Emerging Clonal Interception Program

A pioneering scientific program to anticipate the risk of leukemia induced by previous anticancer treatments.

Project leader: Jean-Baptiste Micol

Patients treated for cancer are at greater risk of developing a second cancer, in particular a blood cancer, or induced hemopathy, in the form of acute myeloid leukemia or myelodysplastic syndrome. The emerging Clonal Interception program, led by Dr. Jean-Baptiste Micol, onco-hematologist at Gustave Roussy, is based on molecular precision medicine techniques. It aims to better understand the pathophysiological mechanisms leading to these induced hemopathies in order to identify predictive biomarkers and develop an intervention program to prevent or delay their onset. Its essential interdisciplinary scope brings together oncologists, hematologists, biologists, bioinformaticians and basic research scientists around a converging interest: avoiding the onset of induced leukemias.   

Cancer patients have an increased prevalence of CHIP* (clonal hematopoiesis of undetermined potential), a precursor of myeloid tumors or secondary hematological malignancies.

A better understanding of the excess risk of induced hematological cancers

The development of molecular precision medicine techniques, and in particular DNA sequencing, has led to a better understanding of the pathophysiological mechanisms of the progressive appearance of these abnormalities, which can be detected in the blood of people who have not yet developed secondary hematological malignancies. Two major risk factors have been demonstrated: age and exposure to anti-cancer treatments. Nevertheless, only a minority of patients will develop an induced hemopathy.

The Clonal Interception program aims to understand how this transition from the pre-leukemic state to secondary hematological malignancy occurs by prospectively evaluating multidimensional factors (genetic, cyto-morphological, environmental and inflammatory). Three main lines of work are integrated:

Reconstructing the clonal architecture of CHIPs over time by studying mutation dynamics in the blood of cancer patients while evaluating factors for transformation to 2nd cancer in a cohort of 115 patients. The goal is to identify molecular factors associated with disease progression from CHIP to a second hematologic cancer.

Characterize these CHIP abnormalities with analysis of hematological parameters and the development of machine learning approaches for cytomorphology image processing.

To determine the role of extrinsic factors (environment and inflammation) and intrinsic to the cells (deregulated pathways) on these CHIP anomalies in order to act upstream on the lifestyle of patients concerned by these excess risks of second cancer or to develop a preventive treatment.

Markers could thus be obtained allowing an early and sensitive detection of the precursors of induced hemopathies.

Building the first French leukemia prevention program 

The ultimate goal of Clonal Interception is to conduct an intervention program to prevent or delay the onset of these secondary hematological malignancies.

The patients concerned by this excess risk of second hematological cancer participating in this research program will also be integrated into Gustave Roussy's personalized prevention program, Interception. They will thus be able to benefit from a day of information and adapted advice.

The fourth and final objective of Clonal Interception is to design a therapeutic program and trial for leukemia interception, which could be the first French leukemia prevention program for cancer patients with high-risk CHIP.

 "By understanding the mechanism of onset of acute leukemia, we may be able to transform an almost incurable disease into one that can be prevented, whether for induced or de novo acute leukemia," concludes Dr. Micol.

To launch this promising program, Dr. Jean-Baptiste Micol's research team has received a starting package of €250,000 from the generosity of Gustave Roussy donors.

*CHIP (clonal hematopoiesis with indeterminate potential): identification of one or more somatic mutations in hematopoietic cells in individuals without hematological disease by sequencing.