Leukaemia, Coagulation, Clinical Trials and Registry Studies

The group consists of several parts with research and other activities:
1. The central office and management of the ALLTogether1 Clinical Trial for treatment of children and young adults in 14 countries in Western Europe.
2.  Clinical research performed by Physicians in the Childhood Cancer Unit and the Paediatric Coagulation Unit at the Karolinska University Hospital.
3. Regulatory support for clinical trials in paediatric oncology in Sweden and within the Nordic Society for Pediatric Hematology and Oncology (NOPHO).
4. Registry-based research (using quality-registries and public health data).
5. Activities in collaboration with the Regional Cancer Center (RCC).

Research/Activity areas with involved staff.

1. ALLTogether1 (Mats Heyman, Johan Malmros, Karin Flood, Jenny Juhlin, Adrian Levitsky)

ALL in young people has excellent treatment outcome with survival about 92% in children and 75% in young adults. Nevertheless, patients still die of disease and, importantly, a relatively large group are over-treated. All patients risk treatment-related death and some suffer long-term side-effects. To show improvement with such good survival, large patient-populations are needed.
Treating physicians from the Nordic countries (NOPHO), the UK (UKALL), the Netherlands (DCOG), Germany (COALL), Belgium (BSPHO), Ireland (SHOP) and France (SFCE) have designed the new treatment-protocol for children and young adults with ALL. The protocol will address over-treatment by two randomizations to treatment-reduction. Two randomizations will test either Inotuzumab or optimized maintenance to reduce relapse-risk. High-risk patients may be offered CAR-T therapy as an alternative to allogeneic stem-cell transplant and patients with ABL-class fusions will receive Tyrosine-kinase inhibitors. In addition to improved clinical outcome, the new protocol will serve as an important platform for further treatment- and translational research.
This study is sponsored by the Karolinska University Hospital and the group contains both the Chief Investigator (Mats Heyman) as well as the Central Office (Karin Flood, Global Trial Manager, Jenny Juhlin, Regulatory Expert, Adrian Levitsky, Chief Data Manager) coordinating the study. 


2. Clinical Research Performed by Physicians in the Childhood Cancer Unit

Intensive care in children with hematologic malignancies in Sweden (Susanna Ranta, Arja Harila-Saari, Mats Heyman)

Children with hematologic malignancies are at risk of disease and treatment-related complications; up to every fifth child has been cared for at intensive care (ICU) due to complications. Children with malignancies in intensive care have higher mortality rate compared to other children. We have retrieves and combines data on children with hematologic malignancies from three different registries; two quality registries (the Swedish Intensive Care Register (SIR) and the Swedish Childhood Cancer Register) and data emerging from a previous study on children at pediatric ICU. We plan to analyze l risk factors by comparing registry data from SBCR on children with and without ICU care. Predictive scores are compared with outcome and other clinical risk factors. The study can support decision-making and help inform the families of prognosis.

Acute neurotoxicity in children with acute lymphoblastic leukaemia (Stavroula Anastosopoulou Susanna Ranta, Arja Harila-Saari, Mats Heyman)

Neurotoxicity, such as posterior reversible encephalopathy syndrome (PRES), cerebral sinus venous thrombosis, seizures and methotrexate related stroke-like syndrome, remains a significant problem in childhood acute lymphoblastic leukemia (ALL) and can affect long-term neurologic outcome. We will explore the frequency, clinical and genetic risk factors and clinical picture of acute severe neurotoxicities. Neurocognitive outcome of the survivors after severe acute neurotoxicity will be studied using Cogstate’s computerized tests.

Impact of Body Mass Index (BMI) on outcome and toxicity in acute lymphoblastic leukemia (Christina Egnell-Gustavsson Susanna Ranta, Arja Harila-Saari, Mats Heyman)

Obesity increases cancer risk and cancer-related toxicity and reduces survival in adults. In children, the significance of malnutrition or obesity is not clear. Our study on BMI in children with acute lymphocytic leukemia (ALL) is based on data on Nordic ALL registries and compared BMI with relapse rate, overall survival and treatment related toxicities. Data from High-dose methotrexate (HDM) database is used to evaluate the relationship between BMI and Methotrexate secretion and kidney function. Data on  methotrexate and mercaptopurine metabolites will be assessed to study whether BMIs are relevant to their levels. The ultimate goal is to better individualize treatment and thus improve the outcome and reduce side effects in high risk groups.

Quality of life, toxicity and the informed consent process for children with acute lymphoblastic leukaemia and their families (Nina Mogensen, Arja Harila-Saari, Mats Heyman)

The project aims to examine health-related quality of life (HRQOL) in children/adolescents and their parents after the end of treatment of ALL, to collect additional data on side effects during treatment and to evaluate parents’ perception on the informed consent-processes within the NOPHO ALL 2008-protocol. This is being done by collecting data in Sweden, Finland and Denmark from questionnaires sent to families after end of NOPHO ALL 2008- treatment. Data on HRQOL, psychosocial factors, side effects and parents’ views on the Informed consent-process are obtained through PedsQL (self-and parent report), SF-36 (parents’ own HRQOL) and one study-specific/tailor-made questionnaire (developed in collaboration with families).

International collaboration for treatment of relapse of ALL – IntReALL (Petter Svenberg).

The NOPHO-group for treatment of relapse of ALL is headed by Petter Svenberg, who is also the Swedish representative in the International BFM-group Resistant Disease Committee (I-BFM RD). Petter coordinates the NOPHO response to initiatives from I-BFM RD and is the national Principal Investigator for upcoming IntReALL trials.


3. Regulatory support for clinical trials in childhood cancer in Sweden and the NOPHO-countries (Jenny Juhlin).

Clinical trials in childhood cancer often involve many countries because of the rarity of the disease entities. Since Sweden and the NOPHO-countries (the Nordic countries, Lithuania and Estonia) are small, the regulatory burden of taking part in multi-national studies is disproportionally large. For this reason, Jenny Juhlin, who is a regulatory expert, acts as a consultant, helping national Principal Investigators with necessary applications to competent authorities, ethical review boards and biobank authorities as necessary. The aim of this is to make sure that Nordic/Baltic children with cancer can take part in the clinical trials that are available.


4. Registry-based studies of childhood acute lymphoblastic leukaemia (Trausti Oskarsson, Arja Harila-Saari, Mats Heyman)

Studies of treatument outcome after relapse of ALL in childhood and registry-based evaluation of bone-health after childhood cancer (Trausti Oskarsson, Arja Harila-Saari and Mats Heyman)

The unique population and quality registries in the Nordic countries enable population-based studies on rare diseases and rare health outcomes.  By using data from the Nordic Society of Paediatric Haematology and Oncology (NOPHO) Acute Lymphoblastic Leukemia (ALL) registry we have identified a large cohort of patients with relapsed childhood ALL. We have collected data on the relapse patterns, risk stratifications, choices of treatment and outcomes with a specific focus on treatment-related mortality.

Although the main goal of a successful cancer treatment is cure, preventing serious treatment-related toxicity and maintaining optimal health in survivors is important as well. Since skeletal growth and development is very active during the childhood and adolescent years, bones and joints are particularly vulnerable to the toxic effects of cancer treatment. We are collaborating with the Adult Life after Childhood Cancer in Scandinavia (ALiCCS) research group to study skeletal adverse events and total joint arthroplasties in childhood cancer survivors in the Nordic countries. In this project we use linkage of data across separate population and quality registries to capture information on skeletal health in childhood cancer survivors.

Validation-study of completeness and outcome in the Swedish Childhood Cancer Registry – together with the Childhood Cancer Epidemiology Group  (Jenny Juhlin, Päivi Lähteenmäki, Mats Heyman)

Registration in the Swedish Childhood Cancer Registry (SCCR) is a national quality-registry (NQR) for childhood cancer with NQR-status since 2012, has very high coverage. Registration in the National Cancer Registry (NCR) is mandatory and serves as gold standard for cancer incidence in Sweden. When these two registries are compared, it has been found that coverage in both registries are high, but that there are patients lacking from both (somewhat lower than 10% for each registry). In order to correct the deficit in the mandatory registration and find out if there is a selection for missed registration in both registries, and if missed registration is a risk-factor for adverse outcomes (low quality of care), a validation-study is performed identifying the children missing in both registries. Comparison with the comprehensive patient-registry will also identify patients missing from both registries.

5. Activities in collaboration with Regional Cancer Center Stockholm (RCC) - (Stefan Söderhäll)

Development of collaboraration between paediatric oncology and home-care units, particularly in remote areas. Support for long-term follow-up of childhood cancer patients. Information to primary health care about symptoms that should alert work-up for childhood malignancy. Transition of childhood cancer patient to adult care. The use of health-care registries for development of childhood cancer care and research.


Group members

Mats Marshall Heyman

Senior lecturer/clinical position

Johan Malmros

Affiliated to research

Susanna Ranta

Affiliated to research

Arja Harila-Saari

Affiliated to research

Petter Svenberg

Affiliated to research

Karin Flood

Project manager

Jenny Juhlin

Research coordinator

Stefan Söderhäll

Affiliated to research

PhD students

Trausti Oskarsson

Affiliated to research

Nina Mogensen

PhD Student