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Cyclophosphamide vs Mycophenylate mofetil for lupus nephritis The curse of living in interesting times? Mary Anne Dooley March, 2009.

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Presentation on theme: "Cyclophosphamide vs Mycophenylate mofetil for lupus nephritis The curse of living in interesting times? Mary Anne Dooley March, 2009."— Presentation transcript:

1 Cyclophosphamide vs Mycophenylate mofetil for lupus nephritis The curse of living in interesting times? Mary Anne Dooley March, 2009

2 Cytotoxic Therapy Prolongs Renal Survival

3 The “NIH Protocol” Improved RENAL not overall survival Improved RENAL not overall survival All classes of renal histology included All classes of renal histology included 100% Caucasian 100% Caucasian Long duration (11 months) of nephritis prior to entry Long duration (11 months) of nephritis prior to entry Excluded patients with renal insufficiency Quarterly cyclophosphamide therapy employed Comorbidities over time not reported

4 Racial Disparity: Renal Survival for Class IV Lupus Nephritis Treated with IV CTX p=0.007 Years from renal biopsy % Probability of renal survival N=39 N=51 M Dooley et al, Kidney Int 1997; 51:

5 Renal Survival by Race at UNC Independent of the following factors: l Age l Duration of SLE l History of hypertension l Hypertension control during therapy l Activity or chronicity indices on renal biopsy l Pattern of corticosteroid therapy

6 Diffuse GN (WHO IV) Austin, Sem Nephrol 19:2, 1999 Majority caucasian cohorts Majority African American cohorts

7 Racial Disparity in response to cyclophosphamide Boumpas, Lancet 340:741, 1992

8 Remission, relapse, and re-remission of proliferative lupus nephritis treated with cyclophosphamide Ioannidis JA et al. Kidney Int 2000; 57: Proportion without re-remission Median time 10 mo 22% failed to remit after 2 yr Proportion without remission Time (mo from starting IV CYC) Remission Time (mo from starting IV CYC) Median time 32 mo Re-remission Proportion without relapse Median time 79 mo 20% relapse after 18 mo Time (mo from starting IV CYC) Relapse

9 Remission rates: MMF vs IVC 16/71 4/69 21/7 1 17/69 37/71 21/69 Intent-to-Treat analysis p = NS p = p = Responding (%)

10 Study endpoints MMFIVC Number randomized 7169 Complete remission 16 4 Partial remission 2117 No remission at 24 weeks on initial regimen 1921 Crossover to alternate regimen 612 Withdrawal from study 915

11 Study withdrawals MMF 6 early 6 early 5 severe disease 5 severe disease 1 non-compliance 1 non-compliance 3 late 3 late 2 crossover refusals 2 crossover refusals 1 toxicity (rash) 1 toxicity (rash) No deaths No deaths IVC 13 early 13 early 3 treatment refusals (1 death) 3 treatment refusals (1 death) 3 severe disease (2 deaths) 3 severe disease (2 deaths) 6 non-compliance (2 with GI toxicity) 6 non-compliance (2 with GI toxicity) 1 lymphopenia 1 lymphopenia 2 late 2 late 2 lost to follow-up 2 lost to follow-up

12 University of Miami Study Methods: Study design & patient population Open label, randomized clinical trial Open label, randomized clinical trial Inclusion criteria Inclusion criteria Adults > 18 years of age, World Health Organization (WHO) classes III, IV, V with proliferation Adults > 18 years of age, World Health Organization (WHO) classes III, IV, V with proliferation Exclusion criteria Exclusion criteria Have received IVCY > 7 doses or AZA > 8 weeks Have received IVCY > 7 doses or AZA > 8 weeks Creatinine clearance < 20 mL/min Creatinine clearance < 20 mL/min Pregnancy Pregnancy Any clinically significant infection within 2 weeks of enrollment Any clinically significant infection within 2 weeks of enrollment

13 AZA IVCY MMF Time (months) Cumulative probability Patient survival p = 0.11, MMF vs IVCY p = 0.02, AZA vs IVCY p = 0.33, MMF vs AZA

14 Free of relapse p = 0.021, MMF vs IVCY p = 0.124, AZA vs IVCY p = 0.222, MMF vs AZA Cumulative probability AZA IVCY MMF Time (months)

15 MMF vs. CTX for Lupus Nephritis 350 Patient Two-Phase study with a 6 month induction followed by up to 3 year maintenance

16 Permanently impaired renal function was defined as a serum creatinine value that was repeatedly 1.4 mg/dl. Houssiau FA. Arthritis Rheum 50: Renal function All patients (n = 85) High-dose IV CYC (n = 44) Low-dose IV CYC (n = 41) Normal Permanently impaired End-stage renal disease 431 Doubling of serum creatinine 817 Impaired renal function 660 Euro-Lupus Nephritis Trial

17 No difference in LD vs HD CTX

18 Rapid response predicts better long-term outcome

19 Dutch Study: WHO class switches CTX vs. AZA

20 Increased chronicity in patients given AZA

21

22 Assessed (n = 460) Randomized (n = 370) Open-label treatment Allocated to MMF (n = 185) Received MMF (n = 184) Withdrawals (n = 35) Due to adverse event (n = 24) Consent withdrawn (n = 6) Other reason (n = 5) Allocated to IVC (n = 185) Received IVC (n = 180) Withdrawals (n = 29) Due to adverse event (n = 13) Consent withdrawn (n = 5) Other reason (n = 11) Maintenance phase Double-blind re-randomization to corticosteroids plus MMF or azathioprine for up to 3 years Primary endpoint: responders in randomized population (n = 370) Excluded (n = 90) Responders MMFIVC

23 Demographic Characteristics: Intent-To-Treat Population MMF (n = 185) IVC (n = 185) Total (n = 370) Male28 (15.1)29 (15.7)57 (15.4) Female157 (84.9)156 (84.3)313 (84.6) Ethnicity Hispanic64 (34.6)67 (36.2)131 (35.4) Non-Hispanic121 (65.4)118 (63.8)239 (64.6) Race White75 (40.5)72 (38.9)147 (39.7) Asian62 (33.5)61 (33.0)123 (33.2) Other48 (25.9)52 (28.1)100 (27.0) Black26 (14.1)20 (10.8)46 (12.4) Non-black other22 (11.9)32 (17.3)54 (14.6)

24 Baseline Disease Characteristics by Race (ITT Population) CaucasianBlackAsianOther MMFIVCMMFIVCMMFIVCMMFIVC (n=75)(n=72)(n=26)(n=20)(n=62)(n=61)(n=22)(n=32) Duration SLE 6.3 (5.9) 7.2 (6.9) 5.7 (8.2) 5.0 (4.1) 3.6 (4.2) 2.3 (2.5) 8.5 (7.2) 5.9 (6.8) Duration LN 3.0 (3.9) 4.3 (6.0) 1.8 (2.1) 2.8 (3.3) 2.8 (3.6) 1.9 (2.2) 3.5 (4.7) 3.0 (4.4) Urine Protein: Cr ratio 3.7 (3.2) 3.8 (3.3) 3.8 (2.9) 3.8 (2.9) 4.7 (5.6) 4.1 (2.8) 4.3 (3.6) 5.0 (3.8) Estimated GFR 83.1 (44.8) 81.7 (38.1) (44.5) 97.1 (56.0) 86.4 (42.6) (47.7) 66.0 (34.9) 91.9 (43.1)

25 Drug Exposure by Race Caucasian (n = 72) Black (n = 20) Asian (n = 61) Other (n = 32) MMF mean daily dose Mean (SD)2.45 (0.46)2.49 (0.45)2.40 (0.77)2.74 (0.45) Min, Max1.0, , , , 3.6 Number of IVC infusions Mean (SD)5.8 (0.8)4.8 (1.6)5.6 (1.2)5.7 (1.1) Min, Max1.0, , 7.0

26 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/m 2 Mean (SD) doses per month: 5.6 (1.1) Oral corticosteroids twice daily

27 Primary Endpoint: Responders at Month 6 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 MMF was not superior to IVC (p = 0.575) MMF IVC

28 Primary Endpoint by Race

29 Primary Endpoint by Ethnicity

30 Response by Region

31 Key Renal Secondary Endpoints Complete remission as defined by: return to normal serum creatinine level proteinuria ≤500 mg/24 hr inactive urinary sediment Remission in each one of these individual parameters Anti-dsDNA, C3, C4 and serum albumin

32 Remission Rates by Renal Criteria No significant differences between groups in complete remission or by individual criteria

33 Patients who experienced AE ≥10% MMFIVC Nausea27 (14.7)82 (45.6) Vomiting25 (13.6)68 (37.8) Headache38 (20.7)47 (26.1) Alopecia20 (10.9)64 (35.6) Diarrhea52 (28.3)23 (12.8) Arthralgia29 (15.8)43 (23.9) Peripheral edema35 (19.0)30 (16.7) Nasopharyngitis25 (13.6)29 (16.1) Hypertension26 (14.1)25 (13.9) Leukopenia11 (6.0)38 (21.1) Upper respiratory tract infection17 (9.2)28 (15.6) Fever12 (6.5)30 (16.7) Cough24 (13.0)16 (8.9) Rash19 (10.3)21 (11.7)

34 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

35 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

36 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

37 Many Patients Do Not Achieve Complete Remission Following Induction 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-treat analysis) Percentage of Patients

38 Importance of Maintaining Complete Remission in Lupus Nephritis 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) N = 86 Results of a long-term prospective study in patients with diffuse lupus nephritis Patient survival without ESRD less than 50% at 10 years with partial remission Percentage of Patients Surviving Without ESRD Patient Survival Without ESRD at 10 Years P< (CR vs PR)

39 Common Maintenance Therapies for Lupus Nephritis Often Do Not Prevent Renal Flare Study Contreras et al. NEJM. 2004; 350(10) Houssiau et al. A&R. 2004; 50(12) Mok et al. A&R. 2004;50(8) Patient Type Primarily 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) 25 – 30 months ** 41 months 36 months Renal Flare (% patients) 29%28% * Maintenance therapy given at physician discretion; 75% of patients received AZA maintenance therapy.


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