Mycophenolate Mofetil Arm Research Articles

A pharmacoeconomic study comparing the use of mycophenolate mofetil or cyclophosphamide as induction therapy in lupus nephritis patients in Egypt

Lupus nephritis (LN) is a major and serious complication of systemic lupus erythematosus (SLE) and is associated with morbidity and mortality. The difference in drug cost between mycophenolate mofetil (MMF) and cyclophosphamide (CYC) inducing regimens becomes a relevant and realistic issue, especially in developing countries. Thus, this study aims to estimate and compare the costs and outcomes of CYC and MMF for better allocation of resources to reduce the burden on the Egyptian healthcare system. A prospective, parallel observational study was conducted at Kasr Al-Aini Hospital between 2018 and 2020. One hundred and twenty-two LN patients were followed up monthly during the study period. Remission and maintenance of renal remission were assessed at 6 and 12months from the start of therapy. Total direct medical costs associated with both regimens were examined. We applied the cost-minimization analysis method from governmental perspective. Besides, a prospective evaluation of reported changes in health-related quality of life using SF-36 was included in our study. There was no statistically significant difference in treatment response at 6 and 12months (RR 0.6 [0.26;1.43] and 0.8 [0.27;2.33]), respectively, as well as the incidence of infection episodes between MMF and CYC group (71.4% versus 70.45%, p > 0.05). The average direct medical expenditures per patient in the MMF group were approximately one and half times more than the CYC group (2339.69 $ versus 1329.03 $, p <0.001). The CYC arm was associated with lower costs than the MMF arm, with equally effective outcomes indicating that CYC is an attractive treatment option.

Peripheral blood gene expression profiling shows predictive significance for response to mycophenolate in systemic sclerosis-related interstitial lung disease

ObjectivesTo characterise the peripheral blood cell (PBC) gene expression changes ensuing from mycophenolate mofetil (MMF) or cyclophosphamide (CYC) treatment and to determine the predictive significance of baseline PBC transcript scores...

Predictive Significance of Serum Interferon-Inducible Protein Score for Response to Treatment in Systemic Sclerosis-Related Interstitial Lung Disease.

Response to immunosuppression is highly variable in systemic sclerosis (SSc)-related interstitial lung disease (ILD). This study was undertaken to determine whether a composite serum interferon (IFN)-inducible protein score exhibits predictive significance for the response to immunosuppression in SSc-ILD. Serum samples collected in the Scleroderma Lung Study II, a randomized controlled trial of mycophenolate mofetil (MMF) versus cyclophosphamide (CYC), were examined. Results were validated in an independent observational cohort receiving active treatment. A composite score of 6 IFN-inducible proteins IFNγ-inducible 10-kd protein, monokine induced by IFNγ, monocyte chemotactic protein 2, β2 -microglobulin, tumor necrosis factor receptor type II, and macrophage inflammatory protein 3β) was calculated, and its predictive significance for longitudinal forced vital capacity percent predicted measurements was evaluated. Higher baseline IFN-inducible protein score predicted better response over 3 to 12 months in the MMF arm (point estimate = 0.41, P = 0.001) and CYC arm (point estimate = 0.91, P = 0.009). In contrast, higher baseline C-reactive protein (CRP) levels were predictive of a worse ILD course in both treatment arms. The predictive significance of the IFN-inducible protein score and CRP levels remained after adjustment for baseline demographic and clinical predictors. During the second year of treatment, in which patients in the CYC arm were switched to placebo, a higher IFN-inducible protein score at 12 months showed a trend toward predicting a worse ILD course (point estimate = -0.61, P = 0.068), while it remained predictive of better response to active immunosuppression in the MMF arm (point estimate = 0.28, P = 0.029). The predictive significance of baseline IFN-inducible protein score was replicated in the independent cohort (rs = 0.43, P = 0.028). A higher IFN-inducible protein score in SSc-ILD is predictive of better response to immunosuppression and could potentially be used to identify patients who may derive the most benefit from MMF or CYC.

Effect of mycophenolate mofetil (MMF) on systemic sclerosis-related interstitial lung disease with mildly impaired lung function: a double-blind, placebo-controlled, randomized trial.

The efficacy and safety of mycophenolate mofetil (MMF) has been studied in patients with systemic sclerosis (SSc)-related interstitial lung disease (ILD) with moderate-severe impairment. There is no study on its use in patients with mildly impaired lung function. The objective of this study is to determine the efficacy and safety of MMF for treating mild SSc-ILD (forced vital capacity (FVC) ≥ 70% predicted). This was a double-blind, randomized, placebo-controlled pilot trial. The subjects with SSc-ILD with FVC ≥ 70% were randomized to receive either MMF (2g/day) or placebo for 6months. FVC, diffusing capacity of lungs for carbon monoxide (DLCO), modified Rodnan skin score (mRSS), Short Form-36 (SF36v2), Mahler's Dyspnoea Index (MDI), and 6-min walk distance (6MWD) were recorded at baseline and at 6months. Forty-one subjects were included in the study (MMF: 20, placebo: 21). FVC decreased by a median of 2.7% (range -21 to 9) in MMF arm and increased by 1% (range -6 to 10) in placebo arm (p = 0.131). SF36v2 scores improved in both the groups. Median change in MDI (3 vs 3), DLCO (1% vs 1.5%), and 6MWD (0m vs 0m) was similar between the study groups. MMF was effective in improving mRSS (-5 vs -1, p = 0.045) compared to placebo. Adverse events occurred with similar frequency in both the study groups. In this pilot study, MMF did not result in significant improvement in lung function in SSc-ILD with minimally impaired lung function, but was effective in reducing the skin tightness. Larger studies are needed to confirm these findings. This study was registered at ClinicalTrials.gov (NCT02896205).

Corticosteroid-Sparing and Optimization of Mycophenolic Acid Exposure in Liver Transplant Recipients Receiving Mycophenolate Mofetil and Tacrolimus: A Randomized, Multicenter Study.

We conducted a randomized multicenter open-label trial in de novo liver transplant recipients to assess the feasibility and potential benefit of a corticosteroid (CS)-free regimen coupled with tacrolimus (Tac) and dose-intensified mycophenolate mofetil (MMF) further adjusted individually. Adult liver transplant recipients were randomized on the day of transplantation to a CS-free regimen with Tac and MMF starting at 3 g/d and dose adjusted from day 5 according to mycophenolic acid (MPA) exposure (arm A) or a regimen with CS maintained up to 6 months, Tac and fixed-dose MMF (2 g/d) (arm B). The primary end point was the proportion of patients who experienced treated biopsy-proven acute rejection (BPAR) during the first year posttransplant. One hundred eighty-seven patients were randomized, and 174 comprised the per-protocol population (87 in each arm). The primary objective of noninferiority was met: 7 patients in arm A (8%) and 8 in arm B (9%) experienced treated BPAR in the first year. Two patients in arm A (2%) and 5 in arm B (6%) lost their graft, and 12-month patient survival was similar in both arms (90.8% vs 89.8%; P = 0.86). Adverse events were comparable between arms, except for a lower incidence of de novo diabetes (19.8% vs 32.6%, P = 0.049) and a higher incidence of leukopenia less than 2000/mm (28.6% vs 9.8%; P = 0.001) and neutropenia (26.7% vs 7.9%; P < 0.001) in arm A. Mycophenolate mofetil at intensified and individually adjusted dose in combination with Tac in de novo liver transplant recipients allows CS discontinuation from day 1 posttransplant with good tolerance and very low rejection incidence.

Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial

SummaryBACKGROUNDTwelve months of oral cyclophosphamide (CYC) has been shown to alter the progression of scleroderma-related interstitial lung disease (SSc-ILD) when compared to placebo. However, toxicity was a concern and without continued treatment the efficacy disappeared by 24 months. We hypothesized that a two-year course of mycophenolate mofetil (MMF) would be safer, better tolerated and produce longer lasting improvements than CYC.METHODSPatients with SSc-ILD meeting defined dyspnea, pulmonary function and high-resolution computed tomography (HRCT) criteria were randomized in a double-blind, two-arm trial at 14 medical centers. MMF (target dose 1500 mg twice daily) was administered for 24 months in one arm and oral CYC (target dose 2·0 mg/kg/day) administered for 12 months followed by placebo for 12 months in the other arm. The primary endpoint, change in forced vital capacity as a percent of the predicted normal value (FVC %) over the course of 24 months, was assessed in a modified intention-to-treat analysis using an inferential joint model combining a mixed effects model for longitudinal outcomes and a survival model to handle non-ignorable missing data. The study was registered with ClinicalTrials.gov, number NCT00883129, and is closed.RESULTSBetween November, 2009, and January, 2013, 142 patients were randomized. 126 patients (63 MMF; 63 CYC) with acceptable baseline HRCT studies and at least one outcome measure were included in the analysis. The adjusted FVC % (primary endpoint) improved from baseline to 24 months by 2.17 in the MMF arm (95% CI, 0.53–3.84) and 2·86 in the CYC arm (95% confidence interval 1·19–4·58) with no significant between-treatment difference (p=0·24), indicating that the trial was negative for the primary endpoint. However, in a post-hoc analysis of the primary endpoint, within-treatment improvements from baseline to 24 months were noted in both the CYC and MMF arms. A greater number of patients on CYC than on MMF prematurely withdrew from study drug (32 vs 20) and failed treatment (2 vs 0), and the time to stopping treatment was significantly shorter in the CYC arm (p=0·019). Sixteen deaths occurred (11 CYC; 5 MMF) with most due to progressive ILD. Leukopenia (30 vs 4 patients) and thrombocytopenia (4 vs 0 patients) occurred more often in patients treated with CYC. In post-hoc analyses, within- (but not between-) treatment improvements were also noted in defined secondary outcomes including skin score, dyspnea and whole-lung HRCT scores.INTERPRETATIONTreatment of SSc-ILD with MMF for two years or CYC for one year both resulted in significant improvements in pre-specified measures of lung function, dyspnea, lung imaging, and skin disease over the 2-year course of the study. While MMF was better tolerated and associated with less toxicity, the hypothesis that it would have greater efficacy at 24 months than CYC was not confirmed. These findings support the potential clinical impact of both CYC and MMF for progressive SSc-ILD, as well as the current preference for MMF due to its better tolerability and toxicity profile.FUNDINGNational Heart, Lung and Blood Institute/National Institutes of Health with drug supply provided by Hoffmann-La Roche/Genentech.

Mycophenolate Mofetil Vs. Methotrexate for the Prophylaxis of Graft-Versus-Host-Disease - Systematic Review and Meta-Analysis of All Comparative Trials

AbstractAbstract 4169 Background:Mycophenolate mofetil (MMF) has emerged as a potential substitute to methotrexate in patients given calcineurin inhibitors for the prophylaxis of GVHD prior to allogeneic hematopoietic cell transplantation. However, a comprehensive literature evaluation of MMF vs. methotrexate is lacking. Objectives:This study aims to compare the efficacy and safety of MMF vs. methotrexate as part of the GVHD prophylaxis regimen in patients given allografts. Methods:Systematic review and meta-analysis of all comparative trials of patients given allografts and administered GVHD prophylaxis with a regimen containing MMF or methotrexate. Electronic search was conducted until June 2012. Primary outcome was acute GVHD. Secondary outcomes were all-cause mortality, relapse rate, non-relapse mortality, chronic GVHD, rate of mucositis, and the time to neutrophil and platelet engraftment. For dichotomous data, relative risks (RR) with 95% confidence intervals (CIs) were estimated and pooled. For continuous variables we calculated weighted mean difference (WMD). Results:Our search yielded 11 trials, 3 were randomized control trials (RCTs) and 8 were either one arm intervention trials compared to historical controls or retrospective studies. There was no difference in the overall incidence of acute GVHD (RR 1.06; 95% CI 0.93–1.21, 11 trials) with similar results in a sensitivity analysis including only RCTs. Conversely, incidence of grade 3–4 acute GVHD was higher in patients given MMF (RR 1.61; 95% CI 1.18–2.20, 6 trials, Figure). However, this association was no longer statistically significant when only patients given allografts from matched siblings or those given myloablative conditioning were analyzed (RR 1.56; 95% CI 0.95–2.55, 5 trials and RR 1.40; 95% CI 0.82–2.39, 4 trials). All cause mortality, non relapse mortality, relapse rate and the incidence of chronic GVHD were comparable between the two groups. Incidence of mucositis was significantly lower in patients given MMF (RR 0.35; 95% CI 0.25–0.49, 8 trials) and the time to neutrophil and platelet engraftment was shorter in the MMF arm (WMD (−4.05); 95% CI (−6.17) – (−1.3), 6 trials and WMD (−3.74); 95% CI (−6.3) – (−1.18), 4 trials, respectively). Conclusions:MMF, compared to methotrexate, given as GVHD prophylaxis is associated with reduced transplantation associated toxicities, however with increased severity of acute GVHD. Further RCTs to identify the subgroups of patients who will benefit the most from MMF are warranted. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Graft-versus-Host Disease: State of the Science

Despite concerted research efforts, prevention and treatment of graft-versus-host disease (GVHD) have not changed significantly over the past 3 decades. The goal of this session is to provide an outline of the current state of the science with respect to the prevention, treatment, and evaluation of acute and chronic GVHD. In addition, we detail those strategies most likely to be at the forefront of clinical research in the upcoming years.

A Randomized Phase II Trial Comparing Tacrolimus and Mycophenolate Mofetil to Tacrolimus and Methotrexate for Acute Graft-versus-Host Disease Prophylaxis

Tacrolimus (Tac) plus methotrexate (MTX) is a standard regimen for graft-versus-host disease (GVHD) prophylaxis. Mycophenolate mofetil (MMF) is sometimes used instead of MTX to minimize toxicity, despite the lack of controlled studies demonstrating efficacy. We conducted a single-center, randomized phase II trial comparing Tac + MMF to Tac + MTX. Intent-to-treat analyses included 42 patients randomized to Tac + MMF and 47 to Tac + MTX. Patient characteristics were not different between the study arms. Patients in the Tac + MMF arm were less likely to experience severe mucositis, require narcotic analgesia and parenteral nutrition, and had earlier hospital discharge. The Tac + MMF arm had the same time to neutrophil recovery, but earlier platelet recovery. The cumulative incidence of grade II-IV acute GVHD (aGVHD) at 100 days was similar (P = .8), but grade III-IV aGVHD was higher in the Tac + MMF arm (19% versus 4%; P = .03); this was predominantly seen in unrelated donor transplants (26% versus 4%; P = .04), and less in related donor transplants (11% versus 4%; P = n.s.). Moderate or severe chronic GVHD was similar (P = .71). There were no significant differences between the arms in relapse, nonrelapse mortality, or overall and relapse-free survivals. MMF was associated with less early toxicity than MTX but was not as effective in preventing severe aGVHD, especially in unrelated donor transplants.

Calcineurin Inhibitor Minimization in the Symphony Study: Observational Results 3 Years after Transplantation

The Symphony study showed that at 1 year posttransplant, a regimen based on daclizumab induction, 2 g mycophenolate mofetil (MMF), low-dose tacrolimus and steroids resulted in better renal function and lower acute rejection and graft loss rates compared with three other regimens: two with low-doses of cyclosporine or sirolimus instead of tacrolimus and one with no induction and standard cyclosporine dosage. This is an observational follow-up for 2 additional years with the same endpoints as the core study. Overall, 958 patients participated in the follow-up. During the study, many patients changed their immunosuppressive regimen (e.g. switched from sirolimus to tacrolimus), but the vast majority (95%) remained on MMF. During the follow-up, renal function remained stable (mean change: -0.6 ml/min), and rates of death, graft loss and acute rejection were low (all about 1% per year). The MMF and low-dose tacrolimus arm continued to have the highest GFR (68.6 +/- 23.8 ml/min vs. 65.9 +/- 26.2 ml/min in the standard-dose cyclosporine, 64.0 +/- 23.1 ml/min in the low-dose cyclosporine and 65.3 +/- 26.2 ml/min in the low-dose sirolimus arm), but the difference with the other arms was not significant (p = 0.17 in an overall test and 0.077, 0.039 and 0.11, respectively, in pair-wise tests). The MMF and low-dose tacrolimus arm also had the highest graft survival rate, but with reduced differences between groups over time, and the least acute rejection rate. In the Symphony study, the largest ever prospective study in de novo kidney transplantation, over 3 years, daclizumab induction, MMF, steroids and low-dose tacrolimus proved highly efficacious, without the negative effects on renal function commonly reported for standard CNI regimens.

Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease

AbstractWe conducted a double-blind, randomized multicenter trial to determine whether the addition of mycophenolate mofetil (MMF) improves the efficacy of initial systemic treatment of chronic graft-versus-host disease (GVHD). The primary endpoint was resolution of chronic GVHD and withdrawal of all systemic treatment within 2 years, without secondary treatment. Enrollment of 230 patients was planned, providing 90% power to observe a 20% difference in success rates between the 2 arms. The study was closed after 4 years because the interim estimated cumulative incidence of success for the primary endpoint was 23% among 74 patients in the MMF arm and 18% among 77 patients in the control arm, indicating a low probability of positive results for the primary endpoint after completing the study as originally planned. Analysis of secondary endpoints showed no evidence of benefit from adding MMF to the systemic regimen first used for treatment of chronic GVHD. The estimated hazard ratio of death was 1.99 (95% confidence interval, 0.9-4.3) among patients in the MMF arm compared with the control arm. MMF should not be added to the initial systemic treatment regimen for chronic GVHD. This trial was registered at www.clinicaltrials.gov as #NCT00089141 on August 4, 2004.

Effect of conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium on maximum tolerated dose and gastrointestinal symptoms following kidney transplantation

Despite the potential tolerability advantage of enteric-coated mycophenolate sodium (EC-MPS), no prospective, randomized trial has evaluated whether conversion from mycophenolate mofetil (MMF) to EC-MPS permits mycophenolic acid dose to be increased or gastrointestinal side-effects to be ameliorated. In a randomized, multicenter, open-label trial, kidney transplant recipients experiencing gastrointestinal side-effects either remained on MMF or switched to an equimolar dose of EC-MPS, adjusted 2 weeks subsequently to target the highest tolerated dose up to 1440 mg/day (EC-MPS) or 2000 mg/day (MMF). Patients were followed up to 12 weeks postrandomization. One hundred and thirty-four patients were randomized. The primary efficacy endpoint, the proportion of patients receiving a higher mycophenolic acid (MPA) dose at week 12 than at randomization, was significantly greater in the EC-MPS arm (32/68, 47.1%) than the MMF arm (10/61, 16.4%; P < 0.001). At the final visit, 50.0% (34/68) of EC-MPS patients were receiving the maximum recommended dose versus 26.2% (16/61) of MMF patients (P = 0.007). Kidney transplant patients receiving reduced-dose MMF because of gastrointestinal side-effects can tolerate a significant increase in MPA dose after conversion to EC-MPS. Patient-reported gastrointestinal outcomes with higher doses of EC-MPS remained at least as good as in MMF-treated controls.

BMT CTN 0302: A Phase II Randomized Trial Evaluating Etanercept, Mycophenolate Mofetil (MMF), Denileukin Diftitox, and Pentostatin in Combination with Corticosteroids in 180 Patients (pts) with Newly Diagnosed Acute Graft Vs. Host Disease (aGVHD)

On behalf of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) GVHD remains a major limitation of allogeneic hematopoietic cell transplantation (HCT). Steroids are the standard initial therapy yet prior data suggested only 35% complete response (CR) at day 28. We report the results of a randomized, four-arm, phase II trial designed to identify the most promising agent(s) for combination with steroids as initial therapy for aGVHD. Between August, 2005 and March, 2008, 180 pts with newly diagnosed aGVHD were randomized to receive steroids (2 mg/kg/day methylprednisolone) plus either: Etanercept, MMF, Denileukin Diftitox or Pentostatin. Pts who received MMF as GVHD prophylaxis in the preceding 7 days were randomized between the 3 non-MMF arms. The primary objective was to estimate the CR rate at day 28 for each of the four agents and evaluate secondary outcomes pertinent to the best agent for testing in a planned followup phase III trial vs steroids alone.PATIENTS AND RESULTS: Median age was 50 yrs (range, 7.5–69.9) with 96% >18 yrs; 39% had AML and 63% were male. The graft was peripheral blood (PB) in 61%, bone marrow (BM) in 25% and cord blood (CB) in 14% of pts. HCT was performed with myeloablative conditioning and/or unrelated donor grafts in 66% and 53%, respectively. Forty-four pts (24%) received MMF as aGVHD prophylaxis and were randomized to a non-MMF arm. At enrollment, 68% of patients had grade I-II aGVHD; 32% had grade III/IV. 53% of pts had visceral organ involvement at the time of enrollment. The treatment arms were balanced except CB grafts were more common in the Denileukin Diftitox arm (26%, p=0.006); PB were more common in the Etanercept arm (78%, p=0.006); and the MMF arm had more myeloablative HCT (82%, p=0.04). The proportion of CR at day 28 were: Etanercept (26%), MMF (60%), Denileukin Diftitox (53%) and Pentostatin (38%), and day 56 CR+PR rates were 59%, 78%, 68%, and 71%, respectively. 6 month chronic GVHD (cGVHD) incidence was: Etanercept (21%), MMF (25%), Denileukin Diftititox (29%), and Pentostatin (24%). Overall survival (OS) at 6 months was Etanercept (59%), MMF (71%), Denileukin Diftitox (63%), and Pentostatin (55%), respectively. After excluding pts who received MMF prophylaxis, the MMF arm still had the highest day 28 CR rate and OS. Overall toxicities and post-randomization infections were less frequent in pts randomized to MMF and Etanercept.CONCLUSIONS: These efficacy and toxicity data, particularly response, survival, cGVHD, and infections, suggest MMF + steroids to be the most promising regimen to compare against steroids alone in a randomized Phase III trial.Treatment ArmOutcomeEtanercept (N=46)MMF (N=45)Denileukin Diftitox (N=47)Pentostatin (N=42)Day 28 CR12 (26%)Skin: 12/36 (33%)27 (60%)Skin: 21/35 (60%)25 (53%)Skin: 17/35 (49%)16 (38%)Skin: 14/34 (41%)L.G.I.: 4/12 (33%)L.G.I.: 12/18 (67%)L.G.I.: 5/14 (36%)L.G.I.: 7/17 (41%)U.G.I.: 5/10 (50%)U.G.I.: 11/12 (92%)U.G.I.:10/14 (71%)U.G.I.: 8/13 (62%)Liver: 2/6 (33%)Liver: 5/7 (71%)Liver: 3/7 (43%)Liver: 2/5 (40%)Day 28 CR (excl. prior MMF )9 (28%)27 (60%)15 (48%)11 (39%)Day 28 CR/PR22 (48%)35 (78%)28 (60%)26 (62%)Day 56 CR/PR27 (59%)35 (78%)32 (68%)30 (71%)Day 56Treatment Failures12 (26%)4 (9%)12 (26%)13 (31%)OS Post-Randomization at 6 months59% (95% CI: 43%–72%)71% (95% CI: 54%–82%)63% (95% CI: 47%–76%)55% (95% CI: 38%–69%)OS Post-Randomization at 6 months (excl. prior MMF)70% (95% CI: 51%–83%)71% (95% CI: 54%–82%)61% (95% CI: 40%–76%)54% (95% CI: 33%–71%)Cum Incidence of Initial D/C of steroids at 9 months34% (95 % CI: 20%–48%)31% (95% CI: 17%–45%)20% (95% CI: 8%–32%)20% (95% CI: 8%–33%)Cum Incidence Day 56 Grade 3–5 Toxicity (%)76% (95% CI: 63%–88%)80% (95% CI: 67%–92%)76% 95% CI: 64%–89%)67% (95% CI: 52%–81%)Cum Incidence Severe/ Life Threatening/Fatal Infections at Day 27047% (95% CI: 32%–62%)44% (95% CI: 29%–59%)58% (95% CI: 43%–72%)56% (95% CI: 40%–71%)Cum Incidence of acute GVHD Flare after CR at Day 9036% (95% CI: 21%–50%)28% (95% CI: 14%–41%)35% (95% CI: 21%–49%)36% (95% CI: 21%–51%)Cum Incidence of cGVHD at Day 18021% (95% CI: 9%–33%)25% (95% CI: 11%–39%)29% (95% CI: 15%–43%)24% (95% CI: 10%–38%)Cum Incidence of Relapse at Day 18014% (95% CI: 3%–24%)10% (95% CI: 1%–19%)9% (95% CI: 1%–19%)13% (95% CI: 2%–24%)

Corticosteroid-free immunosuppression with daclizumab in HCV+ liver transplant recipients: 1-year interim results of the HCV-3 study

This work is a 1-yr interim analysis of a prospective, randomized, multicenter trial evaluating the effect of corticosteroid-free immunosuppression on hepatitis C virus-positive (HCV(+)) liver transplant recipients following liver transplantation (LT). Patients received tacrolimus and corticosteroids (Arm 1; n = 80); tacrolimus, corticosteroids, and mycophenolate mofetil (MMF) (Arm 2; n = 79); or daclizumab induction, tacrolimus, and MMF (Arm 3; n = 153). At 1 yr, 64.1%, 63.4%, and 69.4% of patients achieved the composite primary endpoint of freedom from rejection, freedom from HCV recurrence, and freedom from treatment failure, respectively. Excellent patient and graft survival did not differ significantly among treatment arms. Freedom from HCV recurrence at 1 yr was 61.8 +/- 6.2%, 60.1 +/- 6.1%, and 67.0 +/- 4.3% in Arms 1, 2, and 3, respectively (P = not significant). Freedom from rejection was significantly higher in Arm 3 compared to Arm 1 (93.0 +/- 2.2% vs. 81.9 +/- 4.4%; P = 0.011). Multivariate analysis identified acute rejection (hazard ratio = 2.692; P = 0.001) and donor age (hazard ratio = 1.015; P = 0.001) as significant risk factors for HCV recurrence. HCV recurrence was not influenced by recipient demographics, HCV genotype, or immunosuppression. In conclusion, these results suggest that a corticosteroid-free regimen of tacrolimus and MMF following daclizumab induction is safe and effective in HCV(+) liver transplant recipients.

Everolimus versus Mycophenolate Mofetil in the Prevention of Rejection in De Novo Renal Transplant Recipients: A 3-Year Randomized, Multicenter, Phase III Study

This 36-month, randomized, parallel-group study compared safety and efficacy of two doses of everolimus with mycophenolate mofetil (MMF) in de novo renal-transplant recipients. Renal-allograft recipients received 1.5 mg/day or 3 mg/day of everolimus or 2 g/day of MMF, plus full-dose cyclosporine (CsA) and corticosteroids after randomization. For at least their first year, patients received study medication according to a double-blinded, double-dummy design. Concerns over nephrotoxicity led to a protocol amendment to an open-label design with reduced CsA troughs. Incidences of primary efficacy failure at 36 months (biopsy-proven acute rejection, graft loss, death, or loss to follow-up) were everolimus 1.5 mg/day, 33.7% (65/193); everolimus 3 mg/day, 34.0% (66/194); and MMF, 31.1% (61/196) (P=0.810). Antibody-treated acute rejection at 36 months was significantly lower with everolimus 1.5 mg (9.8%) than MMF (18.4%, P=0.014). Discontinuation for adverse events was more frequent with everolimus and hemolytic uremic syndrome, lymphoproliferative disease, and proteinuria, and higher serum creatinine occurred at increased frequency relative to the MMF arm. Creatinine levels in the everolimus arms were stable in follow-up: the mean rise in creatinine over the first 6 months of the open-label phase was 3 micromol/L or greater with everolimus and 7 micromol/L with MMF. However, serum creatinine levels were lower in the MMF group throughout. Death and graft loss were higher in the everolimus arms (not significant). As part of triple-drug immunosuppression, everolimus (1.5 or 3 mg/day) was as efficacious as MMF, although the side-effect profile featured increased adverse events. Nephrotoxicity/calcineurin-inhibitor-related adverse events will require judicious lowering of CsA exposure with monitoring of everolimus troughs.

Long-Term Administration of Enteric-Coated Mycophenolate Sodium in Kidney Transplant Patients

A large-scale, controlled clinical study has shown that enteric-coated mycophenolate sodium (EC-MPS) is therapeutically equivalent to mycophenolate mofetil (MMF) in de novo renal transplant patients. Safety and efficacy outcomes from an open-label extension of this core study ( n = 122) were compared to those of the MMF arm of two well-controlled randomized studies (RAD B251, n = 141, and RAD B201, n = 150) for the 12- to 36-month posttransplant period. During this period, 33 (27%) EC-MPS patients experienced one or more drug-related adverse event. Sixteen patients (13%) discontinued the extension study due to adverse events. The incidence of all safety parameters was similar in the EC-MPS patients and the MMF-treated patients in the RAD B201 and RAD B251 studies during the 12- to 36-month posttransplant period, as was the frequency of adverse events, infections, malignancies, and hematological abnormalities. During the 24 months of the EC-MPS extension study, four patients died and two lost their graft. Biopsy-proven acute rejection (BPAR) occurred in four patients (3.3%). BPAR, graft loss, and death occurred in a similar proportion of MMF-treated patients in the RAD B201 and RAD B251 studies during months 12 to 36 posttransplant. These findings confirm the safety and efficacy of EC-MPS in maintenance transplant patients at least 1 year posttransplant and suggest that outcomes with EC-MPS are comparable to MMF in this population when used in combination with CsA-ME and steroids.

A prospective randomized trial comparing cyclosporine and short course methotrexate with cyclosporine and mycophenolate mofetil for GVHD prophylaxis in myeloablative allogeneic bone marrow transplantation

Cyclosporine (CSP) and short course methotrexate (MTX) have been the gold standard for GVHD prophylaxis for decades. Problems associated with MTX include increased time to hematopoietic engraftment, mucositis, and other organ toxicities. The combination of CSP with mycophenolate mofetil (MMF) has been used successfully for the prevention of graft rejection and GVHD in nonmyeloablative transplantation. We performed a prospective randomized trial comparing CSP and MTX with CSP and MMF in myeloablative (busulfan based) allogeneic 6/6 matched sibling bone marrow transplantation (BMT). The group receiving MMF (n = 21) had significantly less severe mucositis than did the group receiving MTX (n = 19) (21 vs 65%, P = 0.008). Median time to neutrophil engraftment was more rapid in the MMF group (11 vs 18 days, P < 0.001). The incidence of acute GVHD, as well as 100 day survival, was similar for both groups. The reduced toxicity of the CSP and MMF arm resulted in premature study closure. We conclude that a GVHD prophylaxis regimen of CSP and MMF after a myeloablative allogeneic preparative regimen is associated with faster hematopoietic engraftment, decreased incidence of mucositis, similar incidence of aGVHD, and comparable survival as compared to CSP and MTX.