Safety and preliminary efficacy of combined lenalidomide and CD19 CAR T-cell therapy in relapsed/refractory CLL: A phase I study

Abstract Introduction Despite the clinical efficacy of CD19 CAR-T cells in Non-Hodgkin lymphomas, the clinical efficacy of CD19 CAR T-cell therapy in chronic lymphocytic leukemia (CLL) is at least two times lower. The inability to establish immunological synapses, along with low levels of activation, killing capacity, and proper proliferation of CAR-T cells in CLL, have been identified as contributing factors. Preclinical tests have shown that the immunomodulatory drug lenalidomide can increase the interaction between CLL cells and CD19 CAR T-cells, leading to enhanced activation, proliferation, and killing of CLL cancer cells. Methods This is an open-label, non-randomized Phase I/II clinical trial, VTB-CLL002 (ClinicalTrials.gov identifier: NCT06762431), evaluating the safety and efficacy of CD19 CAR-T cell therapy combined with concomitant and maintenance lenalidomide in patients with relapsed or refractory (R/R) CLL and small lymphocytic lymphoma (SLL). In a 3+3 clinical trial design, patients received escalating doses of autologous T cells transduced with a lentivector encoding a second-generation CD19 CAR-T cell construct (FMC63.IgG4.CD28TM.BBz), with doses ranging from 25 million to 100 million cells.. The administration followed a standard lymphodepletion regimen involving 25 mg/m2/day fludarabine for 3 days, and 250 mg/m2/day cyclophosphamide for 3 days. Patients should have received Ibrutinib for 3 months until day 0, after which they switched to lenalidomide 10 mg orally from day 0 to day +6. At 1 month, patients were assessed for response. Based on minimal residual disease (MRD) status in peripheral blood measured by flow cytometry, MRD-positive patients are suggested to undergo six cycles of combination therapy with lenalidomide and obinutuzumab, while MRD-negative patients receive three cycles of maintenance lenalidomide. The primary endpoints of the study are safety assessments, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), hemophagocytic lymphohistiocytosis (HLH), cytopenias, dose-limiting toxicities, and the determination of the maximum tolerated dose and the recommended Phase 2 dose. The secondary endpoints include efficacy measures such as overall response rate (ORR), complete response (CR), and MRD-negative response rates according to iwCLL2018 response criteria. The clinical trial is still ongoing and actively recruiting additional patients. Results As of the data cutoff on July 31, 2025, a total of 8 patients had been enrolled in the study. The median follow-up duration was 9 months (range: 3 to 24 months). Patients were treated across three dose levels: 3 patients at DL1 (25 million CAR-T cells), 3 patients at DL2 (50 million CAR-T cells), and 2 patients at DL3 (100 million CAR-T cells). The patients had received a median of 2 previous lines of therapy (range: 2 to 6). All patients developed cytokine release syndrome (CRS), with 3 patients (42.8%) experiencing grade 3 CRS or higher. Immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in 4 patients (57%), with 3 patients (42.8%) experiencing grade 3 or higher ICANS. Low grade HLH developed in 3 patients (42.8%). All adverse events of special interest were managed appropriately and never exceeded day 28 post-treatment. The median early ICAHT (Immune Effector Cell-Associated Hematotoxicity) grade was 3 (range: 1 to 4), and the median late ICAHT grade was also 3 (range: 2 to 4). The best ORR was 100%, with all 8 patients achieving CR that was MRD-negative. One patient transitioned from MRD-negative to MRD-positive disease while maintaining a CR and continuing lenalidomide plus obinutuzumab therapy, which was associated with a declining MRD level and reexpansion of CD19 CAR T-cells. All patients are demonstrating an ongoing CR. Conclusion The Phase I/II clinical trial VTB-CLL002 (ClinicalTrials.gov identifier: NCT06762431), investigating concurrent lenalidomide administration with CD19 CAR T-cell therapy in R/R CLL/SLL patients, is demonstrating an encouraging preliminary safety profile that is manageable. Additionally, early signs of improved efficacy have been observed across all dose levels, with a significantly higher ORR, CR and MRD negativity rate compared to monotherapy with existing CAR T-cell products. Ongoing studies involving larger patient cohorts and extended follow-up periods aim to provide further insights into the therapy's efficacy and safety parameters.