Childhood International Protocol – Acute Myeloid Leukaemia 2022

Organisation and development of the CHIP-AML22 study

The development of the CHIP-AML22 started 2020. Some of the central people in the consortium, many with complementary expertise and experiences, were selected to form the Steering Committee (SC) of the CHIP-AML22 protocol. Since April 2000, the SC has met every second week in online meetings. SC members are all co-PIs for the CHIP-AML22 protocol. The overall PI for the AML12 (Prof Abrahamsson, Sweden) is part of the SC as expert consult. The SC is headed by overall Chief Investigator (CI) Professor Kaspers (Netherlands), who is also PI for WP2 (in the EU4H grant) in this application. Kaspers has a position at the Princess Máxima Center (PMC) in Utrecht, Netherlands and it is the PMC that is Sponsor for the CHIP-AML22. Vice-CI is Associate Professor Pronk (Sweden), who is also PI for WP4&WP6 in the EU4H grant and, in addition coordinated the application to the EU. The construction of a new CHIP-AML22 protocol has many different aspects, and for many of these aspects working groups were established. Each working group is headed by a member of the SC. As many of the outcome results from AML12 were an unprecedented improvement, we decided to build CHIP-AML22 largely on the experiences of AML12. For that reason, Prof Abrahamsson, PI for AML12, was attracted to the SC and has delivered very valuable outcome-data from AML12 patients, on which a large part of decisions for CHIP-AML22 were made. However, a thorough literature search and discussions with other international experts/groups were performed that allowed us to make decisions based also on all this gathered knowledge. All of this work has led to new guidelines for supportive care, and formed the basis for the development to the goals as articulated in this application. Many recommendations for the CHIP-AML22 have come from the working groups to the SC and it has been the SC, together with the sponsor, that have drafted the CHIP-AML22 protocol. This proposal has been presented on several occasions to the whole NOPHO-DB-SHIP consortium.

The figure below gives an overview of the structure of the CHIP-AML22 task forces. Together with the national PIs, who are ultimately responsible for the implementation of the protocol in each country, these people form the core of the NOPHO-DB-SHIP consortium.

Steering committee:

• Gertjan Kaspers, NL (Chair and C.I)
• Kees-Jan Pronk, NOPHO (vice-chair and co-C.I)
• Barbara de Moerloose, Belgium (co-C.I)
• Nira Arad-Cohen, Israel (co-C.I)
• Jose (Chema) Fernandes, Spain (co-C.I)
• Jonas Abrahamsson, current C.I (advisor)
• Dominik Turkiewitz (study statistician)

W G backbone, risk-groups & randomisations

Chair: Gertjan Kaspers (B)

• All other members of the steering group

WG diagnostics & risk classification

Chair: Barbara De Moerloose (B)

• Ulrika Norén-Nyström (S)
• Anne Tierens (CAN)
• Valérie da Haas (NL)
• Linda Fogelstrand (S)
• Jan Philippe (B)
• Henrik Hasle (DK)

WG supportive care

Chair: Nira Arad-Cohen, (Isr)

• Jose (Chema) Fernandes
• Bem Zeller (N)
• Daniel Cheull (HK)
• Saul Palmu (FIN)
• Vitor Costa (P)

WG allo-SCT & cellular therapy

Chair: Kees-Jan Pronk (S)

• Karin Mellgren (S)
• Dominik Turkiewitz (S)
• Birgitta Verlsluys (NL)
• Marta Gonzales Vincent (E)

WG preclinical & translational research

Chair: Gertjan Kaspers (B)

• Eva Barragán (E)
• Linda Fogelstrand (S)
• Bianca Goemans (NL)
• Kristian Juul-Dam (DK)
• Tim Lammens (B)
• Shal Israeli (Isr)

Description of the NOPHO-DB-SHIP consortium

NOPHO countries Sweden, Denmark, Finland, Norway, Iceland, Latvia, Estonia and Lithuania, as well as the Netherlands, Belgium, Hong Kong, Spain, Israel and Portugal are all equal members of the NOPHO-DB-SHIP consortium. NOPHO was established already several decennia ago and has since run a number of international NOPHO treatment trials. While preparing for a new “NOPHO-based” treatment protocol for newly diagnosed AML in children around 2012, several other countries expressed interest to join efforts and 2012 the NOPHO-DBH (NOPHO-Dutch Belgium Hong Kong) AML12 study was opened. During AML12 recruitment, also Spain, Israel and Portugal joined the consortium and introduced treated according to the AML12 protocol in those countries. Recently Uruguay and Switzerland expressed interest to join the consortium and partake in CHIP-AML22, and we are currently working to establish national diagnostic routines in these countries that will enable their participation. Members of the NOPHO-DB-SHIP consortium are mainly pediatric oncologists that are nationally responsible for AML-treatment in children in their respective countries. In addition, the NOPHO-DB-SHIP consortium is complemented with members with specific expertise such as molecular/genetic diagnostics, flow cytometry, registries, and statistics.

Structure of the EU4Health project

The EU4H project will aid to implement diagnostic procedures and treatment modalities in CHIP-AML22 in all participating countries within the EU.

More specifically, the aims are to

• 100% inclusion and registration in CHIP-AML22 of eligible patients, regardless of country and/or treatment centre
• Within 2-3 years from the opening of the CHIP-AML22 protocol, WGS/RNAseq is performed on all eligible AML patients, i.e. on 100% of patients that are treatment in CHIP-AML22.
• All available high-quality data is registered for all patients. 
• Within 2-3 years from the opening of the CHIP-AML22 protocol, all eligible patients within our consortium have access to these novel, targeted agents throughout the consortium.
• To register treatment efficacy of these novel agents in each patient treated with these agents and correlate efficacy to genetic data.
• Within 2-3 years from the opening of the CHIP-AML22 protocol, treatment-response by advanced flow MRD is evaluated in 100% of patients, regardless of treatment centre/country.
• Investigate the feasibility to lift these modern, genetic-based MRD methods into clinical practice for all, or at least of selection of patients.

To this purpose, the tasks to reach these goals are divided over a number of WPs (Work Packages). The Pert chart below shows a figure of the structure. WP1 coordinates and manages the project and enables WP2, WP3, WP4 and WP5 to achieve their aims. Thereafter dissemination of results is prepared by WP6. However, prior to dissemination of information to the whole NOPHO-DB-SHIP consortium, contents are always first discussed in the steering committee of CHIP-AML22. This involves also dissemination of results outside the consortium by for instance publication on a website or international literature.

Impact and ambition of the EU4H grant

There is a clear international trend (and wish) towards implementation of more and more advanced genetic diagnostics in health-care clinical praxis, paralleled by an increase fraction of patients that receive tailored and targeted treatment. Although this type of diagnostics and treatment is available throughout the broader field of medicine, it has traditionally been the field of oncology that largely has driven these developments. And, within the field of oncology, it has been pediatric oncology that pioneered many of these endeavors. This is for instance illustrated by the fact that the very first patient with cancer, he had leukemia, that was treated with a chemotherapeutic agent was a child (in 1947), and modern cancer treatment that uses combinations of anti-cancer drug was pioneered in children.

Short-term effects

Implementation of these forefront diagnostics and treatments are however costly, in a period were healthcare as large is under economic and personnel constrains due to the global Corona pandemic, and more recently as the consequence of the war in Ukraine. For that reason, we have at many sites noticed a hesitancy from the healthcare leadership to introduce these novel diagnostics and treatments into the clinic. Without financial means to organize and partly cover costs for these actions, there is a risk for delay. This delay would have direct impact on individual patients, as these would simply not benefit from the full impact of the CHIP-AML22 protocol.

Medium- and long-term effects for AML patients

The more patients that are included in the CHIP-AML22 protocol that undergo full diagnostic workup and received tailored and targeted treatment, the sooner we can make firm conclusions. If these conclusions would imply (and this will likely be the case) that further developments in diagnostics and treatment are required to further improve outcome for children with AML, we wish to come to these conclusions as soon as possible. This would namely mean that we can offer improved diagnostics and treatment to “the next generation” of patients.

Medium- and long-term effects for other patients

Advanced diagnostics and novel treatments are of course not limited to pediatric AML patients. On the contrary, many diseases in both children and adults will benefit from advances in those fields. We hope that our consortium, and especially the work towards the goals of this application, can function as a spearhead for many other areas. As many of the techniques and availability/reimbursement/legislation of novel drugs are shared with others fields/disease, we hope that our work will function as template for other collaborative initiatives in Europe.

Pediatric AML is a relatively rare disease. However, this may in fact be an advantage for our project. To undertake the initiative (especially the advanced diagnostics) in our project for a group a very common diseases (i.e. very large patients number), this may become too much of an effort to pioneer. If we however, within our consortium, could “pave the way” for the implementation of these type of diagnostic in a smaller group of patients, it will likely help such implementation to larger patient groups.

Interview and press release with Kees-Jan Pronk, coordinator if the EU4H grant

Children with leukaemia to gain access to equal treatment via European project coordinated by Skåne University Hospital

All children in Europe with acute myeloid leukaemia will have access to equal treatment. This is the goal of an EU-funded healthcare project that is being coordinated by Skåne University Hospital in tight cooperation with the Princess Máxima Center for Pediatric Oncology in the Netherlands. “We want to be able to offer all children the kind of treatment we really believe in,” says Kees-Jan Pronk, a consultant in paediatric oncology at Skåne University Hospital and an associate professor at Lund University.

In Sweden, about 15 children contract acute myeloid leukaemia (AML) every year. This is a serious form of blood cancer that involves intensive treatment with cytostatic drugs, and in some cases a bone marrow transplant is required. The prognosis is relatively good, and almost 80% of children survive. The treatment these children receive differs around the world, and this is where the CHIP-AML22 research project comes in. The project brings together 14 countries, primarily in Europe, for a treatment study that will investigate how children respond to certain types of treatment. Kees-Jan Pronk is coordinating the EU project, assisted by Elise Witthoff, whereas the sponsor for the CHIP-AML22 is the Princess Máxima Center.

It was recently announced that the European countries taking part will receive funding via the EU’s EU4Health programme. “The study is designed according to current knowledge about the best available treatment for children with AML,” explains Kees-Jan. “Of course, we want to be able to offer all children the type of treatment that we really believe in.”

Advanced methods

In order to provide the best available treatment to children with AML, the treatment must be adapted on the basis of two factors: the genetic changes in the cancer cells that drive the development of the leukaemia itself, and how the patient responds to the initial treatments. These two factors determine how treatment continues after the first phase. “Not all the countries included in the study have set up these advanced methods to check genetic changes and treatment responses. However, the study will give them access to these methods now.”

Targeted drugs

The researchers will also introduce two new, more modern and targeted drugs that will hopefully increase the effectiveness of the treatment and reduce side effects. “These drugs are also not available in all countries, or they are too expensive for some countries and can therefore not be offered to patients.”

In addition, the study will seek answers to a number of scientific questions, and the children included will be randomised to different treatment options, with the aim of increasing treatment effectiveness and reducing side effects. “We know from past experience that this approach is highly successful, and has led to almost 80% of children with AML now being cured. Up until the mid-1970s, not a single child survived this serious disease.”

Benefits for other patient groups

The fact that the EU project is being coordinated by Skåne University Hospital brings advantages for Swedish patients, says Kees-Jan.“We will be very closely involved in developing and improving the care received by these young patients. Some of the knowledge we gain as a result of this project may also be useful for other patient groups, both children and adults.”

Facts about CHIP-AML22, the NOPHO-DB-SHIP consortium and the EU4H grant

• The name stands for Childhood International Protocol – Acute Myeloid Leukaemia 2022 and treats children up to the age of 18 year old with newly diagnosed AML.
• The project is being carried out within an international consortium named NOPHO-DB-SHIP. This consortium includes the NOPHO (Nordic Society Pediatric Hematology Oncology) countries Sweden, Finland, Denmark, Norway, Iceland, Estonia, Latvia, Lithuania, as well as the Netherlands, Belgium, Spain, Hong Kong, Israel and Portugal.
• The Princess Máxima Center for Pediatric Oncology in Utrecht, the Netherlands, will be responsible for the scientific aspects of CHIP-AML22, with Professor Gertjan Kaspers (Utrecht) as Chief Investigator of CHIP-AML22. Skåne University Hospital coordinates the EU funding and implementation, with Associate Professor Kees-Jan Pronk as Vice-Chief Investigator of CHIP-AML22. Elise Witthoff is EU Project Coordinator.
• Uruguay and Switzerland are also likely to join the consortium. Israel, Hong Kong, Uruguay and Switzerland are not part of the EU, and therefore will not benefit from the EU4Health grant.
• The EU funding from the EU4Health Programme (EU4H) will last until the end of 2025, but the study will continue beyond then – until approximately 2030. This is because the researchers need to treat and evaluate a certain number of children in the study in order to find answers to the scientific questions.
• The EU4H project has a budget of EUR 3 million. The EU is financing 80% of the costs. The remaining costs will be borne by the local hospitals.