Low-dose Mycophenolate Mofetil Research Articles

Regular Prophylactic Donor Lymphocyte Infusion Is Effective and Safe to Prevent Relapse after Hematopoietic Cell Transplantation in High-Risk Patients

BackgroundDonor lymphocyte infusion (DLI) is the mainstream therapy for the prevention and treatment of relapse following hematopoietic cell transplantation (HCT). The efficacy of DLI for patients with acute leukemia, however, is limited in previous studies. This may be due to the more rapid proliferative capacity of malignant cells in acute leukemia, since a full response to DLI often requires months. Moreover, DLI is more effective when there is less disease burden to eradicate. Therefore, patients with high risk of relapse may take advantage of an early DLI after HCT. In this study, we applied an early prophylactic DLI in high relapse-risk patients with negative MRD (MRD-) after HCT.Patients and MethodsFrom July 2013 to December 2015, 56 adult patients with high relapse-risk in our center were admitted in this study. High relapse-risk was defined as failure to attain a complete remission (CR) after two cycles of induction therapy (primary induction failure), more than second complete remission (¡ÝCR2), no complete remission before HCT, or increasing MRD before HCT detected by flow cytometry (FCM) or real-time quantitative PCR (RQ-PCR). All patients received modified busulfan/cyclophosphamide¨Cbased myeloablative conditioning regimen. Rabbit antithymocyte globulin was administered for patients receiving unrelated donor HCT or haploidentical HCT. All patients received graft-versus-host disease (GVHD) prophylaxis consisting of cyclosporine A, methotrexate and low-dose mycophenolate mofetil. Post-HCT MRD was monitored at regular intervals with FCM or RQ-PCR. All patients achieved negative MRD post-HCT in our study.ResultsIn total, 56 patients (median age, 36, range, 17-46; 66.1% male) with high relapse risk were included in our study. 15 patients had acute lymphoblastic leukemia; 25 had acute myeloid leukemia; 5 had chronic myelogenous leukemia blast phase; the rest hadT-cell lymphoblastic lymphoma, myelodysplastic syndromes with refractory anemia with excess blasts-2, and peripheral T-cell lymphoma. Among them, 37 (66.1%) received haploidentical-HCT, 16 (28.6%) received matched sibling donor-HCT, and three (5.4%) received unrelated donor-HCT. The median time from HCT to DLI was 82 days (range, 47-160). After a median follow-up of 21 months (range, 7-34), the overall survival (OS) at two years was 78.4%; the disease-free survival (DFS) at two years was 75.4%, with relapse rate of 13.3%. Clinical characteristics were subjected into univariate Cox analysis for OS or relapse rate to find prognostic factors. Neither donor type nor disease type had significant impact on OS or relapse rate in our study. Of note, four patients relapsed after the first DLI underwent chemotherapy combined with a second DLI. Unfortunately, this strategy failed to treat relapse in all of the four patients.The main concern following DLI is the emergence of GVHD. In our study, 19 of the 56 patients (33.9%) developed aGVHD after DLI, mostly Grade I to Grade II (n = 15, 78.9%). cGVHD was observed in 25 of the 56 patients (44.6%), mostly with limited manifestations (n = 20, 80%). Among the deceased 11 patients, only one patient died secondary to GVHD complications due to bronchiolitis obliterans.ConclusionsFor patients with high risk of relapse following HCT, this study indicates that early administration of DLI is effective and safe to prevent relapse. Regular application of DLI for negative MRD patients post-HCT with high relapse risk may be a feasible strategy to prevent future relapse. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Who Is the Better Donor for Young Hematopoietic Transplant Recipients without Siblings: An Older-Aged Haploidentical Parental Donor or a Young Unrelated Donor?

Introduction:Hematopoietic stem cell transplant (HSCT) outcomes from unrelated donor (URD) and haploidentical donor were very close in recent years, and both could be alternative donors for recipients without siblings. But when considering donor age, especially for young recipients (≤30 years) without siblings, whether outcomes can be improved with a young URD rather than older-aged haploidentical parental donors (HPD) is still unknown.Methods:Between 2008 and 2014, a total of 156 young adult patients with hematological malignancies without sibling donors were assigned to receive URD or HPD HSCT in our center. The strategy of donor selection between URD and HPD was as follows: If an HLA suitably matched URD (≥8 of 10 matching HLA-A, -B, -C, -DRB1, and -DQB1 allele loci and ≥5 of 6 matching HLA-A, -B, and -DRB1 antigen loci) was available, patients were assigned to undergo URD-HSCT. If an HLA suitably matched URD was unavailable, patients were assigned to receive HPD-HSCT. Among them, 10 recipients received HSCT from URDs older than 40 years were further excluded. The transplant procedure had been reported previously (Yi Luo et. al. Blood 2014). Briefly, all patients received myeloablative conditioning involving BuCy without total body irradiation. The GVHD prophylaxis consisted of cyclosporin A, methotrexate, and low-dose mycophenolate mofetil. Grafts were granulocyte-colony stimulating factor mobilized peripheral blood stem cells without ex vivo T-cell depletion.Results:The median age of the finally included 146 young recipients was 21 years (range, 15-30 years). Of whom, 67 received HSCT from HPDs and 79 received HSCT from URDs.The median donor age of the HPDs was 46 years (range, 40-53 years), in contrast to 28 years (range, 20-39 years) of the URDs.EngraftmentAll patients achieved myeloid recovery. The median time and the cumulative 15-day incidences of myeloid engraftment were 12 days (range, 8-16 days) and 97.4% in the URD cohort, and 13 days (range, 8-21 days) and 77.6% in the HPD cohort, respectively. Myeloid recovery in the HPD cohort was significantly delayed compared with URD cohort (P<0.001).Two patients in the HPD cohort experienced primary platelet engraftment failure. The median time and the cumulative 30-day incidences of platelet engraftment were 13 days (range, 6-24 days) and 100% in URDs, and 15 days (range, 6-30 days) and 97.0% in HPDs, respectively. Patients receiving HSCT from HPDs experienced significantly delayed platelet recovery compared with those receiving HSCT from URDs (P<0.001).aGVHDThe incidences of grades II-IV aGVHD were 45.5% in the URD cohort and 47.8% in the HPD cohort (P=0.78), respectively. The incidences of grades III-IV aGVHD were 14.3% in the URD cohort and 17.9% in the HPD cohort (P=0.55), respectively.Long-term OutcomesThere was a trend of higher 5-year overall survival (OS) and relapse free survival (RFS) rates for patients transplanted from young URDs in comparison with HPDs (OS: 64.4% vs 59.6% (P=0.23) and RFS: 63.2% vs 49.6%; (P=0.20)),respectively. The relapse rate and non-relapse mortality (NRM) rate were comparable between two cohorts.For standard risk patients, a significantly higher 5-year OS and RFS rate were observed for patients transplanted from young URDs compared with HPDs (OS: 76.3% vs 52.7% (P=0.03) and RFS: 73.2% vs 53.8%; (P=0.04)), respectively. The significantly lower survival rate in the HPD cohort to some extent could be explained by the higher NRM rate in the HPD cohort (HPD 30.8% vs URD 13.9%, P=0.07). While for high risk patients, long-term outcomes were comparable between two cohorts.Conclusion:These data favor a young URD over an older-aged HPD for young recipients without siblings in standard risk; while for those in high risk, transplant outcomes were comparable between a young URD and an old-aged HPD. Moreover, myeloid and platelet recovery were significantly delayed in HPD-HSCT compared with URD-HSCT. DisclosuresNo relevant conflicts of interest to declare.

Low-dose mycophenolate mofetil in tablet form or capsule form combined with tacrolimus in the early period after kidney transplantation: a prospective randomized trial .

The tablet form (500mg) of mycophenolate mofetil (MMF) provides more convenience of taking drugs and cost-effectiveness than the capsule form (250mg). We examined the efficacy and safety of MMF in its different forms combined with tacrolimus in kidney transplant recipients. This multicenter, 26-week, randomized trial was performed to compare the efficacy and safety of the tablet form of MMF versus the capsule form of MMF in 156 kidney transplant recipients. Allograft function, the incidence of efficacy failure (biopsy-proven acute rejection (BPAR), death, graft loss, or loss to follow-up), and adverse events were compared. The mean dose (mg/day) of MMF at 26 weeks was comparable: 1,052.6±194.2 in the tablet group vs. 1,155.6±298.1 in the capsule group (p=0.063). Trough levels of tacrolimus at 26 weeks were comparable. The mean estimated glomerular filtration rate of the tablet group at 26 weeks post-transplant was not inferior to that of the capsule group. The incidence of efficacy failure was similar in the two groups: tablet group, 5.2% and capsule group, 7.7% (difference -2.5%; 95% confidence interval -5.22-10.21%). The incidence of BPAR until 26 weeks post-transplant in the tablet group was 3.9%, compared to 7.7% in the capsule group (p=0.346). There was no significant difference in the incidence of discontinuations and serious adverse events between the groups. Low-dose MMF in tablet form combined with tacrolimus can be considered as an efficacious and safe immunosuppressive regimen in the early period after kidney transplantation. .

Moderator's view: The use of calcineurin inhibitors in the treatment of lupus nephritis.

Lupus nephritis (LN) is one of the most severe manifestations of systemic lupus erythematosus (SLE), affecting ∼50% of patients, and both renal disease and treatment-related toxicity contribute to significant morbidity and mortality. Although our understanding of the aetiopathogenesis of LN is improving, treatment still remains a challenge, with the achievement of complete remission at 1 year in <50% of patients treated with current standard of care immunosuppressive therapy; this is associated with considerable short- and long-term side effects, some of which further contribute to non-adherence. Calcineurin inhibitors (CNIs) have been successfully used in organ transplantation and there is increasing evidence that cyclosporin A (CSA), and especially tacrolimus (TAC), are also effective in the treatment of LN. Randomised controlled trials showed similar efficacy for TAC when compared with mycophenolate mofetil (MMF) and multitarget therapy, including TAC and low-dose MMF, and resulted in significantly more complete remissions and overall responses compared with intravenous cyclophosphamide (CYC). Flares are observed in up to 45% of patients with LN, and an increase in relapse rate following induction with CNIs may be an issue. Most studies on this matter have been restricted to patients from Asia, and studies in more balanced cohorts are desirable. Moreover, there is a need to understand and determine the long-term effects of CNIs on renal function, proteinuria and comorbidities, with a special focus on cardiovascular risk. In this 'Pros and Cons' debate, the potential benefits and disadvantages of CNIs in the treatment of LN will be critically highlighted.

The Effect of Mycophenolate Mofetil on Early Wound Healing in a Rodent Model

BackgroundImmunosuppressant agents are inevitable for solid organ recipients, but may have a negative effect on wound healing that is difficult to measure because of clinical use of a polydrug regime. The evidence on mycophenolate mofetil (MMF) is scarce and contradictory. This study aims to investigate the effect of MMF administration on wound healing.MethodsNinety-six male Wistar rats divided into 4 groups underwent anastomotic construction in ileum and colon at day 0. Three groups received daily oral doses of 20 or 40 mg/kg MMF or saline (control group) from day 0 until the end of the experiment. Half of each group was analyzed after 3 days and half after 7 days. Another group started the medication 3 days after the laparotomy and was analyzed after 7 days, half of this group received 20 mg/kg and half 40 mg/kg MMF. Wound strength in anastomoses and in the abdominal wall was measured using bursting pressure, breaking strength, and histology. Trough levels were measured.ResultsSignificant differences in wound strength were seen in ileum tissue after 3 days, which surprisingly showed a stronger anastomosis in the experimental groups. Bursting pressure as well as breaking strength was higher in the low-dose and high-dose MMF group compared with the control group. A negative effect was measured in abdominal wall tissue for the highest-dose group, which disappeared when the medication was delayed for 3 days. Histology showed poorer bridging of the submucosal layer and more polymorphonuclear cell infiltration in the ileum specimens of the control group compared with the treatment groups.ConclusionsAs a single agent in a preclinical wound healing model in the rat, MMF has no negative effect on healing of bowel anastomoses but might have a negative effect on the healing of abdominal wall.

Con: Cyclophosphamide for the treatment of lupus nephritis.

Kidney involvement is a major determinant for morbidity and mortality in patients with systemic lupus erythematosus. The treatment target of lupus renal disease is to induce and maintain remission and to minimize disease or treatment-related comorbidities. Cyclophosphamide (CYC), in conjunction with glucocorticoids, has conventionally been used for the initial treatment of lupus nephritis. However, the major concerns of CYC are its toxicities, such as infertility, urotoxicity and oncogenicity, which are particularly relevant in women of childbearing age. As a result, maintenance therapy of lupus nephritis with an extended course of CYC pulses has largely been replaced by other immunosuppressive agents such as mycophenolate mofetil (MMF) and azathioprine. Recent randomized controlled trials have demonstrated non-inferiority of MMF to pulse CYC as induction therapy of lupus nephritis. Although MMF as induction-maintenance therapy has been increasingly used in lupus nephritis, its efficacy in the long-term preservation of renal function remains to be elucidated. MMF is not necessarily less toxic than CYC. Meta-analyses of clinical trials show similar incidence of infective complications and gastrointestinal adverse events in both MMF- and CYC-based regimens. However, considering the reduction in gonadal toxicity and the risk of oncogenicity, MMF may be used as first-line therapy of lupus nephritis. Tacrolimus (TAC) has recently been shown to be equivalent to either MMF or CYC for inducing remission of lupus nephritis and may be considered as another non-CYC alternative. Combined low-dose MMF and TAC appears to be more effective than CYC pulses in Chinese patients with lupus nephritis and has the potential to replace the more toxic CYC regimens in high-risk patients. Currently, CYC still plays an important role in the management of lupus nephritis patients with impaired or rapidly deteriorating renal function, crescentic glomerulonephritis or as salvage therapy for recalcitrant disease.

A four-drug combination therapy consisting of low-dose tacrolimus, low-dose mycophenolate mofetil, corticosteroids, and mizoribine in living donor renal transplantation: A randomized study.

Objective:We compared a three-drug combination therapy (control group) consisting of tacrolimus, mycophenolate mofetil, and corticosteroids in living donor renal transplantation with a four-drug combination therapy (study group), in which the doses of tacrolimus and mycophenolate mofetil were halved and the immunosuppressive drug mizoribine was added, in order to determine whether the incidence rates of acute rejection after transplantation between the study group and the control group are similar, whether the study group regimen prevents the occurrence of calcineurin inhibitor–induced renal damage, and whether the study group regimen prevents adverse effects such as diarrhea caused by mycophenolate mofetil.Methods:We investigated the incidence of acute rejection, serum creatinine levels, and estimated glomerular filtration rate and the incidence of adverse effects such as diarrhea.Results:There was no significant difference between the two groups in the incidence of acute rejection. Renal function (estimated glomerular filtration rate and serum creatinine) was maintained in the control group whereas in the study group renal function gradually improved, with a statistical difference observed at 12 months. The incidence of gastrointestinal symptoms including diarrhea was significantly higher in the control group than in the study group. There was no significant difference in the incidence of cytomegalovirus infection and other adverse effects.Conclusion:These results suggest the study group therapy is an effective regimen in preventing acute rejection and the deterioration of renal function. These results also show this therapy can reduce the incidence of adverse effects such as gastrointestinal symptoms.

Evaluation of mycophenolate mofetil or tacrolimus in children with steroid sensitive but frequently relapsing or steroid-dependent nephrotic syndrome.

Approximately 30-40% of children with steroid sensitive nephrotic syndrome have frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS). Mycophenolate mofetil (MMF) and tacrolimus (TAC) are often alternative treatment choices for these patients. A single-center prospective study was conducted to compare the efficacy of MMF or TAC in reducing relapses and maintaining remission in children with FRNS or SDNS. Of the 72 recruited patients, either MMF (20∼30 mg/kg/d, n = 34) or TAC (0.05∼0.15 mg/kg/d, n = 38) was administered for 12 months. The mean 6-month relapse rates decreased from 2.56 episodes before therapy to 0.76 episodes in the first 6 months after therapy (c(2) = 44.362, p < 0.001) and 0.67 in the next 6 months (c(2) = 37.817, p < 0.001) in the MMF group. In the TAC group, the mean 6-month relapse rates decreased from 2.39 episodes before therapy to 0.41 episodes in the first 6 months after therapy (c(2) = 62.242, p < 0.001) and 0.42 in next 6 months (c(2) = 67.482, p < 0.001). No significant difference in the relapse rate was found between the groups (before therapy, c(2) = 0.902, p = 0.637; first 6 months, c(2) = 5.358, p = 0.147; second 6 months, c(2) = 4.089, p = 0.252). And there was also no significant difference in cumulative sustained remission and the incidence of adverse events between two groups. In combination with low-dose steroids, MMF or TAC presented similar efficacy in maintaining remission in children with FRNS/SDNS in the present study. Therapy with MMF or TAC is a promising strategy with a moderate risk of side effects in children who are steroid sensitive but have FRNS/SDNS.

Low-dose Mycophenolate Mofetil in the Treatment of Lupus Nephritis

Low-dose Mycophenolate Mofetil in the Treatment of Lupus Nephritis

Comparison of Allogeneic Hematopoietic Stem Cell Transplant from HLA-Matched Related Donors and from Unrelated Donors for Intermediate- to High-Risk Adult Acute Myeloid Leukemia in Remission

Introduction: Allogeneic hematopoietic stem cell transplant (allo-HSCT) is currently the most powerful method to treat intermediate- to high-risk acute myeloid leukemia (AML). Human leukocyte antigen (HLA) matched related donors (MRD) are considered the best donors in allo-HSCT, but they are only available for a small proportion of patients. With the progress of transplant skills over decades, outcome of unrelated donor (URD) HSCT has improved significantly, and the difference between MRD and URD HSCT has been steadily declining. But the role of URD HSCT has still not been well defined in AML, especially for different risk groups. We therefore compared the results of URD HSCT with MRD HSCT in adult AML patients with intermediate- to high-risk in our center.Methods: During January 2005 to December 2012, 108 adult patients with intermediate- or high-risk AML receiving allo-HSCT in complete remission (CR) in our center were admitted in this study. All patients received a standard-dose cytarabine with anthracycline or homoharringtonine as induction therapy. Consolidation courses include high-dose cytarabine or standard-dose cytarabine with anthracycline, homoharringtonine, or mitoxantrone. After consolidation, all patients received allo-HSCT in CR. High resolution DNA typing for HLA-A, -B, -C, -DRB1, and -DQB1 was performed during CR. Patients with HRD would receive HRD HSCT; while for those without HRD, URD with at least 8/10 locus match were selected as donor source. Among the 108 patients, 51 received grafts from HRD and 62 from URD. The conditioning regimen mainly involved BuCy without total body irradiation. All patients received graft-versus-host disease (GVHD) prophylaxis consisting of cyclosporine A, methotrexate and low-dose mycophenolate mofetil. Rabbit antithymocyte globulin (Thymoglobulin, IMTIX-SangStat, Lyon, France) was also administered to some patients receiving URD HSCT (4.5–6 mg/kg total dose).Results: Most of the baseline characteristics were well balanced between two groups. However, The interval from diagnosis to transplantation differed significantly between two groups, with a median interval of 7 months for HRD group versus 10 months for URD group (P=0.008). Bone marrow was used as graft source in 100% and 80.7% of patients in HRD and URD groups, respectively. Another 19.3% of patients in URD group received peripheral blood stem cell as graft source. The median follow-up was 37.5 months in the whole cohort.The cumulative incidence of acute grade 2 to 4 GVHD was significantly higher in URD group compared with HRD group (40.3% vs. 13.8%, P=0.002). Chronic GVHD and extensive chronic GVHD were also significantly more frequent in URD group (chronic GVHD: 49.2% vs. 29.6%, P=0.037; extensive chronic GVHD: 22.0% vs. 3.7%, P=0.005). The treatment-related mortality (TRM) was significantly higher in the URD group (17.9% vs. 4.3%, P=0.015). While the overall survival (OS), relapse-free survival (RFS), and relapse rate were comparable between two groups (OS at 3 years: HRD 79.9% vs. URD 70.3%, P=0.146; RFS at 3 years: HRD 73.1% vs. URD 66.7%, P=0.239; relapse rate at 3 years: HRD 23.5% vs. URD 18.0%, P=0.643). Clinical characteristics were subjected into univariate and multivariate Cox analysis for OS to find prognostic factors. Cytogenetics, status at transplant (CR1 vs. CR2 to CR3), and MRD levels at transplant were identified as factors that were significantly associated with OS, whereas donor type had no significant impact.When the analysis was done in patients divided by risk stratification, we found that for intermediate-risk patients, the HRD group had a 3-year improved survival rate than URD group (RFS: 85.2% vs. 70.5%, P=0.043; OS: 85.2% vs. 72.7%, P=0.062) with a significantly reduced TRM rate (3.8% vs. 18%, P=0.025). The relapse rate were comparable between two groups (HRD 11.3% vs. URD 12.7%, P=0.649). While for high-risk patients, no differences were observed between two groups in terms of OS, RFS, TRM and relapse rate.Conclusions: For intermediate-risk AML patients, compared with URD HSCT, the results from HRD HSCT were better with improved survival rate and reduced TRM; while for high-risk AML patients, donor types had no effect on transplant outcome. Cytogenetics, status at transplant, and MRD levels at transplant were found to be independent prognostic factors for OS. DisclosuresNo relevant conflicts of interest to declare.

Randomized controlled trial of low-dose intravenous cyclophosphamide versus oral mycophenolate mofetil in treatment of lupus nephritis

Randomized controlled trial of low-dose intravenous cyclophosphamide versus oral mycophenolate mofetil in treatment of lupus nephritis

An in-progress, open-label, multi-centre study (SAILOR) evaluating whether a steroid-free immunosuppressive protocol, based on ATG induction and a low tacrolimus dose, reduces the incidence of new onset diabetes after transplantation.

BackgroundCorticosteroids and calcineurin inhibitors (CNIs) are included in renal transplantation immunosuppressive protocols around the world. Well-known side effects are associated with the use of these drugs, including new onset of diabetes after transplantation (NODAT). Long-term patient survival rates are lower among patients with NODAT. The optimal immunosuppressive protocol would therefore include not using corticosteroids and minimization of CNI use.Methods/DesignThis is a prospective, multi-centre, controlled, randomized, parallel group, open-label study involving kidney transplant patients. The study compares a steroid-free immunosuppressive protocol (study arm A), which is based on low-dose tacrolimus and mycophenolate mofetil (MMF) maintenance therapy together with antithymocyte globulin (ATG) induction, with the conventional immunosuppressive protocol (study arm B), being based on low-dose tacrolimus, MMF and steroids together with interleukin-2 receptor (IL2-R) induction. The study is designed to include most normal-risk patients. It will exclude patients seen as at a high risk of rejection. The primary objective of the study is to assess the cumulative incidence of NODAT in the two study arms 12 months after transplantation using the American Diabetes Association type 2 diabetes diagnostic criteria. The composite measure of freedom from acute rejection, graft survival and patient survival will be evaluated. Renal function and chronic changes in the transplanted kidney will be assessed.DiscussionIf this study confirms conceptual expectations, namely decreased incidence of NODAT, the steroid-free study protocol could be used with all patients. The regimen could be especially beneficial for patients at a high risk of diabetes mellitus.Trial registrationTrial registration: EudraCT 2012-000451-13.

Combined low-dose mycophenolate mofetil and tacrolimus for lupus nephritis with suboptimal response to standard therapy: a 12-month prospective study

The objective of this paper is to evaluate the efficacy of combined mycophenolate mofetil (MMF) and tacrolimus (TAC) for lupus nephritis with suboptimal response to standard therapy. Inclusion criteria for patients: (1) biopsy-confirmed active lupus nephritis; and (2) inadequate response to ≥ 2 immunosuppressive regimens. While prednisolone (≤ 10 mg/day) and angiotensin-converting enzyme inhibitors were continued, immunosuppressive agents were replaced by combined MMF (1 g/day) and TAC (4 mg/day). Patients were followed every 2 months for the clinical response and adverse events at 12 months. Twenty-one patients were recruited (20 women; age 35.8 ± 9.2 years; systemic lupus erythematosus (SLE) duration 111 ± 51 months). The histological classes of lupus nephritis were: IV/III (33%), V+III/IV (33%) and pure V (33%). The creatinine clearance (CrCl), urine protein-to-creatinine ratio (uP/Cr) and serum albumin was 82.4 ± 33 ml/min (<90 ml/min in 57%), 3.27 ± 1.5 and 30.1 ± 5.9 g/l, respectively. Thirteen (62%) patients had active urinary sediments and 17 (81%) patients had active lupus serology. At 12 months, eight (38%) patients had very good response, one (5%) patient had good response and five (24%) patients had partial response. Significant improvement in uP/Cr, albumin, complement C3 and anti-dsDNA titer, and stabilization of CrCl was observed in the responders. Thirty-three adverse events were reported in 18 patients: major infection requiring hospitalization (6%), infection not requiring hospitalization (27%), herpes infection (9%), diarrhea (12%), cramps (9%), dyspepsia (6%), transient increase in serum Cr (6%), alopecia (4%), facial twitching (3%), tremor (3%) and diabetes mellitus (3%). None of these had led to protocol withdrawal. Combined low-dose MMF and TAC is an option for lupus nephritis that fails to respond adequately to standard regimens, with two-thirds of patients improving after 12 months. Longer-term observation is needed to confirm its efficacy and safety.

Combination of low-dose mycophenolate mofetil with cyclosporine and methotrexate as GVHD prophylaxis in unrelated donor allogeneic stem cell transplantation

We report the results of HLA-matched unrelated donor allogeneic stem cell transplantation with new GVHD prophylaxis regimen consisted of cyclosporine, methotrexate and low-dose mycophenolate mofetil in 139 patients with hematologic malignancies. The incidence of grades II-IV and III-IV acute GVHD were 43.0% and 17.3%, respectively. The incidence of chronic GVHD was 42.1%, with 16.5% extensive grade. The cumulative incidence of transplant-related mortality at 100 days and 3 years were 7.9% and 29.7%, respectively. Three-year overall survival, disease-free survival and relapse incidence were 58.7%, 55.3% and 19.6%, respectively. These results suggest the new regime may be effective for the prophylaxis of acute and chronic GVHD in unrelated donor transplantation.

THU0274 Combination of Mycophenolate Mofetil and Tacrolimus for Refractory Lupus Nephritis: A 12-Month Open-Labeled Trial

ObjectivesTo evaluate the efficacy and tolerability of combined low-dose mycophenolate mofetil (MMF) and tacrolimus (Tac) for refractory lupus nephritisMethodsPatients with refractory lupus nephritis were recruited. Inclusion criteria: (1) Active nephritis...

2117 PEDIATRIC STEROID-FREE DECEASED-DONOR RENAL TRANSPLANTATION WITH ALEMTUZUMAB INDUCTION: A SEVEN-YEAR EXPERIENCE

You have accessJournal of UrologyTransplantation & Vascular Surgery: Renal Transplantation, Renal Vascular Surgery1 Apr 20132117 PEDIATRIC STEROID-FREE DECEASED-DONOR RENAL TRANSPLANTATION WITH ALEMTUZUMAB INDUCTION: A SEVEN-YEAR EXPERIENCE Jonathan J. Melquist, Heather N. DiCarlo, Deirdre Connolly, Joseph Caputo, Richard Fine, Katarina Supe-Markovina, Wayne C. Waltzer, and Frank S. Darras Jonathan J. MelquistJonathan J. Melquist Stony Brook, NY More articles by this author , Heather N. DiCarloHeather N. DiCarlo Baltimore, MD More articles by this author , Deirdre ConnollyDeirdre Connolly Stony Brook, NY More articles by this author , Joseph CaputoJoseph Caputo Stony Brook, NY More articles by this author , Richard FineRichard Fine Stony Brook, NY More articles by this author , Katarina Supe-MarkovinaKatarina Supe-Markovina Stony Brook, NY More articles by this author , Wayne C. WaltzerWayne C. Waltzer Stony Brook, NY More articles by this author , and Frank S. DarrasFrank S. Darras Stony Brook, NY More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.2026AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Alemtuzumab (Campath-1H, C1H) is a monoclonal antibody targeting CD52 receptors on B- and T-lymphocytes and is an effective induction agent in renal transplantation. We report a seven-year experience using C1H induction and steroid-free protocol in the pediatric population as safe and effective. METHODS Between 2006 and 2012, 21 pediatric deceased-donor renal transplants were performed at a single academic center. Mean recipient age was 14.3 years (range 4 - 18). Six of the 21 recipients were African-American, 8 were Hispanic, 7 were Caucasian, 14 were male, and 3 were re-transplants. All 21 pediatric recipients received a single intraoperative dose of alemtuzumab (0.6 mg/kg, range 10-30 mg), 3 doses of IV methylprednisolone, tacrolimus (TAC), and low-dose mycophenolate mofetil (MMF). Immunosuppression was maintained using TAC and MMF. RESULTS The average follow-up period was 32 months. All patients had immediate graft function. Graft survival was 95% and patient survival was 100%. Mean 12- and 36-month eGFR were 60.3±28.9 and 56.4±14.4 mL/min/1.73m2, respectively. Two patients developed acute T-cell mediated rejection on average 10.5 months from transplantation (See Figure). One was treated successfully. The other one had a transplant nephrectomy at 20 months for graft failure believed to be secondary to the patient's persistent non-compliance with the immunosuppression regimen. No pediatric recipients developed cytomegalovirus (CMV) infection, post-transplant lymphoproliferative disease (PTLD) or Polyoma BK viral nephropathy. No cases of post-transplant diabetes mellitus (PTDM) or hyperlipidemia have been seen in this group. All 21 patients stayed on TAC and low-dose MMF throughout their post-transplant course. CONCLUSIONS Steroid-free immunosuppression with single dose C1H induction provides adequate and safe immunosuppression in pediatric deceased-donor renal transplant recipients receiving TAC and low-dose MMF maintenance therapy. These results compare favorably with our adult renal transplant experience. The authors plan to continue their current steroid-free protocol in existing and future patients. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e867-e868 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jonathan J. Melquist Stony Brook, NY More articles by this author Heather N. DiCarlo Baltimore, MD More articles by this author Deirdre Connolly Stony Brook, NY More articles by this author Joseph Caputo Stony Brook, NY More articles by this author Richard Fine Stony Brook, NY More articles by this author Katarina Supe-Markovina Stony Brook, NY More articles by this author Wayne C. Waltzer Stony Brook, NY More articles by this author Frank S. Darras Stony Brook, NY More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Immunomodulatory Properties of Mesenchymal Stem Cells Combined with Mycophenolate Mofetil Induce T Cell Regulation and Prolong Renal Allografts Survival in Cynomolgus Monkeys

The induction of tolerance to allografts is one of the major goals in transplantation. Mesenchymal stem cells (MSCs) have been shown to be potent immunomodulatory and immunosuppressive properties in vitro and in vivo. However, to the clinical perspective of MSC-based cell therapy, it has not been clearly defined whether immunosuppressants currently utilized in the clinic may affect immunomodulatory capacities of MSCs. The aim of this study was to investigate the effect of combination therapies of MSCs and mycophenolate mofetil (MMF) on delaying acute rejection of renal allografts in Cynomolgus monkey model. MSCs were isolated from born marrow of Cynomolgus monkey. They were expanded and characterized by morphology, phenotypes and immunosuppressive functions. They were positive for CD90, CD73, CD29, CD105, and negative for CD45, CD34 and MHC-II. Monkeys received adoptive multiple infusions of autogeneic MSCs with a short-term and low-dose of MMF achieved long-term renal graft survival (>90 days post-transplantation) with normal serum creatinine (sCr) concentration and ultrasound imaging of transplanted kidney grafts. Confocal fluorescence microscopy analyses revealed that the transplanted PKH-26 labeled MSCs were found in renal allograft, spleen and lymph nodes of the recipients after the transplantation. The monkeys received MSCs showed high frequencies of CD4+CD25+Foxp3+ regulatory T cells (Tregs). An increased population of interleukin (IL) 10-secreting type 1 T regulatory (Tr1) cells and T helper (Th) 2-dominant cytokine shift were detected in survival recipients. Immunosuppressive effect of MSCs was not only showed in CD4+ and CD8+ cells, but also in their subsets of CD4+CD28+CD95- and CD8+CD28+CD95-naïve T cells. A depression in the percentages of CD4+CD28-CD95+ and CD8+CD28-CD95+ effecter memory T cells was observed in MSC treated recipients at the early stage of the treatment. In conclusion, this study shows synergistic effects of MSCs with short-term and low-dose MMF regimen in promoting renal allograft survival in Cynomolgus monkeys, also provides information to motivate the development of MSC therapy strategies in clinical transplantation.

Recent progress in the treatment of lupus nephritis

The treatment of lupus nephritis has seen significant advances during the past decade mainly due to the publication of well-designed randomized clinical trials (RCTs). The choice of treatment is guided by the histopathologic classification but is also influenced by demographic, clinical, and laboratory characteristics that allow for the identification of patients at risk for more aggressive disease. For the induction arm, low-dose cyclophosphamide regimens and mycophenolate mofetil have been validated as alternatives to the established National Institutes of Health regimen of high-dose cyclophosphamide; for the maintenance phase, azathioprine and mycophenolate compete for treatment of first choice. Rituximab is efficacious in real-life clinical practice but ineffective in clinical trials. The role of recently approved belimumab in lupus nephritis eagerly awaits further documentation. Aggressive management of comorbid conditions, such as hypertension and dyslipidemia, is of utmost importance. Here, we review the latest advances in lupus nephritis therapy with a focus on recent RCTs as well as new biologic agents under development. Furthermore, we propose a therapeutic algorithm in an effort to facilitate clinical decision-making in this gradually changing landscape. Upcoming European and American recommendations should provide further clarification.

Suitable Calcineurin Inhibitor Concentrations for Liver Transplant Recipients in the Chinese Population

Aim The aim was to deduce suitable calcineurin inhibitor concentrations for the Chinese liver transplantation population. Methods We retrospectively studied 97 liver transplant recipients who displayed stable liver and renal function. No grafts were obtained from prisoners, procurements were performed with donor consent conforming to international ethics regulations. At 3, 6, and 12 months, we increased the concentrations and doses of calcineurin inhibitors as well as the values of alanine transaminase and serum creatinine. Results Twenty-eight recipients received cyclosporine and 69 tacrolimus. The mean cyclosporine daily dosages were 203 ± 62 mg at 3, 188 ± 55 mg at 6, and 173 ± 52 mg at 12 months, the tacrolimus daily dosages were 3.08 ± 0.98, 2.82 ± 0.98, and 2.58 ± 0.93 mg, respectively. The corresponding mean cyclosporine peak concentrations (C 2) were 806 ± 322 ng/mL, 681 ± 206 ng/mL, and 644 ± 190 ng/mL and the mean tacrolimus trought concentrations (C 0) 6.61 ± 3.02 ng/mL, 5.85 ± 2.44 ng/mL, and 5.22 ± 2.33 ng/mL, respectively. In both groups, transaminases and serum creatinine were stable over time. Conclusions An individualized immunosuppressive regimen for the local population is necessary. We delayed calcineurin inhibitors with subsequent low-dose mycophenolate mofetil plus minimized calcineurin inhibitors, which seemed to be nephropreotective and safe for Chinese liver transplantation patients.

058 IMPACT OF LEARNING CURVE ON THE SURGICAL COMPLICATIONS AND GRAFT SURVIVAL IN LIVE RENAL TRANSPLANTATION

Sirolimus (RAPA) and corticosteroids (CS) both inhibit wound healing. To evaluate the possibility that RAPA and CS have additive effects on wound healing, we evaluated the effects of corticosteroid avoidance (CSAV) on wound healing complications in patients treated with RAPA.One hundred nine patients treated with a CSAV regimen (no pretransplantation or posttransplantation CS) were compared with a historical control group (n = 72) that received cyclosporine (CsA), mycophenolate mofetil (MMF), and CS. The CSAV group received low-dose CsA, MMF, RAPA, and thymoglobulin induction. Complications were classified as follows: wound healing complications (WHC) or infectious wound complications (IWC). WHC included lymphocele, hernia, dehiscence, diastasis, and skin edge separation. IWC included wound abscess and empiric antibiotic therapy for wound erythema.The CSAV group was largely CS-free: 11% of patients received CS for rejection, 12% of patients received CS for recurrent disease, and 85% of patients are currently off CS. The CSAV group had a significantly lower incidence of WHC (13.7% vs 28%; P = .03) and lymphoceles (5.5% vs 16%; P = .02) than the control group. There was no difference in the incidence of IWC between the 2 groups. Patients who received CSAV were 18% less likely (P = .57) to develop any type of complication, 41% less likely (P = .20) to develop a WHC, and 71% less likely (P = .018) to develop a lymphocele.CSAV in a RAPA-based regimen results in a marked reduction in WHC and lymphoceles. Therefore, CSAV provides a promising approach for addressing WHC associated with RAPA therapy.