Leusden, Netherlands
Leusden, Netherlands

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Niewerth D.,VU University Amsterdam | Franke N.E.,VU University Amsterdam | Jansen G.,Afdeling Reumatologie | Van Meerloo J.,Afdelingen Kinderoncologie Hematologie en Hematologie | And 4 more authors.
Tijdschrift voor Kindergeneeskunde | Year: 2014

Introduction. For children with relapsed acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), there is a need for new therapeutic drugs. Bortezomib (BTZ) is a reversible proteasome inhibitor currently being tested in clinical trials for children with relapsed ALL and AML. BTZ-related toxicity and emergence of resistance has initiated the development of several new irreversible proteasome inhibitors. The aim of this research project is to investigate whether pediatric leukemia cells are sensitive to BTZ and new generation proteasome inhibitors (carfilzomib, ONX 0912 and ONX 0914), and to identify factors that will predict responsiveness of children on treatment with proteasome inhibitors. Methods. Leukemic blast cells of 29 ALL and 10 AML patients were analyzed for sensitivity to BTZ, carfilzomib, ONX 0912, ONX 0914, and the glucocorticoid dexamethasone by MTT cytotoxicity assays. Additionally, protein expression of the functionally-active proteasome subunits was determined by Western blotting and ProCISE, and correlated to proteasome inhibitor sensitivity. Results. ALL cells were significantly more sensitive to all proteasome inhibitors and dexamethasone than AML cells. Besides this, expression of constitutive proteasome subunits relative to immune proteasome subunits was significantly higher in AML cells than in ALL cells. The ratio of immune/constitutive proteasome subunit expression correlated with sensitivity of ALL cells for ONX 0914, and of AML for BTZ and carfilzomib sensitivity. Conclusion. Expression levels of proteasome subunits can be of predictive value how a patient may respond to proteasome inhibitors. As such, this research contributes to a more personalized therapy for children with leukemia in the future.

Delforge M.,Afdeling Hematologie | Michiels A.,Afdeling Hematologie | Doyen C.,UCL Mont Godinne | Kentos A.,Clinique dHematologie | And 13 more authors.
Acta Clinica Belgica | Year: 2011

The prognosis of multiple myeloma patients has significantly improved since the introduction of the novel agents thalidomide, bortezomib and lenalidomide. We report the data of a medical need programme with lenalidomide plus dexamethasone, conducted in Belgium between August 2007 and March 2008, and including 98 relapsed refractory multiple myeloma patients. In addition to chemotherapy and steroids, all patients had received prior treatment with bortezomib, and 84% of them had been exposed to thalidomide. In 52 patients response data could be retrieved by post-hoc analysis. A partial remission or better was achieved in 52% (49% partial and 3% complete response) of patients, despite a median of 5 previous anti-myeloma treatment lines. Responses were rapid while the majority of patients received lenalidomide with once weekly (also called lowdose) dexamethasone. Treatment with lenalidomide plus dexamethasone did prolong overall survival by nearly half a year in this population with end-stage myeloma. Overall response and quality of response were independent of previous response to thalidomide and bortezomib, although the time to progression tended to be shorter in thalidomide- and bortezomib-refractory patients. It can be concluded that lenalidomide plus dexamethasone is an effective and safe treatment regimen in highly refractory multiple myeloma patients, and that these responses are irrespective of previous exposure or sensitivity to thalidomide and bortezomib.

Aldenhoven M.,Afdeling Hematologie | Van Hasselt P.M.,Afdeling Metabole Ziekten | Boelens J.J.,Afdeling Hematologie
Tijdschrift voor Kindergeneeskunde | Year: 2010

For a selected group of inborn errors of metabolism (IEM), stem cell transplantation (SCT) is able to prevent disease progression. This applies mainly to specific lysosomal storage disorders and peroxisomal disorders and only when the SCT is performed early in life and before cerebral involvement has occurred. In Hurler syndrome, X-linked adrenoleukodystrophy and Krabbe disease, promising results have been reported. The success of SCT in IEM has, however, been limited by high graft failure and transplantation-related mortality rates as well as the long interval between diagnosis and SCT due to difficulties finding a suitable stem cell donor. Due to the improved transplantation techniques, the use of unrelated cord blood as a stem cell source and the possibility of using adjuvant intravenous enzyme replacement therapy, the success rate of the procedure can be significantly improved, subsequently considerably improving the prognosis of these severely affected children. Furthermore, a worldwide registry database, for the accurate registration of the (long term) outcome of SCT in IEM, is of utmost importance.

Levitus M.,Afdeling Hematologie | Van Galen K.P.M.,Afdeling Hematologie | Som N.,Afdeling Hematologie | Overbeeke M.A.M.,Afdeling Hematologie | Visser O.,Afdeling Hematologie
Nederlands Tijdschrift voor Klinische Chemie en Laboratoriumgeneeskunde | Year: 2011

Patients treated with hematopoietic stem cell transplantation (HSCT) are not unlikely to require intensive blood component support which is, among other things, dependent on the compatibility and condiditioning regimen of HSCT. Transfusion diffuculties, for instance, massive transfusion requirements, transfusion refractoriness or severe hemolysis, coincide with the change of blood group after ABO-incompatible HSCT and the occurrence of antibodies. Illustrated by three cases, in this paper unexpected laboratory results such as change in blood group, positive direct antiglobulin test and cytopenias causing transfusion difficulties will be discussed. The role of patient or donor derived isoagglutinins against donor or patient type red blood cells in ABO-incompatible HSCT is clarified. Furthermore, we confer the allo- or autoantibodies that can occur and cause difficulties with transfusion or stem cell donation. Transfusion support in HSCT patients requires special consideration and policies in which, in addition to microbiological safety, a high degree immunologic safety by leukocyte depletion, gamma irradiation and careful selection of the best compatible blood group is required to minimize the chance of adverse effects.

Leeksma A.C.,afdeling Hematologie en Stamceltransplantatie | Tamminga R.Y.J.,afdeling Hematologie | Smiers F.J.,afdeling Hematologie en Stamceltransplantatie
Tijdschrift voor Kindergeneeskunde | Year: 2014

Background.: Glanzmann thrombasthenia (GT) is a rare bleeding disorder characterized by absence or dysfunction of the glycoprotein (GP) IIb-IIIa complex on the surface of platelets.Case.: A 5-year old boy, with recurrent severe nose bleeds and frequent hematemesis repeatedly leading to circulatory insufficiency for which intensive care (IC) admissions were necessary. Underlying disorder was a severe inherited Glanzmann thrombasthenia. After developing alloantibodies against GPIIb-IIIa complex on donor platelets (anti-HPA-1 and anti-HPA-3) treatment of bleeding was possible only by activated rFVII. Because of the severity of the bleedings and limited treatment options the patient was eligible for stem cell transplantation (SCT) with bone marrow from his HLA-identical sister. This transplantation was successful and uncomplicated.Conclusion.: Allogeneic stem cell transplantation is curative for Glanzmann thrombasthenia. In case of Glanzmann thrombasthenia with a complicated course this treatment can be considered when a compatible donor is available. © 2014, Bohn, Stafleu van Loghum.

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