Manfred Hummel

A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients : Mycophenolate Mofetil Investigators

BACKGROUND After heart transplantation, 1-year and 5-year survival rates are 79% and 63%, respectively, with rejection, infection, and allograft coronary artery disease accounting for the majority of deaths. Mycophenolate mofetil (MMF), an inhibitor of the de novo pathway for purine biosynthesis, decreases rejection in animals and in human renal transplantation. METHODS In a double-blind, active-controlled trial, 28 centers randomized 650 patients undergoing their first heart transplant to receive MMF (3000 mg/day) or azathioprine (1.5-3 mg/kg/day), in addition to cyclosporine and corticosteroids. Rejection and survival data were obtained for 6 and 12 months, respectively. Because 11% of the patients withdrew before receiving study drug, data were analyzed on all randomized patients (enrolled patients) and on patients who received study medications (treated patients). RESULTS Survival and rejection were similar in enrolled patients (MMF, n=327; azathioprine, n=323). In treated patients (MMF, n=289; azathioprine, n=289), the MMF group compared with the azathioprine group was associated with significant reduction in mortality at 1 year (18 [6.2%] versus 33 deaths [11.4%]; P=0.031) and a significant reduction in the requirement for rejection treatment (65.7% versus 73.7%; P=0.026). There was a trend for fewer MMF patients to have > or = grade 3A rejection (45.0% versus 52.9%; P=0.055) or require the murine monoclonal anti-CD3 antibody or antithymocyte globulin (15.2% versus 21.1%; P=0.061). Opportunistic infections, mostly herpes simplex, were more common in the MMF group (53.3% versus 43.6%; P=0.025). CONCLUSIONS Substitution of MMF for azathioprine may reduce mortality and rejection in the first year after cardiac transplantation.

Effect of anti-CD 20 antibody rituximab in patients with post-transplant lymphoproliferative disorder (PTLD)

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

Identification of early antigen BZLF1/ZEBRA protein of Epstein-Barr virus can predict the effectiveness of antiviral treatment in patients with post-transplant lymphoproliferative disease.

Summary.  Epstein–Barr virus (EBV)‐associated B‐cell lymphoproliferations may arise in solid organ transplant recipients. In these patients, an insufficient control of EBV‐infected B cells commonly occurs. Antiviral treatment against EBV may represent a causal, relatively low‐toxic treatment option. Treatment with foscarnet, an inhibitor of viral‐DNA polymerase, in three patients with EBV‐associated post‐transplant lymphoproliferative disease (PTLD) after heart (n = 2) and heart/kidney transplantation (n = 1), who did not respond to, or were not eligible for reduction of immunosuppression, resulted in complete remission (48+, 27 and 15 months respectively). Response of PTLD to antiviral treatment correlated with the expression of lytic phase antigen BZLF1/ZEBRA protein, an early antigen of lytic EBV‐activity, in the biopsied PTLD specimens.

Epstein–Barr viral load in whole blood of adults with posttransplant lymphoproliferative disorder after solid organ transplantation does not correlate with clinical course

Posttransplant lymphoproliferative disease (PTLD) is closely linked to primary Epstein–Barr virus (EBV) infection. A defect of EBV specific cellular immunity is postulated to play a pivotal role in the etiology of PTLD, but there is some debate as to whether EBV load in the peripheral blood of transplant patients predicts onset of PTLD or relapse after treatment. The current prospective, single-center study was undertaken to investigate the impact of therapy on EBV load in adult patients with PTLD. Fifteen patients with PTLD after solid organ transplantation were included and of these, seven had EBV-associated PTLD. All 15 patients received Rituximab as primary therapy. In cases of treatment failure or relapse after Rituximab treatment, patients received polychemotherapy according to the cyclophosphamide, vincristine, doxorubicin, and prednisone regimen. At onset of PTLD, the median EBV load in the peripheral blood of patients was higher in EBV-associated PTLD than PTLD with no associated EBV infection. After Rituximab therapy, four of seven patients with EBV-associated PTLD achieved long-lasting complete remissions. However, in two of these patients, EBV load increased to reach levels as high as those recorded at onset of PTLD. Another patient showed a dramatic decline of EBV load after the first dose of Rituximab while suffering from progressive disease. The other patient relapsed after Rituximab monotherapy, but his viral load stayed low. In total, discordance in EBV load and clinical course was observed in five of the seven patients with EBV-associated PTLD. We conclude that in adult patients with PTLD, EBV load does not correlate with treatment response and is not suitable as a predictive marker for PTLD relapse.

Treatment of Epstein-Barr virus-induced posttransplantation lymphoproliferative disorder with foscarnet alone in an adult after simultaneous heart and renal transplantation.

BACKGROUND The kind and intensity of immunosuppression as well as Epstein-Barr virus, a transforming herpes virus that selectively infects B lymphocytes and causes infectious mononucleosis, have been implicated in the development of posttransplantation lymph-proliferative disorders (PT-LPD), a life-threatening complication of solid organ transplantation. The morphologic spectrum of PT-LPD ranges from polymorphous hyperplasia to monomorphous B-non-Hodgkin lymphomas. Among different modalities of treatment, reduction of immunosuppression with or without co-administration of antiviral agents may result in PT-LPD regression especially in mononucleosis-like disease. METHODS Nonmononucleosis-like PT-LPD in a simultaneous heart and renal recipient was treated with Foscarnet, a potent inhibitor of different herpes viruses with a low profile of toxicity, although intensive immunosuppression therapy was maintained. RESULTS AND CONCLUSIONS A 4-week course of Foscarnet resulted in relapse-free complete remission (follow-up 10+ months). Thus, antiviral treatment with Foscarnet, may induce prolonged remission in nonmononucleosis-like PT-LPD without reduction of immunosuppression.

Pharmacokinetics and variability of mycophenolic acid from enteric-coated mycophenolate sodium compared with mycophenolate mofetil in de novo heart transplant recipients

Abstract:  Sequential pharmacokinetic assessments were performed at five centers within the context of a multicenter, single‐blind, randomized clinical trial comparing the efficacy and safety of enteric‐coated mycophenolate sodium (EC‐MPS, myfortic®) and mycophenolate mofetil (MMF, CellCept®) in de novo heart transplant recipients. Patients were randomized to either EC‐MPS 1080 mg bid or MMF 1500 mg bid, as part of a triple immunosuppressive therapy including cyclosporine microemulsion. Steady‐state pharmacokinetic profiles of mycophenolic acid (MPA) and its inactive phenolic glucuronide (MPAG) were assessed at weeks 2, 12, and 52. Pharmacokinetic parameters were evaluated in 32 patients (17 on EC‐MPS and 15 on MMF). Dose‐normalized peak (Cmax,ss) and area under the curve (AUCτ,ss) of MPA and MPAG increased between week 2 and week 12 assessments for both treatments. Comparisons between EC‐MPS and MMF showed no statistically significant differences in MPA and MPAG AUCτ,ss, Cmax,ss, and trough (Cmin,ss) values (p‐values ranged from 0.225 to 0.990). Consistent with the delayed release characteristics of EC‐MPS, Cmax,ss occurred approximately one hour later compared with MMF. Inter‐subject coefficients of variation (%CV) for MPA pharmacokinetic parameters of both EC‐MPS and MMF were high (37–72% for AUCτ,ss at weeks 2 and 12). Also within patients, the pharmacokinetics of MPA varied considerably. Specifically, intra‐subject %CVs for MPA AUCτ,ss, Cmax,ss, and Cmin,ss were 28%, 63%, and 34% with EC‐MPS and 54%, 139%, and 41% with MMF respectively. These results indicate that a dose of EC‐MPS 1080 mg bid in combination with cyclosporine provides adequate systemic MPA exposure in de novo heart transplant patients, comparable with MMF 1500 mg bid. Overall, there is a large inter‐ and intra‐subject variability in MPA pharmacokinetic parameters with both treatments.

Salvage chemotherapy for refractory or relapsed post‐transplant lymphoproliferative disorder in patients after solid organ transplantation with a combination of carboplatin and etoposide

Summary.  This pilot study assessed the feasibility and efficacy of salvage chemotherapy (carboplatin and etoposide; CE) supported by granulocyte colony‐stimulating factor (GCSF) in patients with refractory or relapsed post‐transplant lymphoproliferative disorder (PTLD) following solid organ transplantation. Intensified salvage regimens were not feasible for these patients, due to their immunosuppressive conditions and potential organ (especially kidney and bone marrow) malfunctions. Salvage chemotherapy consisted of carboplatin [area under the curve (AUC) 4], on day 1, etoposide (120 mg/m2), on days 1–3 and GCSF (5 μg/kg) starting on day 5. This therapeutic regimen was planned to be repeated every 21 d. Nine patients (seven with refractory, two with relapsed disease) were enrolled. Five patients were heart transplant recipients, three liver transplant recipients and one patient had been a double lung transplant recipient. Five patients achieved a complete remission (CR), with follow‐up at 92, 39, 55+, 17 and 9+ months. One patient showed stable disease after two cycles of CE and one patient had progressive disease. Two patients experienced early deaths, after the first and third cycles of chemotherapy respectively. One died of septic complications and one because of a perforated intestine, which had been infiltrated by lymphoma. In respect of the difficulties experienced in treating patients with refractory or relapsed PTLD after solid organ transplantation, the combination of carboplatin and etopoide with GCSF support (filgrastim) proved to be an effective regimen.