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The Malignant Side of Successful Transplantation

2004; Elsevier BV; Volume: 4; Issue: 2 Linguagem: Inglês

10.1046/j.1600-6143.2003.00366.x

1600-6143

David T. Scadden,

Polyomavirus and related diseases

It takes no convincing of this readership that among the great triumphs of western medicine is the ability to replace a failed organ and enable an otherwise terminally ill individual to return to a productive life. The dark side of that bargain is the compromise in immune function that is the cost of using an allogeneic donor. What Opelz and Dohler document in pages 222–230 of this edition is that one aspect of this cost, insidiously exacted over a very prolonged interval, is often fatal malignant disease. They provide new information about the extent, duration, contributing factors and prognosis of post transplant lymphoma giving substantial impetus to new thinking about this condition. Opelz and Dohler focused on lymphoid malignancy, the most common, but not the only tumor higher in frequency in the immunocompromised. Perhaps the most unexpected finding in their report is the persistence of the risk of lymphoma after the first year after transplant. While year one remains the single year of highest risk, the cumulative risk over a 10 year interval is documented to exceed that of the first year and to have no clear indication of achieving a plateau. Studying approximately 200 000 cases of solid organ transplant in the Collaborative Transplant Study they document an 11.8 fold increase in risk of lymphoma above the nontransplanted population. In the setting of immunodeficiency several features conspire to increase the risk of lymphoid proliferation. The simplest scenario is the one most often attributed to the cause of post transplant lymphoproliferative disease (PTLD): escape of oncogenic viruses from immunologic control. This is the traditional PTLD in which Epstein Barr virus (EBV) latency genes resembling in vitroB cell transformation with EBV are expressed. When prolonged immunosuppression is present, other pathophysiologic mechanisms begin to become more of an issue. The ubiquitous presence of EBV in the tumors begins to be less common, secondary mutations accumulate and more complex mechanisms of B cell transformation become paramount. This issue was not investigated in the report by Opelz and Dohler but will now be important to define, particularly to create methods of evaluating tumor development. If characteristic molecular abnormalities are identified, PCR screening methods for those of highest risk becomes feasible. Are there particular regimens that should be reconsidered because of tumor risk? In this report, FK506 appears to confer independent risk to kidney recipients, but the value of this agent is such that it is unrealistic to think it will be removed from the armamentarium. Rather, are there host features that enhance the risk of certain regimens or of tumor development overall? Genotypic analysis may be revealing in this setting as has occurred in HIV related lymphomas where polymorphisms in chemokine and chemokine receptor genes did segregate with risk (1Rabkin CS Yang Q Yang Q Goedert JJ Nguyen G Mitsuya H Sei S Chemokine and chemokine receptor gene variants and risk of non Hodgkin's lymphoma in human immunodeficiency virus 1 infected individuals.Blood. 1999; 93: 1838-1842Crossref PubMed Google Scholar). A similar approach in post transplant lymphoma may reveal those for whom particular vigilance may be appropriate or for whom specific regimens may be less desirable. Finally, the study of Opelz and Dohler points out the rather damning verdict that we oncologists have done very little over the course of 10 years to affect the long term outlook for patients with post transplant lymphoma. Is this a legacy that will change anytime soon? Enter rituximab (anti CD20) and the answer is likely to be yes. While the introduction of this agent was too recent to be reflected in the data of Opelz and Dohler, numerous small studies have indicated excellent activity in the immediate post transplant setting (50–75% response rates) (2Yang J Tao Q Flinn IW et al.Characterization of Epstein–Barr virus infected B cells in patients with posttransplantation lymphoproliferative disease: disappearance after rituximab therapy does not predict clinical response.Blood. 2000; 96: 4055-4063Crossref PubMed Google Scholar, 3Zilz ND Olson LJ McGregor CG Treatment of post transplant lymphoproliferative disorder with monoclonal CD20 antibody (rituximab) after heart transplantation.J Heart Lung Transplant. 2001; 20: 770-772Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar). It is a minimally toxic approach active in other non Hogkins lymphoma (NHL) settings either alone or in combination with standard cytotoxic chemotherapy (2Yang J Tao Q Flinn IW et al.Characterization of Epstein–Barr virus infected B cells in patients with posttransplantation lymphoproliferative disease: disappearance after rituximab therapy does not predict clinical response.Blood. 2000; 96: 4055-4063Crossref PubMed Google Scholar, 3Zilz ND Olson LJ McGregor CG Treatment of post transplant lymphoproliferative disorder with monoclonal CD20 antibody (rituximab) after heart transplantation.J Heart Lung Transplant. 2001; 20: 770-772Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar. Whether larger studies will confirm its utility and whether it will be of use in the non EBV related, late post transplant lymphoma remains to be determined, but early indications give cause for optimism. The data from Opelz and Dohler have therefore provided important new information about sustained tumor risk and inspired a need for better tools for prediction and treatment. The collective action among many centers that led to this report is a critical base from which to now push the molecular and therapeutic dimensions that can translate into patient benefit.