The potential of individualized dosing of ravulizumab to improve patient-friendliness of paroxysmal nocturnal haemoglobinuria treatment at reduced costs

Contains fulltext : 237767.pdf (Publisher’s version ) (Open Access)Ravulizumab is a very expensive complement C5-inhibitor for the treatment of paroxysmal nocturnal haemoglobinuria, with a fixed-dosing interval of 8 weeks. For lifelong treatment, a cost-effective and patient-friendly dosing strategy is preferred. We therefore explored alternative ravulizumab dosing regimens in silico based on the thorough dose-finding studies of the manufacturer. Extending the interval to 10 weeks or individually extending the interval to a mean of 12.8 weeks based on pharmacokinetic monitoring resulted in noninferior efficacy in terms of lactate dehydrogenase normalization, with drug cost savings up to 37%. We here show the potential of individualized ravulizumab dosing to improve patient-friendliness at reduced costs

Identification of genetic aberrations in myelodysplastic syndromes

Contains fulltext : 100897.pdf (publisher's version ) (Open Access)Radboud Universiteit Nijmegen, 27 november 2012Promotores : Sweep, C.G.J., Witte, T.J.M. de Co-promotor : Jansen, J.H

A patient with redness and swelling of his foot: rheumatoid arthritis?

Contains fulltext : 81028.pdf (publisher's version ) (Open Access

TETs mutaties in myeloide maligniteiten.

Contains fulltext : 89100.pdf (publisher's version ) (Open Access

TET proteins in malignant hematopoiesis.

Contains fulltext : 81442.pdf (publisher's version ) (Closed access

Anti Thymocyte Globulin-Based Treatment for Acquired Bone Marrow Failure in Adults

Idiopathic acquired aplastic anemia can be successfully treated with Anti Thymocyte Globulin (ATG)-based immune suppressive therapy and is therefore considered a T cell-mediated auto immune disease. Based on this finding, several other forms of idiopathic acquired bone marrow failure are treated with ATG as well. For this review, we extensively searched the present literature for evidence that ATG can lead to enduring remissions in different forms of acquired multi- or single-lineage bone marrow failure. We conclude that ATG-based therapy can lead to an enduring hematopoietic response and increased overall survival (OS) in patients with acquired aplastic aplasia. In patients with hypocellular myelodysplastic syndrome, ATG can lead to a hematological improvement without changing the OS. ATG seems less effective in acquired single-lineage failure diseases like Pure Red Cell Aplasia, Amegakaryocytic Thrombocytopenia and Pure White Cell Aplasia, suggesting a different pathogenesis in these bone marrow failure states compared to aplastic anemia. T cell depletion is hypothesized to play an important role in the beneficial effect of ATG but, as ATG is a mixture of polyclonal antibodies binding to different antigens, other anti-inflammatory or immunomodulatory effects could play a role as well.Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

IAPs as therapeutic targets in haematological malignancies.

Item does not contain fulltextBACKGROUND: Regulation of apoptosis is fundamental to maintain the balance between cell survival and cell death. Disruption of this process may have severe consequences, contributing to carcinogenesis. Therapeutic targeting of the proteins that control apoptosis may therefore be used in the treatment of various types of cancer. OBJECTIVE: We address whether regulators of apoptosis could be suitable targets for the treatment of haematological cancers. METHODS: We focus on the emerging role of inhibitor of apoptosis (IAP) proteins in cancer, their modulators and the possibility of therapeutically targeting these proteins in haematological cancer. RESULTS/CONCLUSION: IAPs have emerged as an important novel class of intracellular proteins that regulate apoptosis. Various compounds have been described that may be used to modulate the activity of IAPs, which opens the way to therapeutically targeting these proteins in cancer

A phase I clinical trial to study the safety of treatment with tipifarnib combined with bortezomib in patients with advanced stages of myelodysplastic syndrome and oligoblastic acute myeloid leukemia

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Low-dose parenteral busulfan provides an extended window for the infusion of hematopoietic stem cells in murine hosts.

Contains fulltext : 51610.pdf (publisher's version ) (Closed access)OBJECTIVE: Myeloablative total body irradiation (TBI) in the setting of autologous transplantation of genetically modified hematopoietic stem cells (HSC) is associated with substantial toxicity. Nonmyeloablative doses of TBI are less toxic, but result in low-level engraftment of genetically modified HSCs. As an alternative to TBI, escalating doses of parenteral busulfan were tested for their hematologic toxicity, their ability to promote donor leukocyte engraftment, and the time window for such engraftment. MATERIALS AND METHODS: Hematologic toxicity of busulfan was assessed in C57BL6 mice after single nonmyeloablative doses of intraperitoneal busulfan ranging from 1 to 40 mg/kg by serial complete blood counts monitored up to 40 days. The level of donor engraftment attainable after nonmyeloablative busulfan was determined by infusion of 20 million congenic murine bone marrow nucleated cells (BMNC) following 5 to 40 mg/kg of busulfan. To determine the effects of delayed HSC infusions, BMNCs were infused 1, 10, 15, and 20 days after a single dose of 10 mg/kg of busulfan. RESULTS: Busulfan doses from 1 to 40 mg/kg produced hematologic toxicity that was most pronounced in the 2nd to 3rd week. In transplantation experiments, dose-dependent donor leukocyte engraftment was attained with levels >70% after only 20 mg/kg of busulfan. Similar levels of engraftment were achieved even when infusion of BMNCs was delayed up to 20 days after busulfan injection. CONCLUSION: Nonmyeloablative parenteral busulfan produced transient myelosuppressive effects, clinically relevant levels of engraftment, and an extended time window for HSC infusion in murine hosts