Clinical Outcomes of CLL Patients with Relapsed or Refractory Disease after CD19-Specific CAR-T Therapy

Background Chimeric antigen receptor T-cell (CAR-T) therapy has shown promising efficacy in high-risk CLL but progressive disease after CAR-T is not uncommon. We studied outcomes of pts with relapsed or refractory CLL after CAR-T to establish a benchmark for trials in this setting. Methods CLL pts treated with CD19-specific CAR-T on a clinical trial (NCT01865617) were reviewed. We identified pts with stable or progressive disease (SD/PD) on initial assessment or with relapse after a complete or partial response (CR/PR). Multivariable models included variables related to disease, treatment and CAR-T procedure. Results 28 pts had SD/PD (n=16; 57%) or relapsed (n=12; 43%) disease after CAR-T. Five pts (18%) had prior allo-SCT. Five pts (18%) received bridging therapy after leukapheresis. CAR-T adverse events included CRS in 22 pts (grade 3 in 2) and NT in 7 (grade 3 in 5). 5 of 11 pts who received Venetoclax (Ven) after CAR-T had progressed on it before but had a median duration of response (DOR) of 5 months (2-8) which was not different from pts who were Ven responsive before CAR-T [5 months (1-10); p = 0.95). This was not true for Ibrutinib (IB) with DOR of 2 months (0.5-7) in pre-CAR-T IB failed vs. 12.25 months (6-18.5) in pre-CAR-T IB responsive pts (p = 0.001). Fourteen pts (51%) had repeat CAR-T therapy (CR=3, PR=3) with DOR after second CAR-T of 5.5 months (1-33). Six pts (23%) received an allo-SCT median 6.5 months after CAR-T progression (CR=2, PR=1). History of progression on both IB and Ven before CAR-T was strongly associated with poor OS [hazard ratio (HR) 11.2 (95% CI: 2.5-50.5); p=0.002]. Receiving an allo-SCT after CAR-T progression was associated with an improved OS [HR 0.14 (95% CI: 0.02-0.97); p= 0.04]. [Fig-1] Conclusion This data sets a benchmark for clinical trials that intend to improve outcome of CLL pts with progression after CAR-T. OS after CAR-T progression was significantly shorter in pts who received CAR-T after failing both IB and Ven compared to others. This finding supports referring high-risk CLL pts for CAR-T treatment after progression on IB and while still responsive to Ven. For eligible pts, allo-SCT seems to provide a higher chance of survival in pts who progress after CAR-T.