Recurrent or persistent cardiac allograft rejection: Therapeutic options and recommendations

ELSEVIER

Recurrent or Persistent Cardiac AIIograft Rejection: Therapeutic Options and Recommendations J.K. Kirklin, R.C. Bourge, and D.C. McGiffin HE STANDARD primary treatmer t for cardiac alloT graft rejection is intravenous (I¥) or oral steroid therapy, which usually is successful in reversing the rejection process. The diversity of therapies for recurrent or persistent allograft rejection reflects the lack of solid information about basic issues, including (1) the precise definition of cardiac allograft rejection; (2) the prognostic implications of persisting or recurring cellular infiltrates on endomyocardial biopsy with regard to subsequent graft loss; (3) the effectiveness of various immunosuppressive interventions at eliminating such infiltrates; and (4) the longterm risks of such interventions. Despite these important uncertainties, the bulk of indirect evidence suggests that persisting or recurrent cellular infiltrates of the International Society of Heart and Lung Transplantation grade 3A or higher adversely affect long-term graft function and may contribute to the development of allograft vasculopathy. Strategies to reduce or eliminate such a pattern of histologic rejection are, therefore, justified. For purposes of this discussion, persistent steroid-resistant rejection is rejection in which a biopsy grade of 3A or greater is present on two or more successive biopsies 7 to 10 days apart, each treated with augmented IV or oral steroid therapy. Recurrent steroid-resistant rejec.:ion is defined as

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Months Since Last Rejection or Transplant Fig 2. Hazard function for subsequent rejection after either heart transplantation or any rejection episode during the first year after heart transplantation (from Kubo et al, used with permission2).

three or more rejection episodes treated with augmented immunosuppression occurring within a 2-month period. TIME-RELATED NATURE OF RECURRENT REJECTION

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Although persistent or recurrent steroid-resistant rejection may occur any time after transplantation, it is most likely to occur in the first 6 months, just as for isolated uncomplicated rejection. Approximately 60% of cardiac transplant patients experience one or more rejection episodes during the first 3 months (Fig l). 1 The instantaneous risk or hazard of a subsequent rejection after any given rejection episode is highest during the ensuing 2 months and decreases rapidly thereafter (Fig 2). 2 It decreases with time after transplantation such that the hazard function for subsequent rejection more than 1 year after transplantation is very low (Fig 3). 2 Thus, the problem of steroid-resistant

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Fig 1. Actuarial freedom from first rejection (Kaplan-Meier) (from Kobashigawa et al, used with permission1). TCRD, Transplant Cardiology Research Database.

0041-1345/97/$17.00 PII S0041-1345(97)00855-5 40S

From the Departments of Surgery and Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA. Address reprint requests to James K. Kirklin, MD, Professor of Surgery, University of Alabama at Birmingham, Zeigler Bldg, Birmingham, AL 35294. © 1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010

Transplantation Proceedings, 29 (Suppl 8A), 40S-44S (1997)

CARDIAC ALLOGRAFT REJECTION

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persistent or recurrent rejection prompting major changes in immunosuppression therapy occurs mainly in the first 6 months following transplantation. RECURRENT OR PERSISTENT REJECTION WITH LOW BIOPSY SCORE

Controversy exists regarding the implications of biopsy scores of grades 1B and 23 in aslymptomatic patients. During the first 4 to 6 months after transplantation, an untreated grade 1B or 2 biopsy is associated with a greater than 25% probability of having rejection on the subsequent biopsy, 4 with an even higher likelihood in the presence of multiple prior rejection episodes. 5 Thus, we currently recommend treatment of low grades of rejection (grades 1B and 2) as isolated findings during the. first 2 months and if recurrent during the first 6 months :!ollowing transplantation. Therapy generally includes pulse steroid therapy (IV or oral) and/or augmentation of maintenance immunosuppression. After 6 months, grade 1B or 2 biopsy scores are not predictive of future rejection and probably do not warrant therapy.

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THERAPEUTIC OPTIONS FOR RECURRENT/PERSISTENT REJECTION

In an immunosuppressive program based on cyclosporine (CyA), azathioprine (AZA), and prednisone, the second line of therapy for persistent or recurrent steroid-resistant rejection is usually either OKT3 (Orthoclone OKT®3, Ortho Pharmaceuticals Inc, Raritan, N J) or a polyclonal antilymphocyte (or antithymocyte) preparation (if these modalities were not used as initial "induction" therapy). After these have been administered once, the probability of cytomegalovirus infections and lymphoproliferative disease (particularly with OKT3) may increase with additional administrations. 8 Thus, multiple courses of such therapy are generally avoided, except in the circumstance of life-threatening rejection with severe hemodynamic compromise. The remainder of this paper will focus on the therapeutic options for recurrent or persistent allograft rejection after administration of OKT3 and/or an antilymphocyte preparation. The most common options for subsequent treatment are listed in Table 1. Information is not yet available that indicates the most efficacious (and least toxic) treatment, so

HIGH-RISK FORMS OF RECURREhT OR PERSISTENT REJECTION

When acute rejection is associated with depressed systolic function or clinical signs of low cardiac output necessitating inotropic support, the mortality during that rejection episode and subsequently is importantly increased. In a multiinstitutional study (Cardiac Transplant Research Database), the actuarial probability of death was 40% within 6 months following acute rejection wiLh hemodynamic compromise. 6 In the presence of antidonor HLA antibodies, the likelihood of death from recurrenL rejection leading to allograft loss is especially high (Fig ~).?

Table 1. Therapeutic Options for Recurrent/ Persistent Rejection Tacrolimus Mycophenolate Methotrexate Cyclophosphamide Total lymphoid

irradiation

Plasmapheresis Photopheresis Note: T h e r a p e u t i c o p t i o n s for r e j e c t i o n d e s p i t e s t e r o i d s a n d p r e v i o u s c y t o Lytic t h e r a p y .

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KIRKLIN, BOURGE, AND MCGIFFIN

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phocytes. Methotrexate has proven beneficial in controlling recurrent acute allograft rejection (Fig 5), ]3-I~ usually in a dosage of 2.5 to 5 mg orally every 12 hours for three doses at week b, intervals for 6 to 8 weeks in adults. ]3 The major side effect is leukopenia, which may be severe. A Z A dosage is reduced during methotrexate therapy and may need to be stopped temporarily.

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M o n t h s after T r a n s p l a n t a t i o n Fig 5. Rejection rates during methotrexate therapy. The squares represent mean rejection incidences and mean times since transplantation for patients who started methotrexate therapy (n = 9) <2 months after transplantation; triangles represent patients who started methotrexate therapy > 2 months after transplantation; circles represent t h e - r e l a t e d rejection rates for all other patients (who were not treat~,d with methotrexate; n = 73) undergoing heart transplantation between January 1, 1987 and January 1, 1990. *P = .11 compared with all other patients at the same interval after transplantation, t p = 0001 compared with all other patients at the same interval after transplantation (from Bourge et al, used with permissionS4). MI'X - methotrexate. Pre-MTX = Period posttransplantation withi ~ 3 months of MIX. Post-M-IX = 3 months immediately after MI2X.

we will review the merits of each and offer our own personal recommendations. Conversion From AZA to M y c o p h e n o l a t e Mofetil (MMF)

MMF is a reversible, noncompetitive inhibitor of inosine monophosphate dehydrogenase, a critical enzyme in the de novo pathway for purine synthesis, on which lymphocytes depend for biosynthesis. It has a potential role in recurrent rejection of either the cellular or humoral type, since it provides suppression of T-cell and B-cell activity.`) Furthermore, in vitro studies show an inhibitory effect on smooth muscle proliferation that could provide a theoretical benefit in allograft vasculopathy. 1° The side effects are usually limited to gastrointestinal symptoms, bu~ may rarely include bone marrow suppression. Dose reduction is usually successful in alleviating gastrointestinal symptoms or, more rarely, leukopenia. In nonrandomized studies, M M F has been effective in controlling recurrent, steroid-resistant allograft rejection at doses of 3000 to 3500 mg/d in adults] 1 14 Conversion From AZA to M e t h o t r e x a t e

Methotrexate is a folic acid analog that combines competitively with dihydrofolic reductase and blocks the conversion of dihydrofolic acid to tetrafolic acid (an essential step in D N A synthesis). The immunosuppressive effects likely stern from interference with proliferation of activated lyre-

Cyclopbosphamide is an alkylating agent with marked bone marrow-suppressive effects. Five percent to 20% of the drug is excreted unchanged in urine and may induce hemorrhagic cystitis. The drug should, therefore, be administered in the morning. It has been recommended for suspected humoral-mediated rejection because of more pronounced anti-B-cell activity than that of AZA. ]7 The usual dose is one half the A Z A dose. Conversion From CyA to Tacrolimus

Tacrolimus, like CyA, inhibits the activity of calcineurin, which participates in the pathway for interleukin-2 production. Like CyA, tacrolimus causes the potential major side effect of nephrotoxicity. It is more immunosuppressive than CyA and is frequently used as monotherapy in children and adults] s Studies suggest that conversion from CyA to tacrolimus provides highly effective therapy for recurrent or persistent allograft rejection. 19'2° The therapeutic blood level of tacrolimus is generally 12 to 15 ng/mL To minimize nephrotoxicity, we usually wait 24 hours after the last dose of CyA and then initiate tacrolimus at a dosage of 0.1 mg/kg/d in divided doses with gradual subsequent increases to achieve therapeutic levels. Total L y m p h o i d Irradiation (TLI)

The application of radiation to lymphoid tissue using an inverted y-mantle field induces delayed immunosuppression that is highly effective in the treatment of recurrent rejection. 2] Patients with increased rejection tendency usually experience a reduction in the frequency of rejection episodes to that of standard patients within 2 months of completing TLI (Fig 6). 21'22 The usual protocol involves twice-weekly doses of 80 cGy for 5 weeks, providing a total radiation dose of 800 cGy. A Z A is discontinued after 1 to 2 weeks of therapy depending on the leukocyte count. TLI therapy should be delayed if the white blood cell count remains below 3000. Thrombocytopenia is occasionally marked and may limit the duration of TLI, particularly when the platelet count falls below 100,000/mL. TLI, while effective against recurrent rejection, is not effective against ongoing acute rejection. Its utility depends on reversing acute rejection with other modalities. There are currently insufficient follow-up data to quantify the risk of late malignancies following TLI in immunosuppressed patients. Plasmapheresis/Photopheresis

Multiple studies in renal as well as cardiac transplantation have demonstrated the efficacy of plasmapheresis in the

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Fig 6. Rejection rates in two patient groups. Solid line depicts patients (adult plus pediatric, n = 20) who underwent heart transplantation between January 1, 1990 and January 1, 1992 and received TLI within 2 months of transplantation; dotted line depicts all patients (adult plus pediatric, r = 79) who underwent heart transplantation between January 1, 1987 and January 1, 1992 who did not receive TLI but received a uniform protocol of triple-drug immunosuppression plus OKT3 or rabbit antithymocyte globulin induction; enclosed bars represent _+1 standard error (from Kirklin et al, used with permission21).

treatment of humoral rejection by reducing circulating titers of anti-HLA antibodies. 23'24 Photopheresis involves the extracorporeal administration of ultraviolet light to leukocytes treated with 8-methoxypsotalen, which are then returned to the patient. These partially or lethally damaged cells presumably stimulate the production of anti-idiotypic antibodies in the host. Clinical studies have demonstrated the effectiveness of photopheresis in treating recurrent acute aUograft rejection, 25 as well as in reducing persistently elevated panel-reactive antibody (PRA) levels posttransplant (unpublished data). We have used photopheresis following plasmapheresis for the treatment of recurrent or persistent allograft rejection, particularly early after transplantation and when the rejection is associated with hemodynamic compromise. Although limited clinical data are available for analysis, plasmapheresis c~mbined with subsequent photopheresis has been applied to 17 patients in our institution who either completed or have ongoing therapy. Rejection frequency has been reduced significantly during photopheresis, and posttransplant PRA levels have declined following photopheresis theralzy. Although photopheresis is theoretically effective against B-cell as well as T-cell populations via development of anti-idiotypic antibodies, there are no clinical data to substantiate its effectiveness against humoral rejection. CONSIDERATIONS IN SELECTION OF: THERAPY

In selecting a specific regimen for the treatment of recurrent or persistent allograft rejection, one should consider several general factors. Infants and children receiving CyA immunosuppression should probably undergo conversion to tacrolimus in the presence of persistent or recurrent rejection, since the excellent results with tacrolimus are well established. The presence of hemodynamic compromise or

evidence of humoral rejection is important and may affect the specific recommendations. The patient's travel distance from the medical center may affect the feasibility of using TLI, which requires twice-weekly therapy for 5 weeks, or photopheresis, which requires treatments every 3 to 4 weeks for up to 6 to 12 months. There are also important cost differentials between various therapeutic options. Methotrexate and cyclophosphamide are about equal in cost to AZA, but MMF in our hospital is approximately seven times more expensive than an equivalent dose of AZA. Tacrolimus is slightly more expensive than CyA. The charge for TLI has been approximately $8500 for a 5-week course, but photopheresis charges may approach $75,000 for 1 year of therapy. THERAPEUTIC RECOMMENDATIONS Recurrent/Persistent Rejection in Infants and Children

Because of the small potential for late malignancies after TLI and the vascular access required for photopheresis, these therapies are generally not considered for infants and small children. In this group, our first therapeutic choice is conversion from CyA to tacrolimus. If recurrent rejection is not controlled with this regimen, MMF is substituted for AZA. Recurrent/Persistent Cellular Rejection Without Hemodynamic Compromise

During initial therapy of the acute rejection episode, IV methylprednisolone is administered and MMF is generally substituted for AZA. With further recurrent rejection, TLI is usually recommended, followed by conversion from CyA to tacrolimus. Limited bone marrow reserves would favor another option besides TLI. Humoral Rejection or Acute Cellular Rejection With Hemodynamic Compromise

In the presence of hemodynamic compromise, the highest priority is prompt reversal of left ventricular dysfunction. Initial therapy usually includes IV methylprednisolone, inotropic support, prompt plasmapheresis, and cytolytic therapy with either OKT3 or antithymocyte globulin. A Z A is converted to MMF, and if recurrent rejection persists, CyA is switched to tacrolimus. If the hemodynamic compromise is severe or recurrent, TLI or photopheresis is used after control of the rejection episode. In the presence of probable humoral rejection (hemodynamic compromise with low biopsy score or evidence of anti-HLA antibodies), we currently use plasmapheresis and subsequent photopheresis instead of TLI. The superiority of photopheresis to TLI in this instance is unproven, and further studies are necessary to evaluate its etficacy. REFERENCES

1. Kobashigawa JA, Kirklin JK, Naftel DC, et al: J Heart Lung Transplant 12:355, 1993

44S 2. Kubo SH, Naftel DC, Mills RM Jr, et al: J Heart Lung Transplant 14:409, 1995 3. The International Society for Heart Transplantation: J Heart Lung Transplant 9:587, 1990 4. Rizeq MN, Masek MA, Billingham ME: J Heart Lung Transplant 13:862, 1994 5. Lloveras J-J, Escourrou G, Delisle MB, et al: J Heart Lung Transplant 11:751, 1992 6. Mills RM Jr, Naftel DC, Kirklin JK, et al: J Heart Lung Transplant (in press) 7. George JF, Kirklin JK, Shroyer TW, et al: J Heart Lung Transplant 14:856, 1995 8. Swinnen LJ, Costanzo-Nordin MR, Fisher SG, et al: N Engl J Med 323:1723, 1990 9. Morris RE, Hoyt EG, Murphy MP, e.t al: Transplant Proc 22:1659, 1990 10. Sollinger HW, Eugui EM, Allison AC: Clin Transplant 5:523, 1991 11. Kirklin JK, Bourge RC, Naftel DC, et al: J Heart Lung Transplant 13:444, 1994 12. The Mycophenolate Mofetil Renal Refractory Rejection Study Group: Clin Transplant 10:131, 1996 13. Shaddy RE, Bulock EA, Tani LY, et al: J Heart Lung Transplant 13:1009, 1994

KIRKLIN, BOURGE, AND MCGIFFIN 14. Bourge RC, Kirklin JK, White-Williams C, et al: J Heart Lung Transplant 11:1116, 1992 15. Costarlzo-Nordin MR, Grusk BB, Silver MA, et al: Circulation 78(suppl III):III-47, 1988 16. Olsen SL, O'Connell JB, Bristow MR, et al: Transplantation 50:773, 1990 17. Grauhan O, Mfiller J, Warnecke H, et al: J Heart Lung Transplant 13:$74, 1994 18. Armitage JM, Fricker FJ, del Nido P, et al: J Thorac Cardiovasc Surg 105:464, 1993 19. Hachida M, Hoshi H, Maeda T, et al: Jpn Assoc Thorac Surg 42:1972, 1994 20. Herget S, Heernann U, Friedrich J, et al: Clin Nephrol 45:352, 1996 21. Kirklin JK, George JF, McGiffin DC: J Heart Lung Transplant 12:$293, 1993 22. Salter MM, Kirklin JK, Bourge RC, et al: J Heart Lung Transplant 11:902, 1992 23. Bonomini V: Trans Am Soc Artif Intern Organs 28:599, 1982 24. Partanen J, Nieminen MS, Krogerus L, et al: J Heart Lung Transplant 11:301, 1992 25. Costanzo-Nordin MR, McManus BM, Wilson JE, et al: Transplant Proc 25:881, 1993