Lymphomas After Solid Organ Transplantation: A Collaborative Transplant Study Report

We used the Collaborative Transplant Study database to analyze the incidence, risk, and impact of malignant lymphomas in approximately 200,000 organ transplant recipients. Over a 10-year period, the risk in renal transplant recipients was 11.8-fold higher than that in a matched nontransplanted population (p<0.0001). The majority of lymphomas were diagnosed after the first post-transplant year. Heart-lung transplants showed the highest relative risk (RR 239.5) among different types of organ transplants. In kidney recipients, immunosuppression with cyclosporine did not confer added risk compared with azathioprine/steroid treatment, whereas treatment with FK506 increased the risk approximately twofold. Induction therapy with OKT3 or ATG, but not with anti-IL2 receptor antibodies, increased the risk of lymphoma during the first year. Antirejection therapy with OKT3 or ATG also increased the risk. First-year mortality in renal and heart transplant patients with lymphoma was approximately 40% and 50%, respectively, and showed no improvement in recent years. A pattern of preferential localization to the vicinity of the transplant was noted, and the prognosis of the patient was related to localization. This study highlights the continuing risk for lymphoma with time post-transplantation, the contribution of immunosuppression to increased risk, and continuing poor outcomes in patients with post-transplant lymphoma.     

Toxicity of OKT 3 increases with dosage: a controlled study in renal transplant recipients

In the present study we prospectively compared side effects occurring in 12 patients after the first administration of low-dose OKT3 (0.5 mg twice daily) induction therapy with those in 10 patients who were treated with a conventional dose of OKT3 (5 mg daily) for acute rejection. We also investigated cytokine release and activation of complement and neutrophils as all of these are held responsible for OKT3-induced side effects. Low-dose OKT3 resulted in a significantly decreased side effects score compared to that after a conventional dose of OKT3 (1.8 vs 5.1, p=0.0006). Following the first administration of low-dose OKT3, TNF peak levels were significantly lower than after a conventional dose of OKT3. In contrast to our data on conventional dose OKT3 treatment, the first administration of low-dose OKT3 did not induce complement activation as reflected by C3a and C4b/c levels in plasma. Finally, the increase in neutrophil degranulation products lactoferrin and elastase-₁- was much less following 0.5 mg OKT3 than following 5 mg. We conclude that OKT3-induced toxicity is dose-dependent and is mediated not only by cytokine release but also by activation of complement and neutrophils.     

A randomized prospective study comparing low-dose OKT3 to low-dose ATG for the treatment of acute steroid-resistant rejection episodes in kidney transplant recipients

Acute steroid-resistant rejection episodes in kidney allograft recipients require treatment with antilymphocyte antibodies. Monoclonal anti-CD3 and polyclonal antilymphocyte antibodies have been widely used but seldom compared. Recent data have suggested that these antibodies could be used at reduced doses without jeopardizing their efficacy. In this study, we randomized renal transplant recipients who encountered a first acute steroid-resistant rejection episode to low-dose ATG or low-dose OKT3 treatment. Sixty patients were enrolled in the study. They received prophylactic immunosuppression with cyclosporin, azathioprine, and prednisolone. Treatment of biopsy-proven rejection consisted of a 10-day course of either ATG (n = 31) or OKT3 (n = 29). The total ATG dose was 484 ± 110 mg, i. e., 0.75 mg/kg per day. The total OKT3 dose was 32 ± 4 mg, i. e., 0.05 mg/kg per day. We compared reversion of rejection, side effects, immunodepression, and graft function. Reversion of rejection was similar in the two groups, although we noted a trend in favor of ATG. Results were 3 % vs 10 % early graft failures, 13 % vs 23 % overall graft failures, 28 % vs 38 % 3-month actuarial incidence of rebound rejection, and 89 % vs 81 % 1-year graft survival rate in the ATG and OKT3 groups, respectively. Tolerance was worse in the OKT3 group due to the first-dose syndrome. Infections and cancers occurred with the same frequency. ATG resulted in a deeper and longer decrease in peripheral lymphocyte subsets. Graft function was similar in the two groups. We conclude that low-dose ATG and low-dose OKT3 are equally effective in reversing steroid-resistant acute rejection. Tolerance was better with ATG, which also gave a more potent and longlasting immunodepression. The use of reduced doses of ATG and OKT3 did not appear to lessen their efficacy. Received: 27 June 1997 Received after revision: 15 October 1997 Accepted: 19 November 1997     

Identification of Sites of Degradation in a Therapeutic Monoclonal Antibody by Peptide Mapping

A peptide mapping procedure was developed to locate regions of a monoclonal antibody, OKT3, that undergo chemical modification as the molecule degrades upon storage. The structures of these peptide degradation products were investigated. Deamidation at specific asparagine residues and oxidation of a cysteine and several methionines were found to be major routes of OKT3 degradation. A unique chain cross-linked degradation product was also observed and characterized. Changing the storage conditions of the antibody affected the relative distribution of degradation products. These results were useful in the development of more stable formulations for OKT3, and the methods can be used in the characterization of other monoclonal antibodies intended for therapeutic use.     

OKT3 prophylaxis in liver transplantation

In a randomized prospective study of liver transplant recipients, we compared prophylaxis with OKT3, steroids, and azathioprine to cyclosporine, steroids, and azathioprine. Seventy-two percent of patients receiving OKT3 prophylaxis were rejection free in the first 14 days compared to 41% in the cyclosporine group (P=0.02). However, after 14 days through a mean of 6.3 months, the overall incidence of rejection did not differ between the two groups (74% for the cyclosporine group and 48% for the OKT3 group). There was no increase in the rate of infectious complications noted in the OKT3-treated group. Thirty-nine percent of the OKT3-treated patients developed anti-OKT3 antibodies. Eight patients in the OKT3 group required reuse of OKT3 for rejection. Six of these continued to have greater than 10% CD3-positive cells with retreatment. Five were rescued successfully. With a mean survival of greater than 674±209 days in the OKT3-treated group and 626±242 days in the cyclosporine-treated group, no overall differences in graft and patient survival, liver function, renal function, late rejection incidence, or infectious complications were evident between the two groups. We conclude that OKT3 offers no long-term benefit compared to cyclosporine prophylaxis and should be reserved for treatment of rejection in patients in whom cyclosporine may be contraindicated.     

Prophylactic use of OKT3 in liver transplantation

Liver rejection in the era of cyclosporine-based immunosuppression is approximately 60–70%. Approximately 15–25% of liver transplant patients will require hemodialysis following transplantation. These facts argue for a potent, less nephrotoxic immunosuppressive regimen, especially during the period of vulnerability to these events. Prophylactic use of OKT3 has been suggested as a means to decrease the need for hemodialysis while maintaining potent immunosuppression. The goal of this review is to examine potential benefits and pitfalls of this regimen. A lack of documentation of long-term patient and graft survival, the potential susceptibility to infectious complications, development of sensitization, and the cost must be weighed against the decreased need for hemodialysis and the control of early rejection episodes.     

Dosage of OKT3 independent of body weight: a mistake?

Comparing OKT3 and antithymocyte globulin (ATG) in a prospective study, the dosage difference in regard to body weight (ATG: dependent on body weight/OKT3: independent) does not introduce any obvious source of mistake concerning clinical effectiveness or side effects. One explanation for the lack of influence of body weight may be the high effectiveness of 5 mg of OKT3, reaching a maximal effect even with lower plasma levels in heavier patients. We wonder, therefore, whether the OKT3 dosage could be lowered.     

Simultaneous splenectomy increases risk for opportunistic pneumonia in patients after liver transplantation

Life threatening pneumonias after liver transplantation are often caused by opportunistic pathogens such as Legionella pneumophila, Pneumocystis carinii, Aspergillus species and cytomegalovirus (CMV). Due to the high incidence of morbidity and mortality caused by these pneumonias we reviewed 700 liver transplants for risk factors for the development of opportunistic pneumonia. Immunosuppression was commenced as either cyclosporin A- or tacrolimus-based protocols. In a subgroup of patients, splenectomy was performed simultaneously with liver transplantation ( n=57). Overall 60 opportunistic pneumonias occurred in 700 liver transplants. Using a stepwise logistic regression analysis, we found that OKT3 treatment and simultaneous splenectomy revealed a significantly increased risk for opportunistic pneumonia. Our study identified splenectomy as a major risk factor for the development of opportunistic pneumonia after liver transplantation. In these patients prophylactic protocols and early diagnosis may improve the long-term outcome.     

OKT3 therapy for transfusion-associated graft-versus-host disease in a neonate

Transfusion-associated graft-versus-host disease (TA-GVHD) is a fatal side effect of blood transfusion. The present study describes a case of TA-GVHD in a neonate treated with anti-CD3 monoclonal antibody (OKT3). The patient died of systemic bacterial infection. However, it is suggested that OKT3 suppressed the graft-versus-host reaction due to the improvement in the clinical signs and a change in the human leucocyte antigen (HLA) type on the surface of circulating lymphocytes. A relatively large dose of OKT3 together with steroid pulse therapy and cyclosporin A may be required for the control of TA-GVHD in neonates.     

Reversal of acute glomerular renal allograft rejection: a possible effect of OKT3

Abstract. A major cause of renal allograft loss is glomerulovascular rejection. This case report is about an episode of histologically proven acute glomerular rejection that was successfully reversed. Monoclonal antibody OKT3 may have been the effective agent.