Publications by authors named "Nicole L van Woerden"

2 Publications

  • Page 1 of 1

Intravenous immunoglobulin vs observation in childhood immune thrombocytopenia: a randomized controlled trial.

Blood 2018 08 26;132(9):883-891. Epub 2018 Jun 26.

Department of Pediatric Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.

Management of children with newly diagnosed immune thrombocytopenia (ITP) consists of careful observation or immunomodulatory treatment. Observational studies suggest a lower risk for chronic ITP in children after intravenous immunoglobulin (IVIg) treatment. In this multicenter randomized trial, children aged 3 months to 16 years with newly diagnosed ITP, platelet counts 20 × 10/L or less, and mild to moderate bleeding were randomly assigned to receive either a single infusion of 0.8 g/kg IVIg or careful observation. Primary outcome was development of chronic ITP, which at the time of study initiation was defined as a platelet count lower than 150 × 10/L after 6 months. Two hundred six children were allocated to receive IVIg (n = 102) or careful observation (n = 104). Chronic ITP occurred in 18.6% of the patients in the IVIg group and 28.9% in the observation group (relative risk [RR], 0.64; 95% confidence interval [CI], 0.38-1.08). Platelet counts lower than 100 × 10/L at 12 months (current definition of chronic ITP) were observed in 10% of children in the IVIg group and 12% in the observation group (RR, 0.83; 95% CI, 0.38-1.84). Complete response rates in the first 3 months were significantly higher in the IVIg group. Immunoglobulin G Fc receptor IIb genetic variations were associated with early complete response in both groups. Grade 4 to 5 bleeding occurred in 9% of the patients in the observation group vs 1% in the IVIg group. This trial was registered at www.trialregister.nl as NTR 1563.
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http://dx.doi.org/10.1182/blood-2018-02-830844DOI Listing
August 2018

Methotrexate resistance in relation to treatment outcome in childhood acute lymphoblastic leukemia.

J Hematol Oncol 2015 May 29;8:61. Epub 2015 May 29.

Department of Pediatric Oncology/Hematology, VUmc Cancer Center Amsterdam, VU University Medical Center, Room CCA 4.28, De Boelelaan 1117, 1081HV, Amsterdam, The Netherlands.

Background: Methotrexate (MTX) eradicates leukemic cells by disrupting de novo nucleotide biosynthesis and DNA replication, resulting in cell death. Since its introduction in 1947, MTX-containing chemotherapeutic regimens have proven instrumental in achieving curative effects in acute lymphoblastic leukemia (ALL). However, drug resistance phenomena pose major obstacles to efficacious ALL chemotherapy. Moreover, clinically relevant molecular mechanisms underlying chemoresistance remain largely obscure. Several alterations in MTX metabolism, leading to impaired accumulation of this cytotoxic agent in tumor cells, have been classified as determinants of MTX resistance. However, the relation between MTX resistance and long-term clinical outcome of ALL has not been shown previously.

Methods: We have collected clinical data for 235 childhood ALL patients, for whom samples taken at the time of diagnosis were also broadly characterized with respect to MTX resistance. This included measurement of concentrations of MTX polyglutamates in leukemic cells, mRNA expression of enzymes involved in MTX metabolism (FPGS, FPGH, RFC, DHFR, and TS), MTX sensitivity as determined by the TS inhibition assay, and FPGS activity.

Results: Herein we demonstrate that higher accumulation of long-chain polyglutamates of MTX is strongly associated with better overall (10-year OS: 90.6 vs 64.1%, P = 0.008) and event-free survival (10-year EFS: 81.2 vs 57.6%, P = 0.029) of ALL patients. In addition, we assessed both the association of several MTX resistance-related parameters determined in vitro with treatment outcome as well as clinical characteristics of pediatric ALL patients treated with MTX-containing combination chemotherapy. High MTX sensitivity was associated with DNA hyperdiploid ALL (P < 0.001), which was linked with increased MTX accumulation (P = 0.03) and elevated reduced folate carrier (RFC) expression (P = 0.049) in this subset of ALL patients. TEL-AML1 fusion was associated with increased MTX resistance (P = 0.023). Moreover, a low accumulation of MTX polyglutamates was observed in MLL-rearranged and TEL-AML1 rearranged ALL (P < 0.05).

Conclusions: These findings emphasize the central role of MTX in ALL treatment thereby expanding our understanding of the molecular basis of clinical differences in treatment response between ALL individuals. In particular, the identification of patients that are potentially resistant to MTX at diagnosis may allow for tailoring novel treatment strategies to individual leukemia patients.
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http://dx.doi.org/10.1186/s13045-015-0158-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4455979PMC
May 2015