TRANSPLANTATION Vol. 65, 235–241, No. 2, January 27, 1998
Copyright © 1998 by Williams & Wilkins Printed in U.S.A.
MYCOPHENOLATE MOFETIL FOR THE TREATMENT OF A FIRST
ACUTE RENAL ALLOGRAFT REJECTION
T
HEM
YCOPHENOLATEM
OFETILA
CUTER
ENALR
EJECTIONS
TUDYG
ROUP1,2,3Indiana University Medical Center; Albany Medical College; Montefiore Medical Center, Albert Einstein College of Medicine; California Pacific Medical Center; University of California-Los Angeles Medical Center; Columbia Presbyterian Medical Hospital; University Hospital, University of Western Ontario; University of Wisconsin-Madison; University of California, San Francisco Medical Center; Boston University Medical Center; University of Alabama; Ohio State University; Baylor University Medical Center; Austin Diagnostic Medical Center; Vancouver General Hospital; and Roche Global Development Background.Mycophenolate mofetil (MMF)
signifi-cantly reduces the incidence of acute allograft rejec-tion in renal transplant patients. The effect of adding MMF to the immunosuppressive regimen of patients with established rejection is unknown. The purpose of the current study was to compare the safety and effi-cacy of the addition of MMF to the treatment regimen of an early first acute cellular rejection.
Methods. The study was a blind, double-dummy controlled clinical trial of 221 renal transplant recipients experiencing the first biopsy-proven rejec-tion within 6 months of transplant performed at 15 U.S. and Canadian centers. A total of 113 patients re-ceived MMF (1.5 g twice daily) and intravenous corti-costeroids, and 108 patients received azathioprine (AZA) (1–2 mg/kg/day) and intravenous corticoste-roids. The intravenous corticosteroids in each group consisted of 5 mg/kg/day for 5 days followed by an oral steroid taper. End points for the study were the first use of antilymphocyte therapy, the number of courses of antirejection therapy given during the first 6 months, and graft and patient survival at 1 year.
Results.At 6 months, 16.8% of the MMF-treated pa-tients and 41.7% of the AZA-treated papa-tients required at least one course of antilymphocyte therapy (P<0.0001). The number of patients requiring full courses of antirejection therapy for the treatment of rejection was less in the MMF-treated group (24.8%)
versus the AZA-treated group (58.3%) (P<0.0001). The proportion of patients with the use of antilymphocyte therapy or treatment failure during the first 6 months was 29.2% vs. 51.9% (P50.0006) in the MMF versus the AZA groups, respectively. By 1 year after enrollment, 10 patients (8.9%) in the MMF-treated group lost their graft or died versus 16 patients (14.8%) in the AZA-treated group. More patients in the MMF group with-drew because of an adverse event: 20 patients (17.7%) compared with 11 AZA-treated patients (10.2%).
Conclusions. MMF administered in combination with pulse corticosteroids significantly decreases the subsequent use of antilymphocyte therapy in the treatment of acute renal allograft rejection. In addi-tion to being a safe and effective prophylactic agent, MMF added to steroids improves the rate of reversal of acute rejection episodes.
The results of three multicenter trials has led to the regu-latory approval of mycophenolate mofetil (MMF*) for the prevention of renal allograft rejection in man (1–3). These studies have proven the efficacy of MMF, at either 1 g or 1.5 g b.i.d., to significantly reduce the incidence of renal allograft rejection. The major side effects seen in these studies were gastrointestinal (diarrhea and dyspepsia) and hematologic (leukopenia). Based on the combined safety and efficacy data, the recommended dose for most patients is 1 g b.i.d.
MMF achieves it immunosuppressive activity through its active portion, mycophenolic acid (MPA) (4). MPA is a potent and specific inhibitor of the de novo purine synthesis path-way (5). Intracellularly, MPA binds to and uncompetitively and reversibly inhibits inosine monophosphate dehydroge-nase. This, in turn, blocks the generation of guanosine nu-cleotides and subsequently both T-cell and B-cell prolifera-tion (5–7). In preliminary animal experiments, MMF was shown to prevent development of acute rejection (8 –10). Of further interest in a canine model, when administration of MMF was delayed until rejection was established, MMF ac-tually led to a reversal of the rejection (11). Both in vitro and in vivo, MMF has been shown to have inhibitory effects on proliferative vascular changes. These changes are analogous to the vascular pathology seen in chronically rejecting human allografts. The mechanism of chronic rejection is still under investigation, but both humoral and cellular immune mech-anisms seem to be involved (12). MMF has been shown to
1Presented at the 23rd Annual Meeting of the American Society of
Transplant Surgeons, May 14 –16, 1997, Chicago, IL.
2The members of the study group are:Dr. Mark D. Pescovitz,
Indiana University Medical Center; Dr. D. Conti, Albany Medical College; Dr. S. M. Greenstein, Montefiore Medical Center, Albert Einstein College of Medicine; Dr. S. Inokuchi, California Pacific Medical Center; Dr. J. Rosenthal, University of California-Los An-geles Medical Center; Dr. D. Cohen, Columbia Presbyterian Medical Hospital; Dr. C. Stiller, University Hospital, University of Western Ontario; Dr. J. Pirsch, University of Wisconsin-Madison; Dr. Ste-phen Tomlanovich, University of California, San Francisco Medical Center; Dr. Sang Cho, Boston University Medical Center; Dr. Mark Deierhoi, University of Alabama; Dr. Ronald Ferguson, Ohio State University; Dr. Thomas Gonwa, Baylor University Medical Center; Dr. Ernest Hodge, Austin Diagnostic Medical Center; Dr. P.A. Keown, Vancouver General Hospital; Dr. Eleanor Ramos, Roche Global Development; and Dr. Mercidita T. Navarro, Roche Global Development.
3Address correspondence to: Mark D. Pescovitz, MD, Indiana
University Medical Center, Department of Surgery, Transplant Sec-tion, University Hospital, Room 4258, 550 N. University Blvd., In-dianapolis, IN 46202-5250.
* Abbreviations: ANOVA, analysis of variance; AZA, azathioprine; CMV, cytomegalovirus; CsA, cyclosporine; MMF, mycophenolate mofetil; MPA, mycophenolic acid.
block antibody formation both in vitro (7) and more recently in man (13). These attributes of MMF suggest that it might be an effective drug to treat acute rejection and prevent chronic rejection.
A single acute renal allograft rejection has been shown to be predictive for the development of chronic rejection and subsequent graft loss (14,15). Furthermore, the development of recurrent rejections leads to an even worse prognosis for long-term graft survival (16). Aggressive treatment of a first acute rejection with the more potent immunosuppressive OKT3, as opposed to steroids, resulted in better graft sur-vival over 2 years (17). In a previously reported trial, the open-label use of 1.5 g b.i.d. of MMF in comparison to steroids for the treatment of refractory acute rejection demonstrated a 45% reduction in graft loss or patient death in the MMF group and nearly half the number of recurrent rejections at 6 months (18).
The purpose of the current randomized double-blind study was to compare the safety and efficacy of the addition of MMF to the treatment regimen of an early first acute cellular rejection. The end points were the first use of antilymphocyte therapy, the number of courses of antirejection therapy given during the first 6 months, and graft and patient survival at 1 year. Because acute rejection is such a strong predictor of subsequent chronic rejection, this study will, over the long term, be a test of the ability of MMF to prevent the develop-ment of chronic rejection.
MATERIALS AND METHODS
Study design. This study was a randomized, controlled, double-blind trial of first or second renal transplant recipients to be con-ducted in two phases over 3 years. In phase I, patients with a biopsy-proven rejection at least 7 days, but no more than 6 months, after transplant were randomized to receive MMF and intravenous corticosteroids or azathioprine (AZA) and intravenous corticosteroids as rejection treatment. The study drugs, MMF or AZA, were admin-istered in a double-blind manner. Primary efficacy was evaluated after 6 months of treatment, comparing the proportions of patients in each group who required antilymphocyte therapy for continued (i.e., refractory to corticosteroids) or recurrent rejection. Patients contin-ued in phase I until they had received blinded study medication for at least 1 year. This permitted an unbiased assessment of safety and 1-year patient and graft survival. This interim analysis was per-formed after all patients had reached 1 year of follow up.
In phase II, patients who completed phase I were then provided open label medication. They continue on their respective study drug assignment for the remainder of the 3-year trial. Long-term safety and graft and patient survival will then be assessed. At the time of this report, all patients have completed phase I of the trial; phase II is still ongoing. The study was conducted at 15 centers in North America, with patients enrolled between November 1991 and De-cember 1994. There were 221 patients, overall, enrolled in the trial.
Inclusion/exclusion criteria. Patients older than 18 years with biopsy-proven acute cellular rejection at least 7 days, but no more than 6 months, after the receipt of a first or second transplant from a cadaveric or living nonrelated renal allograft donor were eligible for the study. Only rejection episodes considered appropriate for treatment with intravenous corticosteroids were allowed. Patients were required to have established renal function after transplant, as evidenced by a falling serum creatinine; the serum creatinine must have been less than 5 mg/dl at the time of study entry. Patients were not allowed to have received antilymphocyte antibody induction therapy in the 24 hr preceding the start of treatment. Patients could not have undergone dialysis for 3 days before the entry biopsy. Cyclosporine (CsA) must have been started before study entry.
Women must have had a negative serum pregnancy test. Exclusion criteria included: receiving more than one dose of intravenous corti-costeroids for presumptive or biopsy-proven rejection at any time before study entry; pregnant, nursing, or unwilling to use adequate contraceptive therapy; severe infections requiring antimicrobial therapy; serologic evidence of HTLV-1, human immunodeficiency virus, or hepatitis B surface antigen infections; severe leukopenia (white blood cell count ,2500/mm3); thrombocytopenia (platelet
count ,100,000/mm3); a hemoglobin ,6 g/dl; active peptic ulcer
disease; severe diarrhea; a history of malignancy, except for ade-quately treated skin cancer; and the need for other investigational drugs. Written informed consent was obtained from each patient after the protocol had been approved by each local institutional review board.
Treatment plan.Patients who met the above inclusion criteria and not the exclusion criteria and who signed the informed consent were enrolled in the study. They were equally randomized into two groups, stratifying at each center on the basis of first or second renal al-lograft. Patients were issued two study medications dispensed as capsules containing either MMF and placebo or AZA and placebo. Patients did not receive both AZA and MMF. All patients were initially dosed with six (250 mg each) MMF or matched placebo capsules twice a day, given one-half hour before breakfast and again 12 hr later. The patients were dosed each evening with AZA (50 mg each) or matched placebo capsules at 1–2 mg/kg per day. The first dose of study medication was dispensed on the day of randomization or the following day. Patients were considered noncompliant with study medication if they were regularly taking less than 80% of their study medication, as determined on a monthly basis.
In conjunction with the randomly assigned study medication, all patients received intravenous corticosteroids at a dose of 5 mg/kg per day for 5 days. After the intravenous course, patients received a 5-day oral corticosteroid taper of 100 mg q.d., 80 mg q.d., 60 mg q.d., 40 mg q.d., and 20 mg q.d. or baseline (the dose immediately before the entry rejection). Subsequent rejections treated with steroid ther-apy used the same taper. During phase I, the minimum steroid dose allowed was 10 mg per day. CsA, as the Sandimmune formulation (Sandoz, East Hanover, NJ), was used in all patients; target levels and assay method were established at each center. CsA dose was modified by the investigator as needed for toxicity or other adverse events.
Patients who reached 1 year were then unblinded as to study assignment. During phase II, they were maintained only on the active study drug at the same dose as at the completion of phase I.
Study end points.The primary objective of this study was to compare the efficacy of MMF versus AZA as adjunctive therapy for the treatment of acute renal allograft rejection by determining the proportion of patients in the two study groups who required anti-lymphocyte therapy in the first 6 months after transplant. Patients were required to have a repeat biopsy of the kidney (i.e., after the biopsy that was required to qualify for enrollment into the trial) before initiation of antilymphocyte therapy. The biopsy was read by the local pathologist for evidence of acute cellular rejection, acute vascular rejection, or CsA nephrotoxicity. OKT3 was the preferred medication for treatment of the rejection, however, antilymphocyte therapy with other agents was allowed if OKT3 was contraindicated. Treatment with antilymphocyte therapy was not permitted during the 5-day course of intravenous corticosteroid therapy. If treatment of rejection was required in the 14 days immediately after the initial intravenous steroids, antilymphocyte therapy was specified by pro-tocol for treatment. Beyond the 14-day interval, the use of intrave-nous corticosteroids or antilymphocyte therapy was left to the dis-cretion of the investigator. Other than the biopsy required to document the first rejection after study enrollment (i.e., the primary end point), subsequent rejections did not require biopsy documenta-tion. Because of this, subsequent rejection episodes were defined by the courses of antirejection treatment that the patient received. For the purpose of the study, a full course of treatment was defined as
the use of at least a single dose of antilymphocyte therapy or at least 3 days of corticosteroids at a total cumulative dose of at least 600 mg. Secondary end points included: patient and graft survival at 1, 2, and 3 years after study enrollment; recurrent biopsy-proven rejec-tions and the number of patients who required late biopsies; renal function at 6 months and between 12 and 36 months; the number of courses of antirejection therapy defined as at least 3 days of intra-venous corticosteroids or 5 days of antilymphocyte therapy; the oral steroid and CsA doses and levels at various time points; and, lastly, the number of days of hospitalizations and outpatient visits during the first 6 months of treatment. Graft loss was defined as transplant nephrectomy, retransplantation, dialysis for at least 4 consecutive weeks, patient death, or the patient receiving dialysis at the final study visit.
Late biopsies to document the development of chronic rejection were obtained between 6 and 36 months if there was a consistent increase in serum creatinine of at least 1-month duration that was 25–99% above baseline (the baseline serum creatinine was estab-lished as the average of the two lowest values during the first 6 months after transplant). An additional core biopsy was required if there was a consistent increase in serum creatinine of at least 1-month duration of 100% or more above baseline. Additional core biopsies were obtained at the discretion of the investigator for pre-sumptive chronic rejection.
During phase I, study visits were scheduled at weeks 2 and 4, and at months 2, 3, 4, 6, 8, 10, and 12 after enrollment. At these visits, laboratory tests were performed, as were assessment of adverse events, rejection, opportunistic infections, or malignancies. Labora-tory assessments included a complete blood count with differential and platelet count. The chemistry panel included blood urea nitro-gen, serum creatinine, serum glutamic-oxaloacetic transaminase, serum glutamic-pyruvic transaminase, calcium, phosphorous, total and direct bilirubin, total protein, albumin, glucose, alkaline phos-phatase, lactate dehydrogenase, cholesterol, triglycerides, uric acid, chloride, CO2, potassium, and sodium. Creatinine clearances were
calculated using the Cockcroft-Gault formula at 6 and 12 months. During phase II, study visits were scheduled at 6-month intervals until 3 years after enrollment. The patients had continued observa-tion for adverse events, rejecobserva-tions, opportunistic infecobserva-tions, malig-nancies, and renal function. Patients who terminated prematurely had follow up every 6 months for patient and graft survival and development of malignancies, extending until the patient either died, had been off all immunosuppressive therapy for 1 year, or was 3 years from the date of enrollment.
Dose adjustments.Patients assigned to MMF were to receive 1500 mg b.i.d. for the duration of the study, unless dosing modifica-tion was required for an adverse event. AZA was dosed at 1–2 mg/kg, according to the center-specific practice. In the event of an adverse event that required dosage adjustments, both study drugs were decreased. MMF/placebo study drug was decreased by half to three capsules (750 mg b.i.d.), and the AZA was similarly reduced. In the event of an adverse event that required dose interruption, study drugs could be restarted after discussion with the study sponsor. CsA and oral corticosteroid doses were adjusted based on center-specific criteria. During phase I, steroids were not to decrease below 10 mg per day; in phase II, there was no lower limit for steroid dosing.
Adverse events.At baseline and at each study visit, patients were assessed for the development of adverse events, opportunistic infec-tions, and malignancies. An adverse event was defined as an abnor-mal change in physical findings, symptomatology, or laboratory test values, whether or not it was deemed to be caused by study medica-tion. The severity was graded on a five-point scale and assessed for the probability of relationship to study medication. All adverse events were monitored until resolved or until the clinical outcome was ascertained.
Statistical methods. The primary efficacy end point was first use of antilymphocyte therapy or treatment failure during the first 6 months after enrollment. Treatment failure was defined as graft
loss, death, or premature withdrawal from the study without prior use of antilymphocyte therapy. The primary analysis was performed using the Cochran Mantel-Haenszel general association test, strati-fied by investigator with the five smallest sites (entering less than seven patients per site) pooled (19). The Mantel-Haenszel estimates of relative risk and odds ratio were prepared along with associated 95% confidence intervals. Cumulative incidence of first use of anti-lymphocyte therapy or treatment failure was summarized using Kaplan-Meier estimates.
Comparability of the treatment groups at baseline with respect to continuous variables such as donor age, weight, and cold ischemic time was assessed using a two-factor analysis of variance (ANOVA) with effects for treatment, center, and treatment-by-center interac-tion. Comparability of categorical data such as gender and race was evaluated using the Cochran Mantel-Haenszel general association test.
Cumulative incidence of graft loss or patient death and the 95% confidence intervals for the difference in cumulative proportions at 12 months were prepared using Kaplan-Meier estimates. The num-ber of patients requiring additional full courses of antirejection ther-apy after the initial course of intravenous corticosteroids was sum-marized descriptively. For the purpose of this summary, a full course of antirejection therapy was defined as: (a) at least 3 days of corti-costeroids and a total cumulative dose of at least 600 mg or (b) at least one dose of OKT3, antithymocyte globulin, or antilymphocytic globulin. CsA trough concentrations at 6 and 12 months after enroll-ment were summarized using standardized levels, in view of the fact that investigators reported results according to the assay methods used at their respective sites. Each value of CsA trough concentra-tion was standardized as the ratio of the reported value to the midpoint of the reference range. Maintenance doses of corticoste-roids, expressed in methylprednisolone equivalents, and mainte-nance doses of CsA at 6 and 12 months after enrollment were analyzed using ANOVA with effects for treatment, center, and treat-ment-by-center interaction. Serum creatinine concentrations at each visit during the first 12 months after enrollment were analyzed using a similar ANOVA model. Descriptive summaries of safety data in-cluded all available data as of the data cutoff date and were not limited to the 12-month postenrollment period specified for the effi-cacy analyses.
RESULTS
Two hundred and twenty-one patients were enrolled in the study: 108 of these were assigned AZA and 113 were assigned MMF. All patients assigned to the study received study drug. At baseline, both treatment groups were well balanced and comparable with respect to age, gender, race, cause of renal failure, panel reactive antibody, HLA mismatches, renal function (as measured by serum creatinine), histologic grad-ing of the severity of rejection, time posttransplant at study entry, distribution of first and second transplants, and donor/ recipient cytomegalovirus (CMV) status (Table 1). During the time in which the study was conducted, MMF was investiga-tional so that no patient was receiving MMF at the time of study enrollment. Data were not routinely collected on the use of AZA or the steroid dose at the time of study enrollment nor on the use of induction therapy at the time of transplan-tation. In addition, donor age and cold ischemia time at the time of transplant were similar. Eleven patients (five AZA treated and six MMF treated) needed to be dialyzed in the first week after transplantation. At this interim analysis, 29% (n531) and 65% (n573) of AZA-treated versus MMF-treated patients were still on study. The overall premature withdrawal rate was higher in the AZA arm than the MMF arm (42.6% vs. 33.6%). The excess withdrawals in the AZA
arm were primarily for unsatisfactory therapeutic response (17.6% vs. 1.8%). More patients in the MMF arm were with-drawn for an adverse event (10.2% vs. 17.7%). Withdrawal for noncompliance was similar (4.6% vs. 5.3%, AZA vs. MMF).
First use of antilymphocyte therapy or treatment failure.
Treatment with MMF resulted in a significant reduction in the first use of antilymphocyte therapy or treatment failure during the first 6 months of study from 51.9% in the AZA arm to 29.2% in the MMF arm (P50.0006) (Table 2). In addition to the significant difference in the composite end point, there was also a highly significant reduction in the first use of OKT3 in MMF-treated patients (41.7% vs. 16.8%,P,0.0001). Figure 1 shows the cumulative incidence of first use of antilymphocyte therapy or treatment failure during the first 6 months. The difference between the two groups was
appar-ent within the first month after study enrollmappar-ent and per-sisted throughout the 6-month study period. Figure 2 shows the graft and patient survival during the first 12 months after enrollment. Ten patients (8.9%) in the MMF group died or lost their graft, as compared with 16 patients (14.8%) in the AZA group, a difference of 5.9% (95% confidence interval:
22.6% to 14.5%). Of the 10 MMF patients, 6 grafts were lost from rejection, 1 was lost after cessation of therapy because TABLE 1. Baseline demographics of study population
Parameter AZA (n5108) MMF (n5113) Age (yr, mean6SD) 43.7611.7 43.1611.6 Gender % male (% female) 59.3 (40.7) 63.7 (36.3) Race (%) White 68.5 67.3 Black 21.3 19.5 Asian 6.5 1.8 Hispanic 1.9 8.8 Other 1.9 2.7
Cause of renal failure (%)
Glomerulonephritis 14 25 Diabetes 25 24 Hypertension 12 11 % Panel-reactive antibody (% of patients) ,20% 90 89 $20% 11 11 HLA mismatch (n) 0 5 3 1 4 6 2 6 9 3 22 19 4 35 33 5 25 28 6 10 15 Transplant no. (n) First 94 103 Second 14 10
Time since transplant (days, mean6SD) 32.4622.1 33.2631.4 Serum creatinine at entry (mg/dl, mean6SD) 2.8860.14 2.9460.15 Rejection grade (%) Minimal 3 1 Mild 43 45 Moderate 42 45 Severe 12 9 CMV status donor/recipient (%) Positive/negative 30 24 Positive/positive 39 43 Negative/positive 14 20 Negative/negative 17 14
TABLE 2. First use of antilymphocyte therapy (ALS) or treatment failure during the first 6 months in the study
AZA (n5108) MMF (n5113) First use of ALS or treatment failure 56 (51.9)a 33 (29.2) First use of ALS 45 (41.7)b 19 (16.8)
Graft loss or death 4 (3.7) 2 (1.8)
Other treatment failure 7 (6.5) 12 (10.6) Unsatisfactory response 2 (1.9) 0
Adverse event 1 (0.9) 9 (8.0)
Noncompliance 1 (0.9) 1 (0.9)
Other reason 3 (2.8) 2 (1.8)
an, (%);P50.0006 between AZA and MMF treatment arms. bP,0.0001 between AZA and MMF treatment arms.
FIGURE 1. Kaplan-Meier estimates of the cumulative incidence of first use of antilymphocyte antibody or treatment failure during the first 6 months of the study: AZA at 1–2 mg/kg/day (n5108) (OO); MMF at 1.5 g b.i.d. (n5113) (- - - - -).
FIGURE 2. Kaplan-Meier estimates of graft and patient survival dur-ing the first year after enrollment: AZA at 1–2 mg/kg/day (n5108) (OO); MMF at 1.5 g b.i.d. (n5113) (- - - - -).
of an opportunistic infection, and 3 patients died with func-tioning grafts. Of the 16 AZA patients, 12 grafts were lost from rejection, 2 from technical problems, and 2 patients died with functioning grafts.
Table 3 summarizes the number of patients receiving full courses of immunosuppression administered after the initial treatment during the first 6 months in the study. As was seen with the use of antilymphocyte therapy, MMF resulted in less need for additional courses of corticosteroids. Seven AZA and 11 MMF patients terminated from the study before 6 months without having the need for additional full courses of antirejection therapy after the initial course. Even if these patients are included with those who required additional courses, then MMF use still resulted in significantly fewer courses of antirejection therapy (P,0.0001).
Renal function. The degree of renal function was deter-mined by two methods after study enrollment. At all time points until the 1-year visit, the serum creatinine in the MMF-treated group was numerically lower than the AZA-treated group (Fig. 3,P5NS). For those patients still being followed within the confines of the study, estimated creati-nine clearance was calculated at both 6 and 12 months after enrollment. Both at 6 months (56.8 ml/min vs. 52.8 ml/min, MMF vs. AZA) and at 12 months (62.5 ml/min vs. 59.9 ml/ min) the patients in the MMF had better function, although at neither time point was this statistically significant.
Maintenance immunosuppression. The patients were al-lowed to have dose adjustments for toxicity and therefore received either 1500 mg b.i.d., 750 mg b.i.d., or no MMF each day. The average amounts actually received during the trial are shown (Table 4). On average, the patients in the MMF group received nearly the entire 3 g/day dose. The mainte-nance corticosteroid and CsA doses, as well as normalized CsA levels during the study, were comparable at 6 and 12 months.
Safety. All of the MMF-treated patients and 98% of the AZA-treated patients had an adverse event. Within the MMF group, 94.7% (n5107) had an adverse event thought possibly or probably related to study drug, which was slightly more than in the AZA group (81.5%, n588). Fewer patients had a severe adverse event (69.9%, n579, MMF vs. 72.2%, n578, AZA). Some of the more commonly reported adverse events are summarized (Table 5). The type and incidence of the selected opportunistic infections are listed (Table 6). Among the patients at high risk to develop CMV (i.e., donor positive/ recipient negative), 12 of 32 (37.5%) in the AZA group and 11 of 26 (42.3%) in the MMF group developed CMV disease while in the study.
Malignancies were rare during this 1-year interim study
analysis. Two patients in the MMF group and three patients in the AZA group developed a lymphoma or lymphoprolifera-tive disease. Two of the three AZA patients had also received OKT3 therapy for rejection, whereas neither of the MMF TABLE 3. Number of full courses of immunosuppressive therapy
given after the initial course of corticosteroids during the first 6 months in the study
Therapy given AZA (n5108) MMF (n5113)
No courses 45 (41.7%) 85 (75.2%)
1 course 44 (40.7%) 15 (13.3%)
2 or more courses 19 (17.6%) 13 (11.5%) Antilymphocyte therapy only 36 (33.3%) 11 (9.7%) Corticosteroids only 18 (16.7%) 9 (8.0%) Antilymphocyte therapy and
corticosteroids
9 (8.3%) 8 (7.1%)
FIGURE 3. Serum creatinine (mean6 SEM) during the first year after enrollment: MMF (OO) and AZA (- - - - -).
TABLE 4. Immunosuppressive drug doses
Medication Time in study AZA arm MMF arm
MMFa 6 mo 2.660.53 (2.86) 12 mo 2.660.55 (2.86) AZAb 6 mo 1.4160.47 (1.38) 12 mo 1.4060.45 (1.38) Corticosteroidsc 6 mo 13.260.6 12.960.6 12 mo 10.560.5 10.360.5 CsAd 6 mo 5.260.5 4.960.4 12 mo 4.860.3 4.460.3 CsA levele 6 mo 1.0460.1 1.060.07 12 mo 1.0160.08 0.9160.06 aMMF dose is in g/day; mean6SD (median).
bAZA dose is in mg/kg/day; mean6SD (median). cCorticosteroid dose is in mg/day; mean6SEM. dCsA dose is in mg/kg/day; mean6SEM.
eCsA (mean6SD) level is the normalized level obtained by divid-ing the individual CsA level in ng/ml by the center-specific median target CsA level.
TABLE 5. Number (percentage) of patients demonstrating selected adverse events
Adverse event AZA (n5108) MMF (n5113)
Gastritis 4 (3.7) 12 (10.6) Anorexia 12 (11.1) 23 (20.4) Vomiting 18 (16.7) 27 (23.9) Dyspepsia 21 (19.4) 29 (25.7) Nausea 30 (27.8) 40 (35.4) Diarrhea 42 (38.9) 57 (50.4) Abdominal pain 26 (24.1) 47 (41.6) Peripheral edema 36 (33.3) 49 (43.4) Neuropathy 4 (3.7) 13 (11.5) Dizziness 16 (14.8) 29 (25.7) Insomnia 13 (12) 26 (23) Thrombocytopenia 11 (10.2) 7 (6.2) Leukopenia 40 (37) 44 (38.9) Anemia 44 (40.7) 53 (46.9)
patients had any subsequent treatments for rejection during the follow-up period. Only two other malignancies occurred and both were in the MMF group. These were myeloma in one patient and metastatic lung cancer in another.
There were no clinically significant differences in serum chemistry or hematologic values at any time point between the two treatment groups (data not shown).
DISCUSSION
The primary objective of this double-blind multicenter study was to assess the efficacy of MMF and corticosteroids versus AZA and corticosteroids for the treatment of first acute renal allograft rejection. Characteristics of the patient population at the time of enrollment that may have impacted upon the results of the study were similar between the two groups. Regardless of whether the composite value of first use of antilymphocyte therapy and treatment failure (defined as graft loss, death, or premature withdrawal from the study without prior use of antilymphocyte therapy) or the use of antilymphocyte therapy itself was used as the end point, there was a highly significant advantage of MMF over AZA. As a further reflection of the efficacy of MMF, the rate of additional rejection episodes during the study was also sig-nificantly decreased by the use of MMF. Although the study was not designed to detect significant differences in survival parameters, the reduced rate of use of antilymphocyte ther-apy and subsequent rejections suggested a trend toward im-proved graft and patient survival in the MMF-treated arm. Because episodes of acute rejection are related to subsequent graft loss due to chronic rejection, phase II of the trial, which is still underway, becomes critical (14,15) .
Upon analysis of the data of time to first use of antilym-phocyte therapy, it is clear that even within both treatment arms, a group of patients have an early treatment failure. What factors contribute to the failure of steroid therapy for these patients is not clear but will be the focus of future post hoc analysis. Although it could be argued that the dose of steroids used to treat the index rejection was low, because both treatment groups received the same course of therapy, it is unlikely that this would be an important difference. It is possible that with a higher dose of steroids there would be fewer treatment failures, but there is no reason this should benefit the one group over other. If characteristics could be identified for these patients, then initial treatment with an-tilymphocyte therapy would clearly be the treatment of choice.
Graft function as measured by serum creatinine and cal-culated creatinine clearance was better (although not statis-tically significant) in the MMF-treated patients. This was not due solely to lower CsA levels because the levels were similar
in both groups. The better function may result from a more rapid and complete resolution of the rejection of those pa-tients on MMF. The eventual equilibration of the serum creatinine could be an artifact of survivor bias because more graft loss occurred within the AZA arm leaving the AZA-treated group with better renal function.
The rate of CMV, both viremia and tissue invasive, and
Candidainfections were slightly higher in the MMF group than in the AZA group. In four previous studies, patients who received MMF were noted to have a higher incidence of tissue-invasive CMV disease than those in the control groups. In these studies, the 3 g/day dose (i.e., the dose used in this study) resulted in the highest incidence (1–3,18). This incidence ranged from 6.9% to 11% in the MMF groups ver-sus 1.4% to 6.1% in the AZA groups. The higher level of tissue-invasive disease has been suggested to partly result from the increased gastroscopy performed for stomach irri-tation caused by MMF (2). The rate of both tissue-invasive CMV and CMV syndrome in the current study were the highest reported of any of the MMF trials but were increased in both the MMF and AZA arms. This could be due, in part, to the fact that all patients in the current trial required treatment for rejection to be eligible for the trial. As would be expected, the rate of CMV disease was higher in the donor-positive/recipient-negative combinations and this too was true for both the AZA and MMF groups. CMV prophylaxis was not required to be given within this study. Oral ganci-clovir has been recently shown to be effective in liver trans-plant recipients for the prophylaxis of CMV disease and might therefore be considered for adjunctive therapy, at the very least within the high-risk groups. Viral infections, per se, were not increased in this study because the incidence of other herpes infections did not differ between the groups nor were they higher than those found in the other MMF trials. The overall spectrum of side effects seen in the MMF group was similar to those reported previously, and included leu-kopenia, diarrhea, and other gastrointestinal events. Some-what more patients in the MMF arm had neurologic adverse events that included dizziness, neuropathy, and insomnia. None of these events were more common within the MMF trials for prevention of rejection. Although more patients withdrew from MMF than AZA as a result of adverse events, the rate was no higher than that seen in other studies (1–3,
18). In clinical practice, which is less constrained than study conditions, dose manipulation to t.i.d. dosing or doses be-tween 750 mg b.i.d. and 1500 mg b.i.d. may be effective and associated with less side effects. Although such manipulation was not possible within this trial, during the initial 6 months, most patients tolerated the 3 g/day of MMF (median dose was 2.86 g/day). Whether it is necessary to continue patients on 1500 g b.i.d. of MMF cannot be answered by the current study. The safety of such dosing will be addressed by the long-term results of both this study and the three de novo trials (1–3).
The incidence of malignancy, especially lymphoma, did not differ between the two groups and in fact was lower in the MMF group. The 1.8% rate in the MMF-treated arm was consistent with that in the other MMF trials (1–3,18) and that found with other immunosuppressive regimens (20). The rate of nonmelanoma skin cancers in the current study was higher in both the MMF and control groups than reported previously (1–3). These rates are not in excess of other im-TABLE 6. Summary of opportunistic infections
Infection AZA (n5108) MMF (n5113) CMV syndrome/viremia 16 (14.8%) 23 (20.4%) CMV tissue invasive 16 (14.8%) 20 (17.7%) Herpes simplex 14 (13.0%) 15 (13.3%)
Herpes zoster 6 (5.6%) 8 (7.1%)
Pneumocystis cariniipneumonia 1 (0.9%) 1 (0.9%)
Aspergillus/mucor 0 1 (0.9%)
Candida(mucocutaneous) 17 (15.7%) 28 (24.8%)
munosuppressive regimens. As opposed to lymphoma, which appears early after transplant at the time of maximal immu-nosuppressive drug dosing, skin cancer is insidious, increas-ing in frequency linearly after transplant (20,21). Therefore, only very long-term studies will be able to truly answer the question of the effect of MMF on the rate of skin cancers.
In summary, this study indicates that MMF is a highly effective adjunctive therapy to corticosteroid treatment for acute renal allograft rejection. The reduction in rejection rates and the more rapid and complete reversal of the rejec-tions resulted in a trend toward improved and overall graft survival. The long-term follow up of this study will now be crucial to determine whether the aggressive treatment of early rejection and prevention of subsequent rejections will translate into reduced graft loss and reduced chronic rejec-tion.
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Received 27 May 1997. Accepted 27 August 1997.
