Acute Lymphoblastic Leukemia (ALL) is a life-threatening disease if not treated immediately. It arises from hematopoietic stem cells in the bone marrow that have acquired genomic lesions. The non-functional malignant cells proliferative at the expense of healthy cells, resulting in reduced numbers of platelets and red & white blood cells (pancytopenia).
The disease has a rapid onset and easily spreads to other organs. The treatment of ALL has dramatically improved in the past few decades, largely due to improvements in protocol design, supportive care, and risk stratification. The five-year event-free survival currently is more than 80% for children and 30-70% adults largely depending on age. ALL treatment protocols are intensive, typically involving multiple chemotherapeutic drugs administered over several months or years. The drugs are toxic and may cause substantial long-term morbidity particularly in pediatric patients. Stem cell transplantation is reserved for fit high-risk patients. In contrast to the other hematologic malignancies that are studied in HARMONY, ALL occurs more frequently in children than adults.
As ALL constitutes a rare disease, it is crucial to perform multicenter research. By pooling data from multiple clinical trials, HARMONY researchers aim to create a dataset of ~20,000 ALL patients spanning the entire age range from infants to older patients. We aim to identify 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 ALL include:
Can we identify risk profiles that predict clinical course and drug response?
- Many prognostic factors have already been identified for ALL, e.g., the age of onset, gender, genetic constitution of the malignant cells, and minimal residual disease after chemotherapy. These factors can predict outcomes such as the risk of relapse, but so far, they have largely been studied in isolation. By pooling data of thousands of patients, we will hopefully be able to study combinations of prognostic factors, which may be more robust predictors of disease course and treatment response.
What is the disease pathophysiology, disease course, and treatment outcome in subsets of ALL?
- Given the rarity of the disease and the description of numerous genetic, immunophenotypic and risk subsets, international collaboration is crucial to address outstanding questions about ALL biology.
Can we harmonize the measurement of outcomes in ALL trials?
- Minimal residual disease (MRD) is a sensitive measure of treatment response. Harmonizing procedures will increase the comparability of clinical trials and it will ensure meaningful patient relevant outcomes are respected and aligned with regulators and health technology assessment bodies.
- Type of malignant cells: hematopoietic stem cells.
- Tissue of origin: bone marrow and lymphatic tissue.
- Clinical symptoms: impaired general condition, weakness, fever or infections, anemia, decreased wound healing capacity or hemorrhages.
- Five-year survival in Europe: is more than 80% for children and ranges between 30% to 70% for adults depending on the age group.
- Incidence in Europe: overall incidence of ALL and lymphoblastic lymphoma is 1.28 per 1 million individuals annually.
- Age at diagnosis: most frequent in children aged 1-4 years; rare in adults.
- Relevant outcomes: complete remission after induction, MRD response, remission duration, overall survival, disease-free survival, event-free survival, incidence and localization of relapses, treatment-related deaths, quality of life, late effects.
HARMONY Leadership: ALL
- Nicola Gökbuget, University Hospital Frankfurt, Germany
- Hervé Dombret, GRAALL, Group for Research on Adult Acute Lymphoblastic Leukemia, France and Switzerland
- Jose Maria Ribera, IJC, Josep Carreras Leukaemia Research Institute