Varnimcabtagene Autoleucel (ARI-0001) for Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) and Richter Transformation (RT)
Authors: Ortiz-Maldonado Valentin , Martinez-Cibrian Nuria , Del Campo Balguerías Gonzalo , Español-Rego Marta , Navarro Sergio , Lopez-Oreja Irene , Nadeu Ferran , Cobo Amparo , Brillembourg Helena , Alserawan Leticia , Castella Maria , Benitez-Ribas Daniel , Magnano Laura , Correa Juan Gonzalo , Rivero Andrea , Mozas Pablo , Gine Eva , Rodríguez-Lobato Luis Gerardo , Martínez-Roca Alexandra , Montoro-Lorite Mercedes , Ayora Pilar , Fernández de Larrea Carlos , Pascal Mariona , Setoain Xavier , Esteve Reyner Jordi , Urbano-Ispizua Alvaro , Juan Manel , Delgado Julio 
Published: December 2023

Background: The prognosis of CLL patients that do not respond to targeted therapy is unfavourable, especially in the case of adverse genomic aberrations (e.g. TP53 alterations or complex karyotype) or after transformation to aggressive B lymphoma (Richter transformation, RT). In patients with refractory CLL, anti-CD19 CAR-T (CART19) therapy has achieved complete response (CR) rates of 19-45%, with RT usually excluded from pivotal trials. However, long-term remission in CLL patients still remains a challenge with CART19 therapy.
Methods: We present the outcomes of all patients with relapsed or refractory (R/R) CLL with or without RT treated with the academic CART19 varnimcabtagene autoleucel (var-cel) from November/2017 to May/2023, including patients from the CART19-BE-01 trial and subsequent compassionate use programme. Patients received lymphodepletion with fludarabine (90 mg/m2) and cyclophosphamide (900 mg/m2) followed by 0.1-1 (CLL) and 0.5-5 (RT) x10e6 CART19 cells/kg in single or fractionated administration (10%, 30% and 60%) in a single institution.
Results: A total of 20 patients underwent leukapheresis and var-cel production. At screening patients had a median age of 58 years (44-74), 47% were females, with a median of 4 prior lines of therapy (2-9) including ibrutinib (89%), venetoclax (53%), R-CHOP (58%) and allo-HCT (21%). All patients had high-risk features, including unmutated IGHV (90%), TP53 lesions (89%), complex karyotype (43%) and RT (63%), as well as elevated LDH (74%), extramedullary disease (84%), and CSF infiltration (16%). Median bone marrow infiltration at screening was 18% (3-85), and median tumour metabolic volume (TMV) was 55 ml (0-1217). Var-cel manufacturing was performed in a median of 8 days (7-9). One patient required 2 apheresis and 1 RT patient died due to progressive disease without receiving var-cel. All patients received bridging therapy (BT), based on BTKi (53%), venetoclax (26%), chemotherapy (10%), steroids (10%) and radiotherapy (5%). Despite BT, all patients received var-cel either with stable disease (44%) or progressive disease (56%), in a median of 29 days (18-81) from apheresis to infusion. Fifty-eight percent of patients received 100% of the planned dose. The remainder received 10-30% due to early cytokine release syndrome (CRS), with a final median infused dose of 1 (0.4-5) x10e6 CART19 cells/kg. CRS was observed in 89% of patients, being severe in 11%. Only mild ICANS was developed in 11%. Tocilizumab and corticosteroids were administered in 44% and 17% of patients, respectively. Median duration of CRS and ICANS was 4.5 days (1-17) and 3 days (2-4), respectively. Absolute B-cell aplasia (0 B-cells/mL) was achieved in 94% of patients in a median of 14 days (7-34), with median duration not reached for CLL and RT. Tmax peak CART19 concentration was observed at day +24 (median, 7-148). With a median follow-up of 8,4 months (0.3-66.7), the overall response rate was 83%, with 83% achieving an MRD-negative CR (flow) in bone marrow (BM) and peripheral blood, and 67% achieving CR on extramedullary lesions (PET/CT). Median PFS and DOR was not achieved for either CLL or RT (figure 1). Disease progression was observed in 7 (39%) patients in a median of 63 days (7-237), 43% of which occurred due to CD19-negative antigen escape despite active CART19 persistence. No relapses have been observed after CR was achieved. By univariate analysis there was no significant differences for PFS regarding presence of RT, SD vs PD at infusion, high vs low LDH, BM infiltration (&gt; or &lt; 20%), or TMV (&gt; or &lt; 25 ml). However, PFS was shorter among patients with both, high BM infiltration plus high TMV, in comparison to patients with either low burden at BM and/or TMV (median PFS 2 months vs not reached, p = 0.0293) (figure 2).
Conclusions: Administration of the CART19 var-cel (ARI-0001) was feasible in 95% of CLL/RT patients, with robust and durable var-cel engraftment in 89% of treated patients, and durable complete responses observed in 61% of patients. These initial outcomes or var-cel in this population contrasts with the overall findings of CART19 therapy in CLL/RT and encourages to further develop var-cel on this high-risk population.