Post-transplant de novo malignancies in renal transplant recipients: the past and present.

Post-transplant de novo malignancies are reviewed in three time periods: (i) the azathioprine (AZA) era from 1962 to 1980-1981, (ii) the cyclosporine (CYA) era (1980 to present) in which the calcineurin inhibitors, CYA and tacrolimus (TAC), were the mainstay of recipient immunosuppression, and (iii) the TOR inhibitor era starting in the year 2000. Both transplant registry and transplant center reports on malignancies occurring in the AZA era are reviewed. Reports from transplant centers and from the Cincinnati Transplant Tumor Registry (CTTR) in both the early CYA era (1980s) and the 1900-2000 CYA era are reported. Cancer incidence associated with AZA versus CYA, CYA versus TAC, and AZA versus mycophenolate mofetil (MMF) is compared in both transplant center and registry reports including new, unreported Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) data from 1998 to 2003. The malignancy incidence associated with lymphocyte-depleting antibody and corticosteroid immunosuppression is discussed. Reduced malignancy incidence recently reported with TOR inhibitors is compared with that of conventional immunosuppression. Important nondrug factors influencing the incidence of post-transplant malignancies from seven single and three registry reports are detailed. The substantial role that de novo malignancies play in post-transplant mortality is discussed. Finally, management recommendations for recipients who develop de novo post-transplant malignancies are briefly presented.

Aplastic anemia before bone marrow transplantation and antilymphocyte globulin.

In severe aplastic anemia, disease-dependent mortality was high before allogeneic bone marrow transplantation (BMT) and immunosuppressive therapies (IST) including antilymphocyte globulin became available. However, under supportive therapy alone, spontaneous remissions were observed in up to 20% of severe cases, reflecting the natural course of the disease. Therefore, in evaluating new forms of treatment, one has to keep in mind that remission is not necessarily response, and that final proof of utility of any new therapy still requires a randomized study design. Transition to leukemia or myelodysplasia was rarely observed if the initial diagnosis was accurate. The much higher incidence of leukemias in patients treated by IST, but not by BMT is probably due to the better life expectancy of patients at risk, rather than to a leukemogenic potential of IST itself. 'Outdated' therapeutic modalities, such as androgens or splenectomy, may still be justified as an adjuvant therapy in selected cases.

The crime of saving lives. The FDA, John Najarian, and Minnesota ALG.

The indictment of John Najarian, MD, and Richard Condie at Minneapolis, Minn, on April 10, 1995, was a defining episode in the prolonged agony that has ensued since August 1992, when the federal Food and Drug Administration (FDA) placed Minnesota Anti-Lymphocyte Globulin (MALG) on clinical hold, bringing to an end its use as an immunosuppressive agent for patients undergoing transplantation. The principal charge in the indictment is that from about 1968 until 1992--the whole period of the development and use of MALG--Dr Najarian and Mr Condie conspired to defraud the United States by impeding the FDA in its oversight of biological drugs and that they did so for the purpose of financial gain. If the charges can be considered seriously, they mean that Dr Najarian's purpose in the development and manufacture of MALG was to make money, presumably for himself, and that the possible benefit of MALG to the patients was of secondary concern to him. Several difficulties arise immediately. In 1968, MALG offered a promising new approach to immunosuppression. In a relatively crude form, it had been used at the University of Colorado with striking improvement in the survival of patients undergoing transplantation and transplanted organs, but it was painful to administer by intramuscular injections and, in addition to other side effects, produced muscular spasms. Dr Najarian and his colleagues succeeded in purifying MALG so that the pure globulin could be injected into a central vein. The process of purification was complicated and expensive, so it was hardly practical for each transplant center to produce MALG for itself. Thus, in 1969, when Dr Najarian submitted an investigational new drug application (IND) to the FDA, he stated that his purpose was to manufacture MALG not only for patients at the University of Minnesota Hospital but also for patients at other transplant centers, which were not in a position to make it for themselves. He asked the FDA to approve recovery of the cost of providing MALG to other institutions. The FDA approved Dr Najarian's IND application early in 1970 but did not respond to his request for cost recovery--then, or for the next 15 years. Dr Najarian was free to manufacture MALG and to distribute it to other transplant centers for investigational use, but as for paying for it, that was his problem. The FDA offered no suggestion.