Abstract
PurposeChronic graft versus host disease is a major consequence after allogeneic stem cell transplantation (allo-SCT) and has great impact on patients’ morbidity and mortality. Besides the skin, liver, and intestines, the eyes are most commonly affected, manifesting as severe ocular surface disease. Treatment protocols include topical steroids, cyclosporine, tacrolimus, and ASED. Since these patients often receive systemic immunosuppressant therapy from their oncologists, a topical re-administration of these drugs via ASED with potentially beneficial or harmful effects is possible. The purpose of the study was to determine whether and to which extent systemic immunosuppressants are detectable in ASED.MethodsA total of 34 samples of ASED from 16 patients with hemato-oncological malignancies after allo-SCT were collected during the manufacturing process and screened for levels of cyclosporine, mycophenolic acid, everolimus, and tacrolimus via liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The study followed the tenets of the Declaration of Helsinki and informed consent was obtained from the subjects after explanation of the nature and possible consequences of the study.ResultsCyclosporine was found in 18 ASED samples in concentrations ranging from 6.5–105.0 ng/ml (32.0 ± 22.8 ng/ml, mean ± SD). The concentration range of mycophenolic acid in 19 samples was 0.04–25.0 mg/l (4.0 ± 5.4 mg/l, mean ± SD). Everolimus and tacrolimus concentrations were well below the respective limits of quantification (< 0.6 and < 0.5 ng/ml) of the established LC-MS/MS method in all samples.ConclusionsOur study suggests that orally administered cyclosporine and mycophenolic acid for the treatment of systemic GvHD, but not everolimus and tacrolimus, are distinctly detectable in ASED in relevant concentrations. It is highly likely that these agents affect topical therapy of ocular GvHD. However, the extent of this effect needs to be evaluated in further studies.
Highlights
Graft versus host disease (GvHD) is a major complication following allogeneic hematopoietic stem cell transplantation and related to immunological reactions mainly mediated by donor CD3+ T cells of the CD8+ subset and directed against host tissues [1]
GvHD develops in three stages: the first phase begins with an activation of antigen-presenting cells (APC) in the host tissue by the underlying disease and the conditioning regime, followed by an activation of transplanted donor T cells leading to the second phase, characterized by cellular response, and the third phase, namely the inflammatory effector phase [2]
We developed and validated a liquid chromatography coupled with tandem mass spectrometry (LC-MS/ MS) method to detect and quantify possible residues of selected immunosuppressants in Autologous serum eye drops (ASED)
Summary
Graft versus host disease (GvHD) is a major complication following allogeneic hematopoietic stem cell transplantation (allo-SCT) and related to immunological reactions mainly mediated by donor CD3+ T cells of the CD8+ subset and directed against host tissues [1]. GvHD manifesting during the first 100 days after SCT was considered acute GvHD, while a manifestation after the first 100 days post-SCT was diagnosed as chronic GvHD [3] Since this did not fully capture the distinct clinical differences of the disease entities, the diagnosis of either acute or chronic GvHD is merely reliant on time of onset and includes clinical feature characteristic for one or the other entity. This made further differentiation necessary and led to the addition of late-onset acute GvHD and overlap syndromes. Incidence is reported to be 40–50% for acute GvHD, depending on the type of stem cell transplantation performed, while 30–70% of patients after 100 days will develop chronic GvHD [2]
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