Project Funding Details

Despite the introduction of novel chemo-free approaches, in particular covalent BTK inhibitors (BTKi) and BCL2 inhibitors (BCL2i), chronic lymphocytic leukemia (CLL) remains incurable. Patients with CLL previously exposed to BTKi and BCL2i are a new unmet clinical need with limited standard treatment options. Recent evidence from our group and others points toward an aberrant activation of the canonical/noncanonical NF-κB pathway as a potential mechanism leading to earlier progression and drug resistance. Dimethyl fumarate (DMF) is an anti-inflammatory and immunoregulatory drug targeting NF-kB pathways activation and the NRF2 anti-oxidant circuit and is currently used in clinical practice to treat patients with multiple sclerosis (MS) or psoriasis. Our preclinical data show that DMF acts as anti-inflammatory and pro-apoptotic compound in primary CLL cells, without affecting normal leukocytes viability. DMF treatment may be beneficial to patients with CLL thanks to the targeting of the NF-κB pathway, a CLL specific vulnerability linked to the inflammatory and metabolic state of the leukemic cells. We aim at evaluating efficacy and safety of DMF treatment in patients with relapsed/refractory CLL, and identifying clinical, cellular and molecular factors potentially associated with response to the DMF. We propose a phase 2 interventional clinical trial aimed at evaluating the efficacy and safety of DMF in patients with relapsed/refractory CLL (AIM 1). This study will be conducted as a multicenter, single-arm, open-label trial. Eligible patients (CLL diagnosis, previously exposed to at least 1 covalent BTKi and 1 BCL2i and/or unsuitable for such therapies, n=40) will receive DMF according to the schedule administered in MS (120 mg BID for 7 days, then 240 mg BID until progression or unacceptable toxicity or for 24 months, whichever is longer). Response assessment will be performed every 3 months. Baseline and serial samples from the peripheral blood (PB) of patients enrolled will be characterized in terms of cell viability, oxidative stress response, inflammatory and metabolic response (AIM 2) and by targeted deep-sequencing and RNA sequencing analysis (AIM 3) to identify factors associated with clinical response to DMF (AIM 4). AIM #1 will allow us to define the clinical response to DMF and will provide relevant information on the efficacy of NF-kB targeting in resistant disease. AIM #2 will shed light on the effects of the drug in leukemic and non-leukemic cells subpopulations in the PB of patients while AIM #3 will define their molecular features, at baseline and over DMF treatment, AIM #4 will correlate the cellular and molecular features with clinical response in order to identify predictive characteristics of response to DMF treatment. The successful completion of the project will help provide a proof of principle of the efficacy of NF-kB targeting in in the context of the new unmet clinical need of BTKi and BCL2i exposed patients and also identify an innovative treatment strategy that targets one of the key pathways (i.e. NF-kB) acting in the onset of many other oncological diseases.