Chimeric antigen receptor (CAR) T-cell therapy is curative for many patients with non-Hodgkin lymphoma (NHL). However, toxicity remains a significant barrier. Phosphoinositide 3-kinases (PI3K) inhibition can prevent IL-6 release by myeloid cells using in vitro models of CAR T induced cytokine release syndrome (CRS) (Amatya et al, ASH 2023). Duvelisib is an oral PI3K inhibitor with an established safety profile. Consequently, we performed a trial of duvelisib for CRS prophylaxis with standard-of-care (SoC) anti-CD19 CAR T-cell therapy for NHL (NCT05044039).

This single center phase Ib trial enrolling patients with relapsed/refractory NHL eligible for SoC CAR T-cell therapy into three cohorts. The dose escalation (DE) cohort utilized a 3+3 design with two dose levels (15 mg and 25 mg BID) to establish the recommended phase 2 dose (RP2D) of duvelisib. The DE and standard dosing (SD) cohort received duvelisib from day -2 to +28. The extended dosing (ED) cohort received duvelisib from day -2 to +28 and then for 14 of 28 days for up to 5 cycles.

The primary outcome is safety and tolerability, defined as dose limiting toxicities (DLTs) during the first 30 days of therapy. Patients receiving >50% of doses during the DLT period were evaluable for the primary outcome. Key secondary outcomes include incidence and severity of adverse events (AEs), CRS and immune effector cell associated neurotoxicity syndrome (ICANS), overall response rate (ORR), and progression-free survival (PFS). Patients receiving ≥1 dose of duvelisib were evaluable for the secondary outcomes. Since day -2 to +28 was identical across cohorts, CRS/ICANS are reported for all patients at the RP2D. For disease outcomes, patients in the DE/SD and ED cohorts were analyzed separately. CAR T-cell kinetics, T-cell subsets and cytokine levels were analyzed in peripheral blood.

42 patients were enrolled on the study (DE: 9, SD: 13, ED: 20). Median age was 68 years (range: 28–78), 95% were White, and 67% were male. Diagnoses included DLBCL (n = 20), MCL (6), FL (1) and PBMCL (1). Patients received axi-cel (22), liso-cel (14), brexu-cel (5) and tisa-cel (1).

40 patients were evaluable for the primary endpoint. No patient in any cohorts had a DLT and the RP2D was 25 mg BID. All 39 patients treated at the RP2D were evaluable for the secondary endpoints. 69% of patients experienced CRS at a median of 5 days following cell infusion (range 1-9). 68% did not have CRS in the first 3 days post-infusion. The CRS severity was low (grade 1: 54%, grade 2: 15%, grade 3/4: 0%). 83% (5/6) of patients with grade 2 CRS received axi-cel. ICANS occurred in 36% of patients at a median of 7 days (range: 4-17). The severity of ICANS was variable (grade 1: 18%, grade 2: 8%, grade 3/4: 10%). 71% (5/7) of patients with grade ≥2 ICANS received axi-cel.

39 patients treated at the RP2D were evaluable for disease response (DE/SD: 19, ED: 20). On day +100, the ORR was 53% and 56% with 42% and 44% achieving complete response (CR) in the DE/SD and ED cohorts, respectively. 8% of patients had progressive disease (PD) as best response. The median follow up was 356 days (SD: 547, ED: 206). The median PFS in the DE/SD and ED cohorts was 98 and 310 days, with a 1-year PFS of 35% and 42%.

15 patients had 23 serious adverse events (AEs) requiring hospitalization. 222 severe (grade ≥3) AEs were observed, including 139 severe hematologic AEs. Common non-ICANS/CRS, non-hematologic severe AEs included laboratory abnormalities (electrolyte: 10, LFT: 8) and infections (10), including one case of CMV reactivation. 12 patients enrolled in the study have died, 11 from progressive disease. One patient in the SD cohort died of neutropenic sepsis on day +50.

CAR T-cell expansion by flow cytometry was robust. Compared to historical controls (n = 6), duvelisib-treated patients (n = 17) showed a trend toward higher numbers of CAR T cells, along with a significantly increased CD8+ central memory T cells (p = 0.04). Additional analyses are ongoing, including serum cytokine profiling.

Results of this single center study demonstrate that the addition of duvelisib to CAR T-cell therapy is safe and may prevent grade 3-4 CRS. Duvelisib is also associated with delayed onset of CRS, which may enable outpatient administration of CAR T-cells. Though limited by clinical heterogeneity, ORR and 1-year PFS are comparable to prior reports, suggesting duvelisib does not significantly inhibit CAR T-cell function

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2025
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