Low incidence of acute graft-versus-host disease and recurrent leukaemia in patients undergoing allogeneic haemopoietic stem cell transplantation from sibling donors with methotrexate and dose-monitored cyclosporin A prophylaxis

Abstract

Summary:One of the major aims of allogeneic haemopoietic stem cell transplantation has been the effective suppression of graft-versus-host disease (GVHD) without loss of a graft-versus-leukaemia effect. For GVHD suppression, one of the most frequently used regimens has been the combination of cyclosporin (CsA) and a short course of methotrexate (MTX) although the optimal usage of these agents remains unclear. Here, we report the results of 55 patients with standard risk leukaemia who have undergone allogeneic transplantation using either bone marrow (n = 48) or G-CSF mobilised peripheral blood stem cells (n = 7) using CsA and MTX for GVHD prophylaxis where the dosage of CsA was regularly adjusted to maintain a trough whole blood level of 95-205 ng/ml for the first 50 days post-transplant. To achieve this level of CsA in the immediate post-transplant period, over 40% of patients required dose adjustments of CsA as a result of sub-therapeutic levels on day +1 post-transplant. The achievement of CsA levels within the therapeutic range was expedited following the introduction of a sliding scale for dose adjustment. With this regimen we have observed a low incidence of acute GVHD with only 11% of patients developing уgrade II disease. With a median follow-up of 66 months (range 8-132) the probability of relapse is only 6.6%. The disease-free survival probability for all patients was 72% at 5 years. These results demonstrate that effective GVHD prevention with CsA and MTX can be achieved without a high risk of recurrent leukaemia provided that rapid attainment of therapeutic CsA levels is achieved and maintenance within a low therapeutic range may help to maximise this effect.

Population pharmacokinetics of ciclosporin in haematopoietic allogeneic stem cell transplantation with emphasis on limited sampling strategy

“…In all, insufficient post transplant immunosuppression is one of the most important determinants of relapse risk through its impact on the potency of an immunologically mediated graft vs. malignancy effect. This is particularly relevant in patients undergoing allogeneic HSCT using a reduced-intensity conditioning regimen, where a graft vs. malignancy effect represents the dominant anti-tumour mechanism [4,[17][18][19][20][21][22]. Therefore, a model that predicts ciclosporin pharmacokinetics and dose requirements to achieve the desired therapeutic target in an individual HSCT patient would be highly useful.…”

Relationship between CsA trough blood concentration and severity of acute graft-versus-host disease after paediatric stem cell transplantation from matched-sibling or unrelated donors

“…Unfortunately, therapeutic ranges used to monitor CsA therapy remain empirical 22 and heterogeneous. 17 Only two studies, mainly performed in adults, have shown the positive impact of a monitored CsA regimen on aGVHD incidence and outcome, 23,24 but the results cannot be transposed to children. As goal-oriented individualized CsA regimens require accurate knowledge of the values of effective blood concentrations, the aim of our study was to clarify relationships between TBC and aGVHD incidence, in a population including only children receiving allogeneic MSD-or UD-SCT.…”

Mycophenolate mofetil for the treatment of acute and chronic GVHD is effective and well tolerated but induces a high risk of infectious complications: a series of 21 BM or PBSC transplant patients

“…[2][3][4][5][6][7] Improvement in prophylactic GVHD regimens or treatments remains one of the greatest challenges. 8,9 The most frequently used prophylaxis for GVHD includes the combination of cyclosporine (CsA), corticosteroids, short-course methotrexate, and/or antithymocyte globulin.…”