Titolo progetto: PRIN2022 - Myelodisplasia-related molecular abnormalities and Clonal Hematopoiesis in patients with relapsed-refractory lymphoid malignancies receiving chimeric antigen receptor (CAR) T Cells.

Programma di finanziamento: PRIN 2022

Responsabile scientifico: dott.ssa Eleonora Toffoletti

Ruolo del DAME: coordinatore

Descrizione generale:

Chimeric Antigen Receptor T-cells (CAR-T) therapy is an innovative therapeutic approach that have been recently approved for adult relapsed and/or refractory (R/R) Diffuse Large B Cell Lymphoma (DLBCL) and for acute B lymphoblastic leukemia (B-ALL) of the children and the young adults below 25 years on the basis of the long term survival advantage in comparison with conventional chemotherapy. For example, the rate of complete responders among R/R DLBCL was only 7% in the SCHOLAR-1 chemotherapy study compared to 30-40% in JULIET and ZUMA-1 CAR-T trials. Similar unprecedented clinical results had been achieved in other lymphoid setting, such as in Follicular and Mantle cell Lymphomas and Multiple Myeloma, pointing toward new approvations and timing of administration. However, CAR-T cells are associated with short and late severe adverse effects. Among the late-onset adverse effects, prolonged cytopenias are life-threatening complications that could impact patient survival not only because of the occurrence of infections but also because of the potential risk of myelodisplasia and subsequent secondary Myeloid Neoplasia (t-MN), of whom a few cases have been already reported in the clinical studies. Cytopenia risk factors include burden of previous treatments, age, residual poor bone marrow cellularity, severity of cytokine release syndrome and extent of the hematologic disease at infusion. Moreover, clonal hematopoiesis of indeterminate potential (CHIP), already known to be related with an increased risk of leukemic transformation and with an impaired peripheral blood stem cell (PBSC) collection in autologous stem cell transplant setting, was detected in the peripheral blood (PB) of a few patients before CAR-T administration and it seems to improve the efficacy of CAR-T therapy. The mechanisms by which CHIP influence CAR-T efficacy remain to be elucidated, because CHIP was never evaluated after CAR-T infusion nor in fractionated blood populations. In this project, we will study about 20 patients who will be treated with CAR-T cell therapy (tisa-cel and axi-cel) for the already approved indications in the FVG Network for Cellular Therapies (including Udine, Trieste and Aviano), before and after CAR-T administration. PB, bone marrow and lymphocytoapheresis products will be studied by Next Generation Sequencing, as targeted panel sequencing, by flow cytometry and by Wilms Tumor-1 (WT-1) expression as marker of leukemic transformation. We will analyse the mutational landscape of bone marrow hematopoiesis and separated T lymphocytes of patients who underwent CAR-T cell therapy before and after CAR-T administration. Our objective is searching any sign of myelodisplasia related abnormalities, thereby providing further insight into the mechanism of post CAR-T cytopenias, efficacy and risk of t-MN development.

Partner del progetto:                                                                                

• Università degli Studi di Udine
• Università degli Studi di Trieste

Date inizio e fine progetto: 16.10.2023 – 15.10.2025

Budget totale del progetto: 166.776,00€

Sito web: https://prin.mur.gov.it/ 

Finanziato dall’Unione europea – Next Generation EU