CsA Dose Research Articles

Prior High Dose Chemotherapy and a Higher “Intensity” of the Preparative Regimen Can Influence Outcome after Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) for Acute Myeloid Leukemia (AML) in First Complete Remission (CR1).

In the setting of AML, RIC regimens have emerged as an attractive modality to decrease toxicity. However, toxicity might represent only one aspect of the problem, since AML encompasses a group of chemosensitive diseases, raising concerns that significant reduction of the intensity of the preparative regimen, while increasing immunosuppression, may have a negative impact on long-term outcome. This report describes the comparative results of 31 AML patients in CR1 receiving RIC allo-SCT from an HLA-identical sibling in 2 institutions (Nantes, n=13; and Marseille, n=18) using 2 different “global” treatment approaches (Table below). After achievement of CR1, the “Nantes” approach included administration of one or two courses of consolidation with high-dose cytarabine (HDC), followed immediately by allo-SCT conditioned with a genuine nonmyeloablative, but highly immunosuppressive RIC regimen including fludarabine, low dose busulfan (4 mg/Kg), ATG (5 mg/Kg) and both CsA and corticosteroids for GVHD prophylaxis (“FB1A2” group). The “Marseille” program aimed to deliver after CR1, in addition to HDC, an autologous SCT followed by allo-SCT conditioned with fludarabine, an intermediate dose of busulfan (8 mg/Kg), low dose ATG (2.5 mg/Kg) and CsA alone for GVHD prophylaxis (“FB2A1” group). In the “FB2A1” group, 12 patients (67%) could actually receive the planned auto-SCT. With a median follow-up of 47 months, leukemia-free survival (LFS) in the whole study population was 56% at 5 years. However, the KM estimate of LFS was significantly higher in the “FB2A1” group as compared to the “FB1A2” group (P=0.01; 72% vs. 31% at 5 years). Overall, 8 patients (26%; 95%CI, 11–41%) had relapsed at a median of 320 (range, 241–707) days after diagnosis, and the significant difference between the 2 groups in terms of LFS was likely due to a higher risk of leukemia relapse in the “FB1A2” group (6/13, vs. 2/18; P=0.07). Five patients died from toxicity, for an overall incidence of TRM of 16% (95%CI, 6–34%), with this being comparable between the 2 groups (2/13 vs. 3/18; P=NS). Such comparable TRM despite a more “intensive” approach, translated towards a higher overall survival in the “FB2A1” group as compared to the “FB1A2” group (72% vs. 42% at 5 years; P=0.07). After controlling for relevant factors, in the multivariate analysis, actual performance of auto-SCT prior to RIC allo-SCT (P=0.04; RR=4.9; 95%CI, 1.1–22.4), was significantly predictive of an improved LFS. We conclude that RIC allo-SCT from an HLA-matched related donor represents a valid option for AML patients not eligible for standard allo-SCT. However, in order to achieve optimal results, a comprehensive treatment “package” including some form of high dose therapy prior to RIC allo-SCT and/or semi-intensive cytoreduction/myeloablation incorporated within the RIC regimen is likely necessary to allow sufficient time for the GVL effect. [Display omitted]

Responses and Outcome Following Immunosuppressive Therapy in Large Granular Lymphocyte Leukemia-Associated Pure Red Cell Aplasia: A Nationwide Cohort Study in Japan for the PRCA Collaborative Study Group.

Background: Large granular lymphocyte (LGL) leukemia accounts for a significant part of secondary PRCA. Cyclophosphamide (CPA) therapy has been reported as being useful in the literature. However, because of its rarity, the long-term response and relapse rate after immunosuppressive therapy including CPA in LGL leukemia-associated PRCA are largely unknown, and optimal management of this disorder remains unclear.Objectives: We conducted a nationwide survey of immunosuppressive therapy for PRCA in Japan to elucidate the long-term response and overall survival (OS) of this disorder. This report is a summary focusing on CPA therapy for LGL leukemia-associated PRCA.Methods: The questionnaires were sent to 109 medical institutions in Japan to estimate the number of patients with newly diagnosed acquired PRCA. From a total of 185 patients consisting of 73 idiopathic and 112 secondary PRCA cases, we evaluated 14 patients with LGL leukemia for this report. Endpoints of this study were the response rate and the duration of the response to immunosuppressive therapy and overall survival.Results. Efficacy of the first remission induction therapy was seen in 6 out of 8 patients treated with CPA (75%), 1 out of 4 patients with cyclosporine (CsA) (25%), and 0 of 2 with corticosteroid (0%), respectively. The median initial dose of CPA for the responding patients (n=6) was 100 mg. The initial dose of CsA for the responding patient was 3.7 mg/kg. Two patients, who failed to respond to the initial CPA therapy, received CsA therapy resulting in the response in one patient. Three patients, who failed to respond to the initial CsA therapy, received CPA therapy resulting in the response in all of three patients. Two patients, who failed to respond to the initial prednisolone therapy, received CsA therapy resulting in the response in one patient. We classified the patients with LGL-associated PRCA into the CPA-group (n=9) and the CsA-group (n=3) according to the response to initial or salvage therapy. Relapse was seen in two CPA-responders following discontinuation of maintenance therapy (23, 45 months), whereas no patients relapsed on maintenance CPA therapy. The estimated median duration of the response to CPA was 125 months. The median OS has yet been reached with the median observation period of 89 months.Conclusion: CPA showed an excellent response in LGL leukemia-associated PRCA and CPA-containing regimens were effective to prevent relapse of anemia. However, most patients are still receiving CPA for maintenance therapy, and it remains uncertain whether CPA can induce maintenance-free hematological response.

Induction of Indefinite Cardiac Allograft Survival Correlates With Toll-Like Receptor 2 and 4 Downregulation After Serine Protease Inhibitor-1 (Serp-1) Treatment

Innate immunity provides obstacles to successful organ transplantation, which cannot be prevented by cyclosporine (CsA). Here we have determined the potential of a myxoma viral serpin, Serp-1, with proven anti-inflammatory and antiatherogenic actions, to modulate innate immunity and contribute synergistically with CsA in the prevention of acute cardiac allograft rejection. Brown-Norway rat hearts were heterotopically transplanted into Lewis rats and given either a monotherapy treatment of Serp-1, a subtherapeutic dose of CsA, or the two drugs in combination. A brief treatment of Serp-1 alone, or a subtherapeutic dose of CsA, resulted in a marked decrease in intragraft macrophage infiltration and downregulation of toll-like receptor (TLR)-2, TLR4 and MyD88 at 48 hours posttransplantation, which was associated with significantly reduced numbers of mature dendritic cells. A significant reduction in intragraft T-lymphocyte infiltration was observed with both Serp-1 monotherapy and Serp-1 and CsA combination therapy, with the combination treatment achieving indefinite graft survival (>100 days) with normal histology. The CsA monotherapy group displayed partially reduced lymphocyte infiltration compared to the untreated controls, but failed to inhibit early innate immune graft recognition events such as macrophage infiltration and TLR 2, TLR4, and MyD88, and was ultimately unsuccessful in preventing rejection (36.3+/-7.8 days). Observed suppressive effects of Serp-1 on early innate immune response components such as TLR-2 and 4, and on adaptive responses such as T-cell intragraft infiltration suggests that Serp-1 may modulate the transition from innate to adaptive immunity, exhibiting a synergistic effect on allograft survival when used in combination with a subtherapeutic dose of CsA.

Pharmacokinetics and Pharmacodynamics in Renal Transplant Recipients Under Treatment With Cyclosporine and Myfortic

Introduction Efficacious prophylaxis of acute rejection episodes (ARE) requires adequate exposure to each component of the immunosuppressive treatment from the first days after renal transplantation. The aim of the present study was to evaluate the correlation between cyclosporine (CsA) and mycophenolic acid (MPA) exposure based upon pharmacokinetics (PK) and pharmacodynamics (PD) and 6-month biopsy-proven acute rejection (BPAR) episodes and chronic allograft nephropathy on 6 month protocol biopsies. Patients and methods We examined twenty-two first or second de novo renal transplant recipients treated with steroids, Sandimmune Neoral (CsA) and Myfortic (720 mg twice a day). PK (C0, C2, and AUC 0–12h) for both drugs were determined on days 7, 90, and 180. Calcineurin activity, interleukin-2 and interferon-γ synthesis as well as %CEM were tested at days 7 and 180. CsA dosages were adjusted by C2 monitoring. Collected data included: BPAR during the first 6 months and Banff histological parameters on the 6-month protocol biopsies. Results Eighteen of 22 patients completed 1 year follow-up under treatment. The 6-month BPAR was 18% (4/22). Six-month protocol biopsies in 50% of 14 recipients showed chronic allograft nephropathy 1. At day 7, CsA C2 and AUC median values were 138 ng/mL and 6377 ng × h/mL, while C0 MPA was 1.0 μg/mL and AUC = 23.9 μg × h/mL. CsA C2 medians at 3 and 6 months were 1468 and 1720 ng/mL. MPA-AUC reached therapeutic targets at 3 months (32.3 μg × h/mL) and was 48.3 μg × h/mL at 6 months. Patients with BPAR showed lower CsA AUC ( P = .06) and a significantly lower baseline inhibition of calcineurin activity ( P < .005) than patients with no BPAR. An increase in mesangial matrix in 6-month protocol biopsies correlated with higher CsA C2 ( P = .01). All biomarkers evaluated were significantly inhibited compared with the standard population. Conclusions When Myfortic is administered together with CsA, it is advisable to begin with higher doses (720 mg × 3 days) to reach adequate PK targets and improve BPAR rates. To prevent chronic allograft nephropathy, lower CsA C2 should be targeted from 3 months.

Clinical Evolution in the First 3 Months of Patients After Liver Transplantation in Maintenance Phase Converted From Mycophenolate Mofetil to Mycophenolate Sodium Due to Gastrointestinal Complications

The enteric-coated mycophenolate sodium (EC-MPS) is a new formulation of mycophenolic acid with a gastro-resistant enteric coating, which releases the drug in the intestine, reducing the incidence of the gastrointestinal (GI) adverse effects. The present work provided a summary of 20 patients with liver transplantation and more than a 1 year of treatment with mycophenolate mofetil (MMF) who, after presentation of GI complications, were converted to EC-MPS. The patients were followed over a 3-month period after beginning EC-MPS treatment. The mean age of the cohort was 53 ± 10 years and included 75% men. The reasons for transplantation were ethanol cirrhosis (70%), hepatitis C cirrhosis (30%), hepatocarcinoma (5%), and Wilson’s disease (5%). At baseline, all patients were being treated with cyclosporine (CsA). CsA doses and levels were reduced during follow-up: baseline dose 179 mg/day versus 143 mg/day at 3 months; levels: 90.4 ng/mL versus 85.8 ng/mL, respectively ( P = .017). The administered dose of EC-MPS was 720 mg/day in all cases. The GI complications at baseline were: diarrhea 60% (92% moderate-severe), abdominal discomfort 60% (58% moderate), abdominal pain 45% (44% moderate-severe), gas 40% (38% moderate-severe), nausea 20% (25% moderate), and dyspepsia 20% (mild). After 3 months of EC-MPS treatment, only two patients (10%) displayed moderate diarrhea. The renal evolution was favorable, serum creatinine was reduced, and 24-hour creatinine clearance significantly increased (creatinine: 1.78 ± 1.6 mg/dL at baseline versus 1.30 ± 0.3 mg/dL at 3 months, P = .002; creatinine clearance: 72.8 ± 18 mL/min versus 79.6 ± 13 mL/min, P = .001). Conversion of MMF to EC-MPS in liver transplant recipients solved the GI tolerability problems and improved renal function during the first 3 months, probably due to the concomitant reduction of anticalcineurinic dose.

Single Bolus Antithymocyte Globulin Versus Basiliximab Induction in Kidney Transplantation With Cyclosporine Triple Immunosuppression: Efficacy and Safety

The aim of this prospective randomized study was to examine the effect of induction immunosuppression and low initial cyclosporine (CsA) on the onset of graft function and its long-term consequences. During 1999-2001, 155 patients were randomized to single 9 mg/kg dose antithymocyte globulin (ATG)-Fresenius (group A) or two 20-mg doses of basiliximab (group B) with reduced dose CsA or conventional CsA triple therapy without induction (group C). Delayed function (DGF) was lower in group A than in groups B or C (5.7% vs. 24.1% and 15.9%, P<0.025) and need of dialysis was less in groups A and B compared to C (10.3 and 10.4 vs. 20.0 days, P<0.05). Acute rejections occurred in 11.3%, 12.1% and 20.5%, and the mean (median) time to rejection was 16 (13), 97 (46) and 101 (35) days in groups A, B, and C, respectively (P<0.005). One-and 5-year graft survivals (GS) were 98.1% and 90.6% (group A), 96.6% and 96.6% (group B), and 93.2% and 84.1% (group C). Five-year GS was significantly better in group B than in group C (P<0.05). The death censored 5-year GS in groups A, B, and C were 94.3%, 96.6%, and 90.0% (P=NS). Single high-dose ATG induction was associated with hemodynamic and pulmonary disturbances without, however, serious or long-term consequences. ATG induction significantly reduced DGF. Both induction regimens together with low initial CsA led to significantly less posttransplant dialysis and excellent survival. The high dose ATG was associated with significant hemodynamic and pulmonary side effects during drug infusion.

Cyclosporine monitoring in the early post-transplant period in pediatric liver transplant recipients

Monitoring of CsA blood levels two h post-dose (C2) has shown a higher correlation to drug exposure than monitoring of trough levels (C0) at least in adults, but initial doses and target blood levels of CsA have yet to be established in pediatric transplant patients. The objectives of the study were to describe the pharmacokinetics of CsA administered by NGT in the first days after transplantation and the dose of Sandimmun Neoral required to achieve minimum therapeutic range blood levels. This study included 20 pediatric liver transplant recipients (mean age of 3.2 yr) treated with CsA administered by NGT from day one post-transplant until they were able to ingest oral medication. The study was continued until one yr of post-transplant follow-up. Eight h pharmacokinetic profiles were performed on days one, three, and five post-transplant to determine the minimum dose required to achieve the therapeutic range. All children received an initial dose of 15 mg/kg/day of CsA by NGT. Mean CsA doses administered on days one, three, and five were 16.8, 29.5, and 36.5 mg/kg/day, respectively. Mean C0 levels of 119, 310, and 337 ng/mL and mean C2 levels of 213, 753, and 888 ng/mL were obtained. No correlation was found between C0 and C2 levels and the AUC(0-8 h). Intravenous administration of CsA was required in 55% of patients. The biopsy-confirmed acute rejection rate was 45%, with graft and patient survival rates of 95 and 100%, respectively. Poor absorption of CsA in small children requires a considerable increase in dose. CsA exposure cannot be estimated by single C0 or C2 determinations in the early post-transplant period.

Diagnosis and Treatment for Graft-Versus-Host Disease After Liver Transplantation: Two Case Reports

Aim The diagnosis and treatments were of 2 cases of graft-versus-host disease (GVHD) after liver transplantation are presented herein. Methods The 2 cases were diagnosed at 24 and 32 days after liver transplantation, respectively. Fever, diarrhea, skin rash, and leukopenia were symptoms in both of them. They were treated with methylprednisolone (0.5 g/d, for 3 days), G-CSF, and GM-CSF. The dose of CsA was decreased in 1 of them. Results One patient died of cerebral hemorrhage at 31 days after transplantation. The other 1 responded well to the methylprednisolone and the skin rash disappeared within 1 week after the treatment. He was discharged 50 days after transplantation. Conclusion Clinicians should be familiar with the risk factors, signs, and symptoms associated with GVHD after liver transplantation. Corticosteroids are the choice of treatment for GVHD after liver transplantation. Immunosuppressive agents should be decreased when GVHD is diagnosed.

Single Daily Dose Administration of Cyclosporine in Renal Transplant Recipients

Cyclosporine (CsA) microemulsion has been the mainstay immunosuppressive agent for renal transplant recipients for years. A single daily dosing of cyclosporine (SD) is rarely used. The objective of this study was to evaluate the efficacy of SD versus twice daily dosing of CsA. Retrospective evaluation of SD use was conducted for 44 renal transplant recipients for 12 months (study group). Equal numbers of matched recipients were selected for age, sex, HLA mismatch, donor type, and immunosuppressive regimen (control group). We measured CsA trough (C0) and peak (C2) blood levels, 12-hour CsA profile, and the area under the concentration-time curve (AUC). There were significant differences in C0, C2, and calculated AUC after shifting to SD. In the study group, the mean AUC was 4619 ng/mL/h before versus 6567 ng/mL/h after shifting to SD ( P = .004). This became more therapeutic and identical to the mean AUC in the control group, which was 6551 ng/mL/h. Total daily CsA dose was significantly lower in the study group compared with the control group ( P < .0001). A significantly higher incidence of hepatitis was observed among the study group ( P = .011). There were significantly fewer adverse effects in patients in the study group than the control group. There were no significant differences in graft and patient outcomes between the groups. We concluded that CsA dose should be individualized in renal transplant recipients especially if they have viral hepatitis. SD has the advantage of decreasing dosage and CsA-related adverse effects while maintaining optimal graft function.

Low-Dose Versus High-Dose Cyclosporine Induction Protocols in Renal Transplantation

Background Current immunosuppressive therapies are effective to prevent acute rejection episodes (ARE) and graft loss following renal transplantation. Newer agents now make it possible to develop equally efficacious but better tolerated, less toxic strategies. We compared the efficacy of early low- versus high-dose cyclosporine (CsA) induction therapy in living donor renal transplantation. Methods In this single-center study, 90 consecutive recipients of living donor kidney transplants between November 2002 to October 2003 including 51 females and mean average age of 48.23 years were treated with either CsA (5 mg/kg/d) plus mycophenolae mofetil (MMF; 30 mg/kg/d) and prednisolone (1 mg/kg/d; group 1; n = 42); or CsA (8 mg/kg/d) plus MMF (30 mg/kg/d) and prednisolone (1 mg/kg/d; group 2; n = 48). The 2 groups were matched with respect to age, sex, underlying renal diseases, pretransplantation dialysis period, number of transplantations, and panel-reactive antibody tests. CsA dose tapering was initiated in the 2 group 3 months after transplantation. At the end of the first year, the CsA dose was 3.5 ± 0.65 mg/kg in group 1 and 3.4 ± 0.34 mg/kg in group 2. Prednisolone was tapered within the first 2 months, reaching 10 mg/d in all patients. The MMF dose remained unchanged. The 2 groups were compared with respect to ARE, patient and graft survivals, and clinical outcomes within 2 years after transplantation. Results There were no significant differences between the 2 groups with respect to clinical outcomes, including 2-year patient survival (97.62% vs 97.92%; P = .76), 2-year graft survival (80.32% vs 80.41%; P = .82), ARE (47.61% vs 52.08%; P = .09), or length of immediate postsurgical hospital stay, number of readmissions, total hospitalization days, posttransplantation diabetes mellitus, and infectious, cardiovascular, gastrointestinal, and hematologic complications. There was more hypertension (67.5% vs 50.23%; P = .007), hypertriglyceridemia (45.5% vs 32.64%; P = .005), and elevated liver enzymes in group 2 (12.5% vs 7.14%; P = .018). Conclusions Compared with 8 mg/kg CsA induction therapy, the lower doses of CsA were effective, well tolerated, and safe with relatively fewer side effects.

Single daily dose of cyclosporine in patients with primary glomerulonephritis and nephrotic syndrome

Single daily dose cyclosporine (SDD-CsA) might be a new option providing comparable efficacy, increased compliance and less nephrotoxicity compared to standard twice-daily dose cyclosporine (TDD-CsA). The aim of this trial was to prove the feasibility of SDD-CsA as primary and secondary maintenance therapy in patients with nephrotic syndrome. We treated 25 adult patients with nephrotic syndrome and chronic primary glomerulonephropathy with SDD-CsA for a period of 12 months or more. 12 patients were pre-treated with twice-daily dose cyclosporine (TDD-CsA) and were then switched secondarily to a single daily dose after a median period of 8 months (sSDD-CsA). 13 patients were treated primarily with single daily dose cyclosporine (pSDD-CsA). In primary SDD-CsA patients, proteinuria decreased significantly from 9.2 - 0.8 g/l (p = 0.02) and serum protein increased significantly from 54 - 71 g/l (p = 0.03) during the study period. In secondary SDD-CsA patients, serum protein increased further (64 - 69, p = 0.04) after switching to SDD-CsA. In secondary SDD-CsA patients, the median total daily CsA dose was significantly lower (200 mg) with SDD-CsA compared to previous twice-daily dosing (300 mg, p = 0.01). Serum creatinine did not differ significantly before and after therapy and between the groups. SDD-CsA is effective in patients with nephrotic syndrome as primary and secondary maintenance therapy. SDD-CsA allows for significantly lower total daily doses, probably with less nephrotoxicity.

Case Report of a Kidney Transplant Recipient Converted to Everolimus Due to Malignancy: Resolution of Bronchiolitis Obliterans Organizing Pneumonia Without Everolimus Discontinuation

The use of proliferative signal inhibitors (PSIs) in immunosuppression-related malignancies opens new roads for increasing the survival and quality of life in patients with solid organ transplantation. A 56-year-old female recipient of a living donor renal allograft (1990), who was immunosuppressed with cyclosporine (CsA; Neoral), azathioprine, and steroids, did initially well with acceptable renal function. During the last 5 years she required local therapy due to posterior vaginal lip human papillomavirus (HPV) lesions. In 2000, she discontinued azathioprine and the CsA doses were reduced to 100 mg daily. The local lesion showed a good response to reduced immunosuppression. In February 2005, the lesion reappeared and a biopsy showed malignancy. Local surgery was performed and CsA was replaced by everolimus (EVL; Certican). Two months after treatment initiation, the patient developed cough, dyspnea, and low-grade fever. Chest X-ray showed a lesion at the base of the left lung compatible with pneumonitis. After fiberbronchoscopy a diagnosis of bronchiolitis obliterans organizing pneumonia (BOOP) was obtained. She was treated with increased doses of oral steroids. EVL was never discontinued. The radiological lesion disappeared and the malignancy is currently in remission. In summary, a case of gynecological cancer in a renal transplant recipient was treated by surgical removal. After 1 year of immunosuppression with EVL, no recurrence has been observed. The adverse event (BOOP) was probably related to the PSI treatment and was controlled with an increased dose of steroids without discontinuing EVL.

Limitations of cyclosporine C2 monitoring in pediatric heart transplant recipients

Monitoring CSA levels at two h after dosing (C2) has been shown effective in providing adequate CSA-based immunosuppression in clinical trials in adult transplant recipients, but there is limited data regarding C2 monitoring in pediatric transplant recipients. Given the differences in CSA pharmacokinetics between children and adults, a cohort of stable pediatric transplant recipients was converted from monitoring CSA trough (C0) to C2 levels, to establish the clinical utility and safety of C2 monitoring. After an abbreviated AUC(0-5) to establish baseline exposure, subsequent CSA dosing was adjusted based on C2 levels. Additional evaluation included monitoring for rejection, changes in CSA dose, toxicity, serum chemistries, and infection. Twelve heart transplant recipients were enrolled, with mean age 4.8 yr (range: 0.6-14.0). All patients received microemulsified CSA (Neoral((R)); Novartis Pharmaceuticals, East Hanover, NJ, USA) twice daily. Baseline CSA dose was 5.39 +/- 2.05 mg/kg/day (mean +/- s.d.), with mean C0 = 267 +/- 112, C2 = 1065 +/- 565, and AUC(0-5) = 3817 +/- 1435. Only seven participants showed clear CSA peak levels at two h, with five exhibiting delayed peaks at three to five h post-dose. These seven participants completed 48 wk of study, with mean CSA dose decreasing to 4.55 +/- 3.61 mg/kg/day, maintaining mean C2 599 +/- 211 (vs. target C2 = 800). No significant change in serum creatinine was observed, although GFR increased from 76.9 to 107.6 mL/min/1.73 m(2) (p = 0.11). Five patients failed to achieve target C2 levels (>800) during the first four wk, despite comparable AUC values, and were maintained on trough monitoring (C0). Mean systolic and diastolic blood pressures fell slightly, three minor infections were noted during the study period, and one episode of acute rejection occurred, despite stable CSA dosing. Nearly 50% of stable pediatric transplant recipients failed to achieve adequate peak C2 CSA levels during conversion from C0 to C2 monitoring. Age-dependent differences in CSA absorption and/or clearance pharmacokinetics may explain these findings.

Influence of Early Posttransplantation Prednisone and Calcineurin Inhibitor Dosages on the Incidence of New-Onset Diabetes

Risk for new-onset diabetes (NOD) after renal transplantation is higher with tacrolimus (Tac) than with cyclosporine (CsA), but the extent to which the diabetogenic effect of Tac is dosage dependent or steroid dependent remains uncertain. Patients who received a transplant between 1995 and 2002 were drawn from the United Network for Organ Sharing registry and prescription records and NOD diagnoses from Medicare claims, both provided by the United States Renal Data System. Patients were divided into six groups of steroid and Tac doses at 30 d after transplantation and referenced against CsA. Relative hazards of NOD with Cox proportional hazards regression were estimated incorporating propensity scores for Tac and nonimmunosuppressive factors related to NOD. A total of 8839 patients with valid immunosuppression records and without pretransplantation evidence of diabetes were included in the study. Unadjusted, cumulative, NOD incidence 1 yr after transplantation was 14.6% with CsA and 22.2% with Tac and at 3 yr after transplantation was 23.4% with CsA and 32.9% with Tac (P < 0.0001). Neither higher CsA nor higher steroid dosages were associated with NOD in CsA-treated patients. However, NOD hazard was significantly higher with Tac than with CsA in all six steroid/Tac dosing groups, including the cohort with the lowest dosages of Tac (dosage thresholds at 30 d after transplantation <0.12 mg/kg per d [mean 0.07 mg/kg per d] and steroids (<0.75 mg/kg per d; hazard ratio 1.28; 95% confidence interval 1.10 to 1.48; P = 0.0012). Whereas the incidence of NOD is greatest with high Tac dosages, the increased risk versus CsA is sustained with lower Tac dosages. Higher steroid dosages increase the early diabetogenic effect of Tac but not of CsA.

208: Impact of posaconazole (POS) vs fluconazole (FLU) on cyclosporine (CsA) and tacrolimus (TAC) dosing in hematopoietic stem cell transplant (HSCT) recipients with graft-vs-host disease (GVHD)

Background: HSCT recipients often receive the immunosuppressants CsA or TAC for GVHD concomitantly with an azole for prevention of invasive fungal infection (IFI). As CsA and TAC are metabolized by the cytochrome P450 enzyme, CYP3A4, and azoles are CYP3A4 inhibitors, potential drug interactions are a concern. CsA and TAC dose changes were analyzed in a trial of POS vs FLU as IFI prophylaxis in HSCT recipients with GVHD.

Renal outcome after ciclosporin-induced nephrotoxicity

Renal outcome after ciclosporin (CsA) is not clear in most studies involving patients with many renal comorbid conditions. We first report on renal function recovery after CsA in previously healthy kidney patients. Uveitis patients, enroled in a unique single centre cohort follow-up study initiated in 1987, were prospectively evaluated for plasma creatinine and glomerular filtration rate (GFR) before, during (>2 years) and after (>6 months) CsA therapy. We hypothesized that CsA alters renal function progressively over time according to two additive exponential components (irreversible and reversible) and used a mixed linear model with exponential speed parameters maximizing the likelihood. Twenty-seven patients treated for 60+/-34 months (CsA 5.1+/-2.5 mg/kg/day) were followed up for 56+/-42 months after CsA withdrawal. Baseline creatinine was 0.92+/-0.15 mg/dl. The reversible effect of CsA was quantified as a 0.11+/-0.07 mg/dl increase in creatinine/100 mg CsA/day (P<0.001) and a 6.0+/-3.7 ml/min/1.73 m(2) decrease in GFR/100 mg CsA/day (P<0.0001). The irreversible effect was quantified as a 0.03+/-0.05 mg/dl increase in creatinine/100 g cumulative CsA received (P<0.007) and a decrease of 3.3+/-3.9 ml/min/1.73 m(2) GFR/100 g CsA. Although significant decrease in GFR is induced by low-dose CsA therapy in previously healthy kidney patients, renal function recovery is possible after CsA withdrawal and best predicted by CsA daily dosage. Irreversible loss in GFR is correlated to cumulated CsA exposure. The lowest CsA dosage and shortest exposure time effect as well as unlimited renal monitoring are required in order to provide the best long-term renal outcome.

Combination Treatment With Donor Interleukin-12p35 Silenced Dendritic Cells and Cyclosporine Induces Long-Term Survival of Intestinal Allografts in Rats

Immune tolerance promises to enhance allograft survival while reducing risks inherent to immunosuppressants. In this study, we evaluated the effect of interleukin (IL)-12p35 silenced dendritic cells (DC) combined with cyclosporine (CsA) on induction of immune tolerance in intestinal transplantation. The results showed that combination treatment with donor IL-12p35 silenced DC and a low dose of CsA (8 mg/kg) prolonged rat intestinal allograft survival. However, a higher dose of CsA (20 mg/kg) did not further prolong allograft survival.

Association of Cumulative Cyclosporine Dose with Its Irreversible Nephrotoxicity in Japanese Patients with Pediatric-Onset Autoimmune Diseases

Cyclosporine (CsA)-induced nephrotoxicity can become a major obstacle to continuous use. The aim of this study was to optimize CsA dose to avoid its irreversible nephrotoxicity. Twenty-three Japanese patients with pediatric-onset systemic lupus erythematosus or idiopathic nephrotic syndrome, who were maintained in a stable condition by oral dosing of CsA microemulsion, were enrolled in this study. The patients were stratified into 3 groups; those with no, reversible, and irreversible nephrotoxicity, according to periodically performed renal pathohistological examinations. A higher concentration of CsA in blood (p=0.002-0.011) and a longer duration of CsA treatment (p=0.002) were risk factors for irreversible nephrotoxicity, and the cumulative CsA dose, the product of the maintenance dose and duration of CsA treatment, was predictive of nephrotoxicity (p=0.036). The maximum target blood concentration at 2 h post-dose, C(2), to avoid CsA-induced irreversible nephrotoxicity was 700 ng/ml, although the cumulative CsA dose of 4850 mg/kg would result in a 50% probability of nephrotoxicity.

Pharmacokinetics of mycophenolate mofetil in stable pediatric liver transplant recipients receiving mycophenolate mofetil and cyclosporine

There are few pharmacokinetic data for mycophenolate mofetil (MMF) when used in combination with cyclosporine (CsA) in pediatric liver transplant recipients. The aim of this study was to assess the pharmacokinetics of MMF in stable pediatric liver transplant patients and estimate the dose of MMF required to provide a mycophenolic acid (MPA) exposure similar to that observed in adult liver transplant recipients receiving the recommended dose of MMF (target area under the plasma concentration-time curve from 0 to 12 hours [AUC(0-12)] for MPA of 29 mug.hour/mL in the immediate posttransplantation period and 58 microg x hour/mL after 6 months). A 12-hour pharmacokinetic profile was collected for 8 pediatric patients (mean age 20.9 months) on stable doses of MMF and CsA who had received a liver transplant > or = 6 months prior to entry and who had started on MMF within 2 weeks of transplantation. Mean MMF dosage was 285 mg/m(2) (range, 200-424 mg/m(2)). Of 8 patients, 7 had a MPA AUC(0-12) (range, 11.0-37.2 microg x hour/mL) well below the target. One patient had an AUC(0-12) > or = 58 microg x hour/mL but was considered an outlier and was excluded from analyses. Mean MPA AUC(0-12) and maximum plasma concentration values were 22.7 +/- 10.5 microg x hour/mL and 7.23 +/- 3.27 microg/mL, respectively; values normalized to 600 mg/m(2) (the approved pediatric dose in renal transplantation) were 47.0 +/- 21.8 microg x hour/mL and 14.5 +/- 4.21 microg/mL. In conclusion, assuming that MPA exhibits linear pharmacokinetics, when used in combination with CsA, a MMF dose of 740 mg/m(2) twice daily would be recommended in pediatric liver transplant recipients to achieve MPA exposures similar to those observed in adult liver transplant recipients. This finding should be confirmed by a prospective trial.

Prevention of Graft-Versus-Host Disease (GVHD) with Tacrolimus after Allogeneic Grafting for Hematological Malignancies Following Sub-Myeloablative Conditioning.

Severe acute or chronic GVHD following allogeneic hematopoietic stem cell transplantation therapy (HSCT) has a deleterious effect on the successful treatment of hematological malignancies. We have retrospectively studied mycophenolate mofetil (MMF) and tacrolimus (FK) or cyclosporine (CSA) following allogeneic HCST in the prevention of GVDH and the induction of immune tolerance in 93 patients with hematological malignancies using non-myeolablative pre-transplant conditioning. In the current study, there were 35 patients with leukemia, 36 patients with lymphoma, 12 patients with myelodysplastic syndrome or a myeloproliferative disorder and 10 patients with multiple myeloma. There were 63 women and the median age was 42 (15–75) years. Twenty patients had relapsed after previous autologous or allogeneic HSCT and 45 patients were older than 59 years. The remaining patients had co-morbid medical conditions that precluded the use of chemotherapy/radiotherapy dose-intensive pre-conditioning. Conditioning prior to allogeneic HSCT (94 blood stem cell grafts and 1 marrow graft) was fludarabine (90 mg/m2 in three daily doses) and TBI (200cGy) in 86 patients, fludarabine (120 mg/m2 in 4 daily doses) and cyclophosphamide (50mg/kg) in 5 patients, and TBI (200 cGy) only in 4 patients. Forty-three patients received sibling and 50 unrelated grafts. Median follow-up post transplant is 3.0 (0.2–6.1) years. Five (5.3%) patients did not experience sustained hematological chimerism post-transplant. MMF and FK were administered to 33 recipients and MMF and CSA to 60 recipients. The dose and schedule of MMF, CSA and FK have been published (Laport et al. Blood, 2006 and Fay et al. Blood, 1996.) There was no difference in the degree of HLA mismatching between the two groups of patients. Cumulative incidences were used to estimate the incidence of acute and chronic GVHD, all deaths and disease progressions not related to GVHD being considered as the competing events. The Gray test was used to compare cumulative incidences between groups. The unadjusted cumulative incidence of grade III–IV acute GVHD that required oral or systemic corticosteroid therapy, was 54% (95% CI, 40%–68%) in evaluable patients who received CSA in contrast to 38% (95% CI, 18%–58%) in patients who received FK (p-value=0.25). Furthermore, the unadjusted cumulative incidence of extensive chronic GVHD at 1 year was 45% (95% CI, 32%–58%) for CSA versus 34% (95% CI, 14%–54%) for FK (p-value=0.48). Progression-free survival between patients who received FK or CSA at the time of the analysis of this study is similar (p-value=0.6191). The progression-free survival at 1 year was 43% (95% confidence interval [CI], 24%–62%) for CSA versus 43% (95% CI, 31%–55%) for FK. Analyses of the overall morbidity and the incidence of infectious complications between the 2 groups are ongoing. FK combined with MMF may be superior to CSA and MMF in the prevention of GVHD post sub-myeloablative allogeneic HSCT therapy for hematological malignancies and FK may result in improvement of treatment outcome. We believe further study is warranted.