tacrolimus and Histiocytosis--Langerhans-Cell

This report describes a 16-month-old girl with multi-system Langerhans cell histiocytosis (LCH), who developed end-stage liver disease despite intensive chemotherapy. She underwent a liver transplant at 28 months of age while receiving maintenance chemotherapy for bony lesions. In view of previous reports of a high incidence of acute cellular rejection and post-transplant lymphoproliferative disease (PTLD) in children transplanted for LCH, basiliximab was added to the post-transplant immunosuppression regime of tacrolimus and prednisolone. Sixteen months post-transplant, she has had no episodes of acute rejection or PTLD and her LCH has remained in remission. Current literature regarding liver transplantation (LTx) for LCH and the use of basiliximab in pediatric LTx is reviewed.

Topics: Antibodies, Monoclonal; Basiliximab; Female; Histiocytosis, Langerhans-Cell; Humans; Immunosuppressive Agents; Infant; Liver Failure; Liver Transplantation; Prednisolone; Recombinant Fusion Proteins; Tacrolimus

Topics: Adrenal Cortex Hormones; Aged, 80 and over; Dermatologic Agents; Drug Therapy, Combination; Female; Histiocytosis, Langerhans-Cell; Humans; Tacrolimus; Treatment Outcome

The tuberculostatic compound rifampin (INN, rifampicin) induces the expression of a number of drug metabolism-related genes involved in multidrug resistance (P-glycoprotein and multidrug resistance proteins 1 and 2), cytochromes (cytochrome P450 [CYP] 3A4), uridine diphosphate-glucuronosyltransferases, monoamine oxidases, and glutathione S -transferases. Drugs that depend on these enzymes for their metabolism are prone to drug interactions when coadministered with rifampin. A novel, clinically relevant drug interaction is described between rifampin and mycophenolate mofetil (MMF), a cornerstone immunosuppressive molecule used in solid organ transplantation. Long-term rifampin therapy caused a more than twofold reduction in dose-corrected mycophenolic acid (MPA) exposure (dose-interval area under the concentration curve from 0 to 12 hours [AUC 0-12]) when administered simultaneously in a heart-lung transplant recipient, whereas subsequent withdrawal of rifampin resulted in reversal of these changes after 2 weeks of washout (dose-corrected AUC 0-12 after rifampin withdrawal, 19.7 mg.h.L-1.g -1 versus 6.13 mg.h.L-1.g-1 before rifampin withdrawal [221% change]; dose-uncorrected AUC 0-12 after rifampin withdrawal, 29.6 mg.h/L [daily MMF dose, 3 g] versus 18.4 mg.h/L [daily MMF dose, 6 g] during rifampin administration [60.8% change]). Failure to recognize this drug interaction could potentially lead to MPA underexposure and loss of clinical efficacy. The effect of rifampin on MPA metabolism can, at least in part, be explained by simultaneous induction of renal, hepatic, and gastrointestinal uridine diphosphate-glucuronosyltransferases and organic anion transporters with subsequent functional inhibition of enterohepatic recirculation of MPA.

Topics: Area Under Curve; Chronic Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Enterohepatic Circulation; Glucuronosyltransferase; Heart-Lung Transplantation; Histiocytosis, Langerhans-Cell; Humans; Hypertension, Pulmonary; Male; Metabolic Clearance Rate; Middle Aged; Mycophenolic Acid; Pharmacology, Clinical; Respiratory Insufficiency; Rifampin; Tacrolimus; Time Factors; Uridine Diphosphate; Withholding Treatment

Langerhans cell histiocytosis (LCH) is an unusual indication for orthotopic liver transplantation in children. Data from limited case reports suggest that orthotopic liver transplantation for LCH is associated with excellent survival rates and a low incidence of disease recurrence. However, in our experience, children who have transplantation for LCH appeared to experience a high incidence of refractory rejection and posttransplant lymphoproliferative disease (PTLD).. Data from 398 liver transplants performed in 298 children younger than 16 years of age were reviewed to determine the presence of risk factors for PTLD in patients with LCH and other causes of liver failure.. The incidence of PTLD was significantly higher in children who received transplants for LCH compared with all indications (p < 0.001) and specific indications that were associated with the development of PTLD (p < 0.002). Among patients in whom PTLD developed, there was no significant difference in the incidence of primary Epstein-Barr virus infections in patients who receive transplantation for LCH (4/4, 100%) versus all other indications (12/14, 86%). Children who had transplantation for LCH were older than those who had transplantation for other indications (LCH median age 3.1 years, other indications 1 year). The incidence of rejection, especially refractory rejection, was greater in patients who had transplantation for LCH (100% and 50%, respectively) compared with those who had transplantation for other indications (70% and 10%, p < 0.02 for refractory rejection).. Patients who had transplantation for liver disease related to LCH experienced a 67% long-term survival (median follow up 5.8 years, range 2.1 to 7.5 years). Recurrent LCH occurred in only 33% of patients and was easily managed. However, PTLD developed in two thirds of these patients, perhaps in part because of the high incidence of refractory rejection. This series therefore demonstrates an association between a primary disease process and the development of PTLD. Although the data indicate that children with LCH-induced liver failure benefit from transplantation, special care must be exercised in screening for and preemptive treatment of PTLD.

Topics: Adolescent; Age Factors; Antiviral Agents; Azathioprine; Child; Child, Preschool; Cyclosporine; Follow-Up Studies; Ganciclovir; Glucocorticoids; Graft Rejection; Herpesviridae Infections; Herpesvirus 4, Human; Histiocytosis, Langerhans-Cell; Humans; Immunosuppressive Agents; Incidence; Liver Failure; Liver Transplantation; Lymphoproliferative Disorders; Methylprednisolone; Muromonab-CD3; Prednisone; Recurrence; Retrospective Studies; Risk Factors; Survival Rate; Tacrolimus; Tumor Virus Infections