Pediatric Hematologic Malignancies

Pediatric Malignancies are the second leading cause of mortality in children in developed countries and hematologic malignancies (HMs) account for 40% of pediatric malignancies. Typical symptoms of pediatric HMs are fatigue and frequent infections. Acute lymphoblastic leukemia (ALL) is the most common HM in children; the other HMs that are studied in HARMONY are rare in children.

The treatment of childhood HMs has dramatically improved in the past few decades, largely as a result of improvements in protocol design, supportive care, and risk stratification. The contemporary five-year event-free survival is ~80% for ALL and ~60% for AML in children. Current treatment protocols are intensive, typically involving multiple chemotherapeutic drugs administered over several months or years. Stem cell transplantation is reserved for high-risk patients. Although many pediatric HM patients can be cured, the treatments are highly toxic and may cause substantial long-term morbidity.

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Key questions

Many prognostic factors have already been identified for pediatric HMs, e.g., age of onset, gender, genetic constitution of the malignant cells, and minimal residual disease after chemotherapy. To a certain extent, these factors can predict outcomes such as 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, which may constitute risk profiles that can reliably predict clinical course and drug response, enabling physicians to rapidly select the most promising and least toxic treatment strategy for a particular patient.

Examples of key questions that HARMONY will address for pediatric HMs are:

Can we de-intensify chemotherapy in certain subgroups of patients?

• The side effects of chemotherapy therapy in children are considerable. It is expected that a less intensive treatment will suffice in a substantial number of pediatric patients. However, we need more robust prognostic markers to identify such patients.

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Can we find risk profiles that identify non-responders?

• In a small percentage of pediatric ALL patients, none of the available drugs are effective. These are candidates for allogeneic stem cell transplantation or novel drugs. However, it is currently difficult to predict which children will be non-responders. Integrating data of a variety of prognostic factors may improve this situation.

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What is the optimal cut-off age for treating a patient as a child or an adult?

• The majority of teenagers and young adults with ALL have better outcomes when treated on pediatric rather than adult protocols. However, the precise threshold for treating patients with any given HM as a child or an adult has not been resolved. The analysis of datasets across the entire age spectrum will inform this debate.

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Pediatric HM features

• Type of malignant cells: hematopoietic stem cells in ALL and AML.
• Tissue of origin: bone marrow for ALL and AML.
• Clinical symptoms: varies with subtype of HM, but often fatigue and frequent infections.
• Five-year survival in Europe: event-free five-year survival >80% for pediatric ALL; ~60% for pediatric AML.
• Incidence in Europe: pediatric ALL: 40/1,000,000; pediatric NHL: 15/1,000,000; pediatric AML: 7/1,000,000; pediatric MDS: 3-4/1,000,000; pediatric CML: 1/1,000,000.
• Age at diagnosis: peak incidence for ALL: age 3-5; peak incidence for pediatric AML: age <2.
• Relevant outcomes: overall survival, event-free survival, relapse risk.

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HARMONY Leadership: Pediatric HM

• Anthony Moorman, Newcastle University, United Kingdom
• Dirk Reinhardt, GPOH, Gesellschaft für Pädiatrische Onkologie und Hämatologie, Germany
• Franco Locatelli, OPBG, Ospedale Pediatrico Bambino Gesù, Italy

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