Mycophenolate Mofetil or Mycophenolate Mofetil or Intravenous Intravenous

CyclophosphamideCyclophosphamidefor Lupus Nephritisfor Lupus Nephritis

Prepared by Prepared by

Dr . Nahed SherbiniDr . Nahed Sherbini

The new Englandjournal of medicineestablished in 1812November 24,2005vol. 353 no. 21

Background

Since series and small, prospective, controlled trials suggest that mycophenolate mofetil may be effective for treating lupus nephritis, larger trials are desirable.

Background

IV cyclophosphamide has been the standard of care for treating severe lupus glomerulonephritis.

**Potentially severe toxic effects :

Bone marrow suppression,

Hemorrhagic cystitis,

Opportunistic infections, malignant diseases, and premature gonadal failure.

Mycophenolate mofetil

An immunosuppressive agent approved for the prevention of transplant rejection --used in patients with lupus nephritis refractory to cyclophosphamide and in patients who cannot tolerate cyclophosphamide.

Failure to achieve remission

which is associated with an increased rate of progression to renal failure, is reported in 18 to 57 % of patients who received cyclophosphamide.

Methods (Study DesignMethods (Study Design((

Multicenter, randomized, open label, controlled trial from December 1999 > October 2003 .

Eligibility criteria :

SLE Pt meeting four classification criteria of the American College of Rheumatology &

Renal biopsy documenting lupus nephritis according to the classification of the WHO

WHO ClassificationWHO Classification

Proliferative glomerulonephritis class III (focal(

IV (diffuse(

V (membranous(

Clinical activity as defined by one or more of the following:

*Incident decrease in renal function .*Proteinuria (defined as more than 500 mg

of protein in a 24-hour urine specimen(.*Hematuria (defined as >5 red cells/HPF( presence of cellular casts, increasing

proteinuria with rising levels of serum creatinine, active urine sediment or serologic abnormality (anti-DNA antibodies or hypocomplementemia(.

Exclusion criteria

Creatinine clearance of less than 30 ml per minute. Serum creatinine on repeated testing > 3.0 mg per deciliter.Severe coexisting conditionsImmunosuppressive therapy or conditions requiring IV antibiotic therapy.Prior treatment with MMF or IVC in past 12m.Monoclonal antibody therapy in the past 30 days.Pregnancy or lactation

Treatment protocol

Oral MMF initiated at a dose of 500 mg twice daily, and the dose was increased to 750 mg twice daily at week 2 and advanced weekly to a maximum dose of 1000 mg three times daily unless WBC fell below 3000 .

Treatment protocol

IVC was given as monthly pulses according to a protocol of the National Institutes of Health (NIH). Dosage was modified on the basis of WBC of 2500 at 7-10 days after the infusion.

Prednisone at a dose of 1 mg /kg/ day, with tapering by 10 to 20% at one-week or two.

Study end pointsStudy end points

The primary end point was complete remission at 24 weeks (normalization of abnormal renal measurements and maintenance of baseline normal measurements).

A secondary end point was partial remission at 24 weeks.

ASSIGNMENT AND ASSIGNMENT AND THE RESULTS OF THE THE RESULTS OF THE

STUDYSTUDY

Eligible patients providing Signed consent enrolled

(N=140)

Underwent randomization(N=140)

Assigned to MMF(N=71)Received MMF(N=71)

Assigned to IVC (N=69)Received IVC (N=66)

Declined therapy (N=3)

MMF for 24w (N=56) CR(N=16)

PR(N=21)NR(N=1

Discontinued (N=15)Withdrew before

w12(N=6)Did not have

early response by w12(N=8)

IVC for 24w (N=42) CR(N=4)

PR(N=17)NR(N=21)

Discontinued (N=24)Withdrew before

w12(N=10)Did not have

early response by w12(N=12)

Included in analysis (N=71)Excluded (N=0)

Included in analysis (N=69)Excluded (N=0)

Laboratory Values for Primary and Secondary

End Points.

12 Weeks of Treatment

MMFMMF IVCIVC 95% CI P valueP value

CreatinieCreatinie 0.96±0.36 0.98±0.68 0.02 (-0.17 to 0.21)

0.84

Albumin 3.26±0.29 3.17±0.25 0.09 (-0.01 to 0.19)

0.07

Urine protein

2.50±3.01 2.97±3.06 0.47 (-0.60 to 1.54)

0.39

C3 101.41±22.78

87.80±35.79

13.61 (3.06 to 24.15)

0.01

24 Weeks of Treatment

MMFMMF IVCIVC 95% CI P valueP value

CreatinieCreatinie 0.91±0.25 0.85±0.28 0.06 (-0.5 to 0.17)

0.27

Albumin 3.42±0.42 3.44±0.25 0.02 (-0.12 to 0.16)

0.79

Urine protein

2.03±2.79 1.46±1.27 0.57 (-0.35 to 1.49)

0.22

C3 69.8±29.9 91.8±29.5 4.97(-7.18 to 17.12)

0.42

Immunosuppressive therapy

The mean maximal tolerated dose of MMF was 2680 mg/d of a total of 83 patients receiving MMF --52 (63%) tolerated 3000 mg /d. Of 69 patients in the IVC group 43 (62 %) received 6 m doses of the drug. The cumulative dose of IVC/ patient after 3 m was 3430±355mg, and after 6 months it was 7302±1695 mg.

The mean dose of IVC

completeresponse

909.7±176.0 mg per square meter of body-surface area per month .

partial response 746.0±174.4 mg

no response 725.5±190.3 mg

Adverse events

There were 2 deaths in IVC group during treatment. One patient died cerebral hemorrhage within a week of receiving the first dose.The other patient received two doses, the second of which was delayed by sepsis—death 3w later and was related to active lupus and recurrent sepsis.A 3rd patient declined therapy and died from pulmonary hemorrhage and renal failure at another hospital. There were no deaths in MMF group.

Adverse events

Infection and gastrointestinal side effects accounted.

Severe infections (pneumonia and lung abscess, necrotizing fasciitis, and gram-negative sepsis) occurred only with IVC.

Pyogenic infections were significantly less frequent among patients receiving MMF>IVC.

Adverse events

Hospitalizations for vomiting and dehydration occurred in five patients (a total of seven episodes) receiving IVC.

Diarrhea occurred more with MMF(15 patients) .

Adverse events

Apparent drug-related hematologic toxic effects were uncommon.

Incident neutropenia alone was responsible for a reduction in the dose of IVC at only 8 infusions among 6 patients.

Baseline lymphopenia was present in 22 patients in MMF group and 15 patients in IVC group.

Event No. of Events

Relative Risk (95%CI)

P Value

MMF IVCMMF IVC

11stst renal renal flareflare

88 88 0.98 (0.37–2.61) 0.96

Renal Renal failurefailure

44 77 0.53 (0.15–1.81) 0.31

Death Death 4 84 8 0.48 (0.15–1.60) 0.24

Outcomes during Follow-up after Induction Therapy

CONTCONT. .

Before this trial was completed, two randomized studies comparing mycophenolate mofetil with cyclophosphamide for lupus nephritis were reported.

Chan et al

Reported on a 12-month study involving 42 patients with class IV nephritis in which MMF was as effective as oral cyclophosphamide in inducing remission.

The rate of infectious complications was similar in the 2 treatment groups, but only patients treated with cyclophosphamide had amenorrhea, alopecia, leucopenia, or died.

Hu et al.

Reported on 46 patients with class IV nephritis and concluded that 6 m of MMF was more effective than IVC in reducing proteinuria, hematuria, and autoantibody production.

Cont. ResultsCont. Results

In this short-term study, the toxicity and tolerability to MMF compared favorably with that of cyclophosphamide.

Although upper gastrointestinal symptoms were common in the 2 groups in the MMF group the symptoms tended to be mild and self limited,

whereas in the IVC group dehydration following treatment necessitated 7 hospitalizations.

Serious infections were less common with MMF.

In this prospective controlled study relatively large and involved a heterogeneous cohort, including patients from 19 academic and private-practice centers in the United States.

56% of the patients were blackassociated with poor outcome.

A limitation of the study

The treatment assignment was not blinded. Although this could lead to potential bias in patient recruitment and in the interpretation of results.

Marked differences in side-effect profiles of the two drugs would probably make true blinding difficult.

Potential bias was minimized by selecting a primary end point with the use of objective laboratory measures.

In recent reports, the average time to remission with cyclophosphamide is 10 months.

Low response rate with IVC may reflect an inability to achieve the recommended protocol dosing doses were regulated on the basis of toxic effects, primarily gastrointestinal symptoms.

Another limitation

Short duration of the study.

and the restriction to induction therapy.

Long term experience in clinical trials using IVC shows a relapse rate of up to 45 % in patients with proliferative lupus nephritis despite a complete clinical response to induction therapy.

The long-term follow-up (median, 63 months) in the study by Chan et al. showed a similar rate of renal relapse in both treatment groups with more gradual tapering of the maintenance dose of MMF

In summary

Induction therapy with MMF was superior to IVC in inducing complete remission of lupus nephritis in this study.

MMF appeared to be better tolerated than IVC.

Unresolved issues include determining the flare rate after induction with MMF as compared with that for IVC.

Determining the appropriate dose and duration of MMF maintenance therapy.