Phase 1 Trial of LV20.19 CAR T-Cells for Relapsed, Refractory CLL and Richter's Transformation

Introduction Despite advances in targeted therapies, outcomes for both relapsed/refractory (R/R) CLL and RT remain poor. As part of a multi-cohort Phase 1/2 trial of lentiviral bispecific anti-CD20/anti-CD19 (LV20.19) CAR T cells for R/R B cell malignancies (NCT04186520), patients (pts) with RT were allowed to enroll on a DLBCL cohort and pts with CLL were enrolled on a dedicated Phase 1 arm. We report below initial safety and outcomes with LV20.19 CAR for CLL and RT pts. Methods We conducted a Phase 1/2 single center, prospective trial of LV20.19 CAR T cells at a fixed dose of 2.5 × 10e6 cells/kg manufactured utilizing an adaptive 8/12 day process with CliniMACS Prodigy. Eligible RT pts must have failed two lines of RT directed treatment. CLL pts required two prior lines of therapy, one mandated to be BTK or BCL2 inhibitor. Lugano criteria was utilized for RT response while Hallek iwCLL criteria was used for nodal CLL response. Results 14 pts with R/R RT and CLL received LV20.19 CAR T cells (RT=4 and CLL=10). All pts attained target cell dose. Median age was 65 years (55-75) and 12/14 pts were male (86%). Median lines of prior therapy was 3 (range 2-10). 12 pts (86%) had disease progression on covalent BTKi and venetoclax. Tp53 aberrations were present in 6 pts (43%) and 8 pts (57%) had complex cytogenetics.In terms of safety, 100% (n=14) developed CRS and 93% (n=13) required tocilizumab. There were 2 pts with grade 3 CRS, both with CLL. ICANS occurred in 3 pts (21%); 1 CLL patient (pt) had grade 3 ICANS and another CLL pt had grade 4 ICANS, the latter was found to have CLL involvement in the CSF. ICE-HS (immune effector cell hemophagocytic lymphohistiocytosis like syndrome) occurred at high rates developing in 9 pts (64%). Two CLL pts had grade 3 and grade 4 IEC-HS, respectively. Both met criteria for a dose limiting toxicity (DLT); one died of fungemia related to immunosuppression before disease assessment. The median ferritin in IEC-HS pts was 22454 ng/mL (range 8091-183578). Six (66%) IEC-HS pts required anakinra for management. Among CLL pts, there was no difference in CAR expansion (Figure 1) or polyfunctional strength index of the final product (Figure 2) between pts who did and did not develop IEC-HS. The 1-year non-relapse mortality was 7%.The day 28 ORR for evaluable pts (n=13) was 92% (CR=46%, PR=46%). In responding pts (n=12), day 28 bone marrow was negative for disease. To date, among these 12 pts, only 1 RT pt has relapsed with a median follow-up time of 11 months. The median duration of response was not reached (Figure 3) and the median overall survival was 15 months (Figure 4). Conclusions While LV20.19 CAR T cells were efficacious in CLL and RT it was limited by high rates of IEC-HS especially among CLL pts, a phenomena not commonly seen with other histologies. With two DLTs in the CLL cohort, the dose for future CLL pts was reduced to 1 × 10e6 cells/kg. Additional studies are needed to understand how CLL biology drives CAR IEC-HS.