Concomitant Use Of Cyclosporine Research Articles

Natural Killer (NK) Alloreactivity Seems Not to Play a Role in Preventing Leukemia Relapse in Unmanipulated Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide

BackgroundNatural Killer (NK) cells have been widely studied due to their non-major histocompatibility complex (MHC)-restricted cytotoxicity towards transformed or virally infected target cells. In the setting of hematopoietic stem cell transplantation (HSCT), donor NK cells may be "alloreactive" as their killer immunoglobuline-like receptors (KIRs) do not recognize their ligands on recipient human leukocyte antigen (HLA) class I molecules (i.e. KIR-ligands), leading to NK activation. NK alloreactivity can often occur in haploidentical HSCT (Haplo-HSCT), by means of KIR/KIR-L mismatch in graft versus host (GvH) direction, contributing to graft-versus leukemia (GvL) effect, clearing residual leukemic blasts. In the last decade, several studies have shown that NK cells alloreactivity plays a role in T-depleted Haplo-HSCT leading to higher disease free survival rates for patients transplanted from NK-alloreactive donors; recent studies have also shown that donors having KIR B haplotypes (characterized by the presence of more activating KIR) or expressing KIR2DS1 correlated with a better clinical outcome of transplantation. Thus, these NK cell features might be positively considered in the donor selection strategy.Materials and Methods:We analyzed NK-alloreactivity in the setting of unmanipulated Haplo-HSCT with post-transplant cyclophosphamide for patients affected by acute myeloid leukemia or myelodisplastic syndromes. 101 consecutive patients transplanted from September, 2010 to October, 2014 were enrolled, with the big majority of donors and patients studied for HLA-genotype and KIR.Results:Disease status at HSCT was the most relevant factor affecting outcome (p <0.0001), with 3 y 78% overall survival (OS) and 76% disease free survival (DFS) rates for "early" patients (CR1+CR2, n=61) versus 33% OS and 28% DFS rates for "advanced" patients (CR3 or active disease, n=40). Nor NK-alloreactivity nor the presence of donor KIR-B haplotype nor the presence of donor KIR2DS1 seemed to play a role in preventing leukemia relapse. NK alloreactive patients had DFS rate similar to non-NK alloreactive group (62% vs 59%, p 0.47) with a better, still non-significant trend in OS (72% vs 60%, p 0.14) for NK-alloreactive patients. Similarly, Haplo-HSCT from donors with KIR-B haplotype (with B-content score>=2) or who had KIR2DS1 was not associated with better outcome (p 0.67 and p 0.89, respectively). We observed an high expression of CD56 and inhibitory receptors such as NKG2A on surface of NK cells in post-HSCT samples, suggesting that NK-cell function could be inhibited in unmanipulated haploidentical setting.ConclusionsNK alloreactivity seems not to play a role in preventing leukemia relapse in unmanipulated haploidentical transplantation with post-transplantation. The different immunosuppressive approach of this Haplo-HSCT setting compared to T-depleted Haplo-HSCT, with concomitant use of cyclosporine from early transplant days, which has been shown to interact and possibly inhibit NK cells in vivo, and post transplant cyclophosphamide effects, selectively killing activated T-cell and inducing long-term tolerance, could affect NK efficacy. Further studies are needed to better understand the complexity of this intriguing issue, leading to a more complete definition of NK cell functions in this Haplo-HSCT setting. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Simvastatin-induced myopathy with concomitant use of cyclosporine: case report

Simvastatin has been shown to play an important role in reducing the risk of cardiovascular events caused by atherosclerosis. To promote the understanding of the potential toxicity of simvastatin and individualized treatment in genetic factors, we report a case of a renal transplant in a female patient who had developed acute myopathy after taking simvastatin. By PCR restriction fragment length polymorphism (PCR-RFLP) and allele-specificity polymerase chain reaction (AS-PCR) and direct sequencing. The genotypes of CYP3AP1, CYP3A5, CYP3A4 and SLCO1B1 were analyzed. The patient was identified to have mutant genotypes of CYP3AP1*3/*3 (-44G > A), CYP3A5*3/*3 (6986A > G) and wild genotype of CYP3A4*1/*1 and SLCO1B1*1/*1, which finally led to the elevation of her cyclosporine level except the SLCO1B1*1/*1 genotype and the acceleration of simvastatin-induced acute myopathy. Genetic factors have partly contributed to the development of simvastatin-induced myopathy with concomitant use of cyclosporine, and provided information on the adverse reactions of statins. What is different from other studies is that the SNP of SLCO1B1*5 does not take part in this adverse reaction.

Iron chelation therapy with deferasirox in patients with aplastic anemia: a subgroup analysis of 116 patients from the EPIC trial

AbstractThe prospective 1-year Evaluation of Patients' Iron Chelation with Exjade (EPIC) study enrolled a large cohort of 116 patients with aplastic anemia; the present analyses evaluated the efficacy and safety of deferasirox in this patient population. After 1 year, median serum ferritin decreased significantly from 3254 ng/mL at baseline to 1854 ng/mL (P < .001). Decreases occurred in chelation-naive (3229-1520 ng/mL; P < .001, last-observation-carried-forward analysis), and previously chelated (3263-2585 ng/mL; P = .21, last-observation-carried-forward analysis) patients and were reflective of dose adjustments and ongoing iron intake. Baseline labile plasma iron levels were within normal range despite high serum ferritin levels. The most common drug-related adverse events were nausea (22%) and diarrhea (16%). Serum creatinine increases more than 33% above baseline and the upper limit of normal occurred in 29 patients (25%), but there were no progressive increases; concomitant use of cyclosporine had a significant impact on serum creatinine levels. The decrease in mean alanine aminotransferase levels at 1 year correlated significantly with reduction in serum ferritin (r = 0.40, P < .001). Mean absolute neutrophil and platelet counts remained stable during treatment, and there were no drug-related cytopenias. This prospective dataset confirms the efficacy and well characterizes the tolerability profile of deferasirox in a large population of patients with aplastic anemia. This study was registered at www.clinicaltrials.gov as #NCT00171821.

Can Adalimumab Make a Smooth and Easy Transition from Cyclosporine a Reality? A Case Series of Successful Transitions

Background Cyclosporine, a calcineurin inhibitor of T cells, is an effective treatment option for generalized psoriasis. However, its duration of use is limited to one to two years due to its risk of organ toxicity, while its discontinuation raises concern for relapse. Initiating cyclosporine is often met with reluctance in the absence of a safe, long-term agent with which to transition patients after treatment with cyclosporine. Adalimumab, a tumor necrosis factor inhibitor recently approved for the treatment of psoriasis, may provide a safe alternative for long-term therapy. An experience of using sequential therapy with these two treatments to help prevent relapse in patients transitioning from cyclosporine to adalimumab is described. Methods A series of five representative patients is presented. Patients were informed of the off-label nature of concomitant use of cyclosporine and adalimumab for the treatment of psoriasis. Results Five patients with severe generalized psoriasis, ages 17, 21, 22, 31, and 41, were treated with cyclosporine for one to two years prior to beginning treatment with adalimumab. Cyclosporine was tapered over a period of 6, 12, 12, 8 and 11 weeks respectively and eventually discontinued. There was no decrease in Psoriasis Area and Severity Index (PASI) scores from the time of initiating adalimumab to discontinuation of cyclosporine. Serum labs and blood pressure readings remained normal for all five patients during this period and no adverse events were noted. Conclusion Patients may be smoothly transitioned from cyclosporine to adalimumab through sequential therapy to minimize risk of recurrence of psoriasis. The short duration of three months or less in young healthy individuals may allow safe concomitant use of these two drugs. Whether sequential therapy of cyclosporine and long-term treatment with adalimumab will be successful and safe must be validated by large controlled studies.

Poster 76: Myopathy With Rhabdomyolysis Induced by Concomitant Use of Cyclosporine and Simvastatin: A Case Report

Poster 76: Myopathy With Rhabdomyolysis Induced by Concomitant Use of Cyclosporine and Simvastatin: A Case Report

Rhabdomyolysis after concomitant use of cyclosporine and simvastatin in a patient transplanted for multiple myeloma

Rhabdomyolysis after concomitant use of cyclosporine and simvastatin in a patient transplanted for multiple myeloma

Early renal failure after domino hepatic transplantation using the liver from a compound heterozygous patient with primary hyperoxaluria

To cover the shortage of cadaveric organs, new approaches to expand the donor pool are needed. Here we report on a case of domino liver transplantation (DLT) using an organ harvested from a compound heterozygous patient with primary hyperoxaluria (PHO), who underwent combined liver and kidney transplantation. The DLT recipient developed early renal failure with oxaluria. The time to the progression to oxalosis with renal failure in such situations is unknown, but, based on animal data, we hypothesize that calcineurin inhibitors may play a detrimental role. A cadaveric liver and kidney transplantation was performed in a 52-year-old male with PHO. His liver was used for a 64-year-old patient with a non-resectable, but limited cholangiocarcinoma. While the course of the PHO donor was uneventful, in the DLT recipient early post-operative, dialysis-dependent renal failure with hyperoxaluria developed. Histology of a kidney biopsy revealed massive calcium oxalate crystal deposition as the leading aetiological cause. DLT using PHO organs for marginal recipients represents a possible therapeutic approach regarding graft function of the liver. However, it may negatively alter the renal outcome of the recipient in an unpredictable manner, especially with concomitant use of cyclosporin. Therefore, we suggest that, although DLT should be promoted, PHO organs are better excluded from such procedures.

The relative proportions of sirolimus metabolites in blood using HPLC with mass-spectrometric detection

Measurement of sirolimus in blood as a guide to dose adjustment is an accepted practice. To date, most data have resulted from the use of a chromatographic technique. With the imminent introduction of an immunoassay into this field, there is a need to know whether metabolites that could interfere with the performance of this assay, causing a bias compared with measurements made by a chromatographic assay, vary over a period of time or with changes in concomitant immunosuppressive therapy. This preliminary study measured several sirolimus metabolites in blood samples from a variety of clinical settings, using high-performance liquid chromatography with tandem mass-spectrometric detection. Two metabolites known to cross-react in one immunoassay system, single hydroxylation products and 41-O-demethyl rapamycin, were found to constitute the bulk of the metabolic products. They were also found to form a remarkably stable proportion of all metabolites measured, both with respect to the time since transplantation and the concomitant use of cyclosporine or tacrolimus. It is concluded that the analytical bias due to cross-reactivity with metabolites, inherent in this immunoassay, should be consistent across a wide spectrum of patients receiving the drug.

Co-administration of cyclosporine and ketoconazole in idiopathic childhood nephrosis.

The concomitant use of cyclosporine (CsA) and ketoconazole (keto) in children with nephrotic syndrome (NS) has never been reported in the literature. This retrospective cohort study was conducted to investigate cost saving, safety, and efficacy of co-administration of keto and CsA in children with NS. The study included 186 nephrotic children receiving CsA therapy. Most were steroid dependent or resistant, and the most common pathology was focal segmental glomerulosclerosis (62%). Among our patients, 137 received daily keto therapy (keto group) 50 mg/day in addition to CsA, while 49 received CsA alone (non-keto group). The characteristics of both groups were comparable and the mean (+/-SD) duration of treatment was 22.9 +/- 8.1 months. Co-administration of keto significantly reduced the mean dose of CsA with an overall net cost saving of 37%. It also resulted in a significant improvement of CsA response, more successful steroid withdrawal, and decreased the frequency of renal impairment. Keto was generally well tolerated and safe. We conclude that co-administration of low-dose keto with CsA in children with idiopathic NS is safe, significantly reduces the cost of CsA therapy, and may improve the patient outcome.

Rhabdomyolysis After Concomitant Use of Cyclosporine, Simvastatin, Gemfibrozil, and Itraconazole

OBJECTIVE:To report a case of rhabdomyolysis in a patient receiving cyclosporine, simvastatin, gemfibrozil, and itraconazole.CASE REPORT:Rhabdomyolysis occurring in transplant patients receiving both cyclosporine and the hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor lovastatin has been well documented. The exact mechanism by which this interaction leads to rhabdomyolysis is unknown. Experience with newer agents of the statin drug class in transplant patients is limited. Since the interaction between cyclosporine and HMG-CoA reductase inhibitors involves the CYP3A4 enzyme system, the possibility of amplifying this interaction exists when other drugs affecting the same enzyme system are coprescribed. We describe a case in which a heart transplant recipient stable on a drug regimen that included cyclosporine, simvastatin, and gemfibrozil developed rhabdomyolysis after initiation of the antifungal agent itraconazole.DISCUSSION:Drug—drug interactions due to shared metabolism via the CYP3A4 pathway can result in significant adverse outcomes. This article discusses concurrent use of an HMG-CoA reductase inhibitor with other drugs that inhibit the CYP3A4 isoenzyme, leading to a case of possible fatal rhabdomyolysis.CONCLUSIONS:Clinicians must be aware of drugs metabolized via cytochrome P450 isoenzymes and identify those requiring risk-versus-benefit analysis before prescribing. Patients need to be educated as to signs and symptoms requiring immediate physician intervention.

Correlates of acute renal failure in patients receiving parenteral amphotericin B

While parenteral amphotericin B is an effective therapy for serious fungal infections, it frequently causes acute renal failure (ARF). This study identified correlates of ARF in amphotericin B therapy and used them to develop clinical prediction rules. All 643 inpatients receiving parenteral amphotericin B therapy at one tertiary care hospital were included. Data regarding correlates were obtained both electronically and from manual chart review in a subsample of 231 patients. ARF was defined as a 50% increase in the baseline creatinine with a peak > or =2.0 mg/dL. Among 643 episodes, ARF developed in 175 (27%). In the larger group, the only independent correlate of ARF was male gender (OR = 2.2, 95% CI, 1.5 to 3.3). In the subsample (N = 231), independent correlates of ARF were maximum daily amphotericin dosage, location at the time of initiation of amphotericin therapy, and concomitant use of cyclosporine. These data were used to develop two clinical prediction rules. A rule using only data available at initiation of therapy stratified patients into groups with probability of ARF ranging from 15 to 54%, while a rule including data available during therapy (maximum daily dose) stratified patients into groups with probability of ARF ranging from 4 to 80%. Acute renal failure occurred in a quarter of the patients. Correlates of ARF at the beginning and during the course of amphotericin therapy were identified and then combined to allow stratification according to ARF risk. These data also provide evidence for guidelines for the selection of patients for alternative therapies.

Severe hyperkalemia in two renal transplant recipients treated with standard dose of trimethoprim-sulfamethoxazole

Hyperkalemia is a serious electrolyte disorder and is a frequent finding in renal transplant recipients. Trimethoprim-induced hyperkalemia has been increasingly reported in recent years. We describe two renal transplant recipients who developed end-stage renal disease secondary to familial Mediterranean fever and presented with severe hyperkalemia secondary to the use of standard dose of trimethoprim. One of the patients had potential underlying adrenal insufficiency, which might be a contributing factor for the development of hyperkalemia. We concluded that renal transplant patients receiving even the standard dose of trimethoprim should be monitored closely for the development of hyperkalemia. They should be recognized as a group with increased risk in regard to their concurrent renal insufficiency, concomitant use of cyclosporine, and associated tubulointerstitial disease. Patients with secondary amyloidosis are at even greater risk, and subclinical adrenal insufficiency may be an underlying risk factor for the development of severe, life-threatening hyperkalemia among this group of patients.

Differential effects of cyclosporine A, methylprednisolone, mycophenolate, and rapamycin on CD154 induction and requirement for NFkappaB: implications for tolerance induction.

Recent experimental data indicate that the targeting of the costimulatory molecule CD40-ligand (CD154) may well offer an opportunity for tolerance induction in transplant recipients and patients with autoimmune diseases, although the optimal therapeutic strategy for clinical application of CD154 monoclonal antibody (mAb) is unclear. We undertook vascularized heterotopic cardiac allograft transplantation in completely MHC-mismatched mice, treated recipients with CD154 mAb plus various immunosuppressive agents, and performed flow cytometric analysis of CD154 expression by T cells activated in vitro in the presence of corresponding immunosuppressive agents. We also tested the extent to which CD154 induction was NFkappaB-dependent by using NFkappaB/p50-deficient mice as allograft recipients and as source of cells for in vitro studies of CD154 induction, and through use of proteasome inhibitors to block IkappaBalpha degradation and NFKB activation in wild-type mice. Concomitant use of cyclosporin A or methylprednisolone, but not rapamycin or mycophenolate, inhibited CD154 mAb-induced allograft survival. The differential effects of these agents on CD154 mAb-induced tolerance correlated with their capacity to inhibit activation-induced CD154 expression on CD4+ T cells. Full expression of CD154 expression was found to require NF-kappaB activation, and CD154 mAb was ineffective in NF-kappaB/p50 deficient allograft recipients or control mice in which NF-kappaB activation was blocked by proteasome inhibition. Strategies to use CD154 mAb clinically must take into account the effects of immunosuppressive agents on CD154 induction, which seems to be at least partially NF-kappaB dependent. Our data suggest that ligation of surface-expressed CD154 provides an important signal that modulates T cell activation and thereby contributes to the effects of CD154 mAb, in addition to previously recognized actions involving blockade of CD40/CD154-dependent cell activation and activation-induced cell death.

Antihypertensive effect of amlodipine and lack of interference with cyclosporine metabolism in renal transplant recipients.

The catabolism of various calcium channel blockers through cytochrome P-450 is heterogeneous and may be modified by concomitant use of cyclosporin A. In an open study we investigated the antihypertensive effect and clinical tolerance of the dihydropyridine amlodipine and its effects on cyclosporine kinetics in stable hypertensive renal transplant recipients not taking corticosteroids. Ten adult hypertensive patients grafted for 21.4 +/- 8.9 months and well stabilized with normal renal function were included in the study. Renal artery stenosis was ruled out by normal Doppler echography. After 2 weeks of placebo, amlodipine was started at a daily dose of 5 mg. The dose was then adjusted to 10 mg if necessary. Blood and urine chemistries and whole-blood cyclosporine trough levels were measured weekly. Cyclosporine kinetics were determined on a hourly basis before amlodipine administration and after 4 weeks of treatment. Normal blood pressure was obtained with the use of 5 mg/d amlodipine in 7 patients and 10 mg/d in 3, diastolic blood pressure decreasing from 98.7 +/- 3.8 to 81.3 +/- 9.1 mm Hg (P = .0007). Heart rate slightly increased by 10% (P < .02). The drug was well tolerated, and only minor ankle edema was found in 3 patients. Cyclosporine doses were not modified and cyclosporine levels remained unchanged throughout the study. Cyclosporine kinetic parameters were not significantly different at the beginning and end of the study. Bioequivalence was demonstrated indicating that cyclosporine biotransformation was not altered by the concomitant administration of amlodipine.(ABSTRACT TRUNCATED AT 250 WORDS)