Acalabrutinib in Combination with Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy in Relapsed/Refractory B-Cell Lymphoma: A Phase I/II Study of Safety, Efficacy and Immune Correlative Analysis

Introduction Limitations of effective CD19-targeted chimeric antigen receptor T-cell therapy (CAR T) in relapsed/refractory (R/R) B-cell lymphoma (BCL) include lack of sustained remissions and the potential for adverse effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). BTK inhibitors are immunomodulatory and may enhance CAR T-cell expansion, engraftment and tumor clearance while decreasing the frequency and severity of CRS (Gauthier, et al. Blood 2020). Methods We conducted a phase I/II, open-label trial (NCT04257578) of adult patients meeting FDA-approved criteria for axicabtagene ciloleucel (axi-cel). Acalabrutinib (acala) was continuously administered at 100 mg twice daily over the 3 study phases: 1) Bridging: Between 3 weeks and 24 hours prior to leukapheresis until lymphodepletion (LD), 2) Cell therapy: From LD to 30 days after axi-cel, 3) Maintenance: From 30 days to 1 year after axi-cel or until unacceptable toxicity or disease progression (Figure 1). Axi-cel was administered per institutional practice. The primary endpoint was safety based on rates of grade ≥3 CRS or ICANS within 30 days of axi-cel. We also assessed bridging success rate, overall response rate (ORR) and complete response (CR) rate following axi-cel, progression-free and overall survival and immune response biomarkers. Results As of October 1, 2023, 17 patients have enrolled and 16 have received axi-cel. Fourteen patients had large BCL (12 DLBCL [5 with double/triple hit] and 2 PMBCL) and 3 had FL. Median age was 58 (range 34-74) years and the median number of prior regimens was 3 (range 1-5). Of large BCL patients, 6 (43%) had primary refractory disease and 5 (38%) had relapsed within 12 months of initial therapy; 4 (31%) patients had previous autologous stem cell transplant. Fifteen of 16 patients (94%) who underwent axi-cel were successfully bridged from prior to leukapheresis to LD with single agent acala; 1 received added radiation. After axi-cel, three (19%) patients had grade 3 ICANS which resolved with dexamethasone and anakinra or tocilizumab. No patients received prophylactic dexamethasone. No patients experienced grade ≥3 CRS or any grade hemorrhage or tachyarrhythmia. No patients discontinued acala due to toxicity, meeting an interim safety endpoint. The ORR and CR rate at day 30 post axi-cel was 93% and 71%, respectively. At a median follow-up of 15.8 (range 1.7-31.1) months, 12 (75%) patients are alive and 11 are progression-free. Post axi-cel cytokines peaked at median of day 6 [median IL-6 196 pg/ml (range 20-11803), ferritin 425ng/ml (156-2051), CRP 52.9 mg/L (7.7-239.7)]. Conclusions Acala successfully bridged most patients and when given concurrently with axi-cel, safely maintained high CR rates. CRP and ferritin levels were typically modestly elevated after axi-cel. Severe CRS was not observed and high-grade ICANS was uncommon.