Acute Myeloid Leukemia

Acute Myeloid Leukemia (AML) is characterized by rapid-onset uncontrolled proliferation of hematopoietic progenitor cells due to defects in their maturation program. The malignant cells compete with healthy cells for space in the bone marrow, resulting in reduced numbers of platelets and red & white blood cells (pancytopenia).

---

Complications of pancytopenia (e.g., severe hemorrhages and infections) are a frequent cause of death in these patients. Although the basis of AML treatment (chemotherapy) has not changed for decades, substantial progress has been made with supportive care (i.e., blood transfusions, platelet transfusions, antibiotics, antifungals) and allogeneic stem cell transplantation. As a result, cure rates of 40%-50% can now be achieved in fit patients. However, the outcome of older patients is still very poor, in particular for patients that are not fit for intensive chemotherapy. AML is a relatively rare disease. Commonly affecting elderly individuals, the incidence of AML is expected to increase as a result of the aging of our population and the rising number of cancer survivors (i.e., secondary AML).

---

Key questions

AML survival rates are very poor, in particular in unfit patients, so the main urgent unmet medical need of AML patients is better treatments (i.e., novel drugs, novel drug combinations, and more personalized treatment choices). A large number of new drugs are awaiting clinical application. Careful selection of patient groups that are likely to benefit from these new drugs by detailed molecular profiling is high on the research agenda. By pooling data from multiple clinical trials, HARMONY researchers will create a dataset of ~4000-5000 AML patients. We aim to identify molecular profiles that can predict clinical course and drug response, facilitating personalized patient management. Examples of key questions that HARMONY may address using this dataset include:

How do combinations of genetic mutations relate to disease course and treatment response?

• Recently, major progress has been made in deciphering the genetic landscape of AML using next generation sequencing. More than 200 disease-associated gene mutations have been identified. An individual patient usually harbors several mutations (13 on average). These molecular data are already used to stratify patients in the clinic (i.e., good, intermediate, or poor prognosis) and patients with a good prognosis receive less intensive treatments. HARMONY aims to refine this procedure by investigating if combinations of mutations (i.e., gene-gene interactions) can be used as more precise prognostic markers.

---

How can we improve the measurement of minimal residual disease?

• A traditional treatment outcome in AML is complete remission, i.e., the absence of malignant cells in the bone marrow when examined under a microscope. However, around 50% of patients that show complete remission eventually relapse. Minimal residual disease (MRD) is a more sensitive outcome, but its measurement is not harmonized and standardized yet. By pooling data from multiple trials, HARMONY will be able to analyze MRD data from a large group of patients, with the aim to evaluate which methods have the best predictive value. In addition, we would like to automate the analysis of MRD data.

---

AML Features

• Type of malignant cells: hematopoietic progenitor cells.
• Tissue of origin: bone marrow.
• Clinical symptoms: anemia, frequent infections, hemorrhages.
• Five-year survival in Europe: <30%, particularly dismal outcomes in the elderly.
• Incidence in Europe: ~3-4 per 100,000 per year (30,000 new cases each year)
• Age at diagnosis: most common in elderly men: median age at diagnosis is 70 years.
• Relevant outcomes: complete remission, overall relapse-free survival.

---

HARMONY Leadership: AML

• Gert Ossenkoppele, VUmc, VU University Medical Center Amsterdam, The Netherlands
• Brian Huntly, University of Cambridge, United Kingdom
• Francesco Lo Coco (1955 - 2019)(In memoriam), University of RomeTorVergata, Italy

---