Abstract OPTIMAL

According to RARECARENet (www.rarecarenet.eu), rare cancers are identified as those with an incidence of less than 6 per 100,000 persons per year. Most tumors of hematopoietic and lymphoid tissues belong to this category, including myelodysplastic syndromes (MDS, incidence 1.5), myeloproliferative neoplasms (MPN, 1.3), myelodysplastic/myeloproliferative neoplasms (MDS/MPN, 0.3), acute myeloid leukemia (AML, 3.7) and classical Hodgkin lymphoma (cHL, 2.4). Any of these disorders includes at least a subset of patients with poor clinical outcome and significant unmet medical needs.

All tumors are caused by somatic mutation, that is, the occurrence of abnormalities in DNA sequence of genes. These abnormalities may be generated by inherited predispositions, environmental factors, or random mutations arising during DNA replication in normal stem cells. The identification of recurrent genetic events represents one of the most direct approaches to understand cancer biology. Personalized or precision medicine is a medical model that combines already established clinical–pathological parameters with advanced genomic profiling in order to create innovative diagnostic, prognostic and therapeutic strategies. Hematology has been rapidly transformed by genome characterization. The paradigmatic example is chronic myeloid leukemia, in which the discovery of the BCR-ABL1 fusion gene and its oncogenic properties has translated into targeted therapy and prolonged survival of patients.

Development of infrastructures that can support collection and use of genomic information in the health- care community represents a research priority for rare cancers, while clinical networks are needed to address accrual of sufficient patients for both genomic profiling and conduction of clinical trials. REL (www.rel-lombardia.net) brings together centers of excellence for the study and treatment of hematologic malignancies in Lombardy, a region with a catchment area of about 10 million people. REL promotes the study of hematologic malignancies through: (i) creation of epidemiologic disease-specific registries (ClinicalTrials.gov Identifier: NCT02459743); (ii) establishment of a bio-banking network; (iii) implementation of diagnostic/therapeutic guidelines; (iv) conduction of clinical trials. In 2014, REL created RELab, a genome diagnostics laboratory for hematologic malignancies (www.relab-lombardia.net).

In response to the FRRB call, we undertook this project to study mechanisms of disease in rare hematologic cancers, and rapidly translate findings of these investigations into clinical tools within the REL clinical network. In the next 3 years, we will combine genomic profiling with clinical studies to develop innovative personalized medicine strategies for the following conditions: familial syndromes with inherited predisposition to myeloid malignancies, MDS, MPN, MDS/MPN, AML, and refractory cHL. State-of- art genomic profiling will include mutational characterization of germline and acquired gene mutations as well as gene expression profiling through RNA-seq. In disorders of high genetic complexity, we will combine studies of clonal architecture with analysis of epigenetic alteration. We will preferentially study patients enrolled into observational or interventional clinical trials. Phase I/II as well as innovative clinical trials, aimed to test safety and efficacy of new or repurposed drugs in molecularly characterized patients, will be conducted in collaboration with pharmaceutical companies.

This project requires an effective, sustainable information infrastructure that can integrate the huge amount of molecular and clinical data to be collected, allowing their optimal analysis and utilization. To this purpose, we will create advanced informatics solutions, ranging from the analysis of sequencing data through shared, standardized procedures to the design and implementation of a novel data integration platform called i2b2-Shrine-Hematology, based on the open-source data warehouse of the NIH project i2b2 (www.i2b2.org) and the Harvard initiative Shrine (https://open.med.harvard.edu/project/shrine/).

Relying on this informatics infrastructure, we will analyze the interactions among driver mutations, gene expression, clinical variables and patient outcome to model natural history of disease and impact of treatment. In myeloid neoplasms (MDS, MPN, MDS/MPN, and AML), we aim to identify genomic changes that can be used for classification, risk assignment, enrollment into clinical trials, and prediction of response.

Integrated sequencing analysis will be employed in familial disorders with inherited predisposition to MDS/AML, whose identification is of crucial importance not only for clinical decision- making in affected patients but also for genetic counseling in their relatives. We will also study the so- called age-related clonal hematopoiesis, which is associated with increases in the risk of hematologic cancer and in all-cause mortality. In lymphoid malignancies, we will focus on the molecular mechanisms of therapy resistance in cHL. In specific clinical settings, we will use novel cellular therapies, including cytokine induced killer (CIK) cells and anti-CD19 chimeric antigen receptor (CAR) T cells.

The innovative precision medicine strategies that we plan to define, will be progressively implemented into the REL, and will hopefully become standard of care for all centers of this clinical network. At the same time, the bioinformatic platforms created in this project may serve as invaluable tools for future research projects aimed to address other significant unmet medical needs in hematology oncology.