7.13.09 dooley lupus nephritis(1)

7/27/2019 7.13.09 Dooley Lupus Nephritis(1)

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Cyclophosphamide vs

Mycophenylate mofetil forlupus nephritis

The curse of living in interesting times?

Mary Anne Dooley

March, 2009


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Cytotoxic Therapy Prolongs Renal

Survival


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The NIH Protocol

Improved RENAL not

overall survival

All classes of renal

histology included 100% Caucasian

Long duration (11

months) of nephritisprior to entry

Excluded patients with

renal insufficiency

Quarterly

cyclophosphamidetherapy employed

Comorbidities over time

not reported


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Racial Disparity: Renal Survival for Class IV

Lupus Nephritis Treated with IV CTX

0

20

40

60

80

100

120

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5

Non-blacks

Blacks

p=0.007

Years from renal biopsy

N=39

N=51

M Dooley et al, Kidney Int 1997; 51:1188-1195


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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


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Diffuse GN (WHO IV)

Austin, Sem Nephrol 19:2, 1999

Majority

caucasian

cohorts

MajorityAfrican

American

cohorts


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Racial Disparity in response to cyclophosphamide

Boumpas, Lancet 340:741, 1992

R i i l d i i f


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Remission, relapse, and re-remission of

proliferative lupus nephritis treated with

cyclophosphamide

Ioannidis JA et al. Kidney Int2000; 57:258-264.

Proportionwithout

re-remission

0.0

0.2

0.4

0.6

0.8

1.0

0 20 40 60 80 100 120

Median time 10 mo

22% failed to remit after 2 yr

P

roportionwithout

remission

Time (mo from starting IV CYC)

Remission


Median time 32 mo

0.0

0.2

0.40.6

0.8

1.0

0 20 40 60 80 100 120

Re-remission

P

roportionwithout

relapse

Median time 79 mo

20% relapse after 18 mo0.0

0.2

0.4

0.6

0.8

1.0

0 20 40 60 80 100 120


Relapse


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Remission rates: MMF vs IVC

0

10

20

30

40

50

60

Complete Remission Partial Remission Complete + Partial

Remission

MMF IVC

16/71

4/69

21/7

1 17/69

37/71

21/69

Intent-to-Treat analysis

p= NSp= 0.005

p= 0.009

Respondin

g(%)


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Study endpoints

MMF IVC

Number randomized 71 69

Complete remission 16 4

Partial remission 21 17

No remission at 24 weeks on initial

regimen19 21

Crossover to alternate regimen 6 12

Withdrawal from study 9 15


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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


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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 weeksof enrollment


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19 19 15 10 9 4 2 AZA

20 19 12 6 3 2 1 IVCY

20 20 14 11 6 2 2 MMF

Time (months)

C

umulativeprobability

Patient survival

p= 0.11, MMF vs IVCY

p= 0.02, AZA vs IVCY

p= 0.33, MMF vs AZA

0.00

0.25

0.50

0.75

1.00

0 12 24 36 48 60 72


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MMF vs. CTX for Lupus Nephritis

350 Patient Two-Phase study with a

6 month induction followed by up to

3 year maintenance


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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

Renal functionAll patients

(n = 85)High-dose IV CYC

(n = 44)

Low-dose

IV CYC(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

Euro-Lupus Nephritis Trial


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Rapid response predicts better

long-term outcome


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Dutch Study:

WHO class switches CTX vs. AZA


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Drug Exposure by Race

Caucasian(n = 72)

Black(n = 20)

Asian(n = 61)

Other(n = 32)

MMF mean daily

dose

71 26 61 21

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 IVCinfusions 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


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Treatment Compliance

Oral MMF twice daily

Mean (SD):

2.5 (0.58) (g/day)

IVC in monthly pulses

Mean dose per

infusion:

0.78 g/m2

Mean (SD) doses per

month: 5.6 (1.1)

Oral corticosteroids twice daily

0

10

20

30

40

50

60

70

2 4 6 8 10 12 14 16 18 20 22 24

Week ending dosing period

Prednisone

dailydose(mg/day

,SD)

MMF

IVC

P i E d i


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Primary Endpoint:

Responders at Month 6

56.2%

53.0%

0

20

40

60

80

100

Proportionofpatients

reponding

(%)

Response was judged by a blinded

Clinical Endpoint Committee, by the

criteria:

Decrease in urine protein/creatinineratio (P/CR)

to


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Primary Endpoint by Race

60.456.056.253.2

38.5

54.2

63.9

53.0

0

10

20

30

40

50

60

70

80

90

100

Overall Asian Caucasian Other

Patientsrespondingtotr

eatment(%)

MMF

IVC

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


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Response by Region

52.6%60.7% 56.6% 54.3%

32.0%

47.4%

67.6%

56.2%65.0%

53.0%

0

10

20

3040

50

60

70

80

90

100

Overall Asia Latin America USA/Canada Rest of World

Patientsres

pondingtotreatment(%)

MMF

IVC

*


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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


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Remission Rates by

Renal Criteria

31.4%23.8%

70.3%

8.6%

23.8%27.0%

67.6%

8.1%

0

10

20

30

40

50

60

70

80

90

100

Complete

remission

Serum

creatinine

Urine protein Urine sediment

Patientswithre

mission(%) MMF (n = 185)

IVC (n = 185)

No significant differences between groups in complete remission or byindividual criteria


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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)


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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


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Many Patients Do Not Achieve


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Many Patients Do Not Achieve

Complete Remission Following Induction

23%

77%

94%

6%

0%

20%

40%

60%

80%

100%

Complete Remission Partial or No Remission

Mycophenolate Mofetil

IV Cyclophosphamide

Prevalence of Complete Remission in Lupus Nephritis

Following Induction Therapy (24 weeks)

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)

N = 140

(Intent-

to-treatanalysis)

Percentage

of Patients


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C M i Th i f L N h i i


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Common Maintenance Therapies for Lupus Nephritis

Often Do Not Prevent Renal Flare

StudyContreras et al.

NEJM. 2004; 350(10)

Houssiau et al.

A&R. 2004; 50(12)

Mok et al.

A&R. 2004;50(8)

Patient TypePrimarily Black and Hispanic

with diffuse proliferative

nephritis (n=59)

Primarily Caucasian with

diffuse proliferative

nephritis (n=89)

Chinese patients with

diffuse proliferative

nephritis (n=189)

Therapy

IV CYC induction followed

by maintenance with AZA,

CYC, or MMF with

corticosteroids

High or low dose IV CYC

following by maintenance

AZA with corticosteroids

CYC followed by

maintenance AZA with

corticosteroids*

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

Urine protein (P) > 2 g/d

after complete response

OR doubling of P after

partial response

OR recurrent active

sediment regardless of P

Duration of

Follow-up

(Median)2530 months ** 41 months 36 months

Renal Flare

(% patients)29% 28% 28%

7.13.09 dooley lupus nephritis(1)

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