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BMJ No 7133 Volume 316
Editorial Saturday 7 March 1998
Immunosuppressive drugs after lung transplantation
New agents may improve long term survival
Survival figures after lung transplantation for the period up to 1996 were reported at a recent annual meeting of the International Society of Heart and Lung Transplantation in London. Although quality of life for patients is greatly improved for some years after transplantation, five year survival after heart-lung, single lung, or double lung transplantation is still less than 50%.(1) Mortality in the first 30 days has improved because of advances in surgical technique and in methods of lung preservation,(1) but after 30 days the survival curves in 1988-91 and in 1992-5 are parallel.
The main cause of death between 30 days and a year after transplantation is infection. After a year the main cause is bronchiolitis obliterans syndrome. This fibroproliferative disorder affects the small airways of at least half of patients who survive for three months after transplantation.(2) Its pathogenesis is unclear but it represents a fibrotic repair process occurring after chronic airway injury, and retrospective series have shown that acute lung rejection is an important risk factor for its development.(2) New treatments for bronchiolitis obliterans syndrome and steroid resistant rejection have included trials of inhaled cyclosporin, total lymphoid irradiation, and methotrexate.(3-5) However, since infection is still an important cause of death after lung transplantation,(6) further gains in survival will be difficult to achieve with current immunosuppressive regimens: cyclosporin, azathioprine, steroids, and cytolytic drugs. More effective immunosuppressive drugs are needed, and clinical trials evaluating new immnuosuppressive agents in lung transplantation are planned. Currently, encouraging results have been reported with these drugs after renal transplantation.
Better absorption of a new formulation of cyclosporin-cyclosporin microemulsion formulation (Neoral, Novartis) - increases overall exposure of patient and graft to cyclosporin without an increase in toxicity. The improved pharmacokinetic profile has been shown in healthy human volunteers and stable renal and lung transplant patients, including patients with cystic fibrosis.(7)
Tacrolimus is the United States approved name for FK506 (Prograf, Fujisawa). Gjertson et al examined data from the United Network for Organ Sharing kidney transplant registry on 38 057 patients who had been discharged after their first cadaveric kidney transplant.(8) They compared kidney half life in different treatment groups and found it was 13.8 years for patients taking tacrolimus, 8.8 years for patients taking cyclosporin, and 7.7 years for patients taking other drugs. The authors stated that FK506 seemed to be the first drug significantly to improve long term survival of kidney grafts.
In the only properly controlled study comparing cyclosporin and tacrolimus treatments in lung transplantation there was a trend towards improved survival at two years in the tacrolimus group and a reduction in rejection episodes (0.85/100 patient days for tacrolimus and 1.09/100 patient days for cyclosporin; p=0.07).(9) Notably, however, fewer patients in the tacrolimus group developed obliterative bronchiolitis compared with the cyclosporin group (21.7% versus 35.8%, P=0.025). Tacrolimus may be effective in treating persistent rejection and in slowing down deterioration in airflow that occurs with bronchiolitis obliterans syndrome.(10)
Mycophenolate mofetil (Cellsept, Hoffmann LaRoche) is a morpholinoethyl ester of mycophenolic acid and has been more extensively studied in controlled, open, and blinded clinical trials than any other new immunosuppressant. In all studies mycophenolate has been substituted for azathioprine in triple drug regimens. In a pooled efficacy analysis of three large, randomised, double blind, clinical trials of renal transplantation, the mycophenolate groups showed better survival of grafts and fewer rejection episodes (19.8% and 16.5% for mycophenolate 2 and 3 g versus 40.8% for azathioprine, p<0.0001).(11) There was no difference in infection rates between patients in the azathioprine group and the mycophenolate group.(11)
Three lung transplant centres recently reported their initial experience of mycophenolate mofetil in lung transplantation.(10) None of the studies was properly controlled, and each contained relatively small numbers of patients. All the studies reported significantly fewer episodes of acute rejection, proved by biopsy, without a significant increase in infection. In one paper the authors detected a significantly smaller drop in forced expiratory volume in one second in the mycophenolate group.(10)
Sirolimus (US approved name for rapamycin - Rapimmune, Wyeth, and RAD rapamycin derivative, Novartis) is structurally similar to tacrolimus but has a different mode of action.(12) Recently published phase II trials in renal transplant patients suggest that the drug can decrease acute rejection rates from 40% to less than 10% among patients taking full dose cyclosporin.(13) This improvement is achieved with a small, non-significant increase in infectious complications. The authors suggest that the drug may mitigate the need for long term steroid treatment.
Randomised controlled trials comparing mycophenolate mofetil and rapamycin or rapamycin derivative with azathioprine are now in the planning stages. These new drugs will soon form the basis of new immunosuppressive regimens for use in lung transplantation that are expected to have an impact on long term survival.
Norman Briffa
Research fellow
Randall E Morris
Director
Laboratory for Transplantation Immunology,
Department of
Cardiothoracic Surgery,
Stanford University School of Medicine,
Stanford,
CA 94305-5247,
USA
NB is supported in part by the Sandoz study grant of the European Society of Transplantation.
References
1 Hosenpud J D, Novick R J, Bennett L E, Keck B M, Fiol B, Daily
O P. The Registry of the International Society for Heart and Lung
Transplantation: thirteenth official report-1996. J Heart Lung
Transplant 1996;15:655-74.
2 Bando K, Paradis I L, Similo S, Konishi A, Komatsu K, Zullo T G,
et al. Obliterative bronchiolitis after lung and heart-lung
transplantation. An analysis of risk factors and management. J
Thorac Cardiovasc Surg 1995;110:4-13, 13-4.
3 Iacono A T, Keenan R J, Duncan S R, Smalldone G , Dauber J H,
Paradis I L, et al. Aerosolized cyclosporine in lung recipients with
refractory chronic rejection. Am J Respir Crit Care Med
1996;153:1451-5.
4 The International Society for Heart and Lung Transplantation
16th annual meeting and scientific sessions. New York, New York, March
15-18, 1996. Abstracts. J Heart Lung Transplant
1996;15:S1-114.
5 Dusmet M, Maurer J, Winton T, Kesten S. Methotrexate can halt
the progression of bronchiolitis obliterans syndrome in lung transplant
recipients. J Heart Lung Transplant 1996;15:948-54.
6 Chaparro C, Maurer J R, Chamberlain D, De Hoyos A, Winton T,
Westney G, et al. Causes of death in lung transplant recipients.
J Heart Lung Transplant 1994;13:758-66.
7 Mikhail G, Eadon H, Leaver N, Rogers P, Stephens D,
Banner N, et al. An investigation of the pharmacokinetics, toxicity,
and clinical efficacy of neoral cyclosporin in cystic fibrosis
patients. Transplant Proc 1997;29:599-601.
8 Gjertson D W, Cecka J M, Terasaki P I. The relative effects of
FK506 and cyclosporine on short- and long-term kidney graft survival.
Transplantation 1995;60:1384-8.
9 Keenan R J, Konishi H, Kawai A, Pradis I, Nunley D R, Iacono A T,
et al. Clinical trial of tacrolimus versus cyclosporine in lung
transplantation. Ann Thorac Surg 1995;60:580-4, 584-5.
10 The International Society for Heart and Lung Transplantation
17th annual meeting and scientific sessions. London, England, April
2-5, 1997. Abstracts. J Heart Lung Transplant
1997;16:41-142.
11 Halloran P, Mathew T, Tomlanovich S, Groth C, Hooftman L,
Barker C. Mycophenolate mofetil in renal allograft recipients: a pooled
efficacy analysis of three randomised, double-blind, clinical studies
in prevention of rejection. The International Mycophenolate Mofetil
Renal Transplant Study Groups. Transplantation
1997;63:39-47.
12 Brazelton T R, Morris R E. Molecular mechanisms of action of new
xenobiotic immunosuppressive drugs: tacrolimus (FK506), sirolimus
(rapamycin), mycophenolate mofetil, and leflunomide. Curr Opin
Immunol 1996;8:710-20.
13 Kahan B. Sirolimus: a new agent for clinical renal
transplantation. Transplant Proc 1997;29:48-50.
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