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Efficacy and Safety of Mycophenolate (MMF) Vs Oral Cyclophosphamide (CYC) for Treatment of Scleroderma-Interstitial Lung Disease (Ssc-ILD): Results of Scleroderma Lung Study II

Donald Tashkin, MD; Michael Roth, MD; Philip Clements, MD; Daniel Furst, MD; Dinesh Khanna, MD; Jonathan Goldin, MD; Eric Kleerup, MD; Edgar Arriola, PharmD; Chi-Hong Tseng, PhD; Robert Elashoff, PhD
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University of California Los Angeles, Los Angeles, CA


Chest. 2015;148(4_MeetingAbstracts):637A. doi:10.1378/chest.2331164
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Abstract

SESSION TITLE: Late Breaking Abstracts

SESSION TYPE: Late Breaking Abstract Slide

PRESENTED ON: Tuesday, October 27, 2015 at 08:45 AM - 10:00 AM

PURPOSE: ILD occurs in ~40% of SSc patients and is the leading cause of death. Treating SSc-ILD for 1 yr with oral CYC led to modest but significant improvements in lung function and dyspnea vs. placebo (Tashkin NEJM 2006) but the benefits were lost at 2 yrs (Tashkin AJRCCM 2007). In the present double-blind randomized controlled trial (RCT) we hypothesized that oral MMF for 2 yrs would be safer, better tolerated and at least as efficacious as CYC in patients with SSc-ILD. .

METHODS: 142 SSc-ILD patients from 14 sites were randomized to MMF (≤1.5 g bid) for 2 yrs or CYC (≤2 mg/kg/d) for 1 yr followed by placebo. Inclusion criteria: age 18-75 yrs; disease duration ≤7 yrs; FVC 45-80% pred; presence of any ground glass opacity (GGO) on HRCT. Exclusion criteria: pulmonary hypertension (PHTN) requiring treatment (Rx); DLCO < 40% pred (30-39% pred if no evidence of PHTN); FEV1/FVC <65%; active smoking. Lung function and other measures were assessed q3 mo. The 1o endpoint was % pred FVC over 24 mo assessed using a joint longitudinal model (Elashoff Statist Med 2006).

RESULTS: Of 73 pts randomized to CYC and 69 to MMF, 36 on CYC (~50%) and 20 on MMF (~29%) failed to complete the 24-mo Rx phase. Reasons included Rx failure, AEs, patient preference or compliance, and death. Time to Rx failure or withdrawal favored MMF (p=0.019; log-rank test). FVC % pred improved by 2.86±0.86 (p<0.001) and 2.17±0.85 (p<0.01) in the CYC and MMF arms, respectively, at 24 months (between-Rx difference p=0.24; joint model). DLCO % pred decreased by 2.77±1.35 (p=0.07) in the CYC arm and 0.53±1.23 (p=0.67) in the MMF arm (between- Rx difference favored MMF; p<0.001, joint model). Weight loss (ns) and leukopenia/thrombocytopenia (p<0.05) occurred more often in the CYC arm. SAEs were similar between arms. 16 deaths (CYC 11; MMF 5) occurred during the 2-yr trial.

CONCLUSIONS: Over 24 mo % pred FVC improved in patients assigned to both Rx arms with no significant between-Rx difference. Mean DLCO declined in both arms, but the decline was significant only in the CYC arm. MMF was better tolerated than CYC.

CLINICAL IMPLICATIONS: In this first RCT comparing MMF with CYC in SSc-ILD, both agents appeared to have comparable efficacy, but MMF was better tolerated with significantly fewer Rx failures and premature withdrawals and fewer adverse events. These findings support the increasingly common clinical practice of prescribing MMF for this disease..

DISCLOSURE: The following authors have nothing to disclose: Donald Tashkin, Michael Roth, Philip Clements, Daniel Furst, Dinesh Khanna, Jonathan Goldin, Eric Kleerup, Edgar Arriola, Chi-Hong Tseng, Robert Elashoff

This is an NIH-funded, investigator-initiated randomized controlled trial trial comparing the efficacy and safety of two generic drugs (mycophenolate mofetil and oral cyclophosphamide) for the treatment of scleroderma-related interstitial lung disease, an orphan disease for which no therapeutic agent is currently FDA-approved. While Roche Pharmaceuticals provided the mycophenolate free of charge to the investiators, Roche had no input into the design or conduct of the study nor was it involved in the analysis or interpretation of the data. The author has no financial involvement with Roche..


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