Ricerc@Sapienza

The outcome of adult patients with acute lymphoblastic leukemia (ALL) dramatically improved over the last decade, due to the use of intensive, pediatric-like regimens also in the adult population and also because of the always more refined understanding of the molecular lesions underlying ALL development. On top of this, minimal residual disease (MRD), by means of Immunoglobulins/TCR (IG/TR) markers, is considered the most important prognostic factor for patients¿ stratification and treatment intensification.
The Ph-like subgroup ¿ displaying a transcriptional profile similar to that of Ph+ ALL but lacking the BCR/ABL1 transcript and instead having a number of fusion genes variable from case to case- represent a challenge: 1) since there is no gold standard tool for its recognition; 2) the outcome of these patients, despite treatment intensification, is still dismal. In the trial GIMEMA LAL2317, designed for newly diagnosed B-lineage Ph- ALL, patients received an intensive chemotherapy regimen and 2 cycles of blinatumomab, a bispecific monoclonal antibody, which has proven extremely effective in the setting of relapsed/ refractory cases as well as in patients who remain MRD+ after chemotherapy. While the overall preliminary results of the trial are extremely promising, Ph-like ALL cases, despite the fact that also achieved MRD negativity by IG/TR, there was a significantly higher incidence of overt hematologic relapse, suggesting that in this setting MRD evaluation by IG/TR is not a reliable tool and other markers are urgently needed.
Thus, in the present project, we aim at evaluating MRD by using digital droplet PCR (ddPCR)- a 3rd-generation and more sensitive PCR approach- using, instead of IG/TR markers, patient-specific fusion genes, that will be evaluated at diagnosis and during follow-up in order to rule out if this approach can reveal cases who remain MRD+ positive and therefore need further intensification, based on the use of a tyrosin kinase inhibitor.