Mycophenolate Mofetil in Lung Transplantation

MYCOPHENOLATE

Mycophenolate Mofetil in Lung Transplantation A. Zuckermann, T. Birsan, S. Thaghavi, O. Artemiou, N. Kupilik, G. Dekan, E. Wolner, and W. Klepetko

M

YCOPHENOLATE Mofetil (MMF) is a semisynthetic derivate of the antimetabolite mycophenolic acid. MMF is a potent, non-competitive, reversible inhibitor of the enzyme inosine monophosphate dehydrogenase, thus a selective suppressor of proliferation of both T and B lymphocytes.1 In clinical transplantation it was shown that MMF decreased the incidence of acute rejection in renal and cardiac transplantation.2– 4 At the University of Vienna, MMF has been used since December 1995. The purpose of this work is to report on preliminary experience in lung transplanted patients with MMF as initial immunosuppression (IG) and long-term patients who were switched from azathioprine (AzA) to MMF (SG). PATIENTS AND METHODS Patient Groups The initial group (IG) consisted of 27 patients who were prospectively entered into this study from December 1995 to June 1997. This group consisted of 16 males and 11 females. Average age at time of transplantation was 42.4 6 15.1 (range, 14 – 65) years and four patients (15%) were intubated and in an intensive care unit prior to transplantation. The indications for transplantation were emphysema (n 5 11), cystic fibrosis (n 5 3), primary pulmonary hypertension (n 5 3), idiopathic primary fibrosis (n 5 7), and other (n 5 3). Five patients had previous thoracic operations. Median follow up of these 27 patients was 17 months (range, 6 –24) as of December 1997. No attempt was made to selectively enroll patients in this study based on severity of illness or preoperative status. The switch group (SG) comprised 23 lung-transplanted patients who were switched from azathioprine to MMF between June 1996 and June 1997. Patients were switched 35 6 14 (range, 13– 67) months after transplantation. The group consisted of 8 males and 15 females. Average age at time of switch was 43.2 6 11.5 (range, 20 –57) years. The indications for transplantation were emphysema

(n 5 7), idiopathic primary fibrosis (n 5 5), cystic fibrosis (n 5 1), pulmonary hypertension (n 5 7), and other (n 5 3). Three patients were in long-term follow-up after retransplantation. Median follow up of these 23 patients was 14 months (range, 1–21) as of December 1997. Reasons for switch were cyclosporine (CyA)induced nephropathy (n 5 17) and electively (n 5 6).

Immunosuppressive Therapy In the primary group MMF was administered at a dosage of 2 g/d in two divided doses. During postoperative intubation, MMF was given via a gastric tube. In the switch group, patients were switched from Aza (1.5 mg/kg/d) to MMF (1 g/d in two divided doses). In case of adverse events, MMF was reduced or temporarily discontinued in both groups. All patients in the primary group received ATG induction therapy (Thymoglobuline, Sero-Merieux) during the first 7 days after transplantation. Both patient groups received cyclosporine A and prednisolone as part of a triple drug immunosuppressive maintenance therapy.

Other Agents All primary patients were placed on prophylactic trimetoprim/ sulfametoxalone, nystatin, and gancyclovir. Switch patients received lifelong trimetoprim/sulfametoxalone prophylaxis.

Monitoring of Rejection Rejection of the allograft was assessed by chest x-ray, spirometry, and biopsy.5 Histologic confirmation of at least ISHLT rejection grade A2 by transbronchial biopsy (TBB) was required except for From the Department of Cardiothoracic Surgery, and Department of Pathology, University of Vienna, Vienna, Austria. Address reprint requests to Dr A. Zuckermann, University of Vienna, Department of Cardiothoracic Surgery, Wahringer Gurtel 18-20, A-1090 Vienna, Austria.

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Transplantation Proceedings, 30, 1514–1516 (1998)

MMF IN LUNG TRANSPLANTATION patients with early radiographic infiltrates that responded promptly to methylprednisolone. Surveillance TBBs were performed at 1, 2, 3, 6, and 12 months after transplantation or when clinically indicated. After the first postoperative year, TBBs were performed every 6 months.

Monitoring of Infection Bacterial and fungal cultures were done from donor and recipient bronchus, weekly from urine, sputum, and from every bronchial lavage. Cytomegalovirus (CMV) screening was performed by weekly measurement of CMV serology and detection of CMV early antigen in blood, urine, throat wash, and every lavage. PCR for toxoplasmosis and PCP was performed with each BAL. TBBs were also histologically screened for CMV, PCP, toxoplasmosis, and bacterial or invasive fungal infection.

Statistical Analysis Changes in creatinine levels after switch were compared to preswitch levels by paired t test.

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In the switch group, two major infections were seen. Both patients developed bacterial pneumonia 3 and 4 months after switch. One responded to antibiotic therapy, while the other was fatal. Viral infection made up the main part of all infections in the SG (67%). Viruses involved were either herpes simplex (n 5 6) or herpes zoster (n 5 3). Two patients were positive for Aspergillus in bronchial lavages and were treated with amphotericin for 2 weeks. Lung Function

All IG patients surviving the first year were in BOS stage 0 (ISHLT grading). Twelve-month TBBs in these patients did not show any histologic signs of BO. Six patients had follow up times of over 20 months. Of these patients, only one developed BO (BOS stage 1) at month 20. This patient had one rejection episode and a CMV infection during the first 6 months after transplantation. Switch Therapy

RESULTS Survival

Six-month and 1-year survival in the IG were 84% and 67% respectively. There were no intraoperative deaths. Seventyone percent (n 5 5) of all deaths during the first year after transplantation were due to infectious complications. In the SG, two patients died. The first patient died of infectious complications 3 months after switch and the other died of multi-organ failure 13 months after switch. Rejection

At 6 months posttransplantation there were eight episodes of rejection in six patients of the IG. Beyond 6 months, there were two episodes (months 8 and 10) of rejection in a patient who had no prior rejection and one in a patient with a prior episode of rejection. The mean number of acute rejections in the IG at 6 months was 0.31 6 0.62 per patient. Transbronchial biopsy results higher than grade 2A ISHLT were seen in 10% of the cases. The actual freedom from rejection at 6 and 12 months was 77% and 70%. Rejection episodes were routinely treated methylprednisolone, 1 g IV daily, for 3 consecutive days. In one patient a steroid-resistant rejection occurred which was treated with a 10-day course of OKT3 (5 mg/d). Infection

During the first 6 months after transplantation, the mean number of infections was 1.04 6 0.21 per patient. Most were bacterial infections (0.59 6 0.14 per patient), followed by viral infections (0.26 6 0.10 per patient), and fungal infections (0.19 6 0.08 per patient). Pulmonary and respiratory tract infections made up the main part of infectious complications (66.7%). Although CMV was the most frequent viral infection in the IG (58%), CMV disease was only seen in one case. This patient stopped gancyclovir therapy 7 days after testing CMV early antigen positive in the blood.

Twenty-three lung-transplanted patients were switched from azathioprine to MMF more than 1 year after transplantation. Most patients (n 5 17) were switched to MMF due to CyA-induced nephropathy (creatinine . 2.0 mg/dL). After the switch patients were stepwise lowered in their CyA dosage to achieve CyA levels of # 150 ng/mL. At time of switch patients had mean creatinine levels of 2.51 6 0.64 mg/dL and CyA levels of 192.0 6 72.5 ng/mL. Two patients had to be discontinued from MMF due to massive side effects and were excluded. Two more patients did not benefit from CyA dosage reduction and developed endstage renal failure requiring hemodialysis. At time of longest follow up (13.9 6 5.7 months post-switch), mean creatinine was 1.77 6 0.33 (P 5 .002) with mean CyA levels of 120.4 6 29.8 (P 5 .003). Six more patients were switched electively from AzA to MMF. No attempts to lower CyA dosages were made in this population. All patients had creatinine levels below 2.0 mg/dL at time of switch and remained so at 14.2 6 0.4 months follow up. In the whole switch group only one episode of rejection ocurred during the time of follow up in a patient switched for nephropathy. Pathohistologic examination of a routine TBB 6 months after switch revealed a rejection grade A2 without any worsening in lung function testing. The patient underwent rejection treatment (steroid bolus therapy for 3 days) and remained rejection-free for the remainder of follow-up. All patients in either switch group did not change in their BOS grading during the whole time of follow up. Adverse Events and Side Effects

Both patients groups had a similar number of adverse events. Twelve events in 10 patients (37%) were seen in the initial group compared to 12 events in 8 patients (35%). In the initial group there were more cases of leukopenia (n 5 7; 58% of adverse events) than in the switch group (n 5 1; 8%). Most leukopenic events were in the first week after

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transplantation in combination with ATG and gancyclovir therapy. There was also one case of combined thrombocytopenia with leukopenia in the initial group 3 months after anti-rejection therapy with OKT3. In contrast to hematologic changes, the number of gastrointestinal events (nausea, diarrhea) was lower in the initial group (n 5 3; 25%) compared to the switch group (n 5 7; 58%). Most of the patients with gastrointestinal side effects in the switch group had also blood pressure elevations and/or rashes. In two of these patients, MMF therapy had to be switched back to AzA. In most other cases (initial and switch) dose reduction or temporary discontinuation of MMF helped to overcome side effects. One initial group patient developed PTLD (EBV-associated, polyclonal) 4 months after transplantation. The patients received CyA dosage reduction, acyclovir therapy, and succeeding chemotherapy. During chemotherapy MMF was discontinued. The patient is now 6 months after chemotherapy with complete remission of PTLD. DISCUSSION

These preliminary results with MMF in combination with CyA and low-dose steroid immunosuppression holds tremendous promise as for the future. Clearly, the most important finding of this study was a much lower incidence of acute rejections (overall and biopsy proven) in MMFtreated patients compared to a historical patient cohort at the University of Vienna. Three prospective randomized trials in kidney-transplanted patients showed a significant decrease of clinical and biopsy-proven rejection episodes in MMF treated patients compared to either AzA or placebo treated patients during the first 6 months after transplantation.2– 4 Although 1-year graft survival did not differ between the study groups, MMF-treated patients remained more rejection free and had a better renal function. Results of a prospective randomized trial in cardiac transplantation comparing MMF to AzA showed similar results (results presented at the 17th Annual Meeting of the ISHLT). Acute rejection episodes are the strongest known risk factor for the development of BO (chronic rejection).6 BO, on the other hand, is the most significant long-term cause of morbidity and mortality after lung transplantation. In two pathohistologic studies, Yousem et al.7 found that patients with a higher degree of small airway injury were more prone to BO than others and that patients who worsened after untreated mild rejection episodes developed BO in 50% of cases. Bando et al.8 showed that higher histologic grading and more than three rejection episodes were risk factors for progression of BO.8 In an analysis of 126 recipients of heart–lung allografts, Sharples et al.9 demonstrated that the

ZUCKERMAN, BIRSAN, THAGHAVI ET AL

number of acute rejections in the early phase after transplantation is the most important determinant for development of BO. This finding is in accordance with our data showing a low incidence of BO 1 and 2 years after transplantation. Although MMF seemed to be a more potent immunosuppressive agent, there was no increase in infectious complications in these patients. Another added advantage of MMF is the flexibility it introduces to immunosuppressive management for long term patients. Patients with CyA-induced nephropathy were able to be decreased to significantly lower CyA levels after switching to MMF. These patients had neither a higher rate of acute rejections nor an increase of BO as long as 12 months after switch. This could be obtained with a lower MMF dosage than in kidney and heart studies. Despite the excellent general tolerance by most patients, MMF had to be discontinued in two long-term patients. Both experienced massive gastrointestinal side effects (nausea) combined with hypertonia and rashes. In other patients, dosage reduction helped to reduce side effects. Gastrointestinal side effects could especially be overcome by this approach. Leukopenia in initial patients mostly during the first week in combination with ATG and gancyclovir. As both agents have myelosuppressive side effects, leukopenia was not clearly attributable to MMF alone. In summary, this study shows that MMF is a highly effective new immunosuppressive drug for the prevention of early acute rejection as well as a safe drug to optimize immunosuppression in long-term lung-transplanted patients. MMF appears to have side effects that can be managed easily. Long-term follow-up will be necessary to prove eventual protective effect of MMF against BO. REFERENCES 1. Eugui EM, Almquist SJ, Muller CD, et al: Scand J Immunol 33:161, 1991 2. Sollinger HW, for the U.S. Renal Transplant Mycophenolate Mofetil Study Group: Transplantation 60:225, 1995 3. The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group: Transplantation 61:1029, 1996 4. European Mycophenolate Mofetil Cooperative Study Group: Lancet 345:1321, 1995 5. Yousem SA, Berry GJ, Cagle PT, et al: J Heart Lung Transplant 15:1, 1996 6. Paradis IL, Yousem SA, Griffith BP: In: King TE (ed): Clinics in Chest Medicine. Philadelphia, Penn: Saunders; 1993, p 751 7. Yousem SA, Dauber JA, Keenan R, et al: Transplantation 52:306, 1991 8. Bando K, Paradis IL, Komatsu K, et al: J Thorac Cardiovasc Surg 109:49, 1995 9. Sharples LD, Tamm M, McNeil, et al: Transplantation 61: 560, 1996