Rapid MRD-Negative Responses in Patients with Relapsed/Refractory CLL Treated with Liso-Cel, a CD19-Directed CAR T-Cell Product: Preliminary Results from Transcend CLL 004, a Phase 1/2 Study Including Patients with High-Risk Disease Previously Treated with Ibrutinib

Introduction Treatment of CLL is rapidly evolving, now including oral targeted agents and novel combinations. However, complete response (CR) rates remain low and continuous therapy is required. Eradication of minimal residual disease (MRD) is an increasingly important endpoint and an independent predictor of improved survival. Lisocabtagene maraleucel (liso-cel; JCAR017) is an investigational CD19-directed 4-1BB CAR T cell product administered in a defined composition of CD8:CD4 CAR T cells. TRANSCEND CLL 004 is an open-label Phase 1/2 trial of liso-cel in patients (pts) with relapsed/refractory (R/R) CLL (NCT03331198). Preliminary safety, pharmacokinetic (PK), and efficacy results from the Phase 1 monotherapy dose-finding portion of this study are reported. Methods Pts with CLL/SLL were eligible if they had received 3 (standard risk) or 2 [high risk: del(17p), TP53 mutation, unmutated IGVH, or complex karyotype] prior lines of therapy, including a Bruton's tyrosine kinase inhibitor (BTKi) unless medically contraindicated. Pts with active untreated CNS disease, ECOG >1, or Richter's transformation were excluded. After 3 days of lymphodepletion with fludarabine and cyclophosphamide, pts received liso-cel infusion. Two dose levels (DL) have been tested (DL1=5 × 107 CAR T cells; DL2=1 × 108 CAR T cells). Dose escalation followed a modified toxicity probability-interval-2 (mTIPI-2) algorithm. Dose-limiting toxicities (DLTs) were evaluated for 28 days post liso-cel infusion. Responses were assessed by iwCLL 2008 criteria. MRD was assessed at 10-4 sensitivity by 6-color flow cytometry using peripheral blood and at 10-6 sensitivity by clonoSEQâ (Adaptive) deep sequencing of bone marrow (BM) aspirates. Blood PK of liso-cel was determined using flow cytometry. Serum soluble chemokine and cytokine profiles for 39 analytes were assessed using V-PLEX immunoassays (MSD). Results At the time of data cut, 10 pts received liso-cel: 6 pts treated with DL1 and 4 pts with DL2. The median age was 64.5 years (range 51-76); 7/10 pts had high-risk disease. Pts had received a median of 4 prior therapies (range 3-8), including 9/10 pts who had received prior ibrutinib and 6/10 who previously received venetoclax and ibrutinib. No DLTs were identified. The most common adverse events (AEs) were cytokine release syndrome (CRS) (8/10 pts; all grade [G] 1/2), anemia (7/10 pts), thrombocytopenia (6/10 pts), and leukopenia (5/10 pts). Neurologic events (NE) were reported in 3/10 pts: G1