Abstract Introduction: High-risk mantle cell lymphoma (MCL) is a molecularly complex, heterogeneous disease with frequent relapses and limited treatment options. BTK inhibitors and chimeric antigen receptor (CAR) T cell therapy are among the most highly effective treatment options for MCL. BTK inhibitors may favorably influence CAR T cell efficacy and safety. We report the results from a single-institution, single-arm pilot trial evaluating acalabrutinib plus rituximab (AR) followed by brexucabtagene autoleucel (brexu-cel) in previously untreated high-risk MCL patients (NCT05495464). Methods: Adult patients with MCL with adequate organ function and performance status were eligible if they had high-risk features including blastoid/pleomorphic morphology, high Ki-67 (≥50%), TP53 or other high-risk mutations, complex karyotype, and bulky disease (nodal mass ≥5 cm and spleen size ≥20 cm). Patients received acalabrutinib 100 mg orally twice daily and rituximab IV every 4 weeks for up to 9 cycles, or until partial response (PR) or stable disease (SD), whichever occurred earlier, followed by apheresis, standard lymphodepletion (LD), and brexu-cel infusion. Acalabrutinib was continued until start of LD. After brexu-cel infusion, patients were alternately assigned to acalabrutinib maintenance for up to 24 months starting on day 30 post-CAR-T (N=10) or no maintenance (N=10). The primary objective was to assess safety and efficacy. Minimal residual disease (MRD) was assessed by ClonoSEQ at serial timepoints. CAR-T quantification was performed by flow cytometry using anti-CD19 FMC63-scFv. Results: Among 20 patients treated, the median age was 61 years (range: 44-73) and 85% were male. Other baseline features included classic (50%), blastoid (25%), or pleomorphic (25%) morphology, high Ki-67 (40%), bulky disease (45%), high modified MIPI risk (85%), TP53 aberration (50%), and ≥3 somatic mutations (60%). Non-TP53 mutations were noted in ATM (65%), NSD2 (30%), NOTCH1 (25%), UBR5 (25%), KMT2D (20%), and SMARCA4 (10%). Chromoanagenesis was present in 62% of evaluable patients and 20% had complex karyotype. After one cycle of AR, 95% of patients achieved a PR and 5% had SD. All patients were treated with brexu-cel. At day 30 post-CAR-T, the overall response rate was 100%, 95% with complete response (CR) and 5% with PR. At 6 months, all patients with CR had an ongoing response whereas the single patient with PR had disease progression. With a median follow up of 13.1 months, the median progression-free (PFS) and overall survival (OS) were not reached (1-year PFS 94% and 1-year OS 100%). Undetectable MRD rates on days 0, 15, 30, 90, and 180 relative to brexu-cel infusion were 25%, 70%, 95%, 95%, and 95%, respectively. During AR treatment, only one patient had grade 3 adverse event (AE, skin rash) and there was no grade 4 AEs. After brexu-cel infusion, cytokine release syndrome (CRS) of any grade occurred in all patients and was a maximum of grade 3 in 5% and grade 4 in 10%. Median time to onset of CRS was 3 days (range 0-7). Any grade immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 75% of patients and was a maximum of grade 3 in 30% and grade 4 in 15%. Median time to onset of ICANS was 6 days (range 2-15), and median time to resolution of ICANS was 3 days (range 1-37). All ICANS events resolved. There were no grade 5 CRS or ICANS events. Intensive care was required in 40% with a median duration of 3 days (range 2-25). Grade 3 or 4 neutropenia, thrombocytopenia, and infections were noted in 60%, 20%, and 20%, respectively. CAR T cell numbers peaked 7 days after infusion with a median absolute number of 482 cells/uL (range 0-3468). Peak CAR-T expansion significantly correlated with development of any grade ICANS (P0.05). Conclusions: Our results in this pilot WINDOW-3 trial indicate that AR followed by brexu-cel treatment is highly effective with induction of high rates of undetectable MRD state in patients with previously untreated high-risk MCL. Additional follow-up is needed to assess durability of responses and impact of acalabrutinib maintenance on long-term safety and efficacy. While the incidence of high-grade CRS and ICANS were similar to prior results with brexu-cel in high-risk relapsed or refractory MCL patients, strategies to mitigate these toxicities warrant further investigation. Correlative studies to investigate mechanism of response, resistance, and toxicities are ongoing.
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