Increased Frequency of Posttransplant Lymphomas in Patients Treated With Cyclosporine, Azathioprine, and Prednisone

Wilkinson, Alan H.; Smith, J. L.; Hunsicker, Lawrence G.; Tobacman, Joanne K.; Kapelanski, David P.; Johnson, Maryl R.; Wright, Francis H.; Behrendt, Douglas M.; Corry, Robert J.

doi:10.1097/00007890-198902000-00020

Cited by 166 publications

(43 citation statements)

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“…A heightened risk for lymphoma has also been reported among patients receiving induction therapy with OKT3, especially beyond a threshold cumulative dose (6,9,12). It has been speculated that the intensity of immunosuppression, rather than any individual agent, is a key determinant of lymphoma formation (13,14), a conclusion supported by the higher incidence of lymphoma in recipients of nonrenal transplants, who receive higher doses of immunosuppression (6,15).…”

Section: Introductionmentioning

confidence: 99%

Lymphomas After Solid Organ Transplantation: A Collaborative Transplant Study Report

Opelz

Döhler

2004

American Journal of Transplantation

977

787

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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.

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Section: Introductionmentioning

confidence: 99%

Lymphomas After Solid Organ Transplantation: A Collaborative Transplant Study Report

Opelz

Döhler

2004

American Journal of Transplantation

977

787

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“…[1][2][3] Patients with heart or lung allografts receiving intensive immunosuppressive therapy with CsA, azathioprine and prednisone are especially at risk. 3,4 The most common post-transplant malignancies are lymphoproliferative disorders (non-Hodgkin lymphomas of B cell origin) and solid tumors. [4][5][6] AML following solid organ transplantation is less frequent.…”

Section: Introductionmentioning

confidence: 99%

“…3,4 The most common post-transplant malignancies are lymphoproliferative disorders (non-Hodgkin lymphomas of B cell origin) and solid tumors. [4][5][6] AML following solid organ transplantation is less frequent. 7,8 Several cases with AML post-renal transplantation have been published.…”

Section: Introductionmentioning

confidence: 99%

Post-transplant acute myeloid leukemia (PT-AML)

et al. 1999

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Acute myeloid leukemia following organ transplantation (PT-AML) is a rare event with only a few published cases in the literature. We present three patients who developed AML (FAB M1, M5, M4) after renal, double lung or liver transplantation. Molecular analysis detected a t(9;11) in one patient and documented the recipient origin of AML in a second patient. All patients were treated with chemotherapy. Immunosuppression was reduced to cyclosporin A (CsA) and prednisone in two patients and to prednisone alone in one patient. Two patients achieved a complete remission (CR), with a remission duration of 4.6 months in one patient, the other patient died from septicemia after 15.2 months in CR. One patient was refractory to chemotherapy and died from septicemia. This report together with the documented cases in the literature suggests that PT-AML (1) develops after a median interval of 5 years after transplantation with variable latency (range, Ͻ1-17 years); (2) is heterogeneous with respect to FAB classification; (3) shows chromosomal and molecular changes typical of therapy-related AML (t-AML: −7, +8, 11q23, inv16, t(15;17)); (4) standard chemotherapy is feasible after reduction of immunosuppression and produces a CR rate of 56% with a median remission duration of 4.6 months and an overall survival of 2.6 months; (5) the major complications are early death (25%), Gram-negative septicemia, progressive disease or relapse. This review provides diagnostic and therapeutic experiences and guidelines for the management of this increasing group of post-transplant patients.

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“…This would suggest that at lower effective doses in humans, a tumorigenic response would not be seen. In fact, the incidence of tumor findings in patients on immunosuppressive therapy is low when cyclosporin is administered alone at low doses and increases as the dose is increased or when other immunosuppressive therapy is combined (1 8,124). Further support for this dose-dependent effect is the finding that the lymphoproliferative lesions developing with cyclosporin therapy are reversible upon dosage reduction (1 10).…”

Section: Pharmacologica~biochemical Effectsmentioning

confidence: 99%

Toxicokinetic and Mechanistic Considerations in the Interpretation of the Rodent Bioassay

1994

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When chemicals that are nongenotoxic in conventional assays produce increases in tumor incidence in rodents in chronic bioassays, the determination of the significance of these data for human safety is a challenging task. An important first step in this process is consideration of available data on the mechanism of action and biological properties of the chemical as well as pharmacokinetic and metabolism data in the species showing the response. In recent years, there has been an increase in the understanding of so-called “secondary mechanisms” of carcinogenesis (e.g., thyroid tumors in rats following exposure to enzyme inducers). Application of these data may assist in determination of human risk. There are 2 important questions that will be explored and developed: Are there biological effects produced in the test species that could explain the increase in tumor incidence, and will these effects be reproduced in humans? What is the exposure to the chemical that is associated with the increase in tumors, and how does this relate to exposure in humans?

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Increased Frequency of Posttransplant Lymphomas in Patients Treated With Cyclosporine, Azathioprine, and Prednisone

Cited by 166 publications

References 0 publications

Lymphomas After Solid Organ Transplantation: A Collaborative Transplant Study Report

Lymphomas After Solid Organ Transplantation: A Collaborative Transplant Study Report

Post-transplant acute myeloid leukemia (PT-AML)

Toxicokinetic and Mechanistic Considerations in the Interpretation of the Rodent Bioassay

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