Chronic Lymphocytic Leukemia

P1, N=50, Active, not recruiting, Karolinska University Hospital | Recruiting --> Active, not recruiting

PRMT1 inhibition decreased the asymmetric dimethylarginine of MAST1 at R806 and downregulated the activation of the MAPK pathway by affecting the phosphorylation of MEK1 and ERK1/2 in CLL cells. In summary, our results indicated that PRMT1 promoted CLL tumorigenesis via MAST1-mediated regulation of MEK1 signaling and highlighted the potential of C7280948 as a novel therapeutic agent for CLL treatment.

However, a subset of aged mice with mutated Rps15 eventually develop B-cell leukemia (37% penetrance), which exhibits increased Myc activity with strong pro-survival and proliferation signatures. Mutant RPS15 thus induces both hypo- and hyper-proliferative signals, initially weighted towards cell cycle arrest; and that through translational rewiring, oxidative stress, DNA damage response defects and genomic instability set the stage for the acquisition of additional driving mutations, such as TP53 deletion, that can overcome this cell cycle block to trigger tumorigenesis.

The phase 3 CLL13/GAIA trial assesses three time-limited combinations: venetoclax-rituximab (RV), venetoclax-obinutuzumab (GV), and venetoclax-obinutuzumab-ibrutinib (GIV) compared to chemoimmunotherapy (CIT). Fit patients with CLL without TP53 aberrations were randomized between six cycles of CIT (fludarabine-cyclophosphamide-rituximab [FCR], bendamustine-rituximab [BR]) or 12 cycles of RV, GV or GIV (GIV: ibrutinib continuation until cycle 36 if measurable residual disease [MRD] at months 12/15)...In the GIV arm, clinically relevant QoL improvements occurred later (month 15, after the end of treatment in most patients) than with GV/RV, likely due to a higher treatment-related symptom burden. The trial is registered at clinicltrial.gov with the identifier, NCT02950051.

Furthermore, BIS-LNPs@DCA-siTNF attenuated osteoclastogenesis, restored bone integrity, and improved locomotor performance. These results establish BIS-LNPs@DCA-siTNF as a programmable nanoplatform that overcomes both pharmacological and microenvironmental barriers, offering a promising approach for enhanced AML therapy.

P=N/A, N=50, Recruiting, Mayo Clinic | Trial completion date: Nov 2026 --> Nov 2028 | Trial primary completion date: Nov 2026 --> Nov 2028

P=N/A, N=70, Not yet recruiting, University Hospital, Angers | Trial completion date: Oct 2027 --> Jun 2028 | Initiation date: Sep 2025 --> May 2026 | Trial primary completion date: Sep 2027 --> May 2028

P1, N=437, Active, not recruiting, BeOne Medicines | Trial completion date: Aug 2027 --> May 2027 | Trial primary completion date: Aug 2027 --> May 2027

P2, N=75, Recruiting, Ascentage Pharma Group Inc. | Trial completion date: Dec 2024 --> Dec 2027 | Trial primary completion date: Sep 2024 --> Dec 2026

By applying time stamping to a mouse model of unmutated CLL, we demonstrate that leukemic expansion is driven by B-1 clones that arise prior to postnatal day 10. Importantly, B-1 cells in mice and humans share molecular features with unmutated CLL, altogether supporting a potential contribution of ELO B cells to this disease.

P1, N=135, Active, not recruiting, AbbVie | Recruiting --> Active, not recruiting | N=225 --> 135

P1, N=46, Recruiting, City of Hope Medical Center | Not yet recruiting --> Recruiting | Trial completion date: Jun 2027 --> Feb 2030 | Trial primary completion date: Jun 2027 --> Feb 2030