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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 overall survival All classes of renal histology included 100% Caucasian Long duration (11 months) of nephritis prior to entry

Excluded patients with renal insufficiency Quarterly cyclophosphamide therapy employed Comorbidities over time not reported

Racial Disparity: Renal Survival for Class IV Lupus Nephritis Treated with IV CTX
120 100 80 60 40 20 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5
N=39
N=51

Non-blacks Blacks
p=0.007

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
Proportion without relapse Proportion without remission

1.0 0.8 0.6 0.4 0.2 0.0 0

Remission
Median time 10 mo 22% failed to remit after 2 yr

Relapse

1.0 0.8 0.6 0.4 0.2 0.0 0

Median time 79 mo 20% relapse after 18 mo

20 40 60 80 100 120
Time (mo from starting IV CYC)

20 40 60 80 100 120

Time (mo from starting IV CYC)

Proportion without re-remission

1.0 0.8 0.6 0.4 0.2 0.0 0

Re-remission
Median time 32 mo

20 40 60 80 100 120
Ioannidis JA et al. Kidney Int 2000; 57:258-264.

Time (mo from starting IV CYC)

Remission rates: MMF vs IVC


Intent-to-Treat analysis
60

p = 0.009 37/71

Responding (%)

50 40 30 20 10 0 Complete Remission Partial Remission Complete + Partial Remission

p = NS p = 0.005 16/71 21/7 17/69 1 21/69

4/69

MMF

IVC

Study endpoints
Number randomized Complete remission Partial remission No remission at 24 weeks on initial regimen Crossover to alternate regimen Withdrawal from study MMF 71 16 21 19 6 9 IVC 69 4 17 21 12 15

Study withdrawals
MMF

6 early

IVC

5 severe disease 1 non-compliance 2 crossover refusals 1 toxicity (rash)

13 early

3 late

No deaths

3 treatment refusals (1 death) 3 severe disease (2 deaths) 6 non-compliance (2 with GI toxicity) 1 lymphopenia
2 lost to follow-up

2 late

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


19 20 20 19 19 20 15 12 14 10 6 11 9 3 6 4 2 2 2 AZA 1 IVCY 2 MMF

0.25

0.00

12

24

36

48

60

72

Time (months)

Free of relapse
1.00 Cumulative probability
p = 0.021, MMF vs IVCY p = 0.124, AZA vs IVCY p = 0.222, MMF vs AZA

0.75

0.50

0.25
19 17 19 15 10 17 10 4 12 6 2 8 4 2 3 3 1 2 1 AZA 1 IVCY 1 MMF

0.00

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


Renal function Normal Permanently impaired End-stage renal disease Doubling of serum creatinine All patients (n = 85) High-dose IV CYC (n = 44) Low-dose IV CYC (n = 41)

67 18 4 8

34 10 3 1

33 8 1 7

Impaired renal function

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)

MMF

Randomized (n = 370)
Open-label treatment

IVC

Allocated to MMF (n = 185) Received MMF (n = 184)


Due to adverse event (n = 24) Consent withdrawn (n = 6) Other reason (n = 5)

Allocated to IVC (n = 185) Received IVC (n = 180)


Due to adverse event (n = 13) Consent withdrawn (n = 5) Other reason (n = 11)

Withdrawals (n = 35)

Withdrawals (n = 29)

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 (n = 185) Male Female Ethnicity Hispanic Non-Hispanic Race White Asian Other Black Non-black other 75 (40.5) 62 (33.5) 48 (25.9) 26 (14.1) 22 (11.9) 72 (38.9) 61 (33.0) 52 (28.1) 20 (10.8) 32 (17.3) 147 (39.7) 123 (33.2) 100 (27.0) 46 (12.4) 54 (14.6) 64 (34.6) 121 (65.4) 67 (36.2) 118 (63.8) 131 (35.4) 239 (64.6) 28 (15.1) 157 (84.9) IVC (n = 185) 29 (15.7) 156 (84.3) Total (n = 370) 57 (15.4) 313 (84.6)

Baseline Disease Characteristics by Race (ITT Population)


Caucasian
MMF
(n=75)

Black
MMF
(n=26)

Asian
MMF
(n=62)

Other
IVC MMF
(n=22)

IVC
(n=72)

IVC
(n=20)

IVC
(n=32)

(n=61)

Duration SLE Duration LN Urine Protein: Cr ratio Estimated GFR

6.3
(5.9) 3.0 (3.9) 3.7 (3.2) 83.1 (44.8)

7.2 (6.9) 4.3 (6.0) 3.8 (3.3) 81.7 (38.1)

5.7 (8.2) 1.8 (2.1) 3.8 (2.9) 103.8 (44.5)

5.0 (4.1) 2.8 (3.3) 3.8 (2.9) 97.1 (56.0)

3.6 (4.2) 2.8 (3.6) 4.7 (5.6) 86.4 (42.6)

2.3 (2.5) 1.9 (2.2) 4.1 (2.8) 103.4 (47.7)

8.5 (7.2) 3.5 (4.7) 4.3 (3.6)

5.9 (6.8) 3.0 (4.4) 5.0 (3.8)

66.0 91.9 (34.9) (43.1)

Drug Exposure by Race


Caucasian (n = 72) Black (n = 20) Asian (n = 61) Other (n = 32)

MMF mean daily dose Mean (SD) Min, Max Number of IVC infusions Mean (SD) Min, Max

71 2.45 (0.46) 1.0, 3.3

26 2.49 (0.45) 1.5, 3.2

61 2.40 (0.77) 0.3, 6.8

21 2.74 (0.45) 1.8, 3.6

71 5.8 (0.8) 1.0, 6.0

18 4.8 (1.6) 1.0, 6.0

60 5.6 (1.2) 1.0, 6.0

31 5.7 (1.1) 2.0, 7.0

Treatment Compliance
Oral MMF twice daily
Mean (SD): 2.5 (0.58) (g/day) Oral corticosteroids twice daily
70
Prednisone daily dose (mg/day, SD)

MMF IVC

60 50 40 30 20 10 0 2 4 6 8 10 12 14 16 18 20 22 24 Week ending dosing period

IVC in monthly pulses Mean dose per infusion: 0.78 g/m2 Mean (SD) doses per month: 5.6 (1.1)

Primary Endpoint: Responders at Month 6


Proportion of patients reponding (%)

Response was judged by a blinded Clinical Endpoint Committee, by the criteria: Decrease in urine protein/creatinine ratio (P/CR) to <3 in patients nephrotic at baseline (P/CR 3), or by 50% in patients subnephrotic at baseline (P/CR <3) and Stabilization of serum creatinine level (24-week level 25% of baseline), or improvement

100 80 60 40 20 0 56.2% 53.0%

MMF

IVC

MMF was not superior to IVC (p = 0.575)

Primary Endpoint by Race


MMF
100

Patients responding to treatment (%)

IVC p = 0.575 p = 0.236 p = 0.834 p = 0.033

90 80 70 60 50 40 30 20 10 0

63.9 56.2 53.0 53.2 56.0 54.2

60.4

38.5

Overall

Asian

Caucasian

Other

Primary Endpoint by Ethnicity


100 90
Patients responding to treatment (%)

MMF IVC p = 0.575 p = 0.011 p = 0.249

80 70

60.9

61.0 53.7

60 50 40 30 20 10 0

56.2

53.0

38.8

Overall

Hispanic

Non-Hispanic

Response by Region
Patients responding to treatment (%)
100 90 80 70 60 50 40 30 20 10 0
Overall Asia Latin America USA/Canada Rest of World
65.0% 56.2% 53.0% 52.6% 32.0% 60.7% 67.6% 56.6% 47.4% 54.3%

MMF IVC

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 90 80 70 60 50 40 30 20 10 0
Patients with remission (%)

MMF (n = 185) 70.3% 67.6% IVC (n = 185)

23.8% 27.0% 8.6% 8.1%

31.4% 23.8%

Complete remission

Serum creatinine

Urine protein Urine sediment

No significant differences between groups in complete remission or by individual criteria

Patients who experienced AE 10%


Nausea

MMF
27 (14.7)

IVC
82 (45.6)

Vomiting
Headache Alopecia

25 (13.6)
38 (20.7) 20 (10.9)

68 (37.8)
47 (26.1) 64 (35.6)

Diarrhea
Arthralgia Peripheral edema Nasopharyngitis Hypertension Leukopenia Upper respiratory tract infection Fever Cough Rash

52 (28.3)
29 (15.8) 35 (19.0) 25 (13.6) 26 (14.1) 11 (6.0) 17 (9.2) 12 (6.5) 24 (13.0) 19 (10.3)

23 (12.8)
43 (23.9) 30 (16.7) 29 (16.1) 25 (13.9) 38 (21.1) 28 (15.6) 30 (16.7) 16 (8.9) 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% 80% Mycophenolate Mofetil IV Cyclophosphamide 77% 94%

Percentage of Patients

60% 40% 23% 20% 6% 0% Complete Remission Partial or No Remission

N = 140 (Intentto-treat analysis)

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% 80% 92%
Patient survival without ESRD less than 50% at 10 years with partial remission

Percentage of Patients Surviving Without ESRD

60% 43% 40% 20% 0% Complete Remission Partial Remission

P<0.0001 (CR vs PR)


13%

N = 86
No 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
Study
Patient Type

Contreras et al. NEJM. 2004; 350(10)


Primarily Black and Hispanic with diffuse proliferative nephritis (n=59) IV CYC induction followed by maintenance with AZA, CYC, or MMF with corticosteroids

Houssiau et al. A&R. 2004; 50(12)


Primarily Caucasian with diffuse proliferative nephritis (n=89)

Mok et al. A&R. 2004;50(8)


Chinese patients with diffuse proliferative nephritis (n=189)

Therapy

High or low dose IV CYC following by maintenance AZA with corticosteroids

CYC followed by maintenance AZA with corticosteroids*


Urine protein (P) > 2 g/d after complete response OR doubling of P after partial response OR recurrent active sediment regardless of P

Definition of Renal Flare

Doubling of urine protein / Cr ratio or sCr increase of 50%

Severe renal flare not responding to increase in glucocorticoid dose

Duration of Follow-up (Median)

25 30 months **

41 months

36 months

Renal Flare (% patients)

29%

28%

28%

* Maintenance therapy given at physician discretion; 75% of patients received AZA maintenance therapy.