Cancer in children is rare and almost all research activities involve international partners.
Leukemia is the most frequent type of cancer in children. The most common type is acute lymphoblastic leukemia (ALL); the more rare types include myeloid leukemias including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
The research of the Professor primarily involves the myeloid leukemias.
The Professor is principal investigator of the NOPHO-AML 2004-study which was open to inclusion from 2004 to 2013.
Key scientific issues highlighted in NOPHO-AML 2004:
• Early response to treatment as a predictor of relapse.
• Cytogenetic and molecular biological changes as a predictor of relapse.
• Family donor and unrelated donor transplantation in high-risk AML.
• Minimal residual disease (MRD) monitoring as a predictor of relapse.
• Post consolidation randomization to treatment with gemtuzumab vs. no further treatment.
Several of the above issues have been analyzed and the results have been presented at international meetings and published in peer-reviewed journals.
In 2013, the NOPHO-DBH-AML-protocol started in nine countries with a population of approximately 60 million. The professor's tasks are similar to what is described in the NOPHO-AML-2004-protocol above.
Further research on molecular and biological characteristics will aim at individualised treatment of AML including targeted therapy.
Treatment toxicity and mortality in NOPHO-AML-protocols:
AML survival has increased considerably over the last 20 years:progress is primarily explained by intensifying treatment. Intensive treatment may cause significant side effects and even death. In the period 1984-2003 about 60 treatment-related deaths were recorded in the Nordic countries.
There are few studies reporting on these deaths, and a closer analysis can help us to prevent similar deaths. We have conducted an analysis of joint Nordic data and published several papers on toxicity. An ongoing study will correlate SNP-profile with toxicity.
Early detection of relapse in AML:
In collaboration with many international centers, with Aarhus University Hospital as reference center, molecular genetic studies of blood samples after AML treatment are carried out. Studies will document the kinetics of relapse, how early relapse can be detected and whether treatment of early relapse can improve survival.
Late sequelae of treatment of AML in childhood:
The Nordic countries have been at the forefront the last 20 years in treatment of AML in children. Hardly any studies exist on the long term effects on intensively treated patients (who have not received bone marrow transplants). A study of 140 patients alive more than three years after completion of treatment, invited the former patients to take part in a structured survey. Articles from this study have been published and will be followed by a study of late effects in children with AML who have received bone marrow transplantation.
Late sequelae of childhood cancer in general:
Together with colleagues from the Danish Cancer Registry, we have secured a large data set on children with cancer in the Nordic countries over the last 60 years with long-term survivors followed in disease registers for the last 30 years. The study is called “Adult Life after Childhood Cancer in Scandinavia” (ALiCCS) www.aliccs.org. Several studies are ongoing and chaired from Aarhus University Hospital studying organ-specific, especially renal, hepatic and gastrointestinal, late-effects. Disease-specific studies on ALL, leukemia in Down syndrome, retinoblastoma, and Wilms tumor are also in progress.
Myeloid Leukemia of Down syndrome 2006:
Myeloid leukemia (ML) in children with Down syndrome (DS) has many particular characteristics, and is regarded as a specific form of leukemia (ML-DS). Nordic data has shown that patients with DS can be managed with less intensive treatment. The professor is principal investigator of a European treatment protocol, ML-DS 2006, aiming at a survival rate of at least 85%. Monitoring of minimal residual disease with WT1 expression is centralised at Aarhus University Hospital.
Myelodysplastic Syndrome (MDS):
In 1993, the professor co-founded The European Working Group on myelodysplastic Syndromes in Childhood (EWOG-MDS). He has since the founding of EWOG-MDS been coordinator for the Nordic countries. The group has published numerous articles on MDS and JMML. The professor has been the primary investigator and participated in numerous retrospective and prospective studies.
The studies are carried out in collaboration with the EWOG-MDS-center in Freiburg.
Numerous articles on myeloid leukemias in children have been published in leading international journals. The professor has in the 5-year period from 2010 to the end of 2014 published 71 articles, including 16 in Blood, 3 in Journal of Clinical Oncology, 4 in Leukemia, 5 in British Journal of Haematology, and 1 in Nature Genetics.
The professor has written several review articles and textbook articles, including the large chapter on AML and MDS in the world's leading textbook on paediatric oncology: Pizzo & Poplack, Principles and Practice of Pediatric Oncology.
Ten articles on myeloid leukemia with a focus on genetics and outcome are listed below as examples; all published in recent years:
• A critical review of which children with AML need stem cell procedure. (Hasle H. British Journal of Haematology 2014; 166: 23-33).
• Hospital contacts for endocrine disorders in Adult Life after Childhood Cancer in Scandinavia (ALiCCS) – a population-based cohort study. (de Fine Licht S, Winther JF, Gudmundsdottir T, Holmqvist AS, Bonnesen TG, Asdahl PH, Tryggvadottir L, Anderson H, Wesenberg F, Malila N, Holm K, Hasle H, Olsen JH. Lancet 2014; 383: 1981-9).
• t(6;9)(p22;q34)/DEK-NUP214 rearranged pediatric myeloid leukemia: an international study on 62 patients. (Sandahl JD, Coenen EA, Forestier E, Harbott J, Johansson B, Kerndrup G, Adachi S, Auvrignon A, Beverloo HB, Cayuela JM, Chilton L, Fornerod M, de Haas V, Harrison CJ, Inaba H, Kaspers GJ, Liang DC, Locatelli F, Masetti R, Perot C, Raimondi S, Reinhardt K, Tomizawa D, von Neuhoff N, Zecca M, Zwaan CM, van den Heuvel-Eibrink MM, Hasle H. Haematologica 2014; 99: 865-72).
• 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 (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. Blood 2012; 120: 3187-3205).
• Gemtuzumab ozogamicin as postconsolidation therapy does not prevent relapse in children with AML: results from NOPHO-AML 2004 (Hasle H, Abrahamsson J, Forestier E, Ha SY, Heldrup J, Jahnukainen K, Jónsson OG, Lausen B, Palle J, Zeller B. Blood 2012; 120: 978-984).
• Presence of FLT3-ITD and high BAALC expression are independent prognostic markers in childhood acute myeloid leukemia (Staffas A, Kanduri M, Hovland R, Rosenquist R, Ommen HB, Abrahamsson J, Forestier E, Jahnukainen K, Jónsson OG, Zeller B, Palle J, Lönnerholm G, Hasle H, Palmqvist L, Ehrencrona H. Blood 2011; 118: 5905-5913).
• Quality of health in survivors of childhood acute myeloid leukemia treated with chemotherapy only: A NOPHO-AML study (Mølgaard-Hansen L, Glosli H, Jahnukainen K, Jarfelt M, Jónmundsson GK, Malmros-Svennilson J, Nysom K, Hasle H. Pediatric Blood & Cancer 2011; 57: 1222–1229).
• Response-guided induction therapy in pediatric acute myeloid leukemia with excellent remission rate (Abrahamsson J, Forestier E, Heldrup J, Jahnukainen K, Jónsson OG, Lausen B, Palle J, Zeller B, Hasle H. Journal of Clinical Oncology 2011; 29: 310-315).
• Advances in the prognostication and management of advanced MDS in children (Hasle H, Niemeyer CM. British Journal of Haematology 2011; 154: 185-195).
• Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia (Niemeyer CM, Kang MW, Shin DH, Furlan I, Erlacher M, Bunin NJ, Bunda S, Finklestein JZ, Sakamoto KM, Gorr TA, Mehta P, Schmid I, Kropshofer G, Corbacioglu S, Lang PJ, Klein C, Schlegel PG, Heinzmann A, Schneider M, Stary J, van den Heuvel-Eibrink MM, Hasle H, Locatelli F, Sakai D, Archambeault S, Chen L, Russell RC, Sybingco SS, Ohh M, Braun BS, Flotho C, Loh ML. Nature Genetics 2010; 42: 794-800).
Research is conducted at the clinical facilities for paediatric hematology and oncology at Aarhus University Hospital (AUH), but engages partners in the Nordic countries (NOPHO), in the rest of Europe, and to a lesser extent North America and Japan.
Data are used from already existing databases such as NOPHO or Danish databases.
Research focuses on the clinical characteristics, chromosomal aberrations and mutations, treatment response and acute and chronic complications of leukemia therapy.
Many of the genetic studies are carried out in the cancer-chromosome laboratory at AUH, and when necessary, at relevant laboratories abroad.
Treatment responses assessed with PCR-markers are performed at the hematodiagnostic laboratory at AUH. Treatment response assessed by flow cytometry is carried out in cooperation with Rigshospitalet in Copenhagen.
Important international partners
There is collaboration with clinicians from all university hospitals in the Nordic countries. There is a particularly close collaboration with colleagues at Rikshospitalet Oslo, Queen Silvia Children's Hospital in Gothenburg, Astrid Lindgren Children's Hospital in Stockholm and the University Hospital in Helsinki.
There is collaboration with several European colleagues, primarily from the university hospital in Hannover, Essen, Freiburg, Amsterdam and Rotterdam.
There is also ad hoc collaboration with a number of researchers primarily in North America and Japan and to a lesser extent from other countries in Asia and South America.