mini review

http://www.kidney-international.org & 2012 International Society of Nephrology

Should mycophenolate mofetil replace cyclophosphamide as first-line therapy for severe lupus nephritis?
Jonathan Hogan1,3, Michael H. Schwenk2,3 and Jai Radhakrishnan1
1

Division of Nephrology, Department of Medicine, Columbia University Medical Center, Columbia University College of Physicians and Surgeons, New York, New York, USA and 2Research Pharmacy, Columbia University Medical Center, Columbia University College of Physicians and Surgeons, New York, New York, USA

Available treatments for severe (class III, IV, and V) lupus nephritis (LN) have expanded greatly over the last 40 years. In the 1970s and 1980s, cyclphosphamide (CYC), in combination with glucocorticoids, gained favor as induction and maintenance therapy for severe LN. However, the adverse event profile of CYC led to the search for other medications for severe LN. Beginning in the late 1990s, mycophenolate mofetil (MMF) was introduced as induction and maintenance therapy for severe LN. This review discusses the clinical trial results, pharmacology, costeffectiveness, and adverse effect profiles of CYC compared to MMF for induction and maintenance therapy for severe LN. The authors conclude that MMF should be considered first-line induction and maintenance treatment therapy for severe LN, although CYC may have a place under specific clinical and economic circumstances.
Kidney International (2012) 82, 12561260; doi:10.1038/ki.2012.203; published online 30 May 2012 KEYWORDS: glomerular disease; glomerulonephritis; lupus nephritis

Efficacy of cyclophosphamide (CYC) versus mycophenolate mofetil (MMF) in the treatments of severe lupus nephritis (LN)

Correspondence: Jai Radhakrishnan, Division of Nephrology, Department of Medicine, Columbia University Medical Center, Columbia University College of Physicians and Surgeons, 622 W. 168th Street, PH 4-124, New York, New York 10032, USA. E-mail: jr55@columbia.edu
3

These authors contributed equally to this work.

Received 30 December 2011; revised 10 April 2012; accepted 13 April 2012; published online 30 May 2012 1256

An improvement in renal and patient survival for adults and children with severe (class III/focal proliferative, class IV/ diffuse proliferative, and class V/membranous) LN has occurred over the past four decades with the introduction of new treatment options.1,2 During the 1970s, the results of small clinical trials prompted physicians to add cytotoxic agents to standard glucocorticoid therapy in the treatment of severe LN. Modern therapy for severe LN was ushered in during the 1980s and 1990s, with reports from the National Institutes of Health (NIH), which concluded that chronic treatment regimens containing intravenous (i.v.) CYC and steroids were superior to steroids alone in preserving kidney function.3,4 These differences in renal function were not evident until at least 5 years of treatment, and long-term follow-up data were only available for a few patients. Nevertheless, the conclusion that i.v. CYC was a superior treatment in severe LN led to many more trials as we entered the new millennium. In 2002, the Euro-Lupus Nephritis Trial (ELNT) showed equivalent efcacy and less side effects in a European cohort using an attenuated regimen of i.v. CYC (using six biweekly xed intravenous doses of 500 mg i.v. CYC) compared with the NIH regimen (0.51 g/m2 monthly for 6 months, followed by repeat dosing every 3 months).5 The efcacy of this regimen was conrmed in a subsequent 10-year follow-up study.6 The ELNT regimen reduced the average total induction dose of i.v. CYC from 8.5 to 3.0 g. Despite the decreased side-effect prole of this ELNT regimen (although not statistically signicant), the adverse events associated with i.v. CYC were still notable (including severe infections, bone marrow suppression, gonadal toxicity, hemorrhagic cystitis, and the risk of malignancy). Although outcomes were improving, these adverse events combined with the continued morbidity and mortality associated with severe LN necessitated the advent of alternate therapies. MMF was introduced into use in renal transplant patients in the 1990s and was shown to have a favorable safety prole. Preclinical animal studies then demonstrated that MMF was
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J Hogan et al.: MMF versus cyclophosphamide in severe lupus nephritis

mini review

Table 1 | Trials comparing CYC and MMF during induction therapy of lupus nephritisa
Medication dosage Study Hu Duncan Chan Ginzler Ong Flores-Suarez Choi Wang Tang Traitanon Appel Study type Single NRCT Single NRCT Single open RCT Multicenter open RCT Single open RCT Single open RCT Single open RCT Retrospective controlled study Single NRCT Multicenter open RCT MMF dose CYC dose Complete remission Patients (MMF/CYC) MMF 23/23 10/20 33/31 71/69 19/25 10/10 19/26 9/11 27/25 16/15 135/156 8 10 24 16 5 3 8 4 14 1 16 CYC 5 20 23 4 3 1 12 0 6 2 15 Partial remission MMF 8 8 21 6 3 7 2 5 4 89 CYC 11 7 17 10 1 8 3 10 7 86 2/5 Total 10/19 9/46 83/75 Adverse reactions Deaths 0/0 0/2 9/5 1/1 0/3 Infections 4/7 4/12 19/17 6/6 5/3 2/0 GI 6/10 3/1 77/91 Blood 0/2 0/8 23/12 7/13 1/5

0.50.75 g Q12H 0.751 g/m2 1 g Q12H 0.5 g/m2 1 g Q12H 1 g Q8H 1 g Q12H NR 2 g/day 0.751 g Q12H 0.751 g Q12H 1440 mg/db 2.6 g/day 2.5 g/kg

0.751 g/m2 NR 0.751 g/m2 0.751 g/m2 0.50.75 g/m2 0.51 g/m2 0.75 g/m2

0/0

1/12 1/3 1/6 19/17

0/5 0/2 6/12 77/91

0/2 1/0 3/15 23/12

177/171

9/5

Abbreviations: CYC, cyclphosphamide; GI, gastrointestinal; MMF, mycophenolate mofetil; NR, not recorded; NRCT, non-randomized controlled trial; RCT, randomized controlled trial. Data are from reference 25, which is a meta-analysis of the geographical variation in the response of lupus nephritis to MMF and CYC. a Adapted from Mohan and Radhakrishnan.25 b Enteric coated mycophenolic acid used.

effective as induction treatment in severe LN.7,8 Several randomized clinical studies have since followed in humans (Table 1). The largest trials demonstrated that MMF was equivalent, and possibly superior, to i.v. CYC as induction therapy for severe LN, with a safer side-effect prole.9,10 Ginzler et al.10 randomized 140 patients with severe LN and an average serum creatinine of 1.1 mg/dl to receive oral MMF (mean dose 2.7 gm/d) or NIH-dose i.v. CYC as induction therapy for 24 weeks. In this open-label and multicenter trial, 39 patients (23%) did not complete the full treatment course. A signicantly higher percentage of patients in the MMF group reached the primary end point (complete remission) compared with i.v. CYC at 24 weeks, and more pyogenic infections and hospitalizations occurred in the i.v. CYC group. Appel et al.9 then conducted an open-label trial that randomized 370 patients with severe LN and an average serum creatinine of 1.1 mg/dl to receive prednisone plus either MMF (average dose 2.6 gm/d) or NIH-protocol i.v. CYC for 24 weeks as induction therapy. Although 64 (17%) patients were withdrawn during the trial (the majority for adverse events), the response to treatment at the end of induction therapy was similar in the MMF and i.v. CYC groups, with 56% and 53% of patients responding to treatment, respectively. The percentage of patients who experienced adverse events was similar between treatment groups. These trials validated the use of MMF as a safe and effective induction therapy for severe LN compared with i.v. CYC. A subgroup analysis of the two largest randomized trials comparing MMF with i.v. CYC concluded that MMF was also equivalent specically in class V LN,11 with a trend toward higher rates of lymphopenia and leucopenia in the i.v. CYC group but no difference in rates of infection. The efcacy of
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MMF as induction therapy in class V LN has also been supported by a small, non-randomized prospective study as rst-line therapy,12 as well as second-line therapy in a retrospective case series.13 Moreover, a randomized trial demonstrated that steroids plus MMF or oral CYC followed by azathioprine led to equivalent outcomes at 1 year of follow-up in patients with class IV LN.14 Small retrospective studies have shown that MMF may be a useful therapy in aggressive forms of LN and extrarenal lupus as well. In crescentic LN, a small randomized trial demonstrated that MMF was equivalent to CYC in inducing remission of disease at 12 months of follow-up, but MMF achieved a higher rate of complete remission (54% vs. 27%) over this time period.15 It is noteworthy that B25% of patients in each group had serum creatinine levels 43.0 mg/dl, indicating that MMF is a useful therapy in patients with compromised renal function as well. A small, prospective randomized trial indicated that MMF was superior to i.v. CYC for class IV LN with necrotizing vasculopathy.16 Finally, MMF was as effective as i.v. CYC in preventing non-renal manifestations of lupus in patients who were treated for LN17 and was associated with better quality of life than oral CYC induction therapy (followed by azathioprine maintenance therapy) in patients who had received both treatments for different LN are episodes.18 Taken together, these studies suggest that MMF is equivalent or superior to i.v. CYC as induction therapy for many subtypes of severe LN, in patients with increased serum creatinine levels, and likely has a more favorable side-effect prole. Whereas many earlier studies used i.v. CYC and/or glucocorticoids as maintenance treatment, in the past 8 years randomized trials have established MMF as maintenance therapy for LN. Contreras et al.19 used NIH-regimen i.v. CYC
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as induction therapy, then compared quarterly i.v. CYC, MMF, and azathioprine (all in combination with prednisone) as maintenance therapy. This study demonstrated that MMF and azathioprine were superior to i.v. CYC in preventing the combined end point of patient death and chronic renal failure at 6 years after induction with i.v. CYC. Moreover, the MMF group had the lowest relapse rate and was associated with a lower incidence of adverse events (primary amenorrhea and infections) than i.v. CYC. Recently, two randomized trials demonstrated that MMF is equivalent20 or superior21 to azathioprine as maintenance therapy for LN after 3 years of follow-up. It is noteworthy that the patients in the ALMS Maintenance Trial who were treated with MMF as maintenance therapy after induction treatment with i.v. CYC had less treatment failure events than those treated with MMF as induction therapy, although this difference was not signicant. These trials have demonstrated that MMF is superior to quarterly i.v. CYC, and equivalent or superior to daily oral azathioprine as maintenance treatment for LN. Racial/ethnic and socioeconomic differences have been observed in the serologic and histologic presentation of LN.22,23 This has generated the hypothesis that the mechanism of LN may differ between patients of different races, and that the efcacy of different treatments may also vary between racial groups. Most of the randomized trials that compared i.v. CYC with MMF for LN are single-center studies, and many do not specify the races or ethnicities of the enrolled patients. The ALMS trial is the largest trial for induction therapy for LN with i.v. CYC versus MMF. It was an international, multicenter trial that also collected ethnic and racial data. It was observed that Black and Hispanic patients had higher response rates to MMF compared with i.v. CYC, whereas the two induction therapies were equivalent in the other racial groups.24 A recent meta-analysis conrmed this observation using the location of each trial as a geographical surrogate for the racial background of patients.25 It has also been noted that studies conducted in Asia have higher response rates to treatment than those conducted outside of Asia. At this time, the available data suggest that MMF may be more effective than i.v. CYC in Black and Hispanic patients, but the two treatments are equivalent in other racial groups. There is additional interest in the use of MMF in children with severe LN given the gonadal toxicity associated with CYC. In children with severe LN, there are no prospective, randomized trials that have compared CYC with MMF; all studies have been small and retrospective. The available data suggest that MMF may be an effective maintenance therapy for severe LN, but that i.v. CYC is still the mainstay of induction treatment. It is interesting to note that the largest retrospective analysis of children with LN, which separated patients by era of treatment, showed that renal survival improved signicantly with the addition of MMF in the early 1990s, whereas this effect was not observed with the addition of i.v. CYC.2 Although MMF seems to be a safe and effective maintenance therapy in children, prospective studies are required to establish its use as induction therapy.
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CYC versus MMF: pharmacology, adverse events, and cost

CYC is a prodrug that is metabolized to active (phosphoramide mustard) and toxic (acrolein) metabolites. Phosphoramide mustard is an alkylating agent that cross-links DNA strands to prevent cell division and cause cell death, including loss of ovarian follicles and spermatocytes. Acrolein is believed to be the cause of both cystitis and bladder cancer. Both of these metabolites are derived from hepatic metabolism of CYC to the initial metabolite 4-hydroxycyclophosphamide, which is subsequently converted to aldophosphamide. Aldophosphamide in the plasma is then converted to the active and toxic metabolites. MMF and MMF sodium are prodrugs that are quickly hydrolyzed to the active moiety, mycophenolic acid. Mycophenolic acid is a selective, noncompetitive, reversible inhibitor of inosine monophosphate dehydrogenase, a component of the de novo pathway for guanine nucleotide synthesis. B and T lymphocytes depend on this pathway for cell proliferation, whereas other cell types are able to use alternative pathways. Mycophenolic acid thus reversibly inhibits lymphocyte function and proliferation, including antibody production. With the availability of these less toxic regimens, the following question is raised: is it time to retire CYC from the LN armamentarium? As CYC and MMF are shown to be equivalent as induction therapies for the treatment of LN, it is important to consider the respective severity and relative frequency of their acute/ subacute and chronic toxicities. With respect to the induction treatment of LN, a number of systematic reviews and metaanalyses have been performed. One of the earliest of these analyses included four studies with a total of 268 patients, which found that leukopenia and amenorrhea were more common with CYC than with MMF treatment.26 Similarly, another analysis of three studies (206 patients) found a statistically lower incidence of leukopenia in the MMF treatment group.27 Signicant reductions in the incidence of alopecia, as well as amenorrhea, were seen in the MMFtreated arms of four trials (618 patients) in an analysis by Touma et al.28 (Table 2). In a meta-analysis and metaregression comparing CYC and MMF in 10 studies (847 patients as induction and/or maintenance therapy for LN), there was a signicantly lower risk of developing amenorrhea and leukopenia with MMF.29 As LN is most commonly seen in premenopausal women, some adverse effects of CYC (alopecia and amenorrhea) are especially troubling in this patient group. Whereas short- or long-term therapy with MMF (for LN or in transplantation, respectively) is not associated with ovarian failure, shortcourse (6 months) or long-course (2 years) intermittent monthly/quarterly pulse CYC therapy is associated with a cumulative dose/duration-dependent amenorrhea (incidence reported to be 2356%), which may be permanent.3032 Even if amenorrhea does not occur with CYC, premature menopause may occur years after treatment.31 Leuprolide acetate or goserelin have been advocated as an additional drug therapies to prevent ovarian failure in women, and testosterone to
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Table 2 | Comparison of side effects of CYC and MMF during induction therapy of LNa
CYC (%), n Leukopenia Infections Gastrointestinal Herpes zoster Amenorrhea Alopecia 21 (243) 49.7 (310) 72.2 (310) 7.7 (310) 6.4 (310) 28.4 (=285) MMF (%), n 11 (235) 46.7 (=308) 56.2 (=308) 10.1 (=308) 0.006 (=308) 6.9 (=289)

Table 3 | Cost comparison for LN induction therapy using CYC or MMFa

Mean cost of 6 months of LN induction therapy MMF CYC MMFCYC English pounds d1388 d2994 d1606 US dollars $2138 $4611 $2473

Abbreviations: CYC, cyclphosphamide; LN, lupus nephritis; MMF, mycophenolate mofetil. All patients received concomitant corticosteroid therapy. n=number of patients in each arm. a Data are from Touma et al.28, which examined four trials comparing CYC versus MMF for induction therapy of LN.

Abbreviations: CYC, cyclphosphamide; LN, lupus nephritis; MMF, mycophenolate mofetil. Cost data from are from 2005, according to the UK National Health Service. d1=$1.54. Includes actual drug costs, nursing costs, blood tests, cost to treat infections, clinic visits, and for CYC the costs of ondansetron, goserelin, mesna, and hydration. Does not include costs common to both treatments, e.g., corticosteroid therapy. MMFCYC=difference in cost between MMF and CYC regimens. a Data are from ref. 35.

prevent azoospermia in men; however, this issue has not been studied in randomized controlled trials. The use of CYC is also associated with a risk of developing hemorrhagic cystitis and/or transitional cell carcinoma of the bladder. Although the incidence of these complications seems to be very low with intermittent pulse CYC regimens used for LN, MMF has not been associated with either of them in any of the controlled trials using this agent. Though not in widespread use in the United States, oral CYC is commonly used to treat severe LN in other countries. In two randomized studies comparing oral CYC (2.5 mg/kg/day for 6 months) with MMF, there was no difference in clinical response, but adverse events were higher in the CYC group.14,33 Conversely, in an observational study, using lower doses of oral CYC (1.01.5 mg/kg/day for 24 months), response rates and adverse events were comparable to historical controls.34 Another consideration is the cost/convenience of CYC therapy for glomerulonephritis. Although the price of a course of intravenous pulse CYC injections when calculated by the number of drug vials required may be less expensive than the cost of a course of oral MMF therapy when calculated by the number of tablets required, other expenses such as the cost of the supplies required to prepare an intravenous CYC dose, the personnel who prepare and administer the treatment, and the clinic or ofce/hospital space where the treatment occurs are all costs that need to be factored into the nal cost equation. In addition, if the prevention of hemorrhagic cystitis and monitoring for bladder cancer is desired, factors such as pre/post-hydration, administration of mesna, urine cytology, and cystoscopy/biopsy should be added to the cost estimate. Anti-emetic agents, either prophylactically or treatment emergent would pertain to CYC therapy, whereas with MMF any gastrointestinal side effects, including nausea/vomiting and especially diarrheas, would be managed by a simple dose reduction. A cost-effectiveness study from the United Kingdom comparing MMF with CYC (which considered most of the above-mentioned factors) in the treatment of LN concluded that MMF was less expensive than CYC, and in fact demonstrated that MMF cost about half of what CYC would cost for a 24-week course of induction therapy (Table 3).35 The requirement for an ofce/clinic visit to administer CYC was the
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major factor in determining the cost difference. In addition, treatment with MMF resulted in a superior quality of life and quality-adjusted life years. An additional pharmacoeconomic study conducted in Hong Kong concluded that therapy with CYC was less expensive than with MMF; however, oral CYC was used and a 2-year treatment course was examined.36 Thus, the associated costs of intravenous CYC were not considered, including ancillary drugs for the prevention/treatment of possible side effects (see above). As it included the cost of MMF during maintenance (18 months of treatment), its relevance is diminished (azathioprine, not CYC, was used). Interestingly, the number of days of hospitalization in the CYC group was nearly sixfold greater than in the MMF group, although this did not reach statistical signicance (P 0.055) presumably because of a small sample size (n 44). Final economic issues not yet resolved include the cost differential of MMF versus CYC in resource-limited settings, and the availability of generic MMF.
MMF as preferred treatment for LN

Given the efcacy, favorable side-effect prole, and perhaps cost equivalence of MMF, why then is CYC still in use? There are several explanations that can be forwarded to account for this behavior. First, a change in practice after introduction of new therapies or technologies is usually gradual. Second, the long-term follow-up data for patients treated with MMF are shorter compared with CYC: the Contreras and ALMS maintenance trials reported on 6 and 3 years of follow-up, respectively, compared with up to 200 months with oral CYC1 and 160220 months for i.v. CYC.3,4 Third, the data on the efcacy of CYC versus MMF on the severest forms of LN (e.g., associated with crescentic necrotic lesions/rapidly progressive glomerulonephritis) are limited. Fourth, the recent analysis of MMF versus azathioprine in the ALMS maintenance trial demonstrated that within the group that received MMF as maintenance therapy there was a nonsignicant trend toward increased treatment failure in those who had received MMF versus CYC as induction therapy.21 Finally, evidence supports geographical and racial differences in response rates to induction treatment with MMF versus
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CYC for LN.24,25,37 Physicians may hesitate in shifting their therapeutic strategy for the treatment of LN owing to these reasons. Subsequently, many nephrologists switch from MMF to CYC when there is a lack of a satisfactory response to the former drug (personal observation), despite a lack of reports to support this practice. To summarize, in the authors opinion, MMF should now be considered standard rst-line therapy for severe LN given the favorable efcacy/toxicity prole over i.v. CYC, especially in women of childbearing age and non-Asian patients. Moreover, MMF has been shown to be a superior maintenance therapy to both azathioprine and i.v. CYC. However, i.v. CYC given as a 6-monthly course, the attenuated ELNT regimen, or oral CYC are quite reasonable when compliance is an issue, in developing countries where the cost of MMF is still high, in children, and perhaps in patients with the severest form (Rapidly progressive glomerulonephritis/crescentic) of LN. Long-term studies in these populations, further exploration of differences in treatment response because of geography and race, and the availability of generic MMF would solidify its role as the preferred rst-line therapy for induction and maintenance treatment in severe LN.
DISCLOSURE

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All the authors declared no competing interests.

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