Academic Center for Pediatric Hematological Malignancies

Our primary objective is to provide excellent care for children with hematological malignancies with introduction of more effective and less toxic treatment strategies.
This is supported by our research program which consists of fundamental, clinical and translation research with a focus on targeted therapy and precision medicine, as a main collaborative partner in several international consortia.
Educational activities concern the biology of pediatric hematological malignancies and drug development.

Academic Center of Excellence

Research Activities

The main activities concern:

a) clinical research, i.e. drug development studies (phase 1-2 studies) and therapeutic drug monitoring in pediatric hematological malignancies, as well as phase 3 studies. Especially within the field of drug development studies in Pediatric Oncology this ACE has a lead position in Europe, and is sponsor of several international clinical studies in the development of novel drugs. The other partners in this ACE provide central laboratory diagnostic services for these studies (immunology, genetics, pathology), as well as pharmacodynamic studies at the laboratory of Pediatric Oncology.

b) fundamental research performed at the various involved laboratories, with a focus on elucidating the genetic background of pediatric hematological malignancies to develop targeted/individualized treatment/precision medicine; minimal residual disease quantification; and the role of the microenvironment in these malignancies.

c) translational research mainly focusing on biomarkers and response parameters for clinical trials in pediatric hematological malignancies. These projects are multidisciplinary as they involve several laboratories and subspecialty fields, such as immunology, genetics, pediatric oncology, radiology, the pharmacy and pathology, comprising both biologists, MDs and bioinformaticians.

International collaboration is organized through the I-BFM (the European Leukemia/Lymphoma Expert group)and ITCC (European pediatric drug development consortium), and consists of collaboration with top institutes in Europe such as The Royal Marsden Hospital (London), Institut Gustave Roussy (Paris), Essen (the AML-BFM Study Group), the COALL group (Hamburg), and St Jude Children's Research Hospital in Memphis. In addition collaboration exists with North-American based collaborative groups such the Children's Oncology Group (COG) and the TACL group (Therapeutic Advances in Childhood Leukemia).

Type of

Collaborations

International collaboration is organized through the I-BFM (the European Leukemia/Lymphoma Expert group)and ITCC (European pediatric drug development consortium), and consists of collaboration with top institutes in Europe such as The Royal Marsden Hospital (London), Institut Gustave Roussy (Paris), Essen (the AML-BFM Study Group), the COALL group (Hamburg), and St Jude Children’s Research Hospital in Memphis. In addition collaboration exists with North-American based collaborative groups such the Children's Oncology Group (COG) and the TACL group (Therapeutic Advances in Childhood Leukemia).

Educational

Contributions

Education is provided during the Bachelor phase in the Minor Pediatric Oncology/Hematology program, which is organized by members involved in this ACE. In addition, several staff members lecture in various Bachelor courses during the 1st and 2nd year. This ACE also contributed to the trainig of several research masters students (approximately 2-4 per year).

A Master of Science course 'Biology of Disease' (Prof dr ML den Boer) is organized and focuses on pediatric hematological malignancies. In addition prof ML den Boer is a co-organizer of the Molecular Medicine Graduate School course 'Basic and Translational Oncolcoy. Post-graduate training is organized by Prof dr CM Zwaan in the yearly New Agents in Leukemia Expert Symposium and prof den Boer is co-organizer and in the Board of the ITCC training/educational course, both held in the Netherlands. Dr Beishuizen hosts the International Lymphoma Expert Meeting in 2018. Dr Loeffen hosts the I-BFM Genetic Susceptibility to Lymphoma meeting in Rotterdam in 2016.

Currently 3 fellows in Pediatric Oncology are trained at Erasmus MC. One fellow from another University regularly visits our grand round to improve her knowledge in pediatric hematological malignancies. Several staff members of the Department of Pediatric Oncology have had SET-Q feedback from residents given their role in supervision of 'co-assistenten' and AIO's being trained at the Department of Pediatric Oncology.

In the past few years we had several AIOs for 'profilerings or verdiepinsstages' at the Department of Pediatric Oncology, including from other universities. In total approximately 10 PhD students are currently trained within this ACE at the Department of Pediatric Oncology and Immunology. This consists both of clinical PhDs working on therapeutic drug monitoring and pharmacology, as well as pre-clinical PhDs working at the Laboratories of Prof. Dr M.L. den Boer and Dr. Van der Velden. Moreover we do attract international students who request to work at the Laboratory of Pediatric Oncology. Currently we have post-docs from Portugal and India, and students came from Turkey and Iran.

Patient

Care Activities

Care for Pediatric Hematological Malignancies is labeled as academic care according to the Robijn model (2014:93%). We have been granted a designation as Expertise Centre for Rare Diseases by the Ministry of Health for Pediatric Hematological Malignancies, and have applied for participation in a Pediatric Oncology European Reference Network (ERN).

The extent of care is defined by national or international treatment protocols and by default is multidisciplinary as it involves manydifferent diagnostic services (morphology, pathology, immunophenotyping, genetics, chemistry, radiology and nuclear medicine) and collaboration with almost all pediatric subspecialties which are needed to treat complications, as well as collaboration with pediatric surgery and radiotherapy amongst others. Psychosocial support is delivered by psychologists, social workers and educational/pedagogical staff. Participation in the Erasmus MC Value Based Health Care program is due to start this summer (2016), and will provide outcome measures, although many outcome measures are already available through the nation-wide cancer registration at the Dutch Childhood Oncology Group.

Apart from this we are planning feedback meetings with parents/patients and we have organized feedback meetings with our nursing and medical staff. We have been audited on several studies in pediatric hematological malignancies both by companies and by registrational authorities without critical findings when it comes to implementation and sponsorship of clinical trials. The participating laboratories (immunology, pathology and clinical genetics) are all accredited according to ISO 15189;2012, for which yearly audits take place. Research results have had substantial impact on care, e.g the use of cytarabine in infant protocols, improved risk-group stratification in ALL and AML using genetic aberrations and minimal residual disease testing, new drugs which have been studied and later introduced in the treatment of pediatric hematological malignancies.

Various new drugs (tyrosine kinase inhibitors and MEK-inhibitors) have been or are currently undergoing testing which will be implemented in future pediatric oncology protocols.

Societal Relevance to Research, Education and Patient Care

The ACE has contributed substantially to the development of Standard Of Care guidelines as all pediatric oncologists are active in various disease and protocol committees of the DCOG (Dutch Childhood Oncology Group) or at the international level in European Expert networks such as ITCC, I-BFM, SIOP, etc.

Other contributions are in the field of palliative and supportive care guidelines for the DCOG. The development of the minor in Pediatric Oncology/Hematology is a relevant contribution to the curriculum. Other post-graduate teaching activities concern the ITCC training course and ITCC New Agents in Leukemia symposium, as well as the Lymphoma Expert Group Meeting in 2018. Societal valorization comes from the implementation of risk group stratification for pediatric leukemias which has changed considerably based on technology and studies from Erasmus MC, such as minimal residual disease testing and the identification of novel genetic subgroups such as the Phildelphia-like subgroup in pediatric ALL or the NUP-rearrangements in pediatric AML. Nationwide therapeutic drug monitoring for asparaginase is being implemented by Erasmus MC investigators in this ACE in both pediatric and adult leukemia protocols, which improves prognosis and reduces costs significantly.

When it comes to drug development Erasmus has developed itself as a major partner in early phase clinical trials in pediatric leukemias, and is one of the 5 European institutions in the ITCC Sponsorship Consortium, and collaborates with many partners including parent associations, pharmaceutical industry and regulators. The laboratories involved in this ACE frequently function as central reference laboratories in international new agent studies.

Together with the parent association (VOKK, Vereniging Ouders Kinderen en Kanker) we have pushed for a change in Dutch law regarding medical research in minors, which is awaiting approval by the Senate, and which will improve the access of children with cancer to novel therapies in the Netherlands.

Viability of Research, Education and Patient Care

At the level of patient care there is a regular 'immunology/pathology and genetics' meeting where all new patients with hematological malignancies (leukemias and lymphomas, also including MDS) are discussed together with the medical staff. There is intensive collaboration within the ACE regarding knowledge sharing for instance by implementation of collaborative research projects.

Moreover the laboratories involved in this ACE frequently function as central Laboratories in international (European) drug development studies focusing on hematological malignancies, both in investigator-initiated (bosutinib, inotuzumab) as well as in company-sponsored research (PKC412, dasatinib). PhD students present their work at international meetings such as the I-BFM meeting, and congresses such as EHA, SIOP and ASH.

Several PhD students have performed part of their thesis project in Laboratories in North-America, for instance to learn new techniques which can later be implemented at our laboratory. Several PhD students educated at our laboratory have started international careers, for instance P. van Vlierberghe who is now working group leader on leukemias in Ghent, and Ronald Stam who is a working group leader on infant leukemias (now at Erasmus MC, soon in Princess Máxima Center), Leila Mohammadi Kankahari, computational biology/biostatistics modeling (Teheran, Iran), Ingrid Aries, post-doc in laboratory of Alexjandro Guttierrez, Boston).

Most MDs have continued their career and are in training as radiotherapists, pediatricians, neurologists, clinical geneticists, etc. Regarding research output the dept of Pediatric Oncology published in: - 2012: in total 69 papers, no further analysis on impact was done. - 2013: in total 75 papers, with 58% in Q1 and 36% in the top-10 journals for our field. - 2014: in total 73 papers with 51% in Q1 and 34% in the top-10 journals for our field. The Dept of Immunology (VHJ van der Velden) published 48 papers in the last 5 years (2011-2016) of which 54% was in the top 10 and 67% in the top 25. The Dept of Clinical Genetics (dr B Beverloo) published 38 papers (2011-2016).

Key and relevant publications of the last five years

  • Zwaan CM, Kolb EA, Reinhardt D, Abrahamsson J, Adachi S, Aplenc R, De Bont ES, De Moerloose B, Dworzak M, Gibson BE, Hasle H, Leverger G, Locatelli F, Ragu C, Ribeiro RC, Rizzari C, Rubnitz JE, Smith OP, Sung L, Tomizawa D, van den Heuvel-Eibrink MM, Creutzig U, Kaspers GJ. Collaborative Efforts Driving Progress in Pediatric Acute Myeloid Leukemia. J Clin Oncol. 2015 Sep 20;33(27):2949-62.
  • Kang HJ, Loftus S, Taylor A, DiCristina C, Green S, Zwaan CM. Aprepitant for the prevention of chemotherapy-induced nausea and vomiting in children: a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):385-94.
  • Zwaan CM, Rizzari C, Mechinaud F, Lancaster DL, Lehrnbecher T, van der Velden VH, Beverloo BB, den Boer ML, Pieters R, Reinhardt D, Dworzak M, Rosenberg J, Manos G, Agrawal S, Strauss L, Baruchel A, Kearns PR. Dasatinib in Children and Adolescents With Relapsed or Refractory Leukemia: Results of the CA180-018 Phase I Dose-Escalation Study of the Innovative Therapies for Children With Cancer Consortium. J Clin Oncol. 2013 Jul 1;31(19):2460-8.[IF 18.0]
  • Creutzig U, van den Heuvel-Eibrink MM, Gibson B, Dworzak MN, Adachi S, de Bont E, Harbott J, Hasle H, Johnston D, Kinoshita A, Lehrnbecher T, Leverger G, Mejstrikova E, Meshinchi S, Pession A, Raimondi SC, Sung L, Stary J, Zwaan CM, Kaspers GJ, Reinhardt D. Diagnosis and management of acute myeloid leukemia in children and adolescents: recommendations from an international expert panel, on behalf of the AML Committee of the International BFM Study Group. Blood 2012;120(16):3187-3205. [IF 9.9]
  • Klein K, Kaspers G, Harrison CJ, Beverloo HB, Reedijk A, Bongers M, Cloos J, Pession A, Reinhardt D, Zimmerman M, Creutzig U, Dworzak M, Alonzo T, Johnston D, Hirsch B, Zapotocky M, De Moerloose B, Fynn A, Lee V, Taga T, Tawa A, Auvrignon A, Zeller B, Forestier E, Salgado C, Balwierz W, Popa A, Rubnitz J, Raimondi S, Gibson B. Clinical Impact of Additional Cytogenetic Aberrations, cKIT and RAS Mutations, and Treatment Elements in Pediatric t(8;21)-AML: Results From an International Retrospective Study by the International Berlin-Frankfurt-Münster Study Group. J Clin Oncol. 2015 Dec 20;33(36):4247-58. doi: 10.1200/JCO.2015.61.1947. Epub 2015 Nov 16.
  • Inaba H, Zhou Y, Abla O, Adachi S, Auvrignon A, Beverloo HB, de Bont E, Chang TT, Creutzig U, Dworzak M, Elitzur S, Fynn A, Forestier E, Hasle H, Liang DC, Lee V, Locatelli F, Masetti R, De Moerloose B, Reinhardt D, Rodriguez L, Van Roy N, Shen S, Taga T, Tomizawa D, Yeoh AE, Zimmermann M, Raimondi SC. Heterogeneous cytogenetic subgroups and outcomes in childhood acute megakaryoblastic leukemia: a retrospective international study. Blood. 2015 Sep 24;126(13):1575-84. doi: 10.1182/blood-2015-02-629204. Epub 2015 Jul 27.
  • Pieters R, de Groot-Kruseman H, Van der Velden V, Fiocco M, van den Berg H, de Bont E, Egeler RM, Hoogerbrugge P, Kaspers G, Van der Schoot E, De Haas V, Van Dongen J. Successful Therapy Reduction and Intensification for Childhood Acute Lymphoblastic Leukemia Based on Minimal Residual Disease Monitoring: Study ALL10 From the Dutch Childhood Oncology Group. J Clin Oncol. 2016 Jun 6. pii: JCO646364. [Epub ahead of print]
  • Polak R*, de Rooij B*, Pieters R, Den Boer ML. B-cell precursor acute lymphoblastic leukemia cells use tunneling nanotubes to orchestrate their microenvironment. Blood, 126, 2404-2414 (2015).
  • Van der Veer A, Waanders E, Pieters R, Willemse ME, Van Reijmersdal SV, Russell LJ, Harrison CJ, Evans WE, Van der Velden VHJ, Hoogerbrugge PM, Van Leeuwen F, Escherich G, Horstmann MA, Mohammadi Khankahdani L, Rizopoulos D, De Groot-Kruseman HA, Sonneveld E, Kuiper RP, Den Boer ML. (shared last authorship) Independent prognostic value of BCR-ABL1-like signature and IKZF1 deletion, but not high CRLF2 expression, in children with B-cell precursor ALL. Blood 122: 2622-2629 (2013).
  • Hartsink-Segers SA, Zwaan CM, Exalto C, Luijendijk MWJ, Calvert VS, Petricoin EF, Evans WE, Reinhardt D, De Haas V, Hedtjärn M, Hansen BR, Koch T, Caron HN, Pieters R, Den Boer ML. Aurora kinases in childhood acute leukemia: the promise of Aurora B as therapeutic target. Leukemia, 27, 560-568 (2013).

PhD theses of the last five years

  • Jasmijn de Rooij. Molecular genetic aberrations and their prognostic relevance in pediatric acute myeloid leukemia. (June 14, 2016)
  • Trudy Buitenkamp. Thesis: “Clinical Relevance of Genetic Alterations in Acute Lymphoblastic Leukemia in Children with Down syndrome”, Erasmus MC, Rotterdam (July 2nd, 2014)
  • Marjolein Blink. Thesis: “Clinical Relevance of Genetic Alterations in Acute Myeloid Leukemia in Children with Down syndrome”, Erasmus MC, Rotterdam (Nov 6th, 2013)
  • Iris Hollink, thesis “Molecular genetic insights in cytogenetically normal pediatric Acute Myeloid Leukemia”, Erasmus MC, Rotterdam.(Nov 16, 2011)
  • Eva Coenen. Thesis: “Genetic heterogeneity of MLL gene rearrangements in pediatric AML: identification of new markers with biological and clinical relevance”, Erasmus MC, Rotterdam (June 26, 2013)
  • Arian Van der Veer. Characterization of a newly discovered poor-prognostic genetic subtype of acute lymphoblastic leukemia: BCRABL1-like ALL (May 28th 2014).
  • Ingrid Aries. Mechanisms of drug resistance in pediatric acute leukemia (March 12th 2014).
  • Farhad A. Moqadam. MicroRNA-targeted genes in pediatric acute leukemia (Jan 8th 2014).
  • D. Schotte. MicroRNAs in pediatric acute lymphoblastic leukemia: small players with huge potential (Sept 28th 2011).
  • Jenny Katsman-Kuipers. Altered gene and MiRNA regulation in pediatric acute myeloid leukemia. Erasmus MC, Rotterdam. (June 17, 2015)

Non-scientific publications related to the ACE

Principal coordinator(s)

Collaborating investigator(s)

Last updated: 365 days ago.