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FK 506 and mycofenolate mofetil rescue for acute steroid-resistant and chronic rejection after liver transplantation
ELSEVIER
FK 506 and Mycofenolate Mofetil Rescue for Acute Steroid-Resistant and Chronic Rejection After Liver Transplantation K.-P. Platz, AR. Mueller, R. Neuhaus, H.H. Keck, H. Lobeck, and P. Neuhaus
F
K 506 is a potent immunosuppressive agent for prevention and reversal of acute steroid-resistant and early chronic rejection following liver transplantation.‘,’ We and others1-4 have reported a decreased incidence of chronic rejection in FK 506-treated patients. However, there is still a small group of FK 506-treated patients who will develop acute steroid-resistant or early chronic rejection. In fact, chronic rejection has been reported to be responsible for at least 20% of graft failures following liver transplantation.5 FK 506 has been shown very effective for suppression of T-cell-mediated immune response, but less effective in suppressing the humoral B-cell-mediated response. Therefore, the combination of FK 506 with a B-cell suppressive immunosuppressant like mycofenolate mofetil (MMF) may be of advantage. In the present study, we analyzed the outcome of patients developing acute steroid-resistant and chronic rejection with respect to the kind of rescue treat-
ment. MATERIALS Patients
AND
METHODS
and lmmunosuppression
Between September 1988 and December 1995,700 liver transplantations were performed in 647 patients. Four hundred twenty-eight patients were treated with cyclosporine (CyA)-based immunosuppression in conjunction with prednisolone and azathioprine and antithymocyte/antilymphocyte globulin (ATG/ALG) or BT.563 for induction therapy. Two hundred nineteen patients received FK 506-based immunosuppression primarily in conjunction with prednisolone. Management
of Rejection
Diagnosis of acute rejection was based on clinical (fever, change of color, and amount of bile production) and laboratory (aspartate transaminase [AST], alanine transaminase [ALT], bilirubin, gamma-glutamyl transpeptidase [-@T’l, and alkaline phosphatase) findings and was confirmed by histologic evaluation of graft biopsies. Histologic criteria were used as previously described.4 Patients received methylprednisolone for treatment of acute rejection at a dosage of 500 mg/d for 3 days and either 0KT3 monoclonal antibody (Cilag GmbH, Sulzbach, Germany) or FK 506 (0.1 mg/kg BW twice daily) or the combination of both immunosuppressive agents for steroid-resistant or severe recurrent rejection. MMF (1 g twice daily) was used for rescue therapy in FK 506-treated patients with or without previous 0KT3 therapy. Chronic rejection was defined by established histologic criteria, including vanishing bile duct syndrome (loss of bile ducts >50%) and arterial lesions
(narrowing or occlusion of medium-sized arteries, subintimal foamcell infiltrate, fibromuscular proliferation).6*7 Statistical
Analysis
Kaplan-Meier estimates, Wilcoxon, chi-square, and Kruskal-Wallis tests were used as indicated. Results were expressed as means 5 standard error of the mean. RESULTS Survival
and Incidence
of Acute
and Chronic
Rejection
Cumulative 3-month to 7-year survival rates were similar for CyA- (84.4%) and FK 506 (84.6%)-treated patients. This was also true for the incidence of acute steroidresistant rejection (CyA: 70 of 428 [16.4%] and FK 506: 30 of 219 [13.7%]). The cumulative incidence of acute rejection for an observation period up to 7 years was lower for FK 506- (84 of 219 [38.4%]) than for CyA-treated patients (196 of 428 [45.8%]). In the CyA group, early FK 506 rescue therapy decreased the development of early chronic rejection following severe or recurrent acute rejection (early experience: chronic rejection: 8.7% to 6.3%; 27 of 428 patients). The incidence of early chronic rejection in the FK 506 group is slightly lower with 5.5% (12 of 219 patients). MMF Rescue Therapy
During the last year, MMF rescue therapy has been performed in 25 patients for acute steroid-resistant (n = 20) and early chronic rejection (n = 5). Six patients received FK 506-based immunosuppression and 14 CyA-treated patients were simultaneously rescued with MMF and FK 506 for acute steroid-resistant rejection (Table 1). Two and three patients from the FK 506 and CyA treatment groups, respectively, were rescued for early chronic rejection. Liver function tests and histologic signs of rejection recovered in all but one patient within 4 weeks after onset of MMF rescue therapy. One patient with preexisting recurrent graft hepatitis, who was rescued for early chronic rejection, From the Departments of Surgery and Pathology (H.L.), Virchow Clinic, Humboldt University Berlin, Berlin, Germany. Address reprint requests to Dr Klaus-Peter Platz, Department of Surgery, Virchow Clinic, Humboldt University Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
0041-l 345l97l$l7.00 PII SO041 -1345(97)00714-8
0 1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
2872
Transplantation
Proceedings,
29, 2872-2874
(1997)
FK 506 AND MMF RESCUE FOR CHRONIC REJECTION
2873
Table 1. Treatment and Immunologic Outcome of Acute Steroid-Resistant Rescue n = 84 Successful Failure
Patients
FK 506 (%)
oKT3 (%)
OKT3 + FK 506 (%)
MMF + FK 506
36/84 (42.9)
19/84 (22.6) 16/l 9 (84.2)
15/84 (17.9)
14164 (16.7)
9/15 (72.7)
13/l 4 (92.9)
4/36(11.1)
3/l 9 (15.8)
6/l 5 (40.0)
l/14
2/36 (5.5) 2/36 (5.5)
3/19 (15.8) -
2/15 (13.3) 4/l 5 (26.7)
l/14
32/36
Re-LTX (CR) Death (CR)
Rejection in CyA-Treated
(88.9)
(7.1) (7.1) -
Abbreviations:CR, chronic rejection; Re-LTX, liver retransplant. ‘OKr3 failure; histologicallyproven early CR followed by conversion to FK 506.
showed an improvement in liver function but finally required retransplantation due to recurrent hepatitis C virus (HCV) cirrhosis in conjunction with chronic rejection. These initial experiences compared well with the previous experiences using FK 506 for rescue treatment (Table 1). Side effects were observed in seven patients (Table 2). In two patients (8%) MMF therapy was discontinued due to severe gastrointestinal (GI) symptoms and anemia. In five patients (20%), mild side effects, including diarrhea, leukopenia, anemia, and hair loss, were successfully treated by MMF dose reduction to 0.5 g twice daily. One patient previously retransplanted for chronic rejection in combination with de novo HCV infection finally died due to overimmunosuppression-related meningitis/encephalitis. DISCUSSION
FK 506 has been proven effective for prevention and reversal of liver allograft rejection.‘,’ The macrolide FK 506 has been shown to act via a similar mechanism as CyA. But more potent than CyA, FK 506 is able to reverse acute and early chronic liver allograft rejection.3zR-‘0 Furthermore, some transplant centers have shown a decreased incidence of chronic rejection in FK 506-treated patients.2-4 However, there is still a certain number of patients who will develop acute and chronic rejection under FK 506-based immunosuppression. In fact, the present analysis showed a slightly decreased incidence of acute steroid-resistant and early chronic rejection in FK 506- compared with CyAtreated patients. We have previously shown that acute steroid-resistant and early chronic rejection can be effectively treated with high-dose FK 506 rescue therapy in patients receiving CyA-based immunosuppression.” With respect to rescue success or failure as well as side effects of rescue treatment, initial experiences with the combined use of MMF and FK 506 showed favorable results for the combined therapy vs FK 506 alone. Furthermore, for FK 506-treated patients, Table 2. Side Effects of MMF Rescue Therapy MMF Rescue Therapy
7/25 (28)
Side effects Discontinuation
No. of Patients (o/o)
of MMF
Dose reduction of MMF
2/25 (8) 5/25 (20)
Note: Discontinuationof MMF was performed in two patients due to severe GI symptoms and anemia. Dose reduction was perfoned because of mild GI symptoms (diarrhea), leukopenia, anemia, and hair loss.
0KT3 or ATG/ALG has been the only treatment options in the past. MMF rescue therapy instead of 0KT3 or ATG/ ALG may offer several advantages. First, MMF therapy can be continued over months or years in these patients. Second, side effects associated with 0KT3 like the development of cytomegalovirus (CMV) infections and lymphoproliferative disorders may be avoided. Furthermore, MMF rescue therapy in FK 506-treated patients offers the potential to treat early chronic rejection, which is not promising with the use of OKT3. The initial success rate for MMF rescue therapy for acute steroid-resistant and early chronic rejection in FK 506-treated patients was highly sufficient. The incidence of side effects after MMF rescue therapy was rather low, with discontinuation in 8% of patients and mild GI symptoms or leukopenia in 20% of patients. Lower initial MMF doses in patients with poor liver function and dose reductions in patients with side effects may increase the tolerability of MMF with similar efficacy. The one patient who died had a difficult course after liver transplantation with the development of de novo HCV infection and chronic rejection requiring retransplantation. Therefore, death may be related to several of these circumstances. Observation periods are too short for final conclusions, but initial efficacy and tolerability of MMF have been highly sufficient so far. FK 506-based immunosuppression and FK 506 rescue therapy in CyA-treated patients reduced the incidence of refractory acute and chronic rejection. However, FK 506 therapy failed to prevent acute steroid-resistant and chronic rejection in a small patient population. A possible explanation may be the missing effectivity of FK 506 in suppressing the humoral immune response, which will be sufficiently suppressed by MMF. The ideal treatment for these patients seems to be the rescue therapy with MMF.
REFERENCES 1. European 344:423, 1994
FK 506 Multicentre
2. The U.S. Multicenter .I Med 331:1110, 1994
Liver Study Group: Lancet
FK506 Liver Study Group: N Engl
3. Platz K-P, Mueller AR, Zytowski M, et al: Transplant Proc 27:1111, 1995 4. Neuhaus P, Blumhardt G, Bechstein WO, et al: Transplantation 59:31, 1995 5. Freese DK, Snover DC, Sharp HL, et al: Hepatology 13882, 1991
2874 6. Snover DC, Freese DK, Sharp HC, et al: Am J Surg Path01 ll:l, 1987 7. Demetris AJ, Qquian S, Sun A, et al: Am J Surg Path01 14(suppl 1):49, 1990 8. Demetris AJ, Fung JJ, Todo S, et al: Transplantation 53:1056, 1992
PIATZ,
MUELLER, NEUHAUS
ET AL
9. McDiarmid SV, KIintmalm GB, Busutill RW: Transplant Int 6:305, 1993 10. Winkler M, Ringe B, Jost U, et al: Transplant Int 6:319, 1993 11. Platz K-P, Mueller AR, Zytowski M, et al: World J Surg 20:1052, 1996
FK 506 and Mycofenolate Mofetil Rescue for Acute Steroid-Resistant and Chronic Rejection After Liver Transplantation K.-P. Platz, AR. Mueller, R. Neuhaus, H.H. Keck, H. Lobeck, and P. Neuhaus
F
K 506 is a potent immunosuppressive agent for prevention and reversal of acute steroid-resistant and early chronic rejection following liver transplantation.‘,’ We and others1-4 have reported a decreased incidence of chronic rejection in FK 506-treated patients. However, there is still a small group of FK 506-treated patients who will develop acute steroid-resistant or early chronic rejection. In fact, chronic rejection has been reported to be responsible for at least 20% of graft failures following liver transplantation.5 FK 506 has been shown very effective for suppression of T-cell-mediated immune response, but less effective in suppressing the humoral B-cell-mediated response. Therefore, the combination of FK 506 with a B-cell suppressive immunosuppressant like mycofenolate mofetil (MMF) may be of advantage. In the present study, we analyzed the outcome of patients developing acute steroid-resistant and chronic rejection with respect to the kind of rescue treat-
ment. MATERIALS Patients
AND
METHODS
and lmmunosuppression
Between September 1988 and December 1995,700 liver transplantations were performed in 647 patients. Four hundred twenty-eight patients were treated with cyclosporine (CyA)-based immunosuppression in conjunction with prednisolone and azathioprine and antithymocyte/antilymphocyte globulin (ATG/ALG) or BT.563 for induction therapy. Two hundred nineteen patients received FK 506-based immunosuppression primarily in conjunction with prednisolone. Management
of Rejection
Diagnosis of acute rejection was based on clinical (fever, change of color, and amount of bile production) and laboratory (aspartate transaminase [AST], alanine transaminase [ALT], bilirubin, gamma-glutamyl transpeptidase [-@T’l, and alkaline phosphatase) findings and was confirmed by histologic evaluation of graft biopsies. Histologic criteria were used as previously described.4 Patients received methylprednisolone for treatment of acute rejection at a dosage of 500 mg/d for 3 days and either 0KT3 monoclonal antibody (Cilag GmbH, Sulzbach, Germany) or FK 506 (0.1 mg/kg BW twice daily) or the combination of both immunosuppressive agents for steroid-resistant or severe recurrent rejection. MMF (1 g twice daily) was used for rescue therapy in FK 506-treated patients with or without previous 0KT3 therapy. Chronic rejection was defined by established histologic criteria, including vanishing bile duct syndrome (loss of bile ducts >50%) and arterial lesions
(narrowing or occlusion of medium-sized arteries, subintimal foamcell infiltrate, fibromuscular proliferation).6*7 Statistical
Analysis
Kaplan-Meier estimates, Wilcoxon, chi-square, and Kruskal-Wallis tests were used as indicated. Results were expressed as means 5 standard error of the mean. RESULTS Survival
and Incidence
of Acute
and Chronic
Rejection
Cumulative 3-month to 7-year survival rates were similar for CyA- (84.4%) and FK 506 (84.6%)-treated patients. This was also true for the incidence of acute steroidresistant rejection (CyA: 70 of 428 [16.4%] and FK 506: 30 of 219 [13.7%]). The cumulative incidence of acute rejection for an observation period up to 7 years was lower for FK 506- (84 of 219 [38.4%]) than for CyA-treated patients (196 of 428 [45.8%]). In the CyA group, early FK 506 rescue therapy decreased the development of early chronic rejection following severe or recurrent acute rejection (early experience: chronic rejection: 8.7% to 6.3%; 27 of 428 patients). The incidence of early chronic rejection in the FK 506 group is slightly lower with 5.5% (12 of 219 patients). MMF Rescue Therapy
During the last year, MMF rescue therapy has been performed in 25 patients for acute steroid-resistant (n = 20) and early chronic rejection (n = 5). Six patients received FK 506-based immunosuppression and 14 CyA-treated patients were simultaneously rescued with MMF and FK 506 for acute steroid-resistant rejection (Table 1). Two and three patients from the FK 506 and CyA treatment groups, respectively, were rescued for early chronic rejection. Liver function tests and histologic signs of rejection recovered in all but one patient within 4 weeks after onset of MMF rescue therapy. One patient with preexisting recurrent graft hepatitis, who was rescued for early chronic rejection, From the Departments of Surgery and Pathology (H.L.), Virchow Clinic, Humboldt University Berlin, Berlin, Germany. Address reprint requests to Dr Klaus-Peter Platz, Department of Surgery, Virchow Clinic, Humboldt University Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
0041-l 345l97l$l7.00 PII SO041 -1345(97)00714-8
0 1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
2872
Transplantation
Proceedings,
29, 2872-2874
(1997)
FK 506 AND MMF RESCUE FOR CHRONIC REJECTION
2873
Table 1. Treatment and Immunologic Outcome of Acute Steroid-Resistant Rescue n = 84 Successful Failure
Patients
FK 506 (%)
oKT3 (%)
OKT3 + FK 506 (%)
MMF + FK 506
36/84 (42.9)
19/84 (22.6) 16/l 9 (84.2)
15/84 (17.9)
14164 (16.7)
9/15 (72.7)
13/l 4 (92.9)
4/36(11.1)
3/l 9 (15.8)
6/l 5 (40.0)
l/14
2/36 (5.5) 2/36 (5.5)
3/19 (15.8) -
2/15 (13.3) 4/l 5 (26.7)
l/14
32/36
Re-LTX (CR) Death (CR)
Rejection in CyA-Treated
(88.9)
(7.1) (7.1) -
Abbreviations:CR, chronic rejection; Re-LTX, liver retransplant. ‘OKr3 failure; histologicallyproven early CR followed by conversion to FK 506.
showed an improvement in liver function but finally required retransplantation due to recurrent hepatitis C virus (HCV) cirrhosis in conjunction with chronic rejection. These initial experiences compared well with the previous experiences using FK 506 for rescue treatment (Table 1). Side effects were observed in seven patients (Table 2). In two patients (8%) MMF therapy was discontinued due to severe gastrointestinal (GI) symptoms and anemia. In five patients (20%), mild side effects, including diarrhea, leukopenia, anemia, and hair loss, were successfully treated by MMF dose reduction to 0.5 g twice daily. One patient previously retransplanted for chronic rejection in combination with de novo HCV infection finally died due to overimmunosuppression-related meningitis/encephalitis. DISCUSSION
FK 506 has been proven effective for prevention and reversal of liver allograft rejection.‘,’ The macrolide FK 506 has been shown to act via a similar mechanism as CyA. But more potent than CyA, FK 506 is able to reverse acute and early chronic liver allograft rejection.3zR-‘0 Furthermore, some transplant centers have shown a decreased incidence of chronic rejection in FK 506-treated patients.2-4 However, there is still a certain number of patients who will develop acute and chronic rejection under FK 506-based immunosuppression. In fact, the present analysis showed a slightly decreased incidence of acute steroid-resistant and early chronic rejection in FK 506- compared with CyAtreated patients. We have previously shown that acute steroid-resistant and early chronic rejection can be effectively treated with high-dose FK 506 rescue therapy in patients receiving CyA-based immunosuppression.” With respect to rescue success or failure as well as side effects of rescue treatment, initial experiences with the combined use of MMF and FK 506 showed favorable results for the combined therapy vs FK 506 alone. Furthermore, for FK 506-treated patients, Table 2. Side Effects of MMF Rescue Therapy MMF Rescue Therapy
7/25 (28)
Side effects Discontinuation
No. of Patients (o/o)
of MMF
Dose reduction of MMF
2/25 (8) 5/25 (20)
Note: Discontinuationof MMF was performed in two patients due to severe GI symptoms and anemia. Dose reduction was perfoned because of mild GI symptoms (diarrhea), leukopenia, anemia, and hair loss.
0KT3 or ATG/ALG has been the only treatment options in the past. MMF rescue therapy instead of 0KT3 or ATG/ ALG may offer several advantages. First, MMF therapy can be continued over months or years in these patients. Second, side effects associated with 0KT3 like the development of cytomegalovirus (CMV) infections and lymphoproliferative disorders may be avoided. Furthermore, MMF rescue therapy in FK 506-treated patients offers the potential to treat early chronic rejection, which is not promising with the use of OKT3. The initial success rate for MMF rescue therapy for acute steroid-resistant and early chronic rejection in FK 506-treated patients was highly sufficient. The incidence of side effects after MMF rescue therapy was rather low, with discontinuation in 8% of patients and mild GI symptoms or leukopenia in 20% of patients. Lower initial MMF doses in patients with poor liver function and dose reductions in patients with side effects may increase the tolerability of MMF with similar efficacy. The one patient who died had a difficult course after liver transplantation with the development of de novo HCV infection and chronic rejection requiring retransplantation. Therefore, death may be related to several of these circumstances. Observation periods are too short for final conclusions, but initial efficacy and tolerability of MMF have been highly sufficient so far. FK 506-based immunosuppression and FK 506 rescue therapy in CyA-treated patients reduced the incidence of refractory acute and chronic rejection. However, FK 506 therapy failed to prevent acute steroid-resistant and chronic rejection in a small patient population. A possible explanation may be the missing effectivity of FK 506 in suppressing the humoral immune response, which will be sufficiently suppressed by MMF. The ideal treatment for these patients seems to be the rescue therapy with MMF.
REFERENCES 1. European 344:423, 1994
FK 506 Multicentre
2. The U.S. Multicenter .I Med 331:1110, 1994
Liver Study Group: Lancet
FK506 Liver Study Group: N Engl
3. Platz K-P, Mueller AR, Zytowski M, et al: Transplant Proc 27:1111, 1995 4. Neuhaus P, Blumhardt G, Bechstein WO, et al: Transplantation 59:31, 1995 5. Freese DK, Snover DC, Sharp HL, et al: Hepatology 13882, 1991
2874 6. Snover DC, Freese DK, Sharp HC, et al: Am J Surg Path01 ll:l, 1987 7. Demetris AJ, Qquian S, Sun A, et al: Am J Surg Path01 14(suppl 1):49, 1990 8. Demetris AJ, Fung JJ, Todo S, et al: Transplantation 53:1056, 1992
PIATZ,
MUELLER, NEUHAUS
ET AL
9. McDiarmid SV, KIintmalm GB, Busutill RW: Transplant Int 6:305, 1993 10. Winkler M, Ringe B, Jost U, et al: Transplant Int 6:319, 1993 11. Platz K-P, Mueller AR, Zytowski M, et al: World J Surg 20:1052, 1996