Chronic Lymphocytic Leukemia

P2, N=80, Recruiting, City of Hope Medical Center | Trial completion date: Jan 2026 --> Jan 2029 | Trial primary completion date: Jan 2026 --> Jan 2029

Venetoclax, navitoclax, and obatoclax represented significant advances in apoptosis-targeted therapy, with venetoclax emerging as the most clinically successful agent. However, resistance mechanisms and side effects were significant challenges, necessitating further preclinical and clinical studies to optimize the therapeutic potential of these agents.

P1/2, N=160, Active, not recruiting, Allogene Therapeutics | Trial primary completion date: Aug 2025 --> Feb 2029

P3, N=630, Recruiting, BeOne Medicines

P1/2, N=41, Recruiting, Nurix Therapeutics Inc.

P3, N=465, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2026 --> Dec 2026

P=N/A, N=30, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

Treatment with a rituximab-bevacizumab combination regimen induced a second complete remission, sustained for six months at the time of reporting. Our case highlights the importance of routine CD5 testing in PCDLBCL-LT to identify this distinct subgroup and to guide appropriate differential diagnosis and patient monitoring.

Fifty-three patients received treatment after venetoclax: 29/53 (54.7%) received inhibitors (13 cBTKi, 11 idelalisib, 2 BCL2i, 3 non-covalent BTKi), 19/53 (35.8%) received chemoimmunotherapy (CT: 16 intensive, 3 palliative), 5/53 (9.4%) received hematopoietic stem cell transplantation (HSCT). Despite its limitations, this real-world study provides additional insights into double-exposed patients, who still pose a clinical challenge, demonstrating the superior efficacy of inhibitors over alternative treatment options. Enrollment in clinical trial and treatments with novel molecules, if available, may help address this unmet clinical need.

P1, N=316, Active, not recruiting, Eli Lilly and Company | Trial completion date: Dec 2025 --> Jun 2026

The phase 3 CRISTALLO trial (NCT04285567) compared first-line fixed-duration venetoclax-obinutuzumab (VenO) vs fludarabine, cyclophosphamide, and rituximab (FCR)/bendamustine-rituximab (BR) in patients with chronic lymphocytic leukemia, using undetectable minimal residual disease (uMRD) as the sole primary endpoint. No patient in the VenO arm was deemed high-risk for tumor lysis syndrome following obinutuzumab debulking; no clinical TLS occurred. These results confirm and extend the findings from the GAIA-CLL13 trial, validating increased depth of response with VenO vs chemoimmunotherapies.

Additionally, treatment with revumenib, a menin inhibitor, increased CLL-1 expression in AML cells harboring mixed-lineage leukemia (MLL) fusion genes or the NPM1 mutation, making them more susceptible to 2-23 CAR T cell-mediated cytotoxicity in vitro. These findings suggest that the clinical efficacy of CAR T cells derived from the novel, high-affinity anti-CLL-1 mAb 2-23 should be tested in patients with CLL-1-positive AML and also that combining 2-23 CAR T cells with revumenib may benefit some patients with CLL-1low/- AML.