Title: Validation of the impact of genetic aberrations and host genetic variation in childhood acute lymphoblastic leukemia for integration into clinical practice.

Project Coordinator:
Martin STANULLA (Germany) University Hospital Schleswig-Holstein, Department of Pediatrics, Kiel

Project Partners:
Giuseppe BASSO (Italy) Dipartimento Assistenziale Integrato Sperimentale per la Salute della Donna e del Bambino, Mother and Child Health, Padova
Andrea BIONDI (Italy) Regione Lombardia - Azienda Ospedaliera San Gerardo Hospital, Pediatric Clinics, Monza
Helene CAVE (France) CHU Robert Debré, Université Paris-Diderot, Department of Genetics, Paris
Shai IZRAELI (Israel) Sheba Medical Center, Department of Pediatric Hematology and Oncology, Tel Hashomer
Martina MUCKENTHALER (Germany) University of Heidelberg, Department of Pediatric Oncology, Hematology and Immunology, Heidelberg
Renate PANZER-GRÜMAYER (Austria) St. Anna Kinderspital, Pediatrics, Vienna

Project Abstract:
Nowadays, as a result of these prolonged and well-organized research efforts, childhood acute lymphoblastic leukemia (ALL) can be cured in about 80% of patients mainly by the application of intensive combination chemotherapy regimens. Treatment intensity on contemporary clinical protocols for childhood ALL is adjusted according to prognostic factors predicting the risk of ALL relapse. Yet significant numbers of patients still die due to recurrent disease or the toxicity of treatment and long-term toxicity during lifetime of cured children is a major problem. Hence better personalized adjustment of therapy is urgently needed. Thus, current research activities are aiming at extending our molecular understanding of leukemia and host factors in order to even more specifically account for the mechanisms underlying the differences in treatment response and outcome and to finally address the therapeutic needs of the individual child. Recently, through the application of genome-wide analytical approaches, several candidate biomarkers have been identified for childhood ALL. However, to date, not a single of these markers has been implemented in modern treatment protocols, mainly due to sub-optimal study designs only leading to preliminary and
inconclusive results. In the present proposal we will address the most promising of these new potential biomarkers for treatment stratification in childhood ALL – namely IKZF1 deletions, CRLF2-JAK-STAT and Notch1 pathway aberrations, the early T-cell precursor phenotype, and thiopurine methyltransferase genetics – by rigorous methodological approaches securing an improved translation of emerging molecular information into clinical decision making processes in childhood ALL.

Publishable Summary:
About 25% of patients with acute lymphoblastic leukemia (ALL) in childhood and adolescence are affected by treatment failure - 15% are characterized by a disease relapse. Therefore, better prediction of an individual’s risk of treatment failure by means of biomarker analyses is needed, in order to adjust the intensity of therapy accordingly and thereby to further improve future treatment results. To date, not a single marker of several promising ones detected by genome-wide analytical approaches has been implemented in modern treatment protocols for childhood acute lymphoblastic leukemia (ALL).
Joining forces within the TRANSCALL consortium allowed bringing together existing clinical,diagnostic and research expertise of large national trial groups and promoted communication, collaboration and management of effective translational clinical research on childhood ALL. Most important result in TRANSCALL was the development of a new prognostic profile, IKZF1plus, which allows the identification of approximately 25% of relapses in intermediate and high-risk patients with ALL. In the future, IKZF1plus will be used in clinical practice for more precise therapy control in ALL. It is expected that clinical application of IKZF1plus will further improve treatment results of this disease.


(Project funded under JTC 2011)