Anita Kienesberger is the Chair of the European branch of Childhood Cancer International (CCI Europe). This is the largest umbrella organization for childhood cancer patient organizations in Europe and one of the Partners of the HARMONY Patient Cluster. “Cancer is the second leading cause of mortality in children in developed countries and blood cancer accounts for 40% of childhood cancers. Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children; the other hematologic malignancies are quite rare in this age group. Around 90% of children with ALL are cured, but the treatment protocols are intensive, typically involving multiple chemotherapeutic drugs administered over several months or years. The side effects of these treatments are considerable.”
Professor Anthony Moorman of Newcastle University is an expert in ALL, Acute lymphoblastic leukemia. “We think that a less intensive treatment will suffice in a substantial number of pediatric patients. The key challenge is to develop more robust prognostic markers to identify these patients. With its unique Big Data Platform, the HARMONY Alliance offers excellent opportunities to tackle this challenge.”
Many prognostic factors have already been identified for pediatric ALL, including age of onset, gender, genetic profile of the leukemic cells, and minimal residual disease (MRD – the level of leukemic blasts that remain in the marrow after the first course of chemotherapy). These factors can predict the risk of relapse, but they have largely been studied in isolation so far. By pooling data of thousands of patients, HARMONY researchers will be able to study combinations of prognostic factors. This may allow them to more precisely predict clinical course and drug response, enabling physicians to rapidly select the most promising and least toxic treatment for a particular patient. Moorman: “With the help of CCI Europe and others, we have now gathered approximately 11,000 data sets from patients with ALL in the HARMONY Big Data Platform. At least 8,000 of these are pediatric. We are currently validating the data sets on the platform and we are waiting for another 5,000 data sets to come through the pipeline. As soon as this is done, we can start to address the most urgent research questions. We will first focus on improving the prognostication by combining MRD and the genetic profile of the leukemic cells.”
Kienesberger: “If we combine data from all over Europe and examine the risk factors, maybe we can develop novel treatment regimens that are not so toxic for children. This is what survivors are asking for. So, HARMONY is a very important step forward for CCI Europe."
The HARMONY Alliance is also planning to study rare subtypes of pediatric ALL. Moorman: “By pulling together data from multiple cohorts, HARMONY will allow us to study reasonable numbers of patients with rare subtypes of ALL. For instance, there is a small subgroup of patients who do not respond to any chemotherapy at all. We will try to tease apart what exactly is going on in these high-risk patients. Another example is the T-ALL subtype, which is much rarer than the B-ALL subtype. Only around 20% of patients have the T-subtype and little is known about this particular form.”
The team is also eager to study young adults with ALL. Moorman: “There is a big ongoing debate about how to treat the age group between 15 to 30. Historically, they were treated on adult protocols, but a lot of data now suggest that they should actually be treated on pediatric protocols. In the UK, we now treat everyone up to the age of 24 on a pediatric protocol. The Nordic countries have even raised that cut-off to the age of 45. ALL is at its lowest prevalence in young adults, so there are few patients to inform us about the best treatment protocol. By bringing together many different datasets from the pediatric and the adult community, we will be in the best position to inform this debate. That is something that I am truly looking forward to.”
Across the hematologic malignancies
“Finally, the really big advantage of HARMONY is that it will enable us to perform studies across all hematologic malignancies. For instance, some of the genetic abnormalities that you see in ALL are also seen in other hematologic malignancies. The HARMONY Big Data Platform offers unique opportunities to study the effect of genetic abnormalities across different hematologic malignancies. In addition, many of the drugs that we use to treat ALL are also used to treat other malignancies, particularly myeloma. And targeted drugs such as tyrosine kinase inhibitors should target a genetic abnormality whether it occurs in ALL or AML or myeloma. It will be very interesting to study drug responses across diseases and see how the drugs interact with certain genetic abnormalities. Such studies have been challenging so far because it was very difficult to compile a pan-cancer data set like HARMONY has done,” says Moorman.”
Kienesberger concludes: “The survival for pediatric ALL is fantastic. It is now mainly about better survival. Children with blood cancer still have their lives ahead of them. The research projects that HARMONY is conducting will have a valuable impact on children, teenagers and young adults with cancer.”
HARMONY (since 2017) and HARMONY PLUS (since 2020) have received funding from the Innovative Medicines Initiative 2 Joint Undertaking, under grant agreement No. 116026 for HARMONY and grant agreement No. 945406 for HARMONY PLUS. This Joint Undertaking receives support from the European Union’s Horizon 2020 Research and Innovation Programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA).
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