Publications by authors named "Marc Bierings"

128 Publications

Population pharmacokinetics of clofarabine for allogeneic hematopoietic cell transplantation in paediatric patients.

Authors:
A Laura Nijstad Stefan Nierkens Caroline A Lindemans Jaap Jan Boelens Marc Bierings A Birgitta Versluys Kim C M van der Elst Alwin D R Huitema

Br J Clin Pharmacol 2021 Jan 14. Epub 2021 Jan 14.

Department of Clinical Pharmacy, Division of Laboratory Medicine and Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

Aims: Clofarabine has recently been evaluated as part of the conditioning regimen for allogeneic hematopoietic stem cell transplantation (HCT) in children. Pharmacokinetic (PK) exposure of different agents commonly used in conditioning regimens is strongly related to HCT outcome. Consequently, the PK of clofarabine may be important for outcome. This report describes the population PK of clofarabine in paediatric patients and one adult.

Methods: From 80 paediatric (0.5-18 years) and 1 adult patient (37 years), 805 plasma concentrations were included in pharmacokinetic analyses using nonlinear mixed effects modelling.

Results: A two-compartment model adequately described the PK of clofarabine. Body weight and estimated glomerular filtration rate (eGFR) were included as covariates. Clearance was differentiated into nonrenal and renal clearance (approximately 55% of total clearance), resulting in population estimates of 24.0 L/h (95% confidence interval [CI] 13.7-34.4) and 29.8 L/h (95% CI 23.9-36.1) for a patient of 70 kg with normal renal function, respectively. Unexplained interindividual variability in clearance was 17.8% (95% CI 14.6-22.4). A high variability in exposure was observed (range area under the curve 1.8-6.0 mg/L*h) after body surface area (BSA) based dosing. Interestingly, children with low body weight had a lower exposure than children with a higher body weight, which indicates that the currently practised BSA-based dosing is not adequate for clofarabine.

Conclusion: A clofarabine dosing algorithm based on this PK model, using body weight and eGFR, results in a more predictable exposure than BSA-based dosing. However, the exact target exposure needs to be further investigated.
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http://dx.doi.org/10.1111/bcp.14738DOI Listing
January 2021

Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multinational, Randomized, Noninferiority Phase III Study.

Authors:
Christina Peters Jean-Hugues Dalle Franco Locatelli Ulrike Poetschger Petr Sedlacek Jochen Buechner Peter J Shaw Raquel Staciuk Marianne Ifversen Herbert Pichler Kim Vettenranta Peter Svec Olga Aleinikova Jerry Stein Tayfun Güngör Jacek Toporski Tony H Truong Cristina Diaz-de-Heredia Marc Bierings Hany Ariffin Mohammed Essa Birgit Burkhardt Kirk Schultz Roland Meisel Arjan Lankester Marc Ansari Martin Schrappe Arend von Stackelberg Adriana Balduzzi Selim Corbacioglu Peter Bader

J Clin Oncol 2021 Feb 17;39(4):295-307. Epub 2020 Dec 17.

Goethe University, University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Frankfurt am Main, Germany.

Purpose: Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is efficacious, but long-term side effects are concerning. We investigated whether preparative combination chemotherapy could replace TBI in such patients.

Patients And Methods: FORUM is a randomized, controlled, open-label, international, multicenter, phase III, noninferiority study. Patients ≤ 18 years at diagnosis, 4-21 years at HSCT, in complete remission pre-HSCT, and with an HLA-compatible related or unrelated donor were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine, thiotepa, and either busulfan or treosulfan. The noninferiority margin was 8%. With 1,000 patients randomly assigned in 5 years, 2-year minimum follow-up, and one-sided alpha of 5%, 80% power was calculated. A futility stopping rule would halt random assignment if chemoconditioning was significantly inferior to TBI (EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129).

Results: Between April 2013 and December 2018, 543 patients were screened, 417 were randomly assigned, 212 received TBI, and 201 received chemoconditioning. The stopping rule was applied on March 31, 2019. The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91; 95% CI, 0.86 to 0.95; < .0001) versus chemoconditioning (0.75; 95% CI, 0.67 to 0.81). Two-year cumulative incidence of relapse and treatment-related mortality were 0.12 (95% CI, 0.08 to 0.17; < .0001) and 0.02 (95% CI, < 0.01 to 0.05; = .0269) following TBI and 0.33 (95% CI, 0.25 to 0.40) and 0.09 (95% CI, 0.05 to 0.14) following chemoconditioning, respectively.

Conclusion: Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. We therefore recommend TBI plus etoposide for patients > 4 years old with high-risk ALL undergoing allogeneic HSCT.
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http://dx.doi.org/10.1200/JCO.20.02529DOI Listing
February 2021

CD4+ T-cell reconstitution predicts survival outcomes after acute graft-versus-host-disease: a dual-center validation.

Authors:
Coco de Koning Susan Prockop Ichelle van Roessel Nancy Kernan Elizabeth Klein Jurgen Langenhorst Celina Szanto Mirjam Belderbos Marc Bierings Farid Boulad Dorine Bresters Maria Cancio Kevin Curran Wouter Kollen Richard O'Reilly Andromachi Scaradavou Barbara Spitzer Birgitta Versluijs Alwin Huitema Caroline Lindemans Stefan Nierkens Jaap Jan Boelens

Blood 2021 Feb;137(6):848-855

Pediatric Stem Cell Transplant and Cellular Therapies, Memorial Sloan Kettering Cancer Center, New York, NY.

Acute graft-versus-host-Disease (aGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). We previously showed that early CD4+ T-cell immune reconstitution (IR; CD4+ IR) predicts survival after HCT. Here, we studied the relation between CD4+ IR and survival in patients developing aGVHD. Pediatric patients undergoing first allogeneic HCT at University Medical Center Utrecht (UMC)/Princess Máxima Center (PMC) or Memorial Sloan Kettering Cancer Center (MSK) were included. Primary outcomes were nonrelapse mortality (NRM) and overall survival (OS), stratified for aGVHD and CD4+ IR, defined as ≥50 CD4+ T cells per μL within 100 days after HCT or before aGVHD onset. Multivariate and time-to-event Cox proportional hazards models were applied, and 591 patients (UMC/PMC, n = 276; MSK, n = 315) were included. NRM in patients with grade 3 to 4 aGVHD with or without CD4+ IR within 100 days after HCT was 30% vs 80% (P = .02) at UMC/PMC and 5% vs 67% (P = .02) at MSK. This was associated with lower OS without CD4+ IR (UMC/PMC, 61% vs 20%; P = .04; MSK, 75% vs 33%; P = .12). Inadequate CD4+ IR before aGVHD onset was associated with significantly higher NRM (74% vs 12%; P < .001) and inferior OS (24% vs 78%; P < .001). In this retrospective analysis, we demonstrate that early CD4+ IR, a simple and robust marker predictive of outcomes after HCT, is associated with survival after moderate to severe aGVHD. This association must be confirmed prospectively but suggests strategies to improve T-cell recovery after HCT may influence survival in patients developing aGVHD.
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http://dx.doi.org/10.1182/blood.2020007905DOI Listing
February 2021

Towards homogenization of total body irradiation practices in pediatric patients across SIOPE affiliated centers. A survey by the SIOPE radiation oncology working group.

Authors:
Bianca A W Hoeben Montserrat Pazos Michael H Albert Enrica Seravalli Mirjam E Bosman Christoph Losert Tom Boterberg Farkhad Manapov Inna Ospovat Soraya Mico Milla Candan Demiroz Abakay Jacob Engellau Gregor Kos Stéphane Supiot Marc Bierings Geert O Janssens

Radiother Oncol 2020 Nov 1;155:113-119. Epub 2020 Nov 1.

Dept. of Radiation Oncology, University Medical Center Utrecht, The Netherlands; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.

Background And Purpose: To reduce relapse risk, Total Body Irradiation (TBI) is part of conditioning regimens for hematopoietic stem cell transplantation (HSCT) in pediatric acute leukemia. The study purpose was to evaluate clinical practices regarding TBI, such as fractionation, organ shielding and delivery techniques, among SIOPE affiliated radiotherapy centers.

Methods: An electronic survey was sent out to 233 SIOPE affiliated centers, containing 57 questions about clinical practice of TBI. Surveys could be answered anonymously.

Results: From over 25 countries, 82 responses were collected. For TBI-performing centers, 40/48 irradiated ≤10 pediatric patients annually (range: 1-2 to >25). Most indications concerned acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Four different fractionation schedules were used, of which 12 Gy in 6 fractions was applied in 91% for ALL and 86% for AML. Dose reduction to the lungs, mostly to a mean dose of 8-10 Gy, was applied by 28/33 centers for ALL and 19/21 centers for AML, in contrast to much less applied dose reduction to the kidneys (7/33 ALL and 7/21 AML), thyroid (2/33 ALL and 2/21 AML), liver (4/33 ALL and 3/21 AML) and lenses (4/33 ALL and 4/21 AML). Conventional TBI techniques were used by 24/29 responding centers, while 5/29 used advanced optimized planning techniques.

Conclusion: Across SIOPE, there is a high level of uniformity in fractionation and use of lung shielding. Practices vary regarding other organs-at-risk shielding and implementation of advanced techniques. A SIOPE radiotherapy working group will be established to define international guidelines for pediatric TBI.
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http://dx.doi.org/10.1016/j.radonc.2020.10.032DOI Listing
November 2020

The impact of donor type on the outcome of pediatric patients with very high risk acute lymphoblastic leukemia. A study of the ALL SCT 2003 BFM-SG and 2007-BFM-International SG.

Authors:
Jean-Hugues Dalle Adriana Balduzzi Peter Bader Anna Pieczonka Isaac Yaniv Arjan Lankester Marc Bierings Akif Yesilipek Petr Sedlacek Marianne Ifversen Peter Svec Jacek Toporski Taifun Gungor Jacek Wachowiak Evgenia Glogova Ulrike Poetschger Christina Peters

Bone Marrow Transplant 2021 Jan 4;56(1):257-266. Epub 2020 Aug 4.

St Anna Children's Hospital, Universitätsklinik für Kinder- und Jugendheilkunde, Medizinische Universität Wien, Vienna, Austria.

Allogeneic HSCT represents the only potentially curative treatment for very high risk (VHR) ALL. Two consecutive international prospective studies, ALL-SCT-(I)BFM 2003 and 2007 were conducted in 1150 pediatric patients. 569 presented with VHR disease leading to any kind of HSCT. All patients >2 year old were transplanted after TBI-based MAC. The median follow-up was 5 years. 463 patients were transplanted from matched donor (MD) and 106 from mismatched donor (MMD). 214 were in CR1. Stem cell source was unmanipulated BM for 330 patients, unmanipulated PBSC for 135, ex vivo T-cell depleted PBSC for 62 and cord-blood for 26. There were more advanced disease, more ex vivo T-cell depletion, and more chemotherapy based conditioning regimen for patients transplanted from MMD as compared to those transplanted from MSD or MD. Median follow up (reversed Kaplan Meier estimator) was 4.99 years, median follow up of survivals was 4.88, range (0.01-11.72) years. The 4-year CI of extensive cGvHD was 13 ± 2% and 17 ± 4% (p = NS) for the patients transplanted from MD and MMD, respectively. 4-year EFS was statistically better for patients transplanted from MD (60 ± 2% vs. 42 ± 5%, p < 0.001) for the whole cohort. This difference does not exist if considering separately patients treated in the most recent study. There was no difference in 4-year CI of relapse. The 4-year NRM was lower for patients transplanted from MD (9 ± 1% vs. 23 ± 4%, p < 0.001). In multivariate analysis, donor-type appears as a negative risk-factor for OS, EFS, and NRM. This paper demonstrates the impact of donor type on overall results of allogeneic stem cell transplantation for very-high risk pediatric acute lymphoblastic leukemia with worse results when using MMD stem cell source.
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http://dx.doi.org/10.1038/s41409-020-01014-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796856PMC
January 2021

Myeloablative conditioning for allo-HSCT in pediatric ALL: FTBI or chemotherapy?-A multicenter EBMT-PDWP study.

Authors:
Andre Manfred Willasch Christina Peters Petr Sedláček Jean-Hugues Dalle Vassiliki Kitra-Roussou Akif Yesilipek Jacek Wachowiak Arjan Lankester Arcangelo Prete Amir Ali Hamidieh Marianne Ifversen Jochen Buechner Gergely Kriván Rose-Marie Hamladji Cristina Diaz-de-Heredia Elena Skorobogatova Gérard Michel Franco Locatelli Alice Bertaina Paul Veys Sophie Dupont Reuven Or Tayfun Güngör Olga Aleinikova Sabina Sufliarska Mikael Sundin Jelena Rascon Ain Kaare Damir Nemet Franca Fagioli Thomas Erich Klingebiel Jan Styczynski Marc Bierings Kálmán Nagy Manuel Abecasis Boris Afanasyev Marc Ansari Kim Vettenranta Amal Alseraihy Alicja Chybicka Stephen Robinson Yves Bertrand Alphan Kupesiz Ardeshir Ghavamzadeh Antonio Campos Herbert Pichler Arnaud Dalissier Myriam Labopin Selim Corbacioglu Adriana Balduzzi Jacques-Emmanuel Galimard Peter Bader

Bone Marrow Transplant 2020 08 17;55(8):1540-1551. Epub 2020 Mar 17.

Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents, University Hospital, Goethe University Frankfurt, Frankfurt, Germany.

Although most children with acute lymphoblastic leukemia (ALL) receive fractionated total body irradiation (FTBI) as myeloablative conditioning (MAC) for allogeneic hematopoietic stem cell transplantation (allo-HSCT), it is an important matter of debate if chemotherapy can effectively replace FTBI. To compare outcomes after FTBI versus chemotherapy-based conditioning (CC), we performed a retrospective EBMT registry study. Children aged 2-18 years after MAC for first allo-HSCT of bone marrow (BM) or peripheral blood stem cells (PBSC) from matched-related (MRD) or unrelated donors (UD) in first (CR1) or second remission (CR2) between 2000 and 2012 were included. Propensity score weighting was used to control pretreatment imbalances of the observed variables. 3.054 patients were analyzed. CR1 (1.498): median follow-up (FU) after FTBI (1.285) and CC (213) was 6.8 and 6.1 years. Survivals were not significantly different. CR2 (1.556): median FU after FTBI (1.345) and CC (211) was 6.2 years. Outcomes after FTBI were superior as compared with CC with regard to overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), and nonrelapse mortality (NRM). However, we must emphasize the preliminary character of the results of this retrospective "real-world-practice" study. These findings will be prospectively assessed in the ALL SCTped 2012 FORUM trial.
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http://dx.doi.org/10.1038/s41409-020-0854-0DOI Listing
August 2020

Parental experiences in end-of-life decision-making in allogeneic pediatric stem cell transplantation: "Have I been a good parent?"

Authors:
Hilda Mekelenkamp Arjan C Lankester Marc B Bierings Frans J W Smiers Martine C de Vries Marijke C Kars

Pediatr Blood Cancer 2020 05 5;67(5):e28229. Epub 2020 Mar 5.

Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, The Netherlands.

Background: In pediatric hematopoietic stem cell transplantation (HSCT), the end-of-life (EOL) phase and the loss of the child is often characterized by a sudden deterioration of the child following a period of intensive curative treatment. This demands a fast transition for parents. Therefore, an understanding of the parents' perspective on decision-making in such a complex situation is needed. This study aims to gain insight in parental experiences in EOL decision-making in allogeneic pediatric HSCT.

Methods: A qualitative descriptive study was performed among parents of eight families. Data were thematically analyzed.

Results: All parents were aware of their child's deterioration. Six families were confronted with a rapid deterioration, while two families experienced a gradual realization that their child would not survive. Parental EOL decision-making in pediatric HSCT shows a reflective perspective on the meaning of parenthood in EOL decision-making. Two central themes were identified: "survival-oriented decision-making" and "struggling with doubts in hindsight." Six subthemes within the first theme described the parents' goal of doing everything to achieve survival.

Discussion: Parents experienced EOL decision-making mainly as a process guided by health care professionals (HCPs) based on the child's condition and treatment possibilities. The decision-making is characterized by following opportunities and focusing on hope for cure. In hindsight parents experienced doubts about treatment steps and their child's suffering. HCPs can strengthen the parental role by an early integration of palliative care, providing timely support to parents in the process of imminent loss. Advance care planning can be used to support communication processes, defining preferences for future care.
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http://dx.doi.org/10.1002/pbc.28229DOI Listing
May 2020

Outcome of children relapsing after first allogeneic haematopoietic stem cell transplantation for acute myeloid leukaemia: a retrospective I-BFM analysis of 333 children.

Authors:
Theodor Uden Alice Bertaina Jonas Abrahamsson Marc Ansari Adriana Balduzzi Jean-Pierre Bourquin Corinne Gerhardt Marc Bierings Henrik Hasle Arjan Lankester Kirsten Mischke Andrew S Moore Ian Nivison-Smith Anna Pieczonka Christina Peters Petr Sedlacek Dirk Reinhardt Jerry Stein Birgitta Versluys Jacek Wachowiak Leen Willems Martin Zimmermann Franco Locatelli Martin G Sauer

Br J Haematol 2020 05 3;189(4):745-750. Epub 2020 Feb 3.

Division of Pediatric Hematology and Oncology, Department of Pediatrics, Universities of Medical University Hannover, Hannover, Germany.

Outcome of 333 children with acute myeloid leukaemia relapsing after a first allogeneic haematopoietic stem cell transplantation was analyzed. Four-year probability of overall survival (4y-pOS) was 14%. 4y-pOS for 122 children receiving a second haematopoietic stem cell transplantation was 31% and 3% for those that did not (P = <0·0001). Achievement of a subsequent remission impacted survival (P = <0·0001). For patients receiving a second transplant survival with or without achieving a subsequent remission was comparable. Graft source (bone marrow vs. peripheral blood stem cells, P = 0·046) and donor choice (matched family vs. matched unrelated donor, P = 0·029) positively impacted survival after relapse. Disease recurrence and non-relapse mortality at four years reached 45% and 22%.
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http://dx.doi.org/10.1111/bjh.16441DOI Listing
May 2020

Ribosomal protein gene RPL9 variants can differentially impair ribosome function and cellular metabolism.

Authors:
Marco Lezzerini Marianna Penzo Marie-Françoise O'Donohue Carolina Marques Dos Santos Vieira Manon Saby Hyung L Elfrink Illja J Diets Anne-Marie Hesse Yohann Couté Marc Gastou Alexandra Nin-Velez Peter G J Nikkels Alexandra N Olson Evelien Zonneveld-Huijssoon Marjolijn C J Jongmans GuangJun Zhang Michel van Weeghel Riekelt H Houtkooper Marcin W Wlodarski Roland P Kuiper Marc B Bierings Jutte van der Werff Ten Bosch Thierry Leblanc Lorenzo Montanaro Jonathan D Dinman Lydie Da Costa Pierre-Emmanuel Gleizes Alyson W MacInnes

Nucleic Acids Res 2020 01;48(2):770-787

Amsterdam UMC, University of Amsterdam, Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology and Metabolism, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

Variants in ribosomal protein (RP) genes drive Diamond-Blackfan anemia (DBA), a bone marrow failure syndrome that can also predispose individuals to cancer. Inherited and sporadic RP gene variants are also linked to a variety of phenotypes, including malignancy, in individuals with no anemia. Here we report an individual diagnosed with DBA carrying a variant in the 5'UTR of RPL9 (uL6). Additionally, we report two individuals from a family with multiple cancer incidences carrying a RPL9 missense variant. Analysis of cells from these individuals reveals that despite the variants both driving pre-rRNA processing defects and 80S monosome reduction, the downstream effects are remarkably different. Cells carrying the 5'UTR variant stabilize TP53 and impair the growth and differentiation of erythroid cells. In contrast, ribosomes incorporating the missense variant erroneously read through UAG and UGA stop codons of mRNAs. Metabolic profiles of cells carrying the 5'UTR variant reveal an increased metabolism of amino acids and a switch from glycolysis to gluconeogenesis while those of cells carrying the missense variant reveal a depletion of nucleotide pools. These findings indicate that variants in the same RP gene can drive similar ribosome biogenesis defects yet still have markedly different downstream consequences and clinical impacts.
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http://dx.doi.org/10.1093/nar/gkz1042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954397PMC
January 2020

Recognizing a Non-classical Telomeropathy before Hematopoietic Stem Cell Transplantation in Pediatric Patients: A Case Series.

Authors:
Iris Nederlof Caroline A Lindemans Marc B Bierings Alexander B Mohseny Dorine Bresters Marije Bartels

Hemasphere 2019 Aug 7;3(4):e282. Epub 2019 Aug 7.

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

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http://dx.doi.org/10.1097/HS9.0000000000000282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745921PMC
August 2019

The Complexity of Genotype-Phenotype Correlations in Hereditary Spherocytosis: A Cohort of 95 Patients: Genotype-Phenotype Correlation in Hereditary Spherocytosis.

Authors:
Annelies van Vuren Bert van der Zwaag Rick Huisjes Nathalie Lak Marc Bierings Egbert Gerritsen Eduard van Beers Marije Bartels Richard van Wijk

Hemasphere 2019 Aug 7;3(4):e276. Epub 2019 Aug 7.

Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Hereditary spherocytosis (HS) is a phenotypically and genetically heterogeneous disease. With the increased use of Next Generation Sequencing (NGS) techniques in the diagnosis of red blood cell disorders, the list of unique pathogenic mutations underlying HS is growing rapidly. In this study, we aimed to explore genotype-phenotype correlation in 95 HS patients genotyped by targeted NGS as part of routine diagnostics (UMC Utrecht, Utrecht, The Netherlands). In 85/95 (89%) of patients a pathogenic mutation was identified, including 56 novel mutations. mutations were most frequently encountered (36%, 31/85 patients), primarily in patients with autosomal recessive forms of HS. Three (α-spectrin) mutations showed autosomal dominant inheritance. (ankyrin1) mutations accounted for 27% (23/85 patients) and (β-spectrin) mutations for 20% (17/85 patients). Moderate or severe HS was more frequent in patients with or mutations, reflected by lower hemoglobin concentrations and higher reticulocyte counts. Interestingly, mutations affecting spectrin association domains of , and resulted in more severe phenotypes. Additionally, we observed a clear association between phenotype and aspects of red cell deformability as determined by the Laser assisted Optical Rotational Cell Analyzer (LoRRca MaxSis). Both maximal deformability and area under the curve were negatively associated with disease severity (respectively r = -0.46, p < 0.01, and r = -0.39, p = 0.01). Genotype-phenotype prediction in HS facilitates insight in consequences of pathogenic mutations for the assembly and dynamic interactions of the red cell cytoskeleton. In addition, we show that measurements of red blood cell deformability are clearly correlated with HS severity.
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http://dx.doi.org/10.1097/HS9.0000000000000276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745925PMC
August 2019

Longitudinal development of cancer-related fatigue and physical activity in childhood cancer patients.

Authors:
Elisabeth M Van Dijk-Lokkart Lindsay M H Steur Katja I Braam Margreet A Veening Jaap Huisman Tim Takken Marc Bierings Johannes H Merks Marry M Van den Heuvel-Eibrink Gertjan J L Kaspers Eline Van Dulmen-den Broeder Raphaële R L Van Litsenburg

Pediatr Blood Cancer 2019 12 22;66(12):e27949. Epub 2019 Aug 22.

Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Oncology, Cancer Center Amsterdam, Amsterdam, The Netherlands.

Purpose: Cancer-related fatigue is one of the most distressing side effects of childhood cancer treatment. Physical activity can decrease fatigue and has positive effects on other health outcomes. Most research on physical activity pertains to adults, and the few studies that focus on children have limited follow-up time. This study evaluates cancer-related fatigue in children and its association with physical activity over a one-year time period.

Methods: Sixty-eight children with cancer (7-18 years) were recruited during or within the first year after treatment. Physical activity (Actical activity monitor) and cancer-related fatigue (Pediatric Quality-of-Life Questionnaire Multidimensional Fatigue Scale (PedsQL-MFS), self- and parent- reports) were assessed at baseline, 4 months, and 12 months. PedsQL-MFS scores were compared with Dutch norms. Longitudinal association of cancer-related fatigue with physical activity was evaluated (No. NTR 1531).

Results: Generally, PedsQL-MFS scores were worse than norms at baseline and 4 months, and recovered by 12 months except for the parent-proxy scores in adolescents. Younger children (≤12 years) self-reported comparable or better scores than norms. Physical activity generally improved over time, but patients mostly remained sedentary. During follow-up, increased physical activity was associated with less cancer-related fatigue.

Conclusion: Cancer-related fatigue in children improves over time, and increased physical activity is associated with less cancer-related fatigue. Given the sedentary lifestyle of this population, the positive effect of physical activity on cancer-related fatigue, and the many other health benefits of an active lifestyle, it is important to stimulate physical activity in childhood cancer patients and survivors.
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http://dx.doi.org/10.1002/pbc.27949DOI Listing
December 2019

Predictors for Autoimmune Cytopenias after Allogeneic Hematopoietic Cell Transplantation in Children.

Authors:
Celina L Szanto Jurgen Langenhorst Coco de Koning Stefan Nierkens Marc Bierings Alwin D R Huitema Caroline A Lindemans Jaap J Boelens

Biol Blood Marrow Transplant 2020 01 22;26(1):114-122. Epub 2019 Jul 22.

Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands; Pediatric Blood and Marrow Transplant Program, Princess Máxima Center for Pediatric Oncology and University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands; Stem Cell Transplantation and Cellular Therapies Program, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.

Development of autoimmune cytopenia (AIC) after allogeneic hematopoietic cell transplantation (HCT) is a serious complication requiring urgent intensification of immunosuppressive therapy. The pathophysiology and predictors of AIC are not completely understood. In this retrospective cohort analysis of 380 pediatric patients, we evaluated the incidence, outcomes, and related various variables, including immune reconstitution markers to AIC. Three hundred eighty patients (median age, 7.4 years; range, .1 to 22.7) were included, of which 30 patients (7.8%) developed AIC in 1 (n = 6), 2 (n = 6), or 3 (n = 16) cell lineages at a median of 133 days (range, 46 to 445) after HCT. Using multivariate analysis we found that chemo-naivety before HCT, acute graft-versus-host disease (aGVHD) grades II to IV, and serotherapy were associated with the development of AIC. Development of AIC was preceded by increased levels of IgM, IgA, and IgG. Immune profiles of total absolute lymphocytes were very similar between AIC patients and control subjects. However, CD3CD16CD56 natural killer cells, CD3 T cells, CD3CD4 T cell subset, and CD3CD8 T cell subset were lower in AIC patients. Overall survival was good, at 83% (similar between AIC patients and control subjects). In conclusion, we identified chemo-naivety before HCT, preceding aGVHD grades II to IV, and serotherapy as predictors for development of AIC. Increasing levels of IgM, IgA, and IgG preceded AIC development. These data provide clues to further study the biology of AIC.
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http://dx.doi.org/10.1016/j.bbmt.2019.07.022DOI Listing
January 2020

Transplantation in Children and Adolescents with Acute Lymphoblastic Leukemia from a Matched Donor versus an HLA-Identical Sibling: Is the Outcome Comparable? Results from the International BFM ALL SCT 2007 Study.

Authors:
Adriana Balduzzi Jean-Hugues Dalle Jacek Wachowiak Isaac Yaniv Akif Yesilipek Petr Sedlacek Marc Bierings Marianne Ifversen Sabina Sufliarska Krzysztof Kalwak Arjan Lankester Jacek Toporski Lucia Di Maio Evgenia Glogova Ulrike Poetschger Christina Peters

Biol Blood Marrow Transplant 2019 11 15;25(11):2197-2210. Epub 2019 Jul 15.

St Anna Children's Hospital, UKKJ, MUW, Vienna, Austria.

Eligibility criteria for hematopoietic stem cell transplantation (HSCT) in acute lymphoblastic leukemia (ALL) vary according to disease characteristics, response to treatment, and type of available donor. As the risk profile of the patient worsens, a wider degree of HLA mismatching is considered acceptable. A total of 138 children and adolescents who underwent HSCT from HLA-identical sibling donors (MSDs) and 210 who underwent HSCT from matched donors (MDs) (median age, 9 years; 68% male) in 10 countries were enrolled in the International-BFM ALL SCT 2007 prospective study to assess the impact of donor type in HSCT for pediatric ALL. The 4-year event-free survival (65 ± 5% vs 61 ± 4%; P = .287), overall survival (72 ± 4% versus 68 ± 4%; P = .235), cumulative incidence of relapse (24 ± 4% versus 25 ± 3%; P = .658) and nonrelapse mortality (10 ± 3% versus 14 ± 3%; P = .212) were not significantly different between MSD and MD graft recipients. The risk of extensive chronic (cGVHD) was lower in MD graft recipients than in MSD graft recipients (hazard ratio [HR], .38; P = .002), and the risks of severe acute GVHD (aGVHD) and cGVHD were higher in peripheral blood stem cell graft recipients than in bone marrow graft recipients (HR, 2.06; P = .026). Compared with the absence of aGVHD, grade I-II aGVHD was associated with a lower risk of graft failure (HR, .63; P = .042) and grade III-IV aGVHD was associated with a higher risk of graft failure (HR, 1.85; P = .020) and nonleukemic death (HR, 8.76; P < .0001), despite a lower risk of relapse (HR, .32; P = .021). Compared with the absence of cGVHD, extensive cGVHD was associated with a higher risk of nonleukemic death (HR, 8.12; P < .0001). Because the outcomes of transplantation from a matched donor were not inferior to those of transplantation from an HLA-identical sibling, eligibility criteria for transplantation might be reviewed in pediatric ALL and possibly in other malignancies as well. Bone marrow should be the preferred stem cell source, and the addition of MTX should be considered in MSD graft recipients.
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http://dx.doi.org/10.1016/j.bbmt.2019.07.011DOI Listing
November 2019

Gonadal Function after Busulfan Compared with Treosulfan in Children and Adolescents Undergoing Allogeneic Hematopoietic Stem Cell Transplant.

Authors:
Maura Faraci Tamara Diesch Myriam Labopin Arnaud Dalissier Arian Lankester Andrew Gennery Mikael Sundin Duygu Uckan-Cetinkaya Marc Bierings Anke M J Peters Martina Garwer Ansgar Schulz Gerard Michel Giovanna Giorgiani Bernd Gruhn Franco Locatelli Stefano Giardino Anne Uyttebroeck Fanny Rialland Maija Itäla-Remes Peter Dreger Peter J Shaw Victoria Bordon Paul G Schlegel Karin Mellgren Jose M Moraleda Katharine Patrick Pascale Schneider Charlotte Jubert Anita Lawitschka Nina Salooja Grzegorz W Basak Selim Corbacioglu Rafael Duarte Peter Bader

Biol Blood Marrow Transplant 2019 09 11;25(9):1786-1791. Epub 2019 May 11.

Goethe-Universität, Universitätsklinikum Frankfurt, Frankfurt, Germany.

Gonadal impairment is an important late effect with a significant impact on quality of life of transplanted patients. The aim of this study was to compare gonadal function after busulfan (Bu) or treosulfan (Treo) conditioning regimens in pre- and postpubertal children. This retrospective, multicenter study included children transplanted in pediatric European Society for Blood and Marrow Transplantation (EBMT) centers between 1992 and 2012 who did not receive gonadotoxic chemoradiotherapy before the transplant. We evaluated 137 patients transplanted in 25 pediatric EBMT centers. Median age at transplant was 11.04 years (range, 5 to 18); 89 patients were boys and 48 girls. Eighty-nine patients were prepubertal at transplant and 48 postpubertal. One hundred eighteen children received Bu and 19 Treo. A higher proportion of girls treated with Treo in the prepubertal stage reached spontaneous puberty compared with those treated with Bu (P = .02). Spontaneous menarche was more frequent after Treo than after Bu (P < .001). Postpubertal boys and girls treated with Treo had significantly lower luteinizing hormone levels (P = .03 and P = .04, respectively) compared with the Bu group. Frequency of gonadal damage associated with Treo was significantly lower than that observed after Bu. These results need to be confirmed in a larger population.
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http://dx.doi.org/10.1016/j.bbmt.2019.05.005DOI Listing
September 2019

Effects of a combined physical and psychosocial training for children with cancer: a randomized controlled trial.

Authors:
Katja I Braam Elisabeth M van Dijk-Lokkart Gertjan J L Kaspers Tim Takken Jaap Huisman Laurien M Buffart Marc B Bierings Johannes H M Merks Marry M van den Heuvel-Eibrink Margreet A Veening Eline van Dulmen-den Broeder

BMC Cancer 2018 Dec 27;18(1):1289. Epub 2018 Dec 27.

Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, the Netherlands.

Background: Physical fitness and psychosocial function is often reduced in children during or shortly after cancer treatment. This study evaluates the effect of a combined physical exercise and psychosocial intervention on cardiorespiratory fitness, muscle strength, body composition, psychosocial function and health-related quality of life (HrQoL). In addition, intervention mediators, applicability and adherence were examined.

Methods: This multicenter randomized controlled trial included 68 children with cancer [mean age 13.2 (SD: 3.1) years; 54% male] during treatment or within 12-months post-treatment. The 12-week intervention consisted of 24 individual physical exercise sessions supervised by a physiotherapist, and 6 psychosocial training sessions for children and 2 for parents. Physical fitness and psychosocial function were assessed at baseline, directly post-intervention and at 12 months' post-baseline. Generalized estimating equations were used to simultaneously assess intervention effects at short and long-term. Additionally, we evaluated within-group differences over time. Potential physical and psychosocial mediators in the intervention effect on HrQoL were examined using the product-of-coefficient test. Applicability and adherence were assessed by trainer-report.

Results: This study was able to compare 26 children who received the study intervention, with 33 children who received usual care. No significant differences in the effects of the intervention were found on physical fitness and psychosocial function at short-term. At 12-months follow-up, significantly larger improvements in lower body muscle strength (β = 56.5 Newton; 95% CI: 8.5; 104.5) were found in the intervention group when compared to the control group. Within-group changes showed significant improvements over time in HrQoL and bone density in both groups. Intervention effects on HrQoL were not significantly mediated by physical fitness and psychological function. Intervention applicability was satisfactory with an average session attendance of 67% and 22% dropout (mainly due to disease recurrence).

Conclusions: This 12-week physical exercise and psychosocial training intervention for children with cancer was applicable and showed satisfactory adherence. We found no significant between-group differences in effect, except for a significant improvement in lower body muscle strength at long-term in the intervention group compared to the control group. Yet, both the intervention and the control group showed improvements in bone mineral density and HrQoL over time.

Trial Registration: The trial was registered at the Dutch Trial Registry ( NTR1531 ). Registered 12 November 2008.
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http://dx.doi.org/10.1186/s12885-018-5181-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307314PMC
December 2018

How I manage children with Diamond-Blackfan anaemia.

Authors:
Marije Bartels Marc Bierings

Br J Haematol 2019 01 4;184(2):123-133. Epub 2018 Dec 4.

Department of Stem cell transplantation, Princess Maxima Centre for Paediatric Oncology, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht, the Netherlands.

Diamond-Blackfan anaemia (DBA) is a rare inherited marrow failure disorder, characterized by hypoplastic anaemia, congenital anomalies and a predisposition to cancer as a result of ribosomal dysfunction. Historically, treatment is based on glucocorticoids and/or blood transfusions, which is accompanied by significant toxicity and long-term sequelae. Currently, stem cell transplantation is the only curative option for the haematological DBA phenotype. Whereas this procedure has been quite successful in the last decade in selected patients, novel therapies and biological insights are still warranted to improve clinical care for all DBA patients. In addition to paediatric haematologists, other physicians (e.g. endocrinologist, gynaecologist) should ideally be involved in the care of this chronic condition from an early age, to improve lifelong management of haematological and non-haematological symptoms, and screen for DBA-associated malignancies. Here we provide an overview of current knowledge and recommendations for the day-to-day care of DBA patients.
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http://dx.doi.org/10.1111/bjh.15701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587714PMC
January 2019

The fluid membrane determines mechanics of erythrocyte extracellular vesicles and is softened in hereditary spherocytosis.

Authors:
Daan Vorselen Susan M van Dommelen Raya Sorkin Melissa C Piontek Jürgen Schiller Sander T Döpp Sander A A Kooijmans Brigitte A van Oirschot Birgitta A Versluijs Marc B Bierings Richard van Wijk Raymond M Schiffelers Gijs J L Wuite Wouter H Roos

Nat Commun 2018 11 23;9(1):4960. Epub 2018 Nov 23.

Department of Physics and Astronomy and LaserLab, Vrije Universiteit Amsterdam, 1081 HV, Amsterdam, The Netherlands.

Extracellular vesicles (EVs) are widely studied regarding their role in cell-to-cell communication and disease, as well as for applications as biomarkers or drug delivery vehicles. EVs contain membrane and intraluminal proteins, affecting their structure and thereby likely their functioning. Here, we use atomic force microscopy for mechanical characterization of erythrocyte, or red blood cell (RBC), EVs from healthy individuals and from patients with hereditary spherocytosis (HS) due to ankyrin deficiency. While these EVs are packed with proteins, their response to indentation resembles that of fluid liposomes lacking proteins. The bending modulus of RBC EVs of healthy donors is ~15 kT, similar to the RBC membrane. Surprisingly, whereas RBCs become more rigid in HS, patient EVs have a significantly (~40%) lower bending modulus than donor EVs. These results shed light on the mechanism and effects of EV budding and might explain the reported increase in vesiculation of RBCs in HS patients.
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http://dx.doi.org/10.1038/s41467-018-07445-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251882PMC
November 2018

Autophagy inhibition as a potential future targeted therapy for ETV6-RUNX1-driven B-cell precursor acute lymphoblastic leukemia.

Authors:
Roel Polak Marc B Bierings Cindy S van der Leije Mathijs A Sanders Onno Roovers João R M Marchante Judith M Boer Jan J Cornelissen Rob Pieters Monique L den Boer Miranda Buitenhuis

Haematologica 2019 04 31;104(4):738-748. Epub 2018 Oct 31.

Department of Hematology, Erasmus Medical Center, Rotterdam, the Netherlands.

Translocation t(12;21), resulting in the ETV6-RUNX1 (or TEL-AML1) fusion protein, is present in 25% of pediatric patients with B-cell precursor acute lymphoblastic leukemia and is considered a first hit in leukemogenesis. A targeted therapy approach is not available for children with this subtype of leukemia. To identify the molecular mechanisms underlying ETV6-RUNX1-driven leukemia, we performed gene expression profiling of healthy hematopoietic progenitors in which we ectopically expressed ETV6-RUNX1. We reveal an ETV6-RUNX1-driven transcriptional network that induces proliferation, survival and cellular homeostasis. In addition, Vps34, an important regulator of autophagy, was found to be induced by ETV6-RUNX1 and up-regulated in ETV6-RUNX1-positive leukemic patient cells. We show that induction of Vps34 was transcriptionally regulated by ETV6-RUNX1 and correlated with high levels of autophagy. Knockdown of Vps34 in ETV6-RUNX1-positive cell lines severely reduced proliferation and survival. Inhibition of autophagy by hydroxychloroquine, a well-tolerated autophagy inhibitor, reduced cell viability in both ETV6-RUNX1-positive cell lines and primary acute lymphoblastic leukemia samples, and selectively sensitized primary ETV6-RUNX1-positive leukemia samples to L asparaginase. These findings reveal a causal relationship between ETV6-RUNX1 and autophagy, and provide pre-clinical evidence for the efficacy of autophagy inhibitors in ETV6-RUNX1-driven leukemia.
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http://dx.doi.org/10.3324/haematol.2018.193631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442983PMC
April 2019

Effects of age and genetic variations in VKORC1, CYP2C9 and CYP3A4 on the phenprocoumon dose in pediatric patients.

Authors:
Hedy Maagdenberg Marc B Bierings C Heleen van Ommen Felix Jm van der Meer Inge M Appel Rienk Yj Tamminga Saskia le Cessie Jesse J Swen Tahar van der Straaten Anthonius de Boer Anke H Maitland-van der Zee

Pharmacogenomics 2018 10 12;19(15):1195-1202. Epub 2018 Sep 12.

Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.

Aim: To study the effects of clinical and genetic factors on the phenprocoumon dose requirement in pediatric patients and to develop a dosing algorithm.

Methods: Pediatric patients who used phenprocoumon were invited to participate in a retrospective follow-up study. Clinical information and genotypes of genetic variations in CYP2C9, VKORC1, CYP4F2, CYP2C18 and CYP3A4 were collected and tested with linear regression for association with phenprocoumon dose requirement.

Results: Of the 41 patients included in the analysis, age, VKORC1, CYP2C9*2/*3 and CYP3A4*1B were statistically significantly associated with dose requirement, and together explained 80.4% of the variability in phenprocoumon dose requirement.

Conclusion: Our study reveals that age and genetic variations explain a significant part of the variability in phenprocoumon dose requirement in pediatric patients.
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http://dx.doi.org/10.2217/pgs-2018-0095DOI Listing
October 2018

Outcome of domino hematopoietic stem cell transplantation in human subjects: An international case series.

Authors:
Mirjam E Belderbos Andrew R Gennery Christopher C Dvorak Henric-Jan Blok Dirk-Jan Eikema Juliana M F Silva Paul Veys Bénédicte Neven Rebecca Buckley Theresa Cole Morton J Cowan W Scott Goebel Manfred Hoenig Caroline Y Kuo E Richard Stiehm Robert Wynn Marc Bierings

J Allergy Clin Immunol 2018 11 5;142(5):1628-1631.e4. Epub 2018 Jul 5.

Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands; Department of Pediatric Hematology and Stem Cell Transplantation, Wilhelmina Children's Hospital, Utrecht, The Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2018.06.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226332PMC
November 2018

Allogeneic Stem Cell Transplantation from HLA-Mismatched Donors for Pediatric Patients with Acute Lymphoblastic Leukemia Treated According to the 2003 BFM and 2007 International BFM Studies: Impact of Disease Risk on Outcomes.

Authors:
Jean-Hugues Dalle Adriana Balduzzi Peter Bader Arjan Lankester Isaac Yaniv Jacek Wachowiak Anna Pieczonka Marc Bierings Akif Yesilipek Petr Sedlaçek Marianne Ifversen Sabina Sufliarska Jacek Toporski Evgenia Glogova Ulrike Poetschger Christina Peters

Biol Blood Marrow Transplant 2018 09 14;24(9):1848-1855. Epub 2018 May 14.

St. Anna Children's Hospital, Universitätsklinik für Kinder- und Jugendheilkunde, Medizinische Universität Wien, Vienna, Austria.

Allogeneic hematopoietic stem cell transplantation (HSCT) is beneficial for pediatric patients with relapsed or (very) high-risk acute lymphoblastic leukemia (ALL) in remission. A total of 1115 consecutive patients were included in the ALL SCT 2003 BFM study and the ALL SCT 2007 I-BFM study and were stratified according to relapse risk (standard versus high versus very high risk of relapse) and donor type (matched sibling versus matched donor versus mismatched donor). A total of 148 patients (60% boys; median age, 8.7 years; B cell precursor ALL, 75%) were transplanted from mismatched donors, which was defined as either less than 9/10 HLA-compatible donors or less than 5/6 unrelated cord blood after myeloablative conditioning regimen (total body irradiation based, 67%) for high relapse risk (HRR; n = 42) or very HRR (VHRR) disease (n = 106). The stem cell source was either bone marrow (n = 31), unmanipulated peripheral stem cells (n = 28), T cell ex vivo depleted peripheral stem cells (n = 59), or cord blood (n = 25). The median follow-up was 5.1 years. The 4-year rates of overall survival (OS) and event-free survival were 56% ± 4% and 52% ± 4%, respectively, for the entire cohort. Patients transplanted from mismatched donors for HRR disease obtained remarkable 4-year OS and event-free survival values of 82% ± 6% and 80% ± 6%, respectively, whereas VHRR patients obtained values of 45% ± 5% and 42% ± 5% (P < .001), respectively. The cumulative incidence of relapse was 29% ± 4% and that of nonrelapse mortality 19% ± 3%. The cumulative incidence of limited and extensive chronic graft-versus-host disease was 13% ± 3% and 15% ± 4%, respectively, among the 120 patients living beyond day 100. Multivariate analysis showed that OS was lower for transplanted VHRR patients (P = .002; hazard ratio [HR], 3.62; 95% confidence interval [CI], 1.60 to 8.20) and for patients beyond second complete remission (CR2) versus first complete remission (P < .001; HR, 3.68; 95% CI, 1.79 to 7.56); relapse occurred more frequently in patients with VHRR disease (P = .026; HR, 3.30; 95% CI, 1.16 to 9.60) and for those beyond CR2 (P = .005; HR, 4.16; 95% CI, 1.52 to 10.59). Nonrelapse mortality was not significantly higher for cytomegalovirus-positive recipients receiving cytomegalovirus-negative grafts (P = .12; HR, 1.96; 95% CI, .84 to 4.58). HSCT with a mismatched donor is feasible in pediatric ALL patients but leads to inferior results compared with HSCT with better matched donors, at least for patients transplanted for VHRR disease. The results are strongly affected by disease status. The main cause of treatment failure is still relapse, highlighting the urgent need for interventional strategies after HSCT for patients with residual leukemia before and/or after transplantation.
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http://dx.doi.org/10.1016/j.bbmt.2018.05.009DOI Listing
September 2018

Efficacy and safety of recombinant E. coli asparaginase in children with previously untreated acute lymphoblastic leukemia: A randomized multicenter study of the Dutch Childhood Oncology Group.

Authors:
Inge M van der Sluis Hester de Groot-Kruseman Maroeska Te Loo Wim J E Tissing Cor van den Bos Gertjan J L Kaspers Marc Bierings Wouter J W Kollen Thorsten König Uwe Pichlmeier Hans-Jürgen Kühnel Rob Pieters

Pediatr Blood Cancer 2018 08 4;65(8):e27083. Epub 2018 May 4.

Department of Hemato-oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.

Background: The efficacy and safety of recombinant Escherichia coli-asparaginase (rASNase) was compared to native E.coli asparaginase (Asparaginase medac).

Methods: One hundred and ninety-nine children with newly diagnosed acute lymphoblastic leukemia were randomized to receive one of both agents at a dose of 5,000 U/m² during induction (eight doses) and 10,000 U/m² during the postinduction phase (only high-risk patients; standard- and medium-risk patients received pegaspargase).

Results: Median trough serum asparaginase activity levels were comparable between both groups; they ranged from 143 to 182 U/l during induction and were above the target value of 100 U/l. Complete asparagine depletion in serum was achieved in 97.9% of patients, with no significant differences between both groups. On day 33 (end of induction), only two (2%) evaluable patients in each group had measurable asparagine serum levels, and complete asparagine depletion in the cerebrospinal fluid was achieved in 98.8% and 93.6% of the patients with rASNase and Asparaginase medac, respectively. During induction, 2.1% and 5% of patients developed an allergic reaction to rASNase or Asparaginase medac, respectively. Approximately 41% of the patients in both groups had a clinical allergy or enzyme inactivation to the first dose of any asparaginase preparation in postinduction. A comparable proportion of patients in both groups developed anti-asparaginase antibodies (57%) during repeated administration of asparaginase. Minimal residual disease levels at the end of induction, 5-year event-free survival, and 5-year cumulative incidence of relapse did not differ between both groups.

Conclusion: The efficacy, safety, and immunogenicity of both asparaginase preparations are comparable. This trial was registered at www.clinicaltrials.gov as #NCT00784017; EudraCT number 2006-003180-31.
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http://dx.doi.org/10.1002/pbc.27083DOI Listing
August 2018

Megakaryocyte lineage development is controlled by modulation of protein acetylation.

Authors:
Marije Bartels Anita Govers Roel Polak Stephin Vervoort Ruben van Boxtel Cornelieke Pals Marc Bierings Wouter van Solinge Toine Egberts Edward Nieuwenhuis Michal Mokry Paul James Coffer

PLoS One 2018 26;13(4):e0196400. Epub 2018 Apr 26.

Center for Molecular Medicine and Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands.

Treatment with lysine deacetylase inhibitors (KDACi) for haematological malignancies, is accompanied by haematological side effects including thrombocytopenia, suggesting that modulation of protein acetylation affects normal myeloid development, and specifically megakaryocyte development. In the current study, utilising ex-vivo differentiation of human CD34+ haematopoietic progenitor cells, we investigated the effects of two functionally distinct KDACi, valproic acid (VPA), and nicotinamide (NAM), on megakaryocyte differentiation, and lineage choice decisions. Treatment with VPA increased the number of megakaryocyte/erythroid progenitors (MEP), accompanied by inhibition of megakaryocyte differentiation, whereas treatment with NAM accelerated megakaryocyte development, and stimulated polyploidisation. Treatment with both KDACi resulted in no significant effects on erythrocyte differentiation, suggesting that the effects of KDACi primarily affect megakaryocyte lineage development. H3K27Ac ChIP-sequencing analysis revealed that genes involved in myeloid development, as well as megakaryocyte/erythroid (ME)-lineage differentiation are uniquely modulated by specific KDACi treatment. Taken together, our data reveal distinct effects of specific KDACi on megakaryocyte development, and ME-lineage decisions, which can be partially explained by direct effects on promoter acetylation of genes involved in myeloid differentiation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0196400PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919413PMC
August 2018

Lethal neonatal bone marrow failure syndrome with multiple congenital abnormalities, including limb defects, due to a constitutional deletion of 3' .

Authors:
Lars T van der Veken Merel C Maiburg Floris Groenendaal Mariëlle E van Gijn Andries C Bloem Claudia Erpelinck Stefan Gröschel Mathijs A Sanders Ruud Delwel Marc B Bierings Arjan Buijs

Haematologica 2018 04 8;103(4):e173-e176. Epub 2018 Feb 8.

Department of Genetics, University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht University, Rotterdam, the Netherlands

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http://dx.doi.org/10.3324/haematol.2017.185033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865425PMC
April 2018

Worldwide study of hematopoietic allogeneic stem cell transplantation in pyruvate kinase deficiency.

Authors:
Stephanie van Straaten Marc Bierings Paola Bianchi Kensuke Akiyoshi Hitoshi Kanno Isabel Badell Serra Jing Chen Xiaohang Huang Eduard van Beers Supachai Ekwattanakit Tayfun Güngör Wijnanda Adriana Kors Frans Smiers Reinier Raymakers Lucrecia Yanez Julian Sevilla Wouter van Solinge Jose Carlos Segovia Richard van Wijk

Haematologica 2018 02 14;103(2):e82-e86. Epub 2017 Dec 14.

Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht University, the Netherlands

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http://dx.doi.org/10.3324/haematol.2017.177857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5792292PMC
February 2018

Pediatric Diamond-Blackfan anemia in the Netherlands: An overview of clinical characteristics and underlying molecular defects.

Authors:
Birgit van Dooijeweert C Heleen van Ommen Frans J Smiers Rienk Y J Tamminga Maroeska W Te Loo Albertine E Donker Marjolein Peters Bernd Granzen Hans J J P Gille Marc B Bierings Alyson W MacInnes Marije Bartels

Eur J Haematol 2018 Feb 1;100(2):163-170. Epub 2017 Dec 1.

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

Introduction: Diamond-Blackfan anemia (DBA) is characterized by hypoplastic anemia, congenital anomalies, and a predisposition for malignancies. Most of our understanding of this disorder stems from molecular studies combined with extensive data input from international patient registries.

Objectives: To create an overview of the pediatric DBA population in the Netherlands.

Methods: Forty-three patients diagnosed with DBA from all Dutch university pediatric hospitals were included in this study, and their clinical and genetic characteristics were collected from patient records.

Results: Congenital malformations were present in 24 of 43 patients (55.8%). An underlying genetic defect was identified in 26 of 43 patients (60.5%), the majority of which were found in the RPS19 gene (12 of 43, 27.9%) with 1 patient carrying a mutation in a novel DBA candidate gene, RPL9. In 31 of 35 (88.6%) patients, an initial response to glucocorticoid treatment was observed. Six patients (14.0%) underwent hematopoietic stem cell transplantation, and eleven patients (11 of 43, 25.6%) became treatment-independent spontaneously.

Conclusion: In agreement with previous reports, the Dutch pediatric DBA population is both clinically and genetically heterogeneous. National and international registries, together with more extensive genetic testing, are crucial to increase our understanding of genotype and phenotype correlations of this intriguing disorder.
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http://dx.doi.org/10.1111/ejh.12995DOI Listing
February 2018

Transplant results in adults with Fanconi anaemia.

Authors:
Marc Bierings Carmem Bonfim Regis Peffault De Latour Mahmoud Aljurf Parinda A Mehta Cora Knol Farid Boulad Abdelghani Tbakhi Albert Esquirol Grant McQuaker Gulsan A Sucak Tarek B Othman Constantijn J M Halkes Ben Carpenter Dietger Niederwieser Marco Zecca Nicolaus Kröger Mauricette Michallet Antonio M Risitano Gerhard Ehninger Raphael Porcher Carlo Dufour

Br J Haematol 2018 01 2;180(1):100-109. Epub 2017 Nov 2.

Istituto Giannina Gaslini, Genova, Italy.

The outcomes of adult patients transplanted for Fanconi anaemia (FA) have not been well described. We retrospectively analysed 199 adult patients with FA transplanted between 1991 and 2014. Patients were a median of 16 years of age when diagnosed with FA, and underwent transplantation at a median age of 23 years. Time between diagnosis and transplant was shortest (median 2 years) in those patients who had a human leucocyte antigen identical sibling donor. Fifty four percent of patients had bone marrow (BM) failure at transplantation and 46% had clonal disease (34% myelodysplasia, 12% acute leukaemia). BM was the main stem cell source, the conditioning regimen included cyclophosphamide in 96% of cases and fludarabine in 64%. Engraftment occurred in 82% (95% confidence interval [CI] 76-87%), acute graft-versus-host disease (GvHD) grade II-IV in 22% (95% CI 16-28%) and the incidence of chronic GvHD at 96 months was 26% (95% CI 20-33). Non-relapse mortality at 96 months was 56% with an overall survival of 34%, which improved with more recent transplants. Median follow-up was 58 months. Patients transplanted after 2000 had improved survival (84% at 36 months), using BM from an identical sibling and fludarabine in the conditioning regimen. Factors associated with improved outcome in multivariate analysis were use of fludarabine and an identical sibling or matched non-sibling donor. Main causes of death were infection (37%), GvHD (24%) and organ failure (12%). The presence of clonal disease at transplant did not significant impact on survival. Secondary malignancies were reported in 15 of 131 evaluable patients.
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http://dx.doi.org/10.1111/bjh.15006DOI Listing
January 2018

Infection with a respiratory virus before hematopoietic cell transplantation is associated with alloimmune-mediated lung syndromes.

Authors:
Birgitta Versluys Marc Bierings Jean Luc Murk Tom Wolfs Caroline Lindemans Kors Vd Ent Jaap Jan Boelens

J Allergy Clin Immunol 2018 02 15;141(2):697-703.e8. Epub 2017 Jul 15.

Blood and Marrow Transplantation Program, Department of Pediatrics, University Medical Center Utrecht, Utrecht, The Netherlands; U-DANCE Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: Alloimmune-mediated lung syndromes (allo-LSs) are life-threatening complications after hematopoietic cell transplantation (HCT). Respiratory virus (RV) has been suggested to play a role in the pathogenesis.

Objective: We studied the relation between RV DNA/RNA detection in the upper/lower airways before HCT and the occurrence of allo-LSs.

Methods: We retrospectively analyzed all HCT recipients between 2004 and 2014, in whom real-time PCR for RV was performed in nasopharyngeal aspirates (NPAs) and bronchoalveolar lavage (BAL) fluid before HCT. The main outcome of interest was the presence of an allo-LS, which was defined as idiopathic pneumonia syndrome or bronchiolitis obliterans syndrome. Other outcomes were overall survival and treatment-related mortality. We used Cox proportional hazard models, logistic regression models, and Fine-Gray competing risk regression for analyses.

Results: One hundred seventy-nine children (median age, 6.8 years) were included. RVs were found in 61% (41% in BAL fluid/NPAs and 20% in NPAs only). Rhinovirus was the most frequently detected RV (42%). Allo-LSs occurred in 13%. RV positivity in BAL fluid was a predictor for allo-LSs (hazard ratio, 3.8; 95% CI, 1.4-10.7; P = .01), whereas RV positivity in NPAs only was not. No other predictors were found. Grade II to IV acute graft-versus-host disease related to steroid treatment shows a trend toward a protective effect (odds ratio, 0.16; 95% CI, 0.0-1.3; P = .08). Allo-LSs significantly increased treatment-related mortality (52% ± 10% in allo-LSs and 20% ± 4% in non-allo-LSs, P = .007).

Conclusions: These results show that pre-HCT BAL fluid RV positivity was a predictor for allo-LSs. Screening for RVs before HCT might identify patients at risk for allo-LSs. This could have implications for prevention and treatment and might subsequently influence the outcomes of HCT.
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http://dx.doi.org/10.1016/j.jaci.2017.03.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125836PMC
February 2018