment Outcome

Limited data with adequate sample size exist on the development of posttransplant lymphoproliferative disorder (PTLD) in living donor kidney recipients. We conducted a retrospective cohort study on the data of 10 transplant centers to identify the incidence of PTLD in Iran.. Data of 9917 kidney transplant recipients who received their kidneys between 1984 and 2008 were reviewed. Fifty-one recipients (0.5%) who developed PTLD were evaluated with a median follow-up of 47.5 months (range, 1 to 211) months.. Patients with PTLD represented 24% of all posttransplant malignancies (51 out of 211 cases). There was no relationship between PTLD and sex (P = .20). There were no statistically significance differences considering the age at transplantation between patients with and without PTLD. The late-onset PTLD (70.6%) occurred more frequently compared to the early form. There was no signification relationship between early-onset and late-onset groups in terms of clinical course and outcome. In patients who received azathioprine, PTLD was more frequent when compared to those who received mycophenolate mofetil (P < .001). The lymph nodes were the predominantly involved site (35.3%), followed by the gastrointestinal tract, brain, kidney allograft, lung, ovary, vertebrae, and palatine. Age at diagnosis and the time from transplantation to diagnosis were comparable for various involvement sites of PTLDs. The overall mortality in this series of patients was 51.0%.. Posttransplant lymphoproliferative disorder is a rare but devastating complication and long-term prognosis can be improved with early recognition and appropriate therapy.

Topics: Adolescent; Adult; Aged; Azathioprine; Child; Cohort Studies; Female; Humans; Immunosuppressive Agents; Iran; Kidney Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Survival Analysis; Young Adult

Mycophenolate mofetil (MMF) provides superior prophylaxis against acute rejection when compared with azathioprine (AZA) in heart and renal transplantation. However, it remains unclear whether this results in improved survival or reduced morbidity after heart transplantation.. In a sequential study, 240 cardiac transplant patients were treated with either MMF (n=119) or AZA (n=121) both in combination with cyclosporine and corticosteroids after rabbit antithymocyte globulin induction.. By protocol lower cyclosporine levels were targeted in the MMF group during the first year (e.g. 203+/-52 ng/mL MMF vs. 236+/-59 ng/mL AZA, P=0.0006 at 6 months). Patient survival at 1 year (82% MMF vs. 79% AZA, P=0.55) and at 3 years was similar in both groups. The cumulative probability of receiving antirejection treatment within 1 year was lower in the MMF group, as was biopsy-proven acute rejection with International Society of Heart and Lung Transplantation grade > or =3A (24% vs. 35%, P=0.03). The MMF group also had fewer episodes requiring cytolytic therapy (6% vs. 13%, P=0.04) and more patients had steroids withdrawn by 1 year (66% vs. 32%, P<0.001). Renal function was better in the MMF group with lower creatinine levels at 1 year (133+/-45 vs. 155+/-46 micromol/L, P=0.0004). Calculated creatinine clearance (Cockcroft and Gault formula) at 1 year was also better (MMF 74+/-32 mL/min vs. AZA 62+/-24 mL/min, P=0.004).. Our results suggest that immunosuppression with MMF rather than AZA may allow lower cyclosporine levels, better renal function, and increased steroid weaning at 1 year while also achieving better control of acute rejection.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Azathioprine; Cyclosporine; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Lymphoproliferative Disorders; Male; Metabolic Clearance Rate; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Survival Analysis; Ventricular Function, Left

The objective of this paper was to study the incidence, risk factors, clinical outcome, management and prevention of pure red cell aplasia (PRCA) following major ABO-incompatible allogeneic hematopoietic stem cell transplantation (allo-HSCT). We retrospectively analyzed 11 cases of PRCA from a series of 42 patients undergoing major ABO-incompatible allo-HSCT from April 1997 to December 2005. Eleven out of the 42 patients developed PRCA (26.1%). All the 11 cases of PRCA were in blood group O recipients of grafts from blood group A donor (n = 9) or blood group B donor (n = 2). The following factors were associated with an increased risk of PRCA: (1) blood group O recipient; (2) blood group A donor; and (3) blood group O/A in recipient/donor pair. Only blood group O/A in recipient/donor pair was identified as being significantly associated with the occurrence of PRCA by multivariate analysis. Six patients who received donor-type plasma exchange did not develop PRCA and among them 5 cases were the blood group O recipients. Eight patients obtained spontaneous remission and in the remaining 3 patients 2 with long-lasting PRCA were successfully treated with plasma exchange with donor-type plasma replacement and the other one who was also complicated by EBV-associated lymphoproliferative disorder (EBV-PTLD) responded rapidly to anti-CD20 monoclonal antibody and achieved complete resolution of clinical finding and symptom of both EBV-PTLD and PRCA. We conclude that blood group A/O in donor/recipient pair is identified as being significantly associated with the occurrence of PRCA by multivariate analysis. Donor-type plasma exchange and anti-CD20 monoclonal antibody is an effective approach for the treatment of PRCA. PRCA could be prevented by plasma exchange prior to transplantation.

Topics: ABO Blood-Group System; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20; beta-Thalassemia; Blood Group Incompatibility; Busulfan; Child, Preschool; Cyclosporine; Epstein-Barr Virus Infections; Female; Graft Survival; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia; Lymphoproliferative Disorders; Male; Methotrexate; Middle Aged; Mycophenolic Acid; Plasma Exchange; Red-Cell Aplasia, Pure; Remission, Spontaneous; Retrospective Studies; Risk Factors; Rituximab; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Whole-Body Irradiation

Epstein-Barr virus (EBV)-associated lymphoid proliferations are a well-recognized complication of congenital or acquired systemic immunosuppression. The CNS is a frequent site for development of such lymphoid proliferations. We describe the clinical, imaging, and pathologic observations of a CNS disorder histologically similar to posttransplantation lymphoproliferative disorder that occurred in four patients with autoimmune disease treated with mycophenolate mofetil (MM). Two patients had polymorphous lymphoplasmacytic infiltration of brain parenchyma, and two had monomorphous infiltrations consistent with diffuse large B-cell lymphoma. In situ hybridization for EBV-encoded RNA was positive in all four patients. All patients improved after MM withdrawal and the use of rituximab. Because of a favorable toxicity profile, MM is now being used as steroid-sparing immunomodulatory therapy in autoimmune disorders. Based on our experience presented herein, we recommend caution in patient selection for MM and strict surveillance of those patients with autoimmune disorders who receive MM.

Topics: Aged; Autoimmune Diseases; Brain Diseases; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Immunocompromised Host; Immunosuppressive Agents; In Situ Hybridization; Lymphoproliferative Disorders; Male; Middle Aged; Mycophenolic Acid; RNA, Viral

EBV infection is one of major complications arising in pediatric patients who have undergone renal transplantation. A strong correlation between the grade of immunosuppression and the development of PTLD, one of the most severe EBV-associated diseases, has been recognized. In this study, we monitored the serologic profile in conjunction with peripheral blood EBV-DNA load of 32 children who underwent renal transplantation with tacrolimus as an immunosuppressant. Six patients were EBV-seronegative (EBV-) before the transplantation, and the mean DNA load in the EBV- group was significantly higher than that in the EBV-seropositive (EBV+) group. Seroconversion occurred in five of these patients in a mean period of 22 weeks after the transplantation. The EBV-DNA load in the EBV+ group was maintained at a low level for a year, whereas it increased rapidly to over 1 x 10(5) copies/mL in two patients in the EBV- group three to seven months after the transplantation, which corresponds to the timing of seroconversion, and one of them developed PTLD. These observations suggest that the close monitoring of the EBV-DNA load, along with longitudinal observation of seroconversion, is essential in pediatric renal transplantation, particularly for younger children who are more likely to be EVB-.

Topics: Child; DNA, Viral; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Lymphoproliferative Disorders; Male; Methylprednisolone; Mycophenolic Acid; Polymerase Chain Reaction; Tacrolimus; Viral Load

Posttransplant lymphoproliferative disorder is a rare and often difficult diagnosis in patients with only cutaneous symptoms. A stepwise approach to diagnosis and classification can lead to successful treatment. We report a case of an EBV-associated posttransplant lymphoproliferative disorder (PTLD) occurring on the face with a primary cutaneous presentation. The appropriate diagnosis was made only after multiple biopsies and special stains. There was near complete resolution with decreased levels of iatrogenic immunosuppression. The diagnosis of Posttransplant lymphoproliferative disorder can be difficult to establish. A proper workup will aid in making an accelerated diagnosis and choosing appropriate treatment options.

Topics: Dose-Response Relationship, Drug; Epstein-Barr Virus Infections; Face; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Lung Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Mycophenolic Acid; Prednisone; Pulmonary Fibrosis; Sirolimus; Skin Diseases

Antitumor necrosis factor-alpha antibodies are increasingly being used for the treatment of steroid-refractory acute graft-versus-host disease (GVHD) complicating allogeneic stem cell transplantation. We retrospectively reviewed the outcomes of 16 patients with refractory acute predominantly visceral GVHD treated with combination antithymocyte globulin (ATG), tacrolimus and etanercept +/- mycophenolate mofetil (MMF) at our institution. Overall response rate (CR+PR) was 81%, with median survival post commencing salvage immunosuppression 224 days (range 20-1216 days). In total, eight patients (50%) died, including from progressive GVHD in two cases (13%), infection in five (31%) and relapse of underlying malignancy in one (6%). In comparison to our previous experience of ATG+tacrolimus as treatment for refractory visceral GVHD, both response rate and overall survival were improved with addition of etanercept, with no apparent increase in infectious complications. As such, use of etanercept in combination with ATG +/- MMF for treatment of steroid refractory acute GVHD appears to be associated with high response rates, significant survival and no unexpected toxicity. Further study of this immunosuppression combination in a larger cohort of patients in this setting is indicated.

Topics: Acute Disease; Adolescent; Adult; Anti-Inflammatory Agents; Antilymphocyte Serum; Disease-Free Survival; Drug Resistance; Drug Therapy, Combination; Etanercept; Female; Graft vs Host Disease; Humans; Immunoglobulin G; Immunosuppression Therapy; Immunosuppressive Agents; Infections; Lymphoproliferative Disorders; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Receptors, Tumor Necrosis Factor; Recurrence; Retrospective Studies; Salvage Therapy

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by defective Fas-mediated apoptosis, leading to lymphadenopathy, hepatosplenomegaly, and an increased number of double-negative T cells (DNTs). Treatment options for patients with ALPS are limited. Rapamycin has been shown to induce apoptosis in normal and malignant lymphocytes. Since ALPS is caused by defective lymphocyte apoptosis, we hypothesized that rapamycin would be effective in treating ALPS. We tested this hypothesis using rapamycin in murine models of ALPS. We followed treatment response with serial assessment of DNTs by flow cytometry in blood and lymphoid tissue, by serial monitoring of lymph node and spleen size with ultrasonography, and by enzyme-linked immunosorbent assay (ELISA) for anti-double-stranded DNA (dsDNA) antibodies. Three-dimensional ultrasound measurements in the mice correlated to actual tissue measurements at death (r = .9648). We found a dramatic and statistically significant decrease in DNTs, lymphadenopathy, splenomegaly, and autoantibodies after only 4 weeks when comparing rapamycin-treated mice with controls. Rapamycin induced apoptosis through the intrinsic mitochondrial pathway. We compared rapamycin to mycophenolate mofetil, a second-line agent used to treat ALPS, and found rapamycin's control of lymphoproliferation was superior. We conclude that rapamycin is an effective treatment for murine ALPS and should be explored as treatment for affected humans.

Topics: Animals; Antibodies, Antinuclear; Autoimmune Diseases; Immunosuppressive Agents; Lymphoid Tissue; Lymphoproliferative Disorders; Mice; Mice, Inbred CBA; Mice, Mutant Strains; Mycophenolic Acid; Protein Kinases; Signal Transduction; Sirolimus; T-Lymphocyte Subsets; TOR Serine-Threonine Kinases

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder due to a genetic defect concerning programmed cell death (apoptosis). Most patients are carriers of a heterozygous mutation affecting the TNFRSF6 (Fas). Treatment of autoimmune complications of ALPS includes corticosteroids, gamma-globulin infusions, and in refractory cases, splenectomy, cytostatic agents, and bone marrow transplantation. A 10-year-old boy with ALPS manifested by recurrent febrile episodes, lymphadenopathy, splenomegaly, and cytopenias refractory to corticosteroid therapy is presented. Treatment with mycophenolate mofetil, an immunosuppressive agent typically used in organ transplantation was initiated. This treatment was successful with resolution of thrombocytopenia, decrease in lymphadenopathy, and improvement of his general clinical condition for over 2 years of duration.

Topics: Adrenal Cortex Hormones; Autoimmune Diseases; Child; fas Receptor; Humans; Immunosuppressive Agents; Lymphoproliferative Disorders; Male; Mutation; Mycophenolic Acid; Syndrome; Thrombocytopenia; Time Factors

Nonmyeloablative stem cell transplantation (NST) harnesses the graft-versus-tumor effect while minimizing regimen-related toxicity, and can result in donor chimerism and remission. Acute graft-versus-host disease (GVHD) and infections are major complications after sibling NST. Toxicity of unrelated-donor (UD) NST and the most appropriate GVHD prophylaxis in this setting remain poorly defined. We describe 25 patients who received UD-NST conditioned with fludarabine and cyclophosphamide. The first six patients received cyclosporine (Cs) and mycophenolate mofetil (MMF) (n=5) or methotrexate (MTX) (n=1) as GVHD prophylaxis (group 1) and all developed grade III-IV acute GVHD. The next 19 patients received the same conditioning regimen with the addition of alemtuzumab, and all received Cs/MTX post-transplant. Engraftment and donor chimerism were achieved in all but one evaluable patient. In all, 15 patients died: five of six deaths in group 1 were attributable to acute GVHD, while deaths in group 2 were due to infection or progressive disease (P=0.05). The combination of Cs/MMF is inadequate GVHD prophylaxis for UD-NST. The use of Cs, MTX, and alemtuzumab eliminated severe acute GVHD; its impact on response merits further study.

Topics: Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Lymphoproliferative Disorders; Male; Middle Aged; Mycophenolic Acid; Transplantation Chimera; Transplantation Conditioning; Vidarabine

The introduction of increasingly effective immunosuppressants has raised the question of whether posttransplant lymphoproliferative disorder (PTLD), a complication of immunosuppression, would become more frequent. This study assessed the risk of PTLD in relation to immunosuppression during a period that saw the introduction and eventual market dominance of mycophenolate mofetil (MMF).. A case-control study was conducted at 23 U.S. transplant centers. All participants received a renal-only transplant on or after July 1, 1995. PTLD cases were reported by centers and confirmed by central review. The United Network for Organ Sharing (UNOS) supplemented case ascertainment and identified controls matched on center, transplant date, and age. Center personnel abstracted risk factor and therapy data for cases and up to four controls per case. Cases and controls were compared, using a matched multivariate analysis, to assess the impact of MMF as one component of triple-therapy adjusted for other drug therapies and known risk factors.. Data were collected for 108 PTLD cases and 404 controls. PTLD risk for individuals on triple therapy with MMF was similar to the risk experienced by individuals on triple therapy with no MMF (adjusted odds ratio=1.19; 95% CI 0.55-2.55). There was no dose response relationship between MMF and PTLD risk.. Use of MMF was not associated with an increase in PTLD among patients who received triple immunosuppressive therapy, but an excess in risk as large as 155% or a reduction in risk by as much as 45% cannot be ruled out.

Topics: Case-Control Studies; Confidence Intervals; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Male; Mycophenolic Acid; Odds Ratio; Risk Assessment

Tacrolimus (FK506) and mycophenolate mofetil (MMF) have been reported to increase PTLD risk. The NAPRTCS registry database now has several years of data on FK506 and MMF use in pediatric kidney transplantation. We analyzed the data registry to determine if the risk of PTLD was enhanced by the use of MMF or tacrolimus in initial immunosuppression. Data on day 30 therapy in the PTLD group were compared to corresponding data in patients who did not develop PTLD. Data were analyzed using SAS software and a log-rank test for significance. As of October 2000, there were 108 cases of PTLD in 6720 total transplants(1.60%). The use of MMF at day 30 was not a significant risk factor (0. 78% PTLD rate vs. 1.78% in cohort, RR = 1.05, p = 0.89). The relationship of FK506 with PTLD was linked to transplant era, 1987-95 or 1996-2000. In the earlier era, use of FK506 at day 30 was associated with PTLD (seen in 7/15 patients given FK506, RR = 47.7, p < 0.001). However, in the more recent era, there was no such significant association (seen in 3/313 patients given FK506, RR = 1.28, p = 0.692). There have been no cases of PTLD in 197 patients who received both FK506 and MMF at day 30. We conclude that FK506 and MMF use are not currently associated with increased risk of PTLD in pediatric kidney transplants.

Topics: Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Male; Multicenter Studies as Topic; Mycophenolic Acid; Tacrolimus

Mycophenolate mofetil (MMF) has been increasingly used after liver transplantation (LT) in adults. We report our preliminary experience with MMF as rescue therapy after pediatric LT.. A total of 19 children received MMF for 21 indications. Median age at LT was 30 months (range 7-149). The median initial oral dose of MMF was 23 mg/kg/day (range 12-43) orally. Median follow-up after initiation of MMF therapy was 642 days (range 229-1606).. 1) EFFICACY: MMF was indicated for rejection or insufficient immunosuppression in 16 cases, with normalization of both liver function tests and liver histology in 10 (62%). MMF was successfully used in one patient with post-LT immmune hepatitis and one patient with corticodependence. In three patients with renal function impairment, MMF allowed reduction of cyclosporine A or tacrolimus blood levels, without subsequent rejection. 2) Tolerance: Six patients (32%) experienced eight side effects, mainly gastrointestinal and hematological, which resolved after cessation of MMF in five cases and dose reduction in three. One case of posttransplant lymphoproliferative disease (PTLD) occurred under MMF therapy (5.2%). Four patients had EBV primary infection, while under MMF therapy, without subsequent PTLD. Three patients had CMV primary infection, and five CMV reactivation, under MMF therapy. Seven remained asymptomatic, and one presented with CMV enteritis.. These preliminary results suggest that MMF is an effective and safe immunosuppressant in pediatric LT recipients. Its use is hampered by frequent gastrointestinal and hematological side-effects. MMF does not seem to increase the risk of PTLD nor CMV disease.

Topics: Burkitt Lymphoma; Child; Child, Preschool; Cytomegalovirus Infections; Female; Graft Rejection; Herpesvirus 4, Human; Humans; Liver Transplantation; Lymphoproliferative Disorders; Male; Mycophenolic Acid; Salvage Therapy

Topics: Child; Child, Preschool; Drug Administration Schedule; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphoproliferative Disorders; Methylprednisolone; Muromonab-CD3; Mycophenolic Acid; Postoperative Complications; Prednisone; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors