Davide Rossi

Prof. Davide Rossi obtained the specialization in Internal Medicine and the PhD in Clinical and Experimental Medicine at the University of Eastern Piedmont, where he served as Professor of Hematology until 2015. In 2015 Prof. Rossi moved to Switzerland, where he is head of the Experimental Hematology research program at the IOR, Deputy Head of the Division of Hematology and co-chair of the Clinical Lymphoid Tumors Investigation Program at the Oncology Institute of Southern Switzerland (IOSI). Prof. Rossi’s research focuses on lymphomas and chronic lymphocytic leukemia, with more than 330 publications in international peer-reviewed journals. He is also the principal investigator of national and international clinical trials in the field of chronic lymphocytic leukemia. Prof. Rossi contributed to the development of chronic lymphocytic leukemia guidelines and co-authored the 2016 WHO Classification of Hematologic Malignancies. He serves as Editorial Board Member of Blood (the official Journal of the American Society of Hematology), Blood Cancer Discovery, and HaemaSphere (the official Journal of the European Hematology Association). Prof. Rossi is member of the Organizing Committees of the International Conference on Malignant Lymphoma (ICML) and of the Congress of the European Hematology Association (EHA). Prof. Rossi’s research is funded by grants from the European Research Council, Swiss National Fund, Oncosuisse, Leukemia and Lymphoma Society, Fond’Action and Dr. Ettore Balli Foundation.

Research Focus

The research topic of the Laboratory of Experimental Hematology is the molecular pathogenesis of lymphoma and chronic lymphocytic leukemia, and translation of biological information into markers for disease diagnosis, prognostication and treatment.

Individualized management of patients with chronic lymphocytic leukemia in clinical practice.

The International Prognostic Score for asymptomatic Early-stage chronic lymphocytic leukemia was developed and validated using data from 11 international cohorts of approximately 5000 patients with early stage chronic lymphocytic leukemia. The IPS-E allows more individualized management of patients with chronic lymphocytic leukemia in clinical practice, by leveraging three variables (unmutated IGHV, lymphocytes >15,000/microL, palpable lymph nodes) for stratifing them at diagnosis into three risk groups with differing likelihood of requiring treatment. Compared with other scores, IPS-E calculation needs the assessment of only 1 molecular variable; namely, the IGHV mutation status, the testing of which is broadly available and standardized, and whose result never changes during the course of disease.

Genetic and phenotypic attributes of splenic marginal zone lymphoma.Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous entity at different levels. We sought to provide a unifying view of SMZL by resolving its heterogeneity in subgroups sharing genomic abnormalities, pathway signatures and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter, international study (NCT02945319) by using a multiplatform approach. We carried out a genetic and phenotypic analysis, defined self-organized signatures, validated them in independent primary tumors meta-data and in genetically modified mouse models, and correlated them with outcome data. We identified two prominent genetic clusters in SMZL, termed NNK (58% of cases, from NF-kB, NOTCH and KLF2 modules) and DMT (32% of cases, from DNA-damage response, MAPK and TLR modules). These genetic clusters have distinct underpinning biology. Digital cytometry and in situ profiling segregated two basic types of SMZL immune microenvironment termed inflamed (50% of cases, associated with inflammatory cells and immune checkpoint activation) and non-inflamed (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that could implement its classification and aid the development of rationally designed targeted treatments.

Adaptation of chronic lymphocytic leukemia to ibrutinib is mediated by epigenetic plasticity of residual disease and by-pass signaling via MAPK pathway.

Ibrutinib inhibits the BTK molecule downstream the B-cell receptor. Though highly active in chronic lymphocytic leukemia, detectable minimal residual disease persists for years under ibrutinib until the development of resistance. The study aimed at a multilayer characterization of the adaptation process that allows residual cells to persist despite BTK inhibition. The study has enrolled 33 patients with chronic lymphocytic leukemia treated with ibrutinib. Hundreds of longitudinal leukemia samples have been homogeneously  collected at pre-specified timepoints and were characterized by multilayer systematic approaches to characterize changes in the genetic, epigenetic and single-cell antigen profiles produced by ibrutinib. Minimal residual disease under ibrutinib is largely stable at the genetic level and mutations of the ibrutinib targets (BTK and PLCG2) are not implicated in its survival. Ibrutinib induces chromatin dynamics in the minimal residual disease, and maintains its chromatin in a predominantly closed state. Epigenetic and antigen profiling points towards a rewiring of the B-cell program toward an early lineage developmental and blocked state in the minimal residual disease, whose survival is sustained by MAPK/RAS/ERK signaling. Collectively, our data indicate that the minimal residual disease persisting under ibrutinib adapts its phenotype, mainly in a non-genetic way by maintaining functional competence of the MAPK pathway. The study provides the rationale for combining MAPK pathway inhibitors to BTK inhibitors in order to achieve deeper and longer responses.