Cyclophosphamide vs

Mycophenylate mofetil for

lupus nephritis
The curse of living in interesting times?

Mary Anne Dooley

March, 2009
Cytotoxic Therapy Prolongs Renal
Survival
 The “NIH Protocol”
 Improved RENAL not  Excluded patients with
overall survival renal insufficiency
 All classes of renal  Quarterly
histology included cyclophosphamide
 100% Caucasian therapy employed
 Long duration (11  Comorbidities over time
months) of nephritis not reported
prior to entry
Racial Disparity: Renal Survival for Class IV
Lupus Nephritis Treated with IV CTX

120

100
N=39
80
N=51
Non-blacks
60
Blacks
40
p=0.007
20

0
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5
Years from renal biopsy
M Dooley et al, Kidney Int 1997; 51:1188-1195
 Renal Survival by Race at UNC
Independent of the following factors:
 Age

 Duration of SLE

 History of hypertension

 Hypertension control during therapy

 Activity or chronicity indices on renal biopsy

 Pattern of corticosteroid therapy

Diffuse GN (WHO IV)

Majority
African
American
cohorts

Majority
caucasian
cohorts

Austin, Sem Nephrol 19:2, 1999

Racial Disparity in response to cyclophosphamide

Boumpas, Lancet 340:741, 1992

 Remission, relapse, and re-remission of
proliferative lupus nephritis treated with
cyclophosphamide
Remission Relapse
1.0

Proportion without
1.0
Proportion without

0.8 Median time 10 mo 0.8

remission

relapse
0.6 22% failed to remit after 2 yr 0.6
0.4 0.4
0.2 Median time 79 mo
0.2 20% relapse after 18 mo
0.0 0.0
0 20 40 60 80 100 120 0 20 40 60 80 100 120
Time (mo from starting IV CYC) Time (mo from starting IV CYC)

Re-remission
Proportion without

1.0
re-remission

0.8 Median time 32 mo

0.6
0.4
0.2
0.0
0 20 40 60 80 100 120
Time (mo from starting IV CYC)

Ioannidis JA et al. Kidney Int 2000; 57:258-264.

 Remission rates: MMF vs IVC
Intent-to-Treat analysis
p = 0.009
60
37/71
Responding (%)

50
p = NS
40
p = 0.005
21/7 21/69
30 1 17/69
16/71
20

10 4/69

0
Complete Remission Partial Remission Complete + Partial
Remission

MMF IVC
 Study endpoints
MMF IVC
Number randomized 71 69
Complete remission 16 4
Partial remission 21 17
No remission at 24 weeks on initial
19 21
regimen
Crossover to alternate regimen 6 12
Withdrawal from study 9 15
 Study withdrawals
MMF
 6 early
 5 severe disease
 1 non-compliance
 3 late
• 2 crossover refusals
• 1 toxicity (rash)
 No deaths
IVC
 13 early
 3 treatment refusals
(1 death)
 3 severe disease
(2 deaths)
 6 non-compliance
(2 with GI toxicity)
 1 lymphopenia
 2 late
 2 lost to follow-up
 University of Miami Study Methods:
Study design & patient population
 Open label, randomized clinical trial
 Inclusion criteria
 Adults > 18 years of age, World Health Organization (WHO) classes III, IV,
V with proliferation

 Exclusion criteria
 Have received IVCY > 7 doses or AZA > 8 weeks
 Creatinine clearance < 20 mL/min
 Pregnancy
 Any clinically significant infection within 2 weeks of enrollment
 Patient survival
1.00
Cumulative probability

0.75

0.50
p = 0.11, MMF vs IVCY
p = 0.02, AZA vs IVCY
p = 0.33, MMF vs AZA
0.25
19 19 15 10 9 4 2 AZA
20 19 12 6 3 2 1 IVCY
20 20 14 11 6 2 2 MMF
0.00
0 12 24 36 48 60 72
Time (months)
 Free of relapse
1.00 p = 0.021, MMF vs IVCY
p = 0.124, AZA vs IVCY
p = 0.222, MMF vs AZA
Cumulative probability

0.75

0.50

0.25
19 15 10 6 4 3 1 AZA
17 10 4 2 2 1 1 IVCY
19 17 12 8 3 2 1 MMF
0.00
0 12 24 36 48 60 72
Time (months)
MMF vs. CTX for Lupus Nephritis
350 Patient Two-Phase study with a
6 month induction followed by up to
3 year maintenance
 Euro-Lupus Nephritis Trial
Low-dose
All patients High-dose IV CYC IV CYC
Renal function (n = 85) (n = 44) (n = 41)

Normal 67 34 33
Permanently impaired 18 10 8
End-stage renal disease 4 3 1
Doubling of serum creatinine 8 1 7
Impaired renal function 6 6 0

Permanently impaired renal function was

defined as a serum creatinine value that
was repeatedly 1.4 mg/dl. Houssiau FA. Arthritis Rheum 50:3934-3940
No difference in LD vs HD CTX
Rapid response predicts better
long-term outcome
 Dutch Study:
WHO class switches CTX vs. AZA
Increased chronicity in patients given AZA
 Assessed (n = 460) Excluded (n = 90)

Randomized (n = 370)
MMF IVC
Open-label treatment

Allocated to MMF (n = 185) Allocated to IVC (n = 185)

Received MMF (n = 184) Received IVC (n = 180)
Withdrawals (n = 35) Withdrawals (n = 29)
Due to adverse event (n = 24) Due to adverse event (n = 13)
Consent withdrawn (n = 6) Consent withdrawn (n = 5)
Other reason (n = 5) Other reason (n = 11)

Primary endpoint: responders in randomized population (n = 370)

Responders

Maintenance phase
Double-blind re-randomization to corticosteroids plus MMF or azathioprine for up to 3 years
 Demographic Characteristics:
Intent-To-Treat Population
MMF IVC Total
(n = 185) (n = 185) (n = 370)
Male 28 (15.1) 29 (15.7) 57 (15.4)
Female 157 (84.9) 156 (84.3) 313 (84.6)
Ethnicity
Hispanic 64 (34.6) 67 (36.2) 131 (35.4)
Non-Hispanic 121 (65.4) 118 (63.8) 239 (64.6)
Race
White 75 (40.5) 72 (38.9) 147 (39.7)
Asian 62 (33.5) 61 (33.0) 123 (33.2)
Other 48 (25.9) 52 (28.1) 100 (27.0)
Black 26 (14.1) 20 (10.8) 46 (12.4)
Non-black other 22 (11.9) 32 (17.3) 54 (14.6)
 Baseline Disease Characteristics by Race
(ITT Population)
Caucasian Black Asian Other
MMF IVC MMF IVC MMF IVC MMF IVC
(n=75) (n=72) (n=26) (n=20) (n=62) (n=61) (n=22) (n=32)

Duration 6.3 7.2 5.7 5.0 3.6 2.3 8.5 5.9

SLE (5.9) (6.9) (8.2) (4.1) (4.2) (2.5) (7.2) (6.8)

Duration 3.0 4.3 1.8 2.8 2.8 1.9 3.5 3.0

LN (3.9) (6.0) (2.1) (3.3) (3.6) (2.2) (4.7) (4.4)

Urine 3.7 3.8 3.8 3.8 4.7 4.1 4.3 5.0

Protein: Cr (3.2) (3.3) (2.9) (2.9) (5.6) (2.8) (3.6) (3.8)
ratio
Estimated 83.1 81.7 103.8 97.1 86.4 103.4 66.0 91.9
GFR (44.8) (38.1) (44.5) (56.0) (42.6) (47.7) (34.9) (43.1)
 Drug Exposure by Race

Caucasian Black Asian Other

(n = 72) (n = 20) (n = 61) (n = 32)

MMF mean daily 71 26 61 21

dose
Mean (SD) 2.45 (0.46) 2.49 (0.45) 2.40 (0.77) 2.74 (0.45)

Min, Max 1.0, 3.3 1.5, 3.2 0.3, 6.8 1.8, 3.6

Number of IVC
infusions 71 18 60 31
Mean (SD) 5.8 (0.8) 4.8 (1.6) 5.6 (1.2) 5.7 (1.1)

Min, Max 1.0, 6.0 1.0, 6.0 1.0, 6.0 2.0, 7.0
 Treatment Compliance
Oral MMF twice daily Oral corticosteroids twice daily
Mean (SD): 70 MMF
2.5 (0.58) (g/day) IVC

Prednisone daily dose (mg/day, SD)

60

50

40
IVC in monthly pulses
30
Mean dose per
infusion: 20

0.78 g/m2 10
Mean (SD) doses per
0
month: 5.6 (1.1)
2 4 6 8 10 12 14 16 18 20 22 24
Week ending dosing period
 Primary Endpoint:
Responders at Month 6
Response was judged by a blinded 100
Clinical Endpoint Committee, by the

Proportion of patients reponding

criteria: 80

60 56.2%
Decrease in urine protein/creatinine 53.0%

(%)
ratio (P/CR)
40
– to <3 in patients nephrotic at
baseline (P/CR ≥3), 20
– or by ≥50% in patients
subnephrotic at baseline (P/CR <3) 0

and MMF IVC

Stabilization of serum creatinine MMF was not superior to IVC

level (p = 0.575)
(24-week level ±25% of baseline),
or improvement
 Primary Endpoint by Race
MMF
100
IVC
Patients responding to treatment (%)

90
p = 0.575 p = 0.236 p = 0.834 p = 0.033
80

70 63.9
60.4
60 56.2 56.0 54.2
53.0 53.2
50
38.5
40

30

20

10

Overall Asian Caucasian Other

 Primary Endpoint by Ethnicity
100 MMF
90 IVC

p = 0.575 p = 0.011 p = 0.249

Patients responding to treatment (%)

80

70
60.9 61.0
60 56.2
53.0 53.7

50
38.8
40

30

20

10

0
Overall Hispanic Non-Hispanic
 Response by Region

100
Patients responding to treatment (%)

MMF
90 IVC
80
70 *
60
50
40
65.0% 67.6%
30 56.2% 53.0%
60.7% 56.6% 54.3%
52.6%
47.4%
20
32.0%
10
0
Overall Asia Latin America USA/Canada Rest of World
 Key Renal
Secondary Endpoints
 Complete remission as defined by:
1. return to normal serum creatinine level
2. proteinuria ≤500 mg/24 hr
3. inactive urinary sediment
 Remission in each one of these individual
parameters

 Anti-dsDNA, C3, C4 and serum albumin

 Remission Rates by
Renal Criteria
100 MMF (n = 185)
Patients with remission (%)

90
80 IVC (n = 185)
70.3% 67.6%
70
60
50
40 31.4%
30 23.8% 27.0% 23.8%
20
8.6% 8.1%
10
0
Complete Serum Urine protein Urine sediment
remission creatinine

No significant differences between groups in complete remission or by

individual criteria
Patients who experienced AE ≥10% MMF IVC
Nausea 27 (14.7) 82 (45.6)
Vomiting 25 (13.6) 68 (37.8)
Headache 38 (20.7) 47 (26.1)
Alopecia 20 (10.9) 64 (35.6)
Diarrhea 52 (28.3) 23 (12.8)
Arthralgia 29 (15.8) 43 (23.9)
Peripheral edema 35 (19.0) 30 (16.7)
Nasopharyngitis 25 (13.6) 29 (16.1)
Hypertension 26 (14.1) 25 (13.9)
Leukopenia 11 (6.0) 38 (21.1)
Upper respiratory tract infection 17 (9.2) 28 (15.6)
Fever 12 (6.5) 30 (16.7)
Cough 24 (13.0) 16 (8.9)
Rash 19 (10.3) 21 (11.7)
 Summary of Deaths
 MMF group: 2 deaths in Argentina, 6 in China,
and 1 in Malaysia
 IVC group: 2 deaths in the USA, 2 in China, and
1 in the UK

 MMF group: 7 deaths were due to infections and

none due to SLE
 IVC group: 2 deaths due to infections, 2 due to
SLE
 Summary
 Study did not meet its primary objective of showing that
MMF was superior to IVC
 Response rates with MMF were consistent across racial,
ethnic, and regional groups
 Response rates lower with IVC compared with MMF in
non-Caucasian, non-Asian patients, ethnically Hispanic
patients, and patients in Latin America
 AE profiles for MMF and IVC were broadly similar over
24 weeks, and consistent with previous reports
 Overall incidence of adverse events and infections
similar between racial groups
 Ongoing maintenance phase compares MMF with
azathioprine for up to 3 years
 Degree and durability of remission
not optimal for many patients

 Many patients fail to achieve complete remission

 Less than 50% survival without end-stage renal disease
(ESRD) at 10 years in absence of complete remission.
 Significant rates of renal flare despite maintenance
therapy
 Adverse events can limit effective dosing of common
maintenance therapies for lupus nephritis
 High cost burden associated with lupus nephritis
 Costs escalate with degree of renal damage
 Many Patients Do Not Achieve
Complete Remission Following Induction

Prevalence of Complete Remission in Lupus Nephritis

Following Induction Therapy (24 weeks)

100% 94%

Mycophenolate Mofetil 77%

80%
IV Cyclophosphamide
Percentage
of Patients 60%

40% N = 140
23% (Intent-
20% to-treat
6% analysis)
0%
Complete Remission Partial or No Remission

Complete remission defined as return to within 10% of normal values of serum creatinine, proteinuria, and urine sediment.
Source: Ginzler et al. NEJM. 2005; 353(21)
 Importance of Maintaining
Complete Remission in Lupus Nephritis
Results of a long-term prospective study in patients with diffuse lupus nephritis

Patient Survival Without ESRD at 10 Years

100% 92%
Patient survival without
80% ESRD less than 50% at 10
years with partial remission
Percentage of
Patients 60%
Surviving 43% P<0.0001 (CR vs PR)
Without ESRD 40%

20% 13%

0% N = 86
Complete Partial Remission No Remission
Remission

Partial Remission: 50% reduction in baseline proteinuria to < 1.5 g/d with not more than 25% increase in baseline sCr.
Complete Remission: Proteinuria < 0.33 g/d and serum creatinine < 1.4 mg/dl
Source: Chen et al. Clin J Am Soc Neph. 2008; 3(1)
 Common Maintenance Therapies for Lupus Nephritis
Often Do Not Prevent Renal Flare
Contreras et al. Houssiau et al. Mok et al.
Study
NEJM. 2004; 350(10) A&R. 2004; 50(12) A&R. 2004;50(8)
Primarily Black and Hispanic Primarily Caucasian with Chinese patients with
Patient Type
with diffuse proliferative diffuse proliferative diffuse proliferative
nephritis (n=59) nephritis (n=89) nephritis (n=189)

IV CYC induction followed

High or low dose IV CYC CYC followed by
by maintenance with AZA,
Therapy CYC, or MMF with
following by maintenance maintenance AZA with
AZA with corticosteroids corticosteroids*
corticosteroids

Urine protein (P) > 2 g/d

after complete response
Doubling of urine protein / Severe renal flare not
Definition of OR doubling of P after
Cr ratio or sCr increase of responding to increase in partial response
Renal Flare 50% glucocorticoid dose
OR recurrent active
sediment regardless of P
Duration of
Follow-up 25 – 30 months ** 41 months 36 months
(Median)
Renal Flare
(% patients)
29% 28% 28%
* Maintenance therapy given at physician discretion; 75% of patients received AZA maintenance therapy.