Kalos, Denise

9510 Background: Although acute toxicities associated with adoptive cellular therapy using lifileucel are well described and largely occur within the first 2 weeks of treatment, adverse events beyond this early window remain incompletely characterized. We sought to characterize treatment-related adverse events (AEs) with emphasis on those starting or persisting ≥2 weeks after lifileucel infusion. Methods: We conducted a retrospective multicenter study across three centers (Moffitt Cancer Center, Massachusetts General Hospital, and Mayo Clinic). Patients with advanced melanoma treated with lifileucel were included. The primary endpoint was incidence and characterization of AEs occurring or persisting ≥2 weeks after standard of care lifileucel infusion. Results: Among 79 patients (median follow-up 11 months [95% CI, 9.6–15]), median age was 63 years (range 30–79), 59% were male (n = 47), 41% were female (n = 32), and ECOG PS was 0–1 in 98%. Patients received a median of 5 IL-2 doses (range 0–6). Of 79 patients, 78 experienced treatment-related adverse events that either persisted or occurred >2 weeks after cell infusion. A total of 308 delayed treatment-related adverse events were identified; 96 were new events (31%) and 212 (69%) were continued toxicities that started < 2 weeks after cell infusion. Lymphopenia was the most common delayed or persistent toxicity, occurring in a majority of patients (n = 68/79, 86%). Treatment-associated anemia (n = 59/79, 75%), fatigue (n = 56/79, 71%) and thrombocytopenia (n = 24/79, 30%) were also common. Viral infections occurred in 9.0% (n = 7), including CMV/EBV viremia (n = 1) and respiratory or gastrointestinal viral infections (metapneumovirus, parainfluenza, SARS-CoV-2, and norovirus). Hemophagocytic lymphohistiocytosis (HLH) occurred in 2 patients (n = 2/79, 3%) and was fatal in both cases. No other toxicity related deaths were noted. Autoimmune toxicities directly attributable to TIL included vitiligo in 9% (n = 7; median onset 41 days), uveitis in 5% (n = 4; median onset 26 days), and sensorineural hearing loss in 1% (n = 1; onset 28 days). All patients underwent TIL infusion in the inpatient setting; a total of 14 of 79 patients (18%) were re-admitted after discharge due to treatment-related toxicity (median time from infusion 19 days). Conclusions: In this multicenter real-world cohort, toxicities persisting beyond two weeks were largely driven by lymphodepleting chemotherapy–associated immunosuppression and cytopenias. These findings highlight the importance of structured post-discharge monitoring and support ongoing efforts to de-intensify lymphodepleting chemotherapy to improve safety while maintaining clinical benefit.

9551 Background: Lymphodepleting (LD) chemotherapy is required prior to tumor-infiltrating lymphocyte (TIL) therapy, yet the depth, kinetics, and completeness of peripheral T-cell recovery in practice remain poorly defined. Using a pooled, multi-institution cohort, we characterized longitudinal CD4 and CD8 T-cell reconstitution and the prevalence of CD4 lymphopenia following TIL therapy. Methods: We conducted a retrospective multicenter study across Mayo Clinic, Moffitt Cancer Center, and Massachusetts General Hospital of patients with metastatic melanoma treated with TIL (N = 41, median follow-up 7.6 months). Absolute CD4 and CD8 T-cell counts and CD4:CD8 ratios were assessed at baseline (pre-LD), week 4, month 3, and month 6 post-TIL. Clinically significant CD4 lymphopenia was defined as CD4 < 200 cells/µL. All patients received Pneumocystis jirovecii and antiviral prophylaxis, with antibacterial and antifungal prophylaxis administered per institutional protocols. Post-TIL infections were recorded. Paired changes from baseline were evaluated using Wilcoxon signed-rank testing. Results: Median age was 65 years (range 35-79), and 68% were male. At baseline, 16 patients (39%) had CD4 counts below the institutional lower limit of normal prior to LD. Eighteen patients (44%) received bridging therapy prior to TIL and had lower baseline CD4 and CD8 counts compared with those who did not ( p < 0.05 for both); however, post-TIL CD4 and CD8 recovery trajectories did not differ between groups. CD4 counts declined sharply following LD and demonstrated incomplete and heterogeneous recovery. Median CD4 decreased from 490 cells/µL at baseline to 250 at week 4, 290 at month 3, and 220 at month 6, remaining significantly below baseline at all post-TIL timepoints ( p < 0.05). Clinically significant CD4 lymphopenia was observed in 45% (10/22) of evaluable patients at month 3 and in 50% (44%, 7/16) at month 6. In contrast, CD8 counts increased early after TIL (median 240 to 590 cells/µL at week 4; p = 0.004) and remained higher than baseline at month 6. The CD4:CD8 ratio inverted from a median of 2.02 at baseline to 0.46 at week 4 and remained below 1.0 through month 6, reflecting sustained CD4 suppression despite CD8 recovery. Post-TIL infections occurred despite widespread prophylaxis, including bacterial (13%), viral (10%), and fungal (4.9%) infections. Conclusions: In a multi-institution cohort, LD chemotherapy preceding TIL is associated with profound and prolonged CD4 T-cell suppression, persistent CD4:CD8 inversion, and a high prevalence of CD4 < 200 cells/µL through 6 months. These findings identify delayed immune reconstitution as a common and clinically relevant consequence of TIL therapy and support prospective optimization of antimicrobial prophylaxis duration, vaccination timing, and immune monitoring strategies.

Abstract To examine the activity of ibrutinib in steroid-refractory chronic graft-versus-host disease (SR-cGVHD) after the US Food and Drug Administration approval, we conducted a multicenter retrospective study. Data were standardly collected (N = 270 from 19 centers). Involved organs included skin (75%), eye (61%), mouth (54%), joint/fascia (47%), gastrointestinal (GI) (26%), lung (27%), liver (19%), genital (7%), and others (4.4%). The National Institutes of Health (NIH) severity was mild in 5.7%, moderate 42%, and severe 53%. Thirty-nine percent had overlap subtype. Karnofsky performance status (KPS) was ≥80% in 72%. The median prednisone was 0.21 mg/kg (0-2.27). Ibrutinib was started at a median of 18.2 months after cGVHD onset and in earlier lines of therapy (second line, 26%; third, 30%; fourth, 21%; fifth, 9.6%; sixth, 10%; seventh or higher, 1.2%). Among evaluable patients, the 6-month NIH overall response rate (ORR; complete response [CR]/partial response [PR]) was 45% (PR 42%; CR 3%). The median duration of response was 15 months (range, 1-46). Liver involvement had association with 6-month ORR (multivariate [MVA] odds ratio, 5.49; 95% confidence interval [CI], 2.3-14.2; P &lt; .001). The best overall response was 56%, with most (86%) achieving by 1 to 3 months. With a median follow-up for survivors of 30.5 months, failure-free survival (FFS) was 59% (53%-65%) at 6 months and 41% (36%-48%) at 12 months. On MVA, increased age (hazard ratio [HR], 1.01; 95% CI, 1.0-1.02; P = .033), higher baseline prednisone (HR, 1.92; 95% CI, 1.09-3.38; P = .032), and lung involvement (HR, 1.58; 95% CI, 1.1-2.28; P = .016) had worse FFS. Ibrutinib discontinuation was most commonly due to progressive cGVHD (44%) or toxicity (42%). These data support that ibrutinib has activity in SR-cGVHD, provide new insight into factors associated with response and FFS, and demonstrate the toxicity profile associated with discontinuation.