Use Of Mycophenolate Mofetil Research Articles

Randomized trial of enteric-coated mycophenolate sodium versus mycophenolate mofetil in multi-system autoimmune disease.

BackgroundThe use of mycophenolate mofetil (MMF) in autoimmune disease is often limited by adverse effects. In this single-centre, open label, parallel design study, we investigated whether enteric-coated mycophenolate sodium (MS) is better tolerated and therefore more efficacious than MMF in primary systemic vasculitis (PSV) and systemic lupus erythematosus (SLE).MethodsForty patients with vasculitis or systemic lupus erythematosus (SLE) due to commence MMF for active disease or remission maintenance were randomized to receive either 1440 mg/day MS or 2000 mg/day MMF (18 PSV, 2 SLE per group) in addition to corticosteroids. Random allocation was performed by minimization for age, diagnosis and renal function using a computer algorithm. Twenty-five were treated for active disease (5 first-line therapy, 20 salvage therapy) and 15 for remission maintenance. The composite primary end point was treatment failure and/or drug intolerance over 12 months. Treatment failure was defined as failure to achieve remission by 6 months or disease relapse and treatment intolerance was defined as inability to tolerate and maintain the target dose of MS or MMF within 12 months.ResultsForty patients were included in the analyses. MS was associated with a lower primary end point rate [hazard ratio (HR) 0.37; 95% CI 0.17–0.80; P = 0.012] (11/20, 55% patients) compared with MMF (17/20, 85% patients). Treatment failure alone was less common in the MS group (HR 0.28; 95% CI 0.095–0.82; P = 0.020), although drug intolerance did not differ between groups (HR 0.53; 95% CI 0.20–1.42; P = 0.21). Despite randomization, patients in the MMF group may have had a higher baseline risk for treatment failure; more MMF patients had refractory disease and granulomatosis with polyangiitis (Wegener's). A glomerular filtration rate (GFR) ≤40 mL/min was associated with intolerance. Serious adverse events were common (55% MMF and 45% MS patients).ConclusionsNo differences in treatment tolerance were observed between the MS and MMF groups. Despite similar treatment intolerance, MS was associated with improved efficacy in PSV and SLE compared with MMF. However, baseline group imbalances in factors potentially affecting remission and relapse may have influenced the results. Treatment intolerance was common and strongly associated with low GFR. Further treatment trials are warranted to investigate the effect of GFR on mycophenolic acid pharmacokinetics and clinical outcomes (ISRCTN83027184; EUDRACT 2005-002207-16; Funding Novartis UK).

Immunizations following solid-organ transplantation.

To highlight the latest evidence for the use of key vaccines that are recommended in organ transplant candidates and recipients. Influenza vaccine is the best studied vaccine; factors affecting immunogenicity of this vaccine include time from transplant, use of mycophenolate mofetil and type of transplant. Newer formulations of influenza vaccine are available, but data for these are limited. Updated recommendations include giving conjugated pneumococcal vaccine to adult transplant candidates and recipients followed by the polysaccharide vaccine to increase serotype coverage. Human papillomavirus vaccine should also be given to transplant recipients, although the immunogenicity may be suboptimal. Quadrivalent meningococcal conjugate vaccine needs to be given in special circumstances such as to patients who are starting eculizumab therapy. Live vaccines in general are contraindicated, although increasing safety data are emerging for Varicella vaccine. Herpes Zoster vaccine may be offered prior to transplant, although the utility of this strategy regarding protection from shingles after transplant is not known. Newer vaccines such as inactivated zoster vaccine and vaccines for the prevention of cytomegalovirus are under study. Immunization for organ transplant recipients is an important part of pretransplant evaluation and the long-term care of the transplant recipient.

Mycophenolate mofetil versus methotrexate for prevention of graft-versus-host disease in people receiving allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is associated with improved outcomes for people with various hematologic diseases; however, the morbidity and mortality resulting from acute and subsequently chronic graft-versus-host disease (GVHD) pose a serious challenge to wider applicability of allo-HCT. Intravenous methotrexate in combination with a calcineurin inhibitor, cyclosporine or tacrolimus, is a widely used regimen for the prophylaxis of acute GVHD, but the administration of methotrexate is associated with a number of adverse events. Mycophenolate mofetil, in combination with a calcineurin inhibitor, has been used extensively in people undergoing allo-HCT. Conflicting results regarding various clinical outcomes following allo-HCT have been observed when comparing mycophenolate mofetil-based regimens against methotrexate-based regimens for acute GVHD prophylaxis. to assess the effect of mycophenolate mofetil versus methotrexate for prevention of acute GVHD in people undergoing allo-HCT. to evaluate the effect of mycophenolate mofetil versus methotrexate for overall survival, prevention of chronic GVHD, incidence of relapse, treatment-related harms, nonrelapse mortality, and quality of life. We searched Cochrane Central Register of Controlled Trials (CENTRAL) and MEDLINE from inception to March 2014. We handsearched conference abstracts from the last two meetings (2011 and 2012) of relevant societies in the field. We searched ClinicalTrials.gov, Novartis clinical trials database (www.novctrd.com), Roche clinical trial protocol registry (www.roche-trials.com), Australian New Zealand Clinical Trials Registry (ANZCTR), and the metaRegister of Controlled Trials for ongoing trials. Two review authors independently reviewed all titles/abstracts and selected full-text articles for inclusion. We included all references that reported results of randomized controlled trials (RCTs) of mycophenolate mofetil versus methotrexate for the prophylaxis of GVHD among people undergoing allo-HCT in this review. Two review authors independently extracted data on outcomes from all studies and compared prior to data entry and analysis. We expressed results as risk ratios (RR) and 95% confidence intervals (CI) for dichotomous outcomes and hazard ratios (HR) and 95% CIs for time-to-event outcomes. We pooled the individual study effects using the random-effects model. Estimates lower than one indicate that mycophenolate mofetil was favored over methotrexate. We included three trials enrolling 177 participants (174 participants analyzed). All participants in the trials by Keihl et al. and Bolwell et al. received cyclosporine while all participants enrolled in the trial by Perkins et al. received tacrolimus. However, the results did not differ by the type of calcineurin inhibitor employed (cyclosporine versus tacrolimus). There was no evidence for a difference between mycophenolate mofetil versus methotrexate for the outcomes of incidence of acute GVHD (RR 1.25; 95% CI 0.75 to 2.09; P value = 0.39, very low quality evidence), overall survival (HR 0.73; 95% CI 0.45 to 1.17; P value = 0.19, low-quality evidence), median days to neutrophil engraftment (HR 0.77; 95% CI 0.51 to 1.17; P value = 0.23, low-quality evidence), incidence of relapse (RR 0.84; 95% CI 0.52 to 1.38; P value = 0.50, low-quality evidence), non-relapse mortality (RR 1.21; 95% CI 0.62 to 2.36; P value = 0.57, low-quality evidence), and incidence of chronic GVHD (RR 0.92; 95% CI 0.65 to 1.30; P value = 0.62, low-quality evidence). There was low-quality evidence that mycophenolate mofetil compared with methotrexate improved platelet engraftment period (HR 0.87; 95% CI 0.81 to 0.93; P value < 0.0001, low-quality evidence). There was low-quality evidence that mycophenolate mofetil compared with methotrexate resulted in decreased incidence of severe mucositis (RR 0.48; 95% CI 0.32 to 0.73; P value = 0.0006, low-quality evidence), use of parenteral nutrition (RR 0.48; 95% CI 0.26 to 0.91; P value = 0.02, low-quality evidence), and medication for pain control (RR 0.76; 95% CI 0.63 to 0.91; P value = 0.002, low-quality evidence). Overall heterogeneity was not detected in the analysis except for the outcome of neutrophil engraftment. None of the included studies reported any outcomes related to quality of life. Overall quality of evidence was low. The use of mycophenolate mofetil compared with methotrexate for primary prevention of GVHD seems to be associated with a more favorable toxicity profile, without an apparent compromise on disease relapse, transplant-associated mortality, or overall survival. The effects on incidence of GVHD between people receiving mycophenolate mofetil compared with people receiving methotrexate were uncertain. There is a need for additional high-quality RCTs to determine the optimal GVHD prevention strategy. Future studies should take into account a comprehensive view of clinical benefit, including measures of morbidity, symptom burden, and healthcare resource utilization associated with interventions.

Mycophenolate mofetil use after unrelated hematopoietic stem cell transplantation for prophylaxis and treatment of graft-vs.-host disease in adult patients in Japan.

Our previous study of 301 patients who received hematopoietic stem cell transplantation (HSCT) from related donors demonstrated the efficacy of mycophenolate mofetil (MMF) for prophylaxis and treatment of graft-vs.-host disease (GVHD). In this study, we investigated the safety and efficacy of MMF in 716 adult patients who received unrelated HSCT. The incidences of Grade II-IV and III-IV acute GVHD in the prophylactic administration group were 38.3% and 14.3%, respectively. These rates were not statistically significant when evaluating the MMF dosage and graft source. The incidences of limited and extensive chronic GVHD were 16.6% and 11.1%, respectively. In the therapeutic administration group, 69.1% of the subjective symptoms for both acute and chronic GVHD improved. With respect to the adverse events, 75 infections and 50 cases of diarrhea were observed, and the frequency of these events increased with increasing MMF dose. The overall survival rate was 36.4% after a median follow-up period of threeyr. This study shows that MMF is safe and effective for the prevention and treatment of GVHD in patients who have received HSCT from unrelated donors.

A Simplified Clinical Risk Score to Predict Acute Kidney Injury After Living-Donor Liver Transplantation.

Background: We identified the incidence and risk factors for acute kidney injury (AKI) after living donor liver transplantation and constructed a simplified risk scoring model to determine a clinical risk score for the prediction of AKI. Methods: We retrospectively reviewed 525 cases of thoracic aortic surgery. Multivariate logistic regression analysis was used to evaluate risk factors for predicting AKI defined by RIFLE criteria. A scoring model was developed in a derivation cohort (n = 300), and was validated on the remaining patients. The scoring model was developed with a score based on regression β-coefficient, and was compared with previous model as measured by the area under the ROC curve (AUC). Results: The incidence of AKI was 55.7%, and 18.0% required renal replacement therapy. Independent risk factors for AKI were MELD score ≥20, Diabetes mellitus, graft weight-to-recipient body weight ratio < 0.7%, blood loss/body weight > 60ml/kg, cold ischemic time ≥80 min, overexposure to calcineurin inhibitor, hypoalbuminemia, intraoperative furosemide dose > 2 mg/kg, and combined use of mycophenolate mofetil. The clinical score was valid in predicting AKI, and the AUC was 0.78 (95% CI: 0.71 to 0.82), and was similar to that in the validation cohort 0.77 (95% CI: 0.72 to 0.82; P= 0.98). Our risk scoring model showed a better performance compared with previously reported model. Conclusions: Our risk scoring model would provide useful information about the risk of postoperative AKI in patients undergoing liver transplantation.

Hepatitis C Increases Risk of CMV Disease in Kidney Transplant Recipients: The National Experience in Taiwan.

Objective: This national prospective cohort study aimed to evaluate risk factors for cytomegalovirus (CMV) disease in kidney transplant recipients (KTRs). Methods:From January 1, 1997, through December 31, 2009, we selected all de novo kidney transplant recipients from Taiwan National Health Insurance Research Database. The Cox proportional hazards regression model was used to determine which variables were related significantly to the development of CMV disease. Results: Of 4501 KTRs, the mean age was 45.2±12.3 and 52.5% were male. In a mean follow up of 5.4 years, 341 (7.6%) have episodes of CMV disease. The overall prevalence of CMV disease was 14.8 per 1000 patient-years. The cumulative incidences of CMV disease in KTR were 2.6% in 3 months, 3.9% in 6 months, 4.8% in 1 year, 6.9% in 5 years and 7.6% in 10 years. The repeated CMV disease occurred in 80 (23.5%) of KTRs. Hepatitis C infection was associated with the development of CMV disease in KTRs (hazard ratio, 1.87 [95% CI, 1.25˜2.81], P<0.01) and the incidence rate was 27.9 per 1000 patient-year.Figure: No Caption available.Moreover, the other independent risk factors for CMV disease identified in multivariate analysis were treatment with mycophenolate mofetil or mycophenolic acid and children less than 18 years (hazard ratios, 1.67 [95% CI, 1.23˜2.27, P<0.01], 1.94 [95% CI, 1.45˜2.58, P<0.01] and 3.32 [95% CI, 2.06˜5.34, P<0.0001], respectively).Table: No Caption available.Conclusions:Hepatitis C infection, children and the use of mycophenolate mofetil or mycophenolic sodium increase the risk of CMV disease in Taiwanese KTRs. Our results contribute to develop the preventive strategy of CMV infection in KTRs.

Epstein–Barr Virus Infection in Adult Renal Transplant Recipients

Epstein-Barr virus (EBV) DNAemia in the first year posttransplantation has been studied extensively. There is a paucity of information on prevalence and sequelae of EBV infection in adult renal transplantation beyond the first year. This single-center study examines the relationship between EBV DNAemia and demographic, immunosuppressive, hematologic and infection-related parameters in 499 renal transplant recipients between 1 month and 33 years posttransplant. Participants were tested repeatedly for EBV DNAemia detection over 12 months and clinical progress followed for 3 years. Prevalence of DNAemia at recruitment increased significantly with time from transplant. In multivariate adjusted analyses, variables associated with DNAemia included EBV seronegative status at transplant (p = 0.045), non-White ethnicity (p = 0.014) and previous posttransplant lymphoproliferative disease (PTLD) diagnosis (p = 0.006), while low DNAemia rates were associated with mycophenolate mofetil use (p < 0.0001) and EBV viral capsid antigen positive Epstein-Barr nuclear antigen-1 positive serostatus at transplant (p = 0.044). Patient and graft survival, rate of kidney function decline and patient reported symptoms were not significantly different between EBV DNAemia positive and negative groups. EBV DNAemia is common posttransplant and increases with time from transplantation, but EBV DNAemia detection in low-risk (seropositive) patients has poor specificity as a biomarker for future PTLD risk.

AB0526 Pregnancy Outcomes in Women with Systemic Lupus Erythematosus from A Mexican Cohort

BackgroundSystemic lupus erythematosus (SLE) is a multisystemic autoimmune disorder that disproportionally affects women, especially in their reproductive years. SLE is associated with considerable pregnancy-related morbidity, including fetal loss, preterm birth...

Proton-pump inhibitors do not influence serum magnesium levels in renal transplant recipients.

Severe hypomagnesemia has been reported with use of proton-pump inhibitors (PPIs). We assessed the effect, if any, of PPI use on serum magnesium level in a cross-sectional analysis of a large published cohort of renal transplant recipients (RTRs). Between February 2004 and February 2006, 512 consecutive prevalent RTRs were enrolled at two university hospitals in Belgium (Brussels and Ghent). Serum creatinine was 1.5 ± 0.7 mg/dl, and estimated glomerular filtration rate (eGFR) 53 ± 19 ml/min/1.73 m(2). Mean (and median) magnesium level was 1.91 ± 0.23 mg/dl. PPIs were prescribed in 20 % (n = 101) of cases. At multivariable analysis, PPI use was not an independent predictor of serum magnesium level or hypomagnesemia. The independent predictors of a lower serum magnesium level were the use of tacrolimus, cyclosporin and sirolimus, the absence of use of mycophenolate mofetil, lower levels of parathyroid hormone and higher eGFR. This study is the first to analyze the potential impact of PPIs on magnesium level in a large, representative cohort of RTR patients. Our results suggest that PPIs may be used without particular fear of favoring hypomagnesemia-related side effects in RTRs, an important finding in a population at high risk of hypomagnesemia.

Association studies of cytochrome P450, family 2, subfamily E, polypeptide 1 (CYP2E1) gene polymorphisms with acute rejection in kidney transplantation recipients

Recent studies have shown that single-nucleotide polymorphisms (SNPs) are associated with allograft rejection in kidney transplantation recipients. We evaluated the possible association between SNPs of the cytochrome P450, family 2, subfamily E, polypeptide 1 (CYP2E1) gene, and acute rejection (AR) among renal transplant patients in a Korean population. We conducted a case-control association study in 63 AR and 284 non-AR kidney transplant recipients. The SNPs of CYP2E1 were genotyped by direct sequencing. Recipient sex (p = 0.023) and the use of tacrolimus (p = 0.017) were significantly different between the two groups. The use of mycophenolate mofetil (MMF) and antibody induction therapy was significantly lower in the AR group. Multiple logistic regression models (codominant, dominant, recessive, and log-additive models) adjusted by sex and type of immunosuppressive regimens were applied to determine the odds ratios (ORs), 95% confidence intervals (CIs), and p-values. The rs2515641 of CYP2E1 showed significant differences between the AR patient group and non-AR group (p = 0.003, OR = 2.55, 95% CI = 1.37-4.75 in the codominant 1 model; p = 0.002, OR = 2.61, 95% CI = 1.43-4.77 in the dominant model; p = 0.0035, OR = 2.13, 95% CI = 1.29-3.50 in the log-additive model). The allele of the rs2515641 SNP also showed a significant association (p = 0.004, OR = 1.99, 95% CI = 1.24-3.21). This study suggests that the CYP2E1 polymorphism may be related to the development of AR in Korean kidney transplantation recipients.

Decreased immunoglobulin G levels after living‐donor liver transplantation is a risk factor for bacterial infection and sepsis

Several studies have suggested an association between post-transplant immunoglobulin (Ig) levels and the development of infection in solid organ transplantation. We therefore conducted exploratory analyses of potential factors associated with bacterial infection/sepsis after living-donor liver transplantation (LDLT). Blood samples from 177 recipients who received primary LDLT between September 1999 and November 2011 were available for study. Hypogammaglobulinemia was defined as having at least 1 IgG level <650 mg/dL within 7 days after LDLT. Risk factors for developing post-transplant bacterial infection and sepsis within 3 months after LDLT were analyzed. Fifty (28.2%) recipients experienced bacterial infection within 3 months of LDLT. Eighty-four (47.5%) recipients had hypogammaglobulinemia, although no recipients had hypogammaglobulinemia before LDLT. Hypogammaglobulinemia, undergoing hepaticojejunostomy, and portal pressure at closure >15 mmHg were independent risk factors for developing bacterial infection within 3 months of LDLT (P < 0.0001 P = 0.0008, and P = 0.011, respectively). The odds ratio (OR) and confidence interval (CI) for hypogammaglobulinemia were 4.79 and 2.27-10.7, respectively. Twenty-four (13.6%) recipients developed bacterial sepsis within 3 months. Hypogammaglobulinemia, operative time >14 h, model for end-stage liver disease score >15, and no mycophenolate mofetil use were independent risk factors for developing bacterial sepsis (P = 0.009, P = 0.001, P = 0.003, and P = 0.005, respectively). The OR and CI for hypogammaglobulinemia were 3.83 and 1.38-12.0, respectively. Hypogammaglobulinemia within 7 days of LDLT was a significant risk factor for post-transplant bacterial infection and sepsis.

Optimization of the treatment with immunosuppressants and biologics in inflammatory bowel disease.

Many placebo controlled trials and meta-analyses evaluated the efficacy of different drugs for the treatment of inflammatory bowel disease (IBD), including immunosuppressants and biologics. Their use is indicated in moderate to severe disease in non responders to corticosteroids and in steroid-dependent patients, as induction and maintainance treatment. Infliximab, as well as cyclosporine, is considered a second line therapy in the case of severe ulcerative colitis, or non-responders to intravenous corticosteroids. An adequate dosage and duration of therapy with thiopurines should be reached before evaluating their efficacy. Methotrexate is a valid option in patients with Crohn's disease but its use is confined to patients who are intolerant or non-responders to thiopurines. Evidence for the use of methotrexate in ulcerative colitis is insufficient. The use of thalidomide and mycophenolate mofetil is not recommended in patients with inflammatory bowel disease, these treatments could be considered in case of failure of all other therapeutic options. In patients with moderately active ulcerative colitis, refractory to thiopurines, the use of tacrolimus is considered an alternative to biologics. An increase of the dose or a decrease in the interval of administration of biological treatment could be useful in the presence of an incomplete clinical response. In the case of primary failure of an anti-tumor necrosis factor alpha a switch to another one should be considered. Data on the efficacy of combination therapy are up to now insufficient to consider this strategy in all IBD patients. The final outcome of the treatment should be considered the clinical remission, with mucosa healing, and not the clinical response. The evaluation of serum concentration of thiopurine methyl transferase activity, thiopurine metabolites, biologic serum levels and antibiologic antibodies could be useful for the management of the treatment but it has not been routinely applied in clinical practice. The evidence of high risk development of lymphoma and cutaneous malignancies should be considered in patients treated with immunosuppressants and biologics for a long period.

PReS-FINAL-2175: Pharmacokinetics of mycophenolate mofetil in children with lupus and clinical findings in favour of therapeutic drug monitoring

The use of mycophenolate mofetil (MMF) in children with Systemic Lupus Erythematosus (SLE) is increasing. However, the clinical benefit of its monitoring has been scarcely studied, and little is known about its pharmacokinetics (PK) in this context.

A Pilot Study Of Continuous Infusion Mycophenolate Mofetil For Graft Versus Host Disease Prophylaxis

Mycophenolate mofetil (MMF), an ester prodrug of mycophenolic acid (MPA) has been used successfully for graft-versus-host disease (GVHD) prophylaxis. Most MMF dosing regimens and pharmacokinetic (PK) parameters have been established in solid organ transplant recipients. Empiric fixed-dose-escalation strategies have failed to achieve target MPA exposure, especially in the early period following conditioning therapy. We hypothesized that a PK-based dosing approach using a novel continuous infusion (CI) method of MMF will be able to achieve and maintain target MPA exposure. The objective of this study was to evaluate the safety and feasibility of this MMF dosing approach in pediatric BMT recipients. Fifteen patients were enrolled in the study. The median age at transplant was 8.4 years (0.9 – 21.5); eight were female and seven were male. Thirteen patients were transplanted for hematologic malignancies and two patients for nonmalignant diseases. Stem cell sources included matched-sibling bone marrow in seven, 10/10 allele matched donor bone marrow in four, and unrelated cord blood in four cases. All patients received a myeloablative conditioning regimen with either cyclophosphamide-TBI (n=8) or busulfan-cyclophosphamide (n=7). In addition, of eight unrelated donor transplants, six patients received equine ATG and two received fludarabine. All patients received cyclosporine A and MMF for GVHD prophylaxis. Intravenous (IV) cyclosporine was initiated on day -2 as a continuous infusion (target blood level: 160 to 250 ng/mL). IV MMF was started on day “0” in a dose of 15 mg/kg every 8 hours. After a minimum of five doses, serial blood samples were collected within one dosing interval for the 1st PK analysis. Using these results, MMF was converted from intermittent IV to CI administration to target total MPA AUC0-24 of 40-80 mcg/mL/hr. MMF dose was adjusted to maintain a total MPA steady-state concentration (Css) of 1.7-3.3 mcg/mL. CI MMF was converted to every-8-hour oral dosing when patients were tolerating oral medications. A 2nd PK study was performed after a minimum of five oral doses, and dose adjustments were made to maintain a total MPA trough concentration (Ctrough) of 1-3.5 mcg/mL. MMF was continued until day 42, and in the absence of acute GVHD, tapered off over 8 weeks. On the initial 15 mg/kg q8 IV MMF dose schedule, MPA half-life was 1.3±1.3 hrs and AUC0-24 was 44.3±60.3 mg* hr/L. During the CI schedule, MMF dose was 44±16 mg/kg/day and MPA AUC0-24 38.4±20.7 mg* hr/L, and thirteen of fifteen (87%) patients achieved MPA Css within target of 1.7–3.3 mcg/mL. On conversion to oral route, median MMF dose was 45±19mg/kg/day, MPA half-life 1.95±2.3 hrs and AUC0-24 38.3±16.0 mg* hr/L. MPA clearance was 17±14 ml/min/kg. Higher steady state MPA concentrations were achieved with CI method (Css 1.6 ±0.9 mcg/mL) compared with intermittent IV or oral dosing (Ctrough 0.7±0.9 mcg/mL). All patients achieved neutrophil engraftment at 13 ± 11 days post-transplant, and platelet engraftment at 45 ± 72 days post-transplant. Seven out of 15 patients (47%) developed stage I-IV acute GVHD. Three patients had stage III-IV aGVHD (20%); they were steroid-refractory but went into remission with additional therapy. For 11 patients with a minimum of one year follow-up post-transplant, one (9%) developed “overlap” chronic GVHD. MMF was discontinued without weaning in four patients: in three of them due to concern of delay in blood count recovery and all of them achieved hematopoietic engraftment, and in one patient with severe aGVHD due to potential concern for MMF gut toxicity. One patient with severe congenital neutropenia developed autologous hematopoietic recovery by day 52. One patient with ALL died of relapse 150 days after transplant. With a median follow-up of 23 months (range 100 days to 3.6 y), 14 out of 15 patients are alive, and one-year event-free survival and overall survival are 83% and 92% respectively. In conclusion, we show that continuous infusion of MMF is feasible and well-tolerated. In this pilot PK study, we observed no toxic deaths, excellent engraftment, and low rates of grade III-IV aGVHD and cGVHD. The PK studies showed significantly lower half-life and higher drug clearance in pediatric BMT recipients compared to stable pediatric renal transplant patients. This regimen deserves further validation in a larger cohort of pediatric patients undergoing myeloablative transplantation. Disclosures: Off Label Use: Use of Mycophenolate Mofetil for Graft versus Host Disease Prophylaxis.

Herpes Zoster Vaccination in SLE: A Pilot Study of Immunogenicity

Patients with systemic lupus erythematosus (SLE) are at increased risk of herpes zoster (HZ). Although a vaccine for HZ has been approved by the US Food and Drug Administration, its use in immunocompromised individuals remains controversial because it is a live-attenuated virus vaccine. We performed a pilot study of the immunogenicity of the HZ vaccine (Zostavax) in patients with SLE. Ten patients with SLE and 10 control subjects ≥ age 50 years participated in this open-label vaccination study. All were seropositive for varicella zoster virus (VZV). Patients with SLE were excluded for SLE Disease Activity Index (SLEDAI) > 4, or use of mycophenolate mofetil, cyclophosphamide, biologics, or > 10 mg prednisone daily. Followup visits occurred at 2, 6, and 12 weeks. Clinical outcomes included the development of adverse events, particularly HZ or vesicular lesions, and SLE flare. Immunogenicity was assessed with VZV-specific interferon-γ-producing enzyme-linked immunospot (ELISPOT) assays and with antibody concentrations. All subjects were women. Patients with SLE were slightly older than controls (60.5 vs 55.3 yrs, p < 0.05). Median baseline SLEDAI was 0 (range 0-2) for patients with SLE. No episodes of HZ, vesicular rash, serious adverse events, or SLE flares occurred. Three injection site reactions occurred in each group: mild erythema or tenderness. The proportion of subjects with a > 50% increase in ELISPOT results following vaccination was comparable between both groups, although absolute SLE responses were lower than controls. Antibody titers increased only among controls following vaccination (p < 0.05). The HZ vaccination yielded a measurable immune response in this cohort of patients with mild SLE taking mild-moderate immunosuppressive medications. No herpetiform lesions or SLE flares were seen in this small cohort of patients. ClinicalTrials.gov ID:NCT01474720.

Rejection after conversion to a proliferation signal inhibitor in chronic heart transplantation

We sought to determine the incidence, risk factors, and consequences of acute rejection (AR) after conversion from a calcineurin inhibitor (CNI) to a proliferation signal inhibitor (PSI) in maintenance heart transplantation. Relevant clinical data were retrospectively obtained for 284 long-term heart transplant recipients from nine centers in whom CNIs were replaced with a PSI (sirolimus or everolimus) between October 2001 and March 2009. The rejection rate at one yr was 8.3%, stabilizing to 2% per year thereafter. The incidence rate after conversion (4.9 per 100 patient-years) was significantly higher than that observed on CNI therapy in the pre-conversion period (2.2 per 100 patient-years). By multivariate analysis, rejection risk was associated with a history of late AR prior to PSI conversion, early conversion (<5 yr) after transplantation and age <50 yr at the time of conversion. Use of mycophenolate mofetil was a protective factor. Post-conversion rejection did not significantly influence the evolution of left ventricular ejection fraction, renal function, or mortality during further follow-up. Conversion to a CNI-free immunosuppression based on a PSI results in an increased risk of AR. Awareness of the clinical determinants of post-conversion rejection could help to refine the current PSI conversion strategies.

Impact of Graft-versus-Host Disease Prophylaxis on Outcomes after Myeloablative Single-Unit Umbilical Cord Blood Transplantation

Myeloablative single-unit umbilical cord blood transplantation (sUCBT) using busulfan, thiotepa, fludarabine, and antithymocyte globulin (Grupo Español de Trasplante Hematopoyético [GETH]-2005 protocol) resulted in high rates of engraftment and high antitumor activity. We designed a new graft-versus-host disease prophylaxis, substituting long-term steroids with mycophenolate mofetil together with a slight reduction of antithymocyte globulin (GETH/Gruppo Italiano Trapianto Midollo Osseo [GITMO]-2008 protocol). The results in 145 consecutive patients were compared with those obtained in 88 patients from the previous GETH-2005 trial. The cumulative incidence (CI) of myeloid engraftment at 60 days for patients in the GETH-2005 and GETH/GITMO-2008 trials was 94% and 88%, respectively, at a median time to neutrophil recovery of 19 and 23 days, respectively (P < .0001). In the multivariable analyses, platelet engraftment, acute and chronic graft-versus-host disease, nonrelapse mortality, relapse, and event-free survival were not significantly different. The 3-year event-free survival rate in the GETH/GITMO-2008 trial was 66%, 31%, and 25% for patients transplanted in early, intermediate, and advanced stages of the disease, respectively (P < .0001). This study confirms that myeloablative sUCBT using busulfan-based conditioning is a valuable strategy for patients with hematological malignancies. The use of mycophenolate mofetil apparently had an adverse effect on myeloid engraftment, and therefore a cautious use of this agent is warranted in the UCBT setting.

Risk Factors of Glucocorticoid-Induced Diabetes Mellitus in Systemic Lupus Erythematosus

Background: The aim of this study was to investigate the prevalence and associated factors of glucocorticoid-induced Diabetes mellitus (GIDM) in patients with systemic lupus erythematosus (SLE) under glucocorticoid therapy.&#x0D; Methods: Patients with SLE who had received high-dose glucocorticoid therapy (prednisolone≥1 mg/kg/day) at Rasoul Akram and Firoozgar hospitals were recruited during 2006-2011.&#x0D; Results: A total of 81 patients with SLE were evaluated. 21 patients (25.9%) of them developed GIDM after high-dose glucocorticoid therapy. Univariate analysis of data showed that old age, family history of diabetes mellitus (DM) and use of Mycophenolate mofetil were factors that would increase the likelihood of GIDM.&#x0D; Conclusion: In summary, GIDM was developed among 25.9% of patients with SLE after high-dose glucocorticoid therapy. Old age, family history of DM and use of Mycophenolate mofetil were determined to be factors responsible for increasing the risk of developing GIDM.

SP0092 Latest advances in connective tissue disorders

The licensing of belimumab for use in active systemic lupus erythematosus (SLE) has ushered in a new era for the connective tissue diseases (CTDs) based on a better understanding of...

Randomized Controlled Trial of High-Dose Intradermal Versus Standard-Dose Intramuscular Influenza Vaccine in Organ Transplant Recipients

The immunogenicity of standard intramuscular (IM) influenza vaccine is suboptimal in transplant recipients. Also, recent studies suggest that alloantibody may be upregulated due to vaccination. We evaluated a novel high-dose intradermal (ID) vaccine strategy. In conjunction, we assessed alloimmunity. Transplant recipients were randomized to receive IM or high-dose ID vaccine. Strain-specific serology and HLA alloantibody production was determined pre- and postimmunization. In 212 evaluable patients (105 IM, 107 ID), seroprotection to H1N1, H3N2 and B strains was 70.5%, 63.8% and 52.4% in the IM group, and 71.0%, 70.1%, 63.6% in the ID group (p=ns). Seroconversion to ≥1 antigen was 46.7% and 51.4% in the IM and ID groups respectively (p=0.49). Response was more likely in those≥6 months posttransplant (53.2% vs. 19.2%; p=0.001). Use of mycophenolate mofetil was inversely associated with vaccine response in a dose-dependent manner (p<0.001). Certain organ subgroups had higher response rates for influenza B in the ID vaccine group. Differences in anti-HLA antibody production were detected in only 3/212(1.4%) patients with no clinical consequences. High-dose intradermal vaccine is an alternative to standard vaccine and has potential enhanced immunogenicity in certain subgroups. In this large cohort, we also show that seasonal influenza does not result in significant alloantibody production.