Combination Of Sirolimus Research Articles

Long-Term Outcome of Methotrexate-Free GVHD Prophylaxis Using Sirolimus and Tacrolimus in Matched Related (MRD) and Unrelated Donor (URD) Peripheral Blood Stem Cell Transplantation (PBSCT).

Methotrexate (Mtx) is an antiproliferative agent associated with toxicity and delayed engraftment after transplantation. Sirolimus is an immunosuppressive mTOR inhibitor that acts synergistically when administered with tacrolimus. We assessed the combination of sirolimus and tacrolimus without Mtx after MRD and URD PBSCT in concurrent trials. Methods Eligible subjects had HLA-A, B, C and DRβ1 matched MRD and URD donors. Conditioning consisted of cytoxan (1800 mg/m2 x 2 days) and TBI (14 Gy, 7 fractions with lung shielding). Tacrolimus (serum conc. 5–10 ng/mL) and sirolimus (serum conc. 3–12 ng/mL) were given as GVHD prophylaxis. No Mtx was given. G-CSF (5 μg/kg/day) was administered from day+12 until neutrophil engraftment as needed. PCP, VZV, and HSV prophylaxis was used, and CMV was treated pre-emptively. No routine anti-fungal prophylaxis was given. Results 53 MRD and 30 URD recipients were enrolled between 7/2002 and 8/2005. The median number of stem cells infused was lower in MRD recipients (7.6 x106 CD34+ cells/kg vs. 10.2 x106 CD34+ cells/kg, p<0.001). Neutrophil engraftment was similar in MRD and URD patients (14 vs. 13.5 days, p=0.2). Platelet engraftment to 20 x106/ml (12 vs. 12 days, p=0.13) and to 100 x106/ml (17.5 vs. 17 days, p=0.32) were similar in the two cohorts. The median time to hospital discharge was 19 days in both groups (p=0.95), with only 2 deaths prior to discharge. Acute lung injury (IPS/DAH) occurred in only 1 subject and was not fatal. 7 (8.4%) subjects developed hepatic veno-occlusive disease (VOD) and was the cause of death in 4. Thrombotic microangiopathy (TMA) was noted in 6 subjects (MRD 5, URD 1; combined incidence 7.3%) and resolved with the elimination of tacrolimus. Renal function recovered in all individuals and TMA did not contribute to the cause of death in any subject. The cumulative incidence of grade II–IV acute GVHD was 20.5%, and was not different between cohorts (18.9 vs. 23.3%, p=0.78). There were only 3 cases of grade III–IV acute GVHD (2 MRD, 1 URD). In a competing risk model (relapse/death as competing risk) the cumulative incidence of chronic GVHD was 52.4% and was not different between groups (50.9 vs. 53.3%, p=0.67). The median follow-up of all surviving patients is 29.5 months from transplantation. Non-relapse and relapse-related mortality at 30 days was 0%. At 100 days they were 4.8% and 1.2% respectively (overall 100 day mortality 6%), without differences in cohorts. Relapse-free survival for the entire group was 72.3% and 68.1% at 1 and 2 years (MRD 71.7% and 66.0%; URD 73.3% at both times points, log rank p=0.6). Overall survival at 1 and 2 years is 77.1% and 71.7% (MRD 77.4% and 69.8%; URD 76.7% at both time points, log-rank p=0.67). The causes of death (n=24) include relapse(13), VOD(4), late pulmonary disease(3), GVHD(2), infection and organ failure(2). Conclusions Sirolimus in lieu of Mtx in a tacrolimus-based GVHD prophylactic regimen is associated with lower transplant-related toxicity, lower rates of acute GVHD and excellent outcomes than would be expected with a Mtx-based regimen. Moreover, MRD and URD outcomes appear to be equivalent, suggesting that the historical disparity in outcomes between MRD and URD transplantation can be abrogated with effective GVHD prophylaxis. This regimen is worthy of further study and broader use in MRD and URD PBSCT.

Sirolimus in combination with mycophenolate mofetil leads to greater exposure to mycophenolic acid than ciclosporin,

Sirolimus in combination with mycophenolate mofetil leads to greater exposure to mycophenolic acid than ciclosporin,

Use of Sirolimus to Facilitate Steroid Withdrawal From a Cyclosporine Regimen

Objective Chronic steroid therapy has been associated with many comorbidities of transplant immunosuppression. Because sirolimus blocks one of the sites affected by steroids, we sought to examine whether substituting this drug mitigated these toxicities. Methods We used intent-to-treat methodology to compare the clinical outcomes and laboratory results between 30 renal transplant recipients converted from steroids to sirolimus with a cohort of demographically matched subjects who were transplanted concurrently with the study group and maintained on steroids. All patients received ongoing cyclosporine-based immunosuppression. To compensate for pharmacokinetic interactions with sirolimus, the cyclosporine exposure was markedly reduced in the study group. Statistical comparisons utilized analysis of variance, chi-square tests, and log rank evaluation of Kaplan–Meier curves. Results Conversion from prednisone to sirolimus was accomplished without difficulty in 27 of 30 patients. Treatment failures among the converted patients were due to chronic allograft nephropathy ( n = 1), recurrence of original disease ( n = 1), or chronic rejection ( n = 2). By intent-to-treat analysis, the outcomes were similar in the study versus concurrent control groups. Laboratory values showed triglyceridemia as an adverse reaction to sirolimus, and reduced leukocytes, to steroid withdrawal. The observed clinical benefits solely reflected the markedly reduced cyclosporine exposure. Based on responses to a questionnaire administered prior to versus 12 and 24 months after steroid withdrawal, several domains revealed improvements in subjective complaints. Conclusion Conversion from prednisone to sirolimus in combination with cyclosporine was easily accomplished in most renal transplant recipients. Although a 2-year follow-up failed to reveal objective benefits of the maneuver (other than those consequent to reduced cyclosporine exposure), most patients reported a subjectively improved health status.

Initial Single-Center Experience With Sirolimus After Lung Transplantation

Background Standard immunosuppression after lung transplantation includes calcineurin inhibitors, mycophenolate mofetil, and steroids. Long-term survivors of lung transplantation are often confronted with chronic kidney disease, by definition related to the intake of calcineurin inhibitors. Sirolimus has been increasingly proposed as an alternative immunosuppressive agent due to its absence of nephrotoxicity, which could be used in selected patients. Methods We prospectively administered sirolimus as an alternative to calcineurin inhibitors in 10 lung transplantation recipients with persistent drug nephrotoxicity. They were switched from tacrolimus to sirolimus. Four patients also had bronchiolitis obliterans syndrome. The conversion scheme consisted of an immediate stop of tacrolimus and an 6 to 8-mg loading dose of sirolimus, followed by 4 mg/d. After 5 days, the sirolimus dose was adjusted to maintain trough levels between 12 and 18 ng/mL or 6 and 12 ng/mL for combined sirolimus and tacrolimus. Patients were monitored for renal and graft function as well as clinical status. Results A significant decrease in creatinine was observed after 1 week of treatment ( P = .011). Azotemia decreased after 1 month, remaining stable ( P < .01). Pulmonary function tests did not show significant modification from before sirolimus, inception in patients with or without bronchiolitis obliterans syndrome. There were seven infections. One patient died of complications related to bronchiolitis obliterans. Conclusion Sirolimus was a useful alternative immunosuppressant, allowing significant tacrolimus withdrawal in transplant recipients with renal impairment. Sirolimus administration allowed recovery of renal function with low morbidity; it was useful for rescue of chronic renal impairment after lung transplantation.

Sirolimus Monotherapy Versus Sirolimus in Combination with Steroids and/or MMF for Immunosuppression After Liver Transplantation

Calcineurin inhibitor (CI)-associated renal dysfunction has emerged as a major cause of morbidity and mortality after liver transplantation. In this retrospective study, we compared the efficacy, safety, and renal protective effect of sirolimus monotherapy (Group A; n = 26) with sirolimus in combination (Group B; n = 34) with steroids and/or mycophenolate mofetil (MMF) in liver transplant recipients who were switched from CI. Patients were switched abruptly or over a period of 2-4 weeks and followed for 17 +/- 10 months. Preconversion renal biopsies in five of six patients showed histological features consistent with CI nephrotoxicity. Serum creatinine increased in the year prior to conversion from 1.7 +/- 0.4 to 2.1 +/- 0.7 mg/dl (P = 0.009) and improved thereafter (1 month, 1.7 +/- 0.6, P < 0.001; 6 months, 1.6 +/- 0.5, P < 0.001; last follow-up, 1.7 +/- 0.9, P = 0.02); only four patients showed a significant decline in renal function after conversion. Seven (11.3%) patients experienced acute rejection (Group A, two; Group B, five; P = NS) and this resulted in the discontinuation of sirolimus in one patient. Fifty-four adverse events occurred in 40 (67%) patients, with similar numbers of adverse events in Group A and Group B. Most episodes of rejection (5/7; 71%), adverse events (45/54; 83%), and discontinuations (5/8; 63%) occurred within 6 months of conversion. We conclude that both sirolimus monotherapy and sirolimus in combination with prednisone and/or MMF are efficacious and safe in liver transplant recipients. Conversion to sirolimus was associated with an immediate improvement in renal function that was sustained during the follow-up.

Tacrolimus and Sirolimus Cause Insulin Resistance in Normal Sprague Dawley Rats

Tacrolimus-sirolimus immunosuppression has improved islet graft survival but may affect islet function. We studied the effects of tacrolimus, sirolimus, or both in normal adult male Sprague Dawley rats. Glucose and insulin response to oral glucose load and pancreas pathology were evaluated after two weeks of daily tacrolimus (1-8 mg/kg/day), sirolimus (0.08-8 mg/kg/day), or low-dose sirolimus (0.08 mg/kg/day) plus tacrolimus (1 mg/kg/day) treatment compared to controls. Tacrolimus and sirolimus each caused dose-dependent hyperglycemia with hyperinsulinemia in response to oral glucose compared to controls, suggesting insulin resistance. At the highest doses of sirolimus, fasting insulin concentrations were high and did not increase with oral glucose suggesting loss of first phase insulin release. The combination of low doses of tacrolimus and sirolimus, at concentrations used in clinical transplantation, resulted in hyperglycemia without hyperinsulinemia after oral glucose administration. The combination of tacrolimus and sirolimus decreased islet size, and increased islet apoptosis more than either medication alone, or controls. In summary, short-term therapy with either tacrolimus or sirolimus causes insulin resistance in normal rats. Combination tacrolimus-sirolimus causes greater islet changes suggesting early islet failure.

The combination of sirolimus plus an mTOR inhibitor has potential for the treatment of patients with recurrent glioma,

The combination of sirolimus plus an mTOR inhibitor has potential for the treatment of patients with recurrent glioma,

Sirolimus pharmacokinetics in pediatric renal transplant recipients receiving calcineurin inhibitor co‐therapy

We have previously reported sirolimus (SRL) pharmacokinetics (PK) in pediatric renal transplant recipients on a calcineurin inhibitor (CNI)-free protocol. We now report pediatric SRL PK in pediatric renal transplant patients receiving SRL + CNI. SRL was dosed to achieve target trough levels between 10 and 20 ng/mL. We performed 49 SRL PK profiles in pediatric renal transplant recipients receiving SRL in combination with either cyclosporine (CsA; 25 profiles), or tacrolimus (TCL; 24 profiles). Ten of the SRL + TCL profiles were obtained from children receiving SRL on a b.i.d. dosing regimen. All other SRL profiles were q.d. regimens. We calculated, the maximum concentration (C(max)), AUC, apparent clearance (aCL; dose/AUC) for dose in mg/m(2), and mean residence time (MRT). SRL levels were measured at 6 and 7 time points for b.i.d. and q.d. dosing, respectively. Regression analysis of SRL trough values vs. AUC showed good correlation in the SRL q.d. + CsA, SRL q.d. + TCL, and SRL b.i.d. + TCL groups (r(2) = 0.95, 0.68, and 0.44, respectively). SRL aCL corrected for body surface area was higher in children aged 0-5 yr receiving SRL with either CsA or TCL. SRL dosing schedule should be tailored to each patient. Higher SRL aCL may be present in younger children when administered with CNI.

Incidence of Posttransplant Diabetes Mellitus in Kidney Transplant Recipients Immunosuppressed With Sirolimus in Combination With Cyclosporine

Sirolimus (SRL) in combination with Cyclosporine A (CsA) and steroids has been shown to lower the incidence of acute renal allograft rejection episodes, allowing CsA sparing. We retrospectively compared the incidence of posttransplant diabetes mellitus (PTDM) among kidney transplant recipients (KTx) immunosuppressed with SRL+CsA versus CsA alone. Patients were divided into two groups: SRL+CsA (n = 38) versus CsA (n = 48). Mean follow-up was 53.9 ± 17.1 months. Seventeen/86 subjects (19.8%) developed diabetes after transplantation (7 IFG, 8.1%; 10 PTDM, 11.6%). The incidence was significantly higher in SRL+CsA (12/38 patients, 31.6%) compared with CsA (5/43 patients, 10.4%) ( P = .0144, odds ratio 3.97). More patients required treatment in the SRL+CsA compared to CsA alone cohort (13.2% vs 2.1%, P = .051): 4 pts (10.5%) became insulin- dependent among SRL+CsA, vs none in the CsA group. Use of OHD was similar in both groups (2.6% SRL+CsA vs 2.1% CsA). There were no significant differences between the two groups in terms of age, sex distribution, BMI, or serum creatinine at 1 to 3 and 5 years from transplantation. All PTDM patients are alive at follow-up, while two grafts were lost due to chronic renal allograft dysfunction. Within the limits of a small retrospective study, we observed that SRL in combination with CsA increased the diabetogenic potential of CsA. A possible explanation of our findings is that higher CsA doses were used in the early experience with SRL+CsA; therefore the higher incidence of PTDM that we observed in the SRL+CsA combination may be a sign of toxicity. Careful monitoring of blood levels is mandatory in the SRL+CsA combination to avoid pleiotropic toxicity.

Co-administration of sirolimus alters tacrolimus pharmacokinetics in a dose-dependent manner in adult renal transplant recipients

A combination of tacrolimus (TAC) and sirolimus (SIR) has recently proved to be a very effective immunosuppressive regimen in organ transplantation. In pediatric transplant recipients, co-administration of these two drugs has been shown to result in a significant decrease of exposure to TAC, whereas conflicting data have been obtained regarding this pharmacokinetic interaction in adults. The aim of this study was to investigate the effect of SIR on TAC pharmacokinetics in adult transplant recipients. Sixteen adult patients (mean age 38 ± 8 years), who had been on standard TAC plus low-dose SIR immunosuppressive treatment for 6 months after renal transplantation, were enrolled for a TAC pharmacokinetic study before and 15 days after discontinuing SIR. Eight patients had received SIR 0.5 mg day −1 and eight patients 2 mg day −1. TAC doses remained the same in all patients after SIR withdrawal. After discontinuing SIR, statistically significant, dose-dependent increases were observed in area under the curve (AUC), peak ( C max) and trough ( C min) TAC concentrations (+15–20% and +27–32%, after discontinuing the 0.5 and the 2 mg day −1 doses, respectively). Proportional decreases were consistently observed in apparent oral clearance (−13% and −23%). Very good correlations were found between TAC AUC and C min, both before and after SIR withdrawal ( R 2 = 0.94, P < 0.0001 and R 2 = 0.97, P < 0.0001, respectively). Our findings clearly demonstrate that the SIR-induced reduction in TAC exposure also takes place in adults and is, therefore, a general, age-independent phenomenon. Hence, TAC levels need to be carefully monitored in transplant recipients of any age, in order to avoid possible TAC overexposure upon SIR discontinuation.

Improved Renal Function after Conversion from Tacrolimus/Sirolimus to Tacrolimus/Mycophenolate Mofetil in Kidney Transplant Recipients

There is limited data on the potential nephrotoxicity of sirolimus (SRL) and tacrolimus (TAC) in combination. We reviewed the course of 97 kidney transplant patients treated with SRL and reduced-dose TAC. Conversion from SRL to mycophenolate mofetil (MMF) was prescribed in a minority (n = 19) for various nonrenal side effects. We compared outcomes of converted patients to those remaining on TAC/SRL (n = 78). TAC levels were increased in converters (P = 0.009). Rejection rates were similar between groups over 18 months (21% vs. 16%, p = ns). Serum creatinine (Cr) and MDRD glomerular filtration rate (GFR) were similar between groups at nadir and six-months, but at 18 months the percent change from six-month Cr was +17% in non-converters vs. -10% in converters (P = 0.004 for the difference). The difference in GFR between groups at 18 months was also significant (P = 0.01). By multivariate analysis, only conversion to MMF was associated with a greater percent change in Cr from 6 to 18 months (P = 0.015). Conversion to MMF also correlated with higher GFR at 18 months independent of rejection, delayed graft function, and ethnicity. Conversion from TAC/SRL to TAC/MMF led to improved renal function despite increased TAC exposure after conversion.

The combination of sirolimus and tacrolimus for primary immunosuppression after heart transplantation –3-year-results

Objectives: Sirolimus and tacrolimus are immunosuppressants competing for the same binding-protein. This study evaluated the efficacy and safety of the immunosuppressive combination tacrolimus and sirolimus after heart transplantation using subtherapeutic trough levels for each compound.

Comparison of methotrexate- versus sirolimus-containing graft-versus-host disease prophylaxis regimens after myeloablative stem cell transplantation

Background: Graft-versus-host disease (GvHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). Methotrexate in combination with a calcineurin inhibitor (CM) is considered standard GvHD prophylaxis. Studies suggest that sirolimus in combination with a calcineurin inhibitor (SC) is effective in preventing GvHD and minimizing transplant-related morbidity and mortality. We sought to compare costs and clinical outcomes between the two different GvHD regimens. Method: A total of 159 patients with hematological diseases underwent myeloablative HLA-matched HSCT at the Dana-Farber Cancer Institute between June 2000 and December 2004 using Cytoxan and TBI conditioning. GvHD prophylaxis was either CM (n=97) or SC (n=62). Inpatient costs for the first transplant year of 94 CM and 47 SC recipients were obtained. Multivariate analyses were conducted including baseline factors: GvHD prophylaxis, patient age, sex matching, donor type, CMV serological status, disease status, stem cell source, and year of transplantation. In addition, for the cost analysis a full model was examined considering both baseline and post-transplant events [neutrophil engraftment, grade II to IV aGvHD, veno-occlusive disease, idiopathic pneumonia/diffuse alveolar hemorrhage, infection, severe organ toxicity, and in-hospital death]. Results: CM recipients were more likely to have unrelated donors, BM grafts, and to be transplanted in earlier years than SC recipients. Univariate and multivariate comparisons of outcomes, costs and days of initial hospitalization are presented in Table 1. The SC regimen was associated with faster engraftment, less acute GvHD and better DFS and OS. Days of initial hospitalization and costs were lower for SC in the univariate model but not the multivariate model. Use of an unrelated donor was the only significant predictor of high costs considering baseline factors. In contrast, in the full model, grade II to IV aGvHD, late engraftment, and in-hospital death were the significant factors associated with high costs. Conclusion: Both OS and DFS in the SC group were higher in the multivariate analysis, probably due to early engraftment and reduced incidence of grade II to IV aGvHD seen in SC group. However, we could not detect the impact of GvHD prophylaxis on inpatient costs for the first transplant year. The SC regimen is a promising alternative to CM and larger multi-center randomized trial is planned through the NIH-funded Clinical Trials Network. | | Univariate analysis | Multivariate analysis | |:-----------------------------------------------------:| ------------------- | --------------------- | ------- | | Variables | CM | SC | P-value | HR (Ratio*) (CM vs SC) | P-value | | Median age, yrs [range] | 40 [18–58] | 43 [18–65] | 0.28 | - | - | | Neutrophil engraftment, median [range] | 17 [10–35] | 13 [8–17] | <0.0001 | 0.21 | <0.0001 | | Cumulative incidence of grade II–IV aGvHD at 100 d | 37±5 | 18±5 | 0.01 | 2.61 | 0.02 | | Cumulative incidence of extensive cGvHD at 1 y | 24±5 | 22±6 | 0.75 | 1.70 | 0.21 | | Disease-free survival at 1 y | 52±5 | 71±6 | 0.0051 | 2.50 | 0.0044 | | Overall survival at 1 y | 53±5 | 72±6 | 0.01 | 1.61 | 0.01 | | Inpatient costs during the first post-transplant year | $110,081 | $101,697 | 0.03 | 1.14* | 0.30 | | Days of initial hospitalization | 33 | 27 | 0.0008 | 0.99* | 0.91 | Table 1

50: The combination of sirolimus and tacrolimus for primary immunosuppression after heart transplantation – 3-year results

50: The combination of sirolimus and tacrolimus for primary immunosuppression after heart transplantation – 3-year results

Islet Transplantation: Steeple Chase and the Next Hurdle

Islet Transplantation: Steeple Chase and the Next Hurdle

Influence of Co‐Medication with Sirolimus or Cyclosporine on Mycophenolic Acid Pharmacokinetics in Kidney Transplantation

The pharmacokinetics of mycophenolic acid (MPA)--the active metabolite of mycophenolate mofetil (MMF)--is significantly influenced by co-medications. The impact of sirolimus on daily MPA exposure, however, has not been investigated so far. As a part of the study aimed at investigating the efficacy of Campath-1H induction therapy in a steroid-free regimen in kidney transplantation, MPA plasma levels were serially measured in 21 patients treated with low-dose sirolimus (SRL) or low-dose CsA both in addition to low-dose MMF over 12 months post-operatively. Full pharmacokinetic profiles were compared at month 6 and 12 post-surgery. Mean dose-adjusted MPA trough levels were 4.4-fold higher in patients on combined SRL and MMF than in those given CsA and MMF. Pharmacokinetic studies demonstrated that mean MPA C(max) and T(max) were comparable in the two groups, while mean MPA AUC(0-12) was higher in SRL than CsA treated patients. The pharmacokinetic profile of SRL- but not of CsA-group showed a second peak consistent with the enterohepatic recirculation of MPA. These findings suggest that SRL and CsA have different effects on MPA metabolism and/or excretion eventually affecting its immunosuppressive property and/or toxicity. CsA, but not SRL, inhibits MPA enterohepatic recirculation, reducing MPA daily exposure.

Immunosuppressive treatment and progression of histologic lesions in kidney allografts

Renal transplantation is the best therapeutic option for patients with end-stage renal disease. Although short-term results are excellent, long-term graft survival has not improved substantially in recent times. Chronic allograft nephropathy (CAN) and death with a functioning graft are the most important causes of graft loss. Recent evidence shows that nephrotoxicity of calcineurin inhibitors contributes to CAN, and the introduction of non-nephrotoxic drugs such as mycophenolate mofetil (MMF) and mammalian target of rapamycin inhibitors may provide new immunosuppressive strategies to improve long-term results after renal transplantation. MMF decreases the risk of developing chronic allograft failure and is useful for treating established CAN, because it has a beneficial effect on allograft fibrosis. Treatment with sirolimus (SRL), a basic immunosuppressive drug given in association with MMF, may offer better renal function, decrease the prevalence of CAN, and downregulate expression of genes responsible for the progression of CAN than treatment with cyclosporine A (CsA). SRL also permits an early elimination of CsA from SRL-CsA-steroid regimens and shows better renal function and improved renal histology without risk of rejection. Notably, this approach improves graft survival at 4 years. Further multicenter studies are needed to determine whether both approaches produce similar results by comparing immunosuppression caused by SRL-based and tacrolimus (TAC)-based treatments. Because TAC is the most commonly used anticalcineurin drug, it is important to compare the effects of steroid-TAC-SRL treatment with and without elimination of TAC. Finally, although caution is needed, the use of non-nephrotoxic immunosuppressive treatment may change the natural history of CAN.

Comparison of Methotrexate- Versus Sirolimus- Containing Graft-Versus-Host Disease Prophylaxis Regimens after Myeloablative Stem Cell Transplantation.

Background:Graft-versus-host disease (GvHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). Methotrexate in combination with a calcineurin inhibitor (CM) is considered standard GvHD prophylaxis. Studies suggest that sirolimus in combination with a calcineurin inhibitor (SC) is effective in preventing GvHD and minimizing transplant-related morbidity and mortality. We sought to compare costs and clinical outcomes between the two different GvHD regimens.Method:A total of 159 patients with hematological diseases underwent myeloablative HLA-matched HSCT at the Dana-Farber Cancer Institute between June 2000 and December 2004 using Cytoxan and TBI conditioning. GvHD prophylaxis was either CM (n=97) or SC (n=62). Inpatient costs for the first transplant year of 94 CM and 47 SC recipients were obtained. Multivariate analyses were conducted including baseline factors: GvHD prophylaxis, patient age, sex matching, donor type, CMV serological status, disease status, stem cell source, and year of transplantation. In addition, for the cost analysis a full model was examined considering both baseline and post-transplant events [neutrophil engraftment, grade II to IV aGvHD, veno-occlusive disease, idiopathic pneumonia/diffuse alveolar hemorrhage, infection, severe organ toxicity, and in-hospital death].Results:CM recipients were more likely to have unrelated donors, BM grafts, and to be transplanted in earlier years than SC recipients. Univariate and multivariate comparisons of outcomes, costs and days of initial hospitalization are presented in Table 1. The SC regimen was associated with faster engraftment, less acute GvHD and better DFS and OS. Days of initial hospitalization and costs were lower for SC in the univariate model but not the multivariate model. Use of an unrelated donor was the only significant predictor of high costs considering baseline factors. In contrast, in the full model, grade II to IV aGvHD, late engraftment, and in-hospital death were the significant factors associated with high costs.Conclusion:Both OS and DFS in the SC group were higher in the multivariate analysis, probably due to early engraftment and reduced incidence of grade II to IV aGvHD seen in SC group. However, we could not detect the impact of GvHD prophylaxis on inpatient costs for the first transplant year. The SC regimen is a promising alternative to CM and larger multi-center randomized trial is planned through the NIH-funded Clinical Trials Network.Table 1Univariate analysisMultivariate analysisVariablesCMSCP-valueHR (Ratio*) (CM vs SC)P-valueMedian age, yrs [range]40 [18–58]43 [18–65]0.28--Neutrophil engraftment, median [range]17 [10–35]13 [8–17]<0.00010.21<0.0001Cumulative incidence of grade II–IV aGvHD at 100 d37±518±50.012.610.02Cumulative incidence of extensive cGvHD at 1 y24±522±60.751.700.21Disease-free survival at 1 y52±571±60.00512.500.0044Overall survival at 1 y53±572±60.011.610.01Inpatient costs during the first post-transplant year$110,081$101,6970.031.14*0.30Days of initial hospitalization33270.00080.99*0.91

Superior Outcomes in Renal Transplantation after Early Cyclosporine Withdrawal and Sirolimus Maintenance Therapy, Regardless of Baseline Renal Function

It has become increasingly important to refine therapeutic strategies according to individual patient characteristics. We evaluated the long-term impact of renal function at the time of withdrawing cyclosporine (CsA) in renal allograft recipients receiving sirolimus (SRL), CsA, and steroids (ST). At 3 months+/-2 weeks, 430 of 525 patients were eligible to be randomized to remain on triple-therapy (SRL-CsA-ST, n=215) or to have CsA withdrawn (SRL-ST, n=215). Patients were divided into quartiles according to their baseline (last value before randomization) calculated GFR: <or=45 ml/min (quartile 1, n=104), >45 to 56 ml/min (quartile 2, n=105), >56 to 67 ml/min (quartile 3, n=112), and >67 ml/min (quartile 4, n=107). All data were included (ITT analysis). At 4 years, calculated GFR for SRL-CsA-ST vs. SRL-ST was 22.1 vs. 37.7 ml/min (P=0.017), 38.6 vs. 56.6 ml/min (P<0.001), 50.7 vs. 66.8 ml/min (P=0.006), and 62.7 vs. 71.4 ml/min (P=0.436), for quartiles 1 to 4, respectively. Death-censored graft loss ranged from 21.2% vs. 7.7% (SRL-CsA-ST vs. SRL-ST, P=0.092) in quartile 1 to 5.5% vs. 1.9% (P=0.618) in quartile 4. The incidence of death and biopsy-confirmed acute rejection also decreased with increasing baseline GFR, but was not significantly different between treatments. Overall, more patients remained on therapy in the SRL-ST group (46.3% vs. 57.9%, P=0.020). Early and complete withdrawal of CsA from a combination of SRL, CsA, and steroids was preferable to continuing on this regimen, regardless of baseline renal function. The benefit was most marked in patients with a baseline calculated GFR<or=45 ml/min.

Individualization of Immunosuppressive therapy: I. Sirolimus Improves Outcomes in African-American Renal Transplant Recipients

Introduction African-American renal transplant recipients are prone to acute rejection episodes and graft loss owing to genetic, pharmacokinetic, cultural, and socioeconomic factors. While more intense exposures to antirejection agents can mitigate this propensity, heightened immunosuppressive regimens are accompanied by an array of toxicities. Our study sought to examine the impact of a combination of sirolimus (SRL) and cyclosporine (CsA) on the outcomes of African-Americans vs Caucasians. Materials and Methods The outcomes of African-Americans treated with either CsA-prednisone (Pred, n = 90) or SRL-CsA-Pred (n = 86) were compared with 148 SRL-CsA-Pred-treated Caucasians. Results The addition of SRL to a CsA-Pred regimen reduced the rate of acute rejection episodes within 2 years in African-Americans from 43.3% to 17% ( P = .004), a value similar to that observed in Caucasian patients (18%). At 2 years, the graft survival rate of 79% among African-American patients treated with SRL-CsA-Pred was similar to that in the Caucasian cohort (80%). The respective patient survival rates also were similar: 93% and 90%, respectively. Multivariate analysis of 5-year outcomes among patients treated with SRL-CsA-Pred revealed the hazard ratios of African-Americans vs Caucasians to actually be reduced for acute rejection (.22; P = .01) and for death (.15; P = .01), but similar for chronic rejection (.77; P = NS) and graft loss (1.03; P = NS). Conclusion The use of SRL-based regimens mitigated the otherwise enhanced risk for acute rejection episodes or graft loss otherwise experienced by CsA-treated African-American renal transplant recipients.