Paper Details

ABSTRACT

BACKGROUND

CD19-directed CAR T-cell therapy is an option for patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), but efficacy remains limited. In clinical trials, liso-cel achieved a 47% overall response rate (ORR), 18% complete response rate (CRR), and a 57% 12-month progression-free survival (PFS) rate (median 11.9 months), while brexu-cel showed more modest activity and its development was discontinued in CLL. In CLL patients with Richter transformation (RT), excluded from these trials, real-world data showed ORRs of 65%, CRRs of 46%, and a median PFS of 8 months. This study evaluated the safety, efficacy, and durability of varnimcabtagene autoleucel (var-cel), a hospital-based CD19-directed CAR T-cell therapy, in CLL patients with or without RT across four Spanish centers.

METHODS

This is a retrospective multicenter study of patients with R/R CLL/RT treated with var-cel in the CART19-BE-01 trial (NCT03144583) and the subsequent compassionate-use program. Patients received lymphodepletion with fludarabine (30 mg/m²/day) and cyclophosphamide (300 mg/m²/day) for 3 days, followed by fractionated var-cel administration. Target doses were 1.0 or 5.0 × 106 CAR T cells/kg for CLL and RT, respectively. Key efficacy outcomes included ORR, CRR, PFS, duration of response (DOR), overall survival (OS), and undetectable measurable residual disease (MRD) rate by multiparameter flow cytometry. Efficacy was assessed according to iwCLL2018 criteria for CLL and Lugano criteria for RT.

FINDINGS

Between Oct 2017 and Jan 2026, 42 patients underwent leukapheresis; 38 received var-cel, including 20 with CLL and 18 with RT. Median age at infusion was 64 years (range 30–78) and 37% were female. High-risk features included 27 (87%) cases with unmutated IGHV and 27 (77%) with del(17p)/TP53 aberrations. Patients with CLL had received a median of three prior lines of therapy: all were exposed to a BTK inhibitor, and 16 (80%) to venetoclax. Among patients with RT, 15 (83%) had received prior CLL-directed therapy and 16 (89%) had relapsed or refractory disease after R-CHOP; median prior therapy comprised four lines overall, including two CLL-directed and two RT-directed lines. Median vein-to-vein time was 37 days (IQR, 29–46).

Any-grade cytokine release syndrome (CRS) occurred in 34 (89%) of 38 infused patients and was grade 3 or higher in one (2.6%). Any-grade immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in two (5%) patients; no grade 3 or higher events were observed. ­

Overall response was achieved in 32 of 38 patients (84%): 16 (80%) with CLL and 16 (89%) with RT. CR was achieved in 25 patients (66%): 12 (60%) with CLL and 13 (72%) with RT. Undetectable MRD in bone marrow and/or peripheral blood was achieved in 15 (83%) of 18 evaluable patients with CLL. One patient underwent consolidative allo-HCT while in remission.

With a median follow-up of 28.6 months, median PFS, DOR, and OS for the overall cohort were not reached. Estimated 12-/24-month PFS rates were 72%/62%; corresponding DOR rates were 78%/63%, and OS rates were 86%/83%. In patients with CLL, median PFS and DOR were 24.8 and 23.9 months, respectively, whereas median OS was not reached. Estimated 12-/24-month PFS rates were 74%/54%, DOR rates were 81%/48%, and OS rates were 95%/95%. In patients with RT, median PFS, DOR, and OS were not reached. Estimated 12-/24-month PFS rates were 71%/71%, DOR rates were 75%/75%, and OS rates were 76%/70%. Seven deaths occurred (2 CLL and 5 RT), all due to disease progression or relapse; the non-relapse mortality rate was 0%. Among patients achieving CR, the 2-year cumulative incidence of relapse was 17% (95% CI, 5-35). Notably, relapses after CR occurred only in CLL patients, whereas no relapses were observed among patients with RT. Among 14 relapse/progression events, four (29%) were associated with CD19-negative escape and nine (64%) occurred despite ongoing CAR T-cell detection.

CONCLUSIONS

Var-cel induced deep and durable responses with a favorable safety profile in high-risk CLL and RT, including a predominantly TP53-altered population. Disease control was particularly encouraging in RT, with ~70% PFS at one year and no relapses among patients reaching a CR, achieved almost entirely without consolidative allo-HCT.