Sharp, John

Abstract Introduction: Older adults (OAs) with classic Hodgkin lymphoma (cHL) have inferior survival compared with younger patients (pts). NAVD has been widely adopted in clinical practice for frontline (1L) treatment of OAs with advanced stage cHL based on the subset analysis of S1826 study (Rutherford et al, JCO 2025) showing a 1-year progression-free survival (PFS) of 93% and 1-year overall survival (OS) of 95% after NAVD (n = 50) which remained durable on longer-term follow up. Another phase 2 study (Torka et al, JCO 2025) showed that NAVD is a highly effective and well-tolerated 1L regimen in OAs with cHL (n=40) across a wide range of geriatric impairments. Adverse events (AEs) and efficacy have not been reported in OAs treated with NAVD outside of a clinical trial. Hence, we sought to evaluate safety profile and efficacy outcomes of OAs with cHL treated with 1L NAVD in a real-world setting (RWS). Methods This is a multicenter retrospective cohort study of adults (≥18 years) with cHL treated with 1L NAVD between 2023 and 2025 at 20 US academic sites. Baseline characteristics and outcomes of pts ≥60 years were evaluated as a pre-planned subset analysis. The safety evaluable cohort received at least 1 cycle of NAVD and included pts who had not yet completed treatment. The efficacy evaluable cohort had completed 6 cycles of treatment including end of treatment (EOT) PET-CT and included pts who intended to complete treatment but died or discontinued due to progressive disease or AEs. The primary endpoint was EOT overall response rate (ORR). Secondary endpoints included EOT complete response rate (CRR), PFS and OS. PFS and OS were analyzed using the Kaplan Meier method. Results Among 311 pts, 81 were OAs (26%). Median age of the OA cohort was 70 (range 60-88) yrs, 65% male, 84% Caucasian, 71% nodular sclerosis subtype, 58% stage 4 disease, 59% B symptoms, 14% bulky disease (>7.5 cm), 69% extranodal sites, 41% EBV positive, 54% hypoalbuminemia, 49% IPS ≥ 4 and10% had an autoimmune disease. G-CSF was given in 81% pts. All 81 pts were evaluable for safety; 74% experienced a grade 3+ (≥G3) AE, 54% had ≥G3 hematological AE, 48% had ≥G3 neutropenia, 17% had febrile neutropenia. Infection rate was 28% with 10% ≥G3, neuropathy rate was 23% with 4% ≥G3. One infusion reaction was noted. Treatment related hospitalizations rate was 23% with median duration of 7 (range 1-16) days. There were 24 immune related AEs (IrAE) (30%) of which 5 were ≥G3. Most common IrAE was hypothyroidism (n=5), followed by inflammatory arthritis (n=4), pneumonitis (n=2, ≥G3, n=1), hepatitis (n=2, both ≥G3), adrenal insufficiency (n=2, ≥G3, n=1), colitis (n=2), and rash (n=2). One patient each had autoimmune neutropenia, sarcoidosis of lung/skin and myocarditis (≥G3). Overall, 15% pts required steroids with resolution of IrAEs in 56% cases, 30% (n=7) pts required continued therapy (levothyroxine in 4 pts, steroids in 3 pts, medical tx for heart failure in 1 pt). Treatment was interrupted in 22%, reduced in 22%, and discontinued in 23% pts. Nivolumab was discontinued in 14% pts. Among all pts (n=81), 81% had an interim PET-CT after 2-4 cycles. The ORR and CR rate at interim PET-CT were 100% and 81%, respectively. In the efficacy evaluable pts (n=52; 24 still on therapy), the EOT ORR and CRR were 93.2% and 84% in OAs compared to 96.8% and 91.7% in pts <60yrs, respectively. At a median follow up of 10.2 mo (range 0.27-28.52), the 1-yr PFS was 90.6% (95% CI: 82.7%-99.3%) in OAs and 95.5% (95% CI: 91.6%- 99.6%) in pts <60 yrs (p=0.044). 1-yr OS was 97.5% (95% CI: 94.1-100%) and not evaluable in pts <60yrs (p=0.017). None of the baseline features were predictive of response, additional analysis to understand impact on AEs and survival is ongoing. Among the 5 pts with progression/relapse, 4 were primary refractory. 4 pts received 2nd line (2L) therapy.79 pts are alive at data cut off, 2 deaths occurred- 1 infection-related and other unknown; both after the 1st cycle. Conclusions In this largest RWS cohort of OAs treated with NAVD we showed comparable response rates, AEs and 1-year survival outcomes to those in the pivotal S1826 trial. Notably, rates of ≥G3 AEs including infections, neuropathy and IrAEs remained low and manageable. Although survival significantly improved with NAVD compared to historical data, outcomes of OAs remained inferior compared to pts <60 yrs. Our data reinforces the use of NAVD as the preferred 1L option for OAs with advanced stage cHL.

Abstract Introduction: NAVD has become a standard-of-care for frontline (1L) treatment (tx) of advanced stage cHL, based on the results of the S1826 study. S1826 demonstrated a 1-year progression free survival (PFS) of 94% for NAVD compared to 86% for brentuximab vedotin-AVD, which remained durable at 2 years (Herrera et al, NEJM 2024). Adverse events (AEs) and efficacy have not been reported in patients (pts) treated with NAVD outside of a clinical trial. Hence, we sought to evaluate safety profile and efficacy outcomes of pts with cHL treated with 1L NAVD in a real-world setting (RWS). Methods: In this multicenter retrospective cohort study, we included pts ≥18 years with cHL treated with 1L standard of care NAVD between 2023 and 2025 at 20 US academic sites. The safety evaluable cohort received at least 1 cycle of NAVD and included pts who have not completed tx. The efficacy evaluable cohort had completed 6 cycles of tx including end of treatment (EOT) PET-CT and included pts who intended to complete tx but died or discontinued due to progressive disease or AEs. The primary endpoint was EOT overall response rate (ORR). Secondary endpoints included EOT complete response rate (CRR), PFS and overall survival (OS). PFS and OS were calculated from the start date of tx and analyzed using the Kaplan Meier method. Results: A total of 311 pts with cHL were treated with NAVD with 26% of pts with tx ongoing (n=83) and 73% with tx completed (n=228). Baseline demographics included 55% male pts, 60% with stage IV disease (stage IIB, n=4) and 84% with nodular sclerosis subtype. Median age was 37 years (range 18-88), 29% had bulky disease (>7.5 cm), 28% were EBV positive (n=74/268), 8% had history of an autoimmune disease, and 31% had an IPS 4-7. G-CSF was given in 64% of pts. All patients were safety evaluable. Tx was interrupted (any length) in 24%, reduced in 12%, and discontinued in 14%. The most common reason for dose reduction was neuropathy in 4%. Nivolumab was discontinued in 10% and all therapy in 3.7% due to toxicity. Any AE and any grade 3 or higher AE (>G3) were observed in 92% and 62%, respectively. Neutropenia of any grade occurred in 68% (48% >G3), infection in 25% (10% >G3), and neuropathy in 30% (2.8% >G3). Hospitalization for an AE occurred in 20% (4.5% febrile neutropenia). Among pts with complete data (n=305), any immune related AE (irAE) occurred in 78 pts (25.6%) with any >G3 irAE in 23 pts (7.5%). The most common irAEs included hypothyroidism (7.9%, all grade 1-2), hepatotoxicity (1.6% G1/G2, 3.3% >G3), inflammatory arthritis (3% G1/G2, 0.6% >G3), rash (2.6%, all grade 1-2), and colitis (1% G1/G2, 1% >G3). Other notable >G3 irAEs included adrenal insufficiency (n=2), AKI/ATN (n=1), myocarditis (n=1), diabetes (n=1) and pancreatitis (n=1). Of 84 irAE events, 47 (56%) have had complete resolution. Among all pts, 14.4% (n=45) required systemic steroids at any time (intravenous in 4.1%), 3.2% (n=10) require ongoing steroids/immunosuppression and 8.3% other therapy for an irAE (n=23 levothyroxine, n=1 hemodialysis, n=1 heart failure tx, n=1 insulin). Among all pts, 265 (85%) had an interim PET-CT after 2-4 cycles. The ORR and CRR at interim PET-CT were 97% and 78%, respectively. In the efficacy evaluable population (n=228), the EOT ORR and CRR were 96% and 90%. The median follow up was 10.2 mo (range 0.27-28.52). The 1-year PFS and OS estimates were 93.8% (95% CI: 90.8-98.4%) and 99.1% (95% CI: 97.9-100%), respectively. In multivariable analysis (MVA), only IPS score (OR 0.6, 95%CI: 0.59-0.60) was associated with lower CRR. In Cox univariable analysis, EBV+ status (HR=14.8, 95% CI: 3.2-69.2), IPS score (HR=1.5, 95% CI: 1.0-2.2), and ESR (HR=1.02, 95% CI: 1.00-1.04) were associated with worse PFS. Among the 11 pts with progression/relapse, 9 were primary refractory. 10 pts were started on second line (2L) therapy, and all pts are alive (1 pt pending 2L tx initiation). There were 2 deaths: one related to infectious complications and other unknown and both occurred after the first cycle of therapy. Conclusions: Pts treated with NAVD in a large RWS showed comparable response rates and 1-year survival outcomes to those in the pivotal S1826 trial. Most AEs were similar and grade 1-2, but close monitoring of irAEs is necessary given the potential long-term toxicity of checkpoint inhibitors and potential for ≥G3 irAEs (7.5%) in this young patient population. Our data supports the use of NAVD for 1L advanced stage cHL.

Introduction: Scant data exist on prognostic factors, survival and treatment (Tx)-related outcomes in SCNSL. We conducted a multicenter international analysis to identify prognostic factors and outcomes in SCNSL at diagnosis (de novo), or after frontline Tx (1L) either with (concomitant) or without (isolated) systemic (syst) relapse. Methods: This study collected data from patients (pts) treated between 2001-2023 at 35 centers. Overall (OS) and progression-free survival (PFS) were calculated from SCNSL diagnosis to first event (death for OS, relapse/death for PFS) or last follow-up. Uni- (UVA) and multivariable (MVA) Cox analyses were performed to assess prognostic factors; Kaplan-Meier method was used to estimate survival. Results: 1173 (US: 863, UK: 273, Canada: 37) pts with SCNSL were included. Baseline characteristics were median age: 62 years (interquartile range 52.5-69), male sex: 58.7%, elevated LDH: 71.1%, stage III/IV: 88.6%, HIV: 3%, transformed LBCL (tLBCL): 13.8%, non-germinal center B-cell like (non-GCB) subtype: 52.3%, double expressor (DE): 40%, MYC rearrangement (MYC-R): 28.3%, MYC/BCL2 double hit: 16.6%, MYC/BCL2/BCL6 triple hit (TH): 6.1%. Among 522 pts with de novo SCNSL, 84.2% had involvement of a single CNS compartment (44.7% brain parenchyma; 40.4% leptomeningeal [lepto]). 1L regimens included 36.2% R-CHOP with high-dose methotrexate (HD-MTX), 12.5% MARIETTA-type, and 9.8% R-CODOX-M/IVAC; 54.6% received intrathecal chemotherapy. Consolidation Thiotepa-based autologous stem cell transplant (TT-ASCT) occurred in 15.3%. The majority of pts who underwent TT-ASCT had previously achieved CR or PR in syst (92.5%) and CNS (72.5%) compartments. At median follow-up 25.7 months (mos), subsequent relapse was observed in 27.5% TT-ASCT recipients: 36.3% had isolated CNS, 27.4% syst, and 36.3% concomitant. 588 pts presented with SCNS after 1L (66.2% isolated, 33.8% concomitant). Brain parenchyma involvement was observed in 56.8%, lepto in 22.6%. Tx included 31.6% HD-MTX combination (eg, R-MPV, MTR); 18.4% HD-MTX +/- rituximab; 16.2% MARIETTA-type; and 9.4% platinum-based regimen. Consolidation TT-ASCT occurred in 22.4% (n=132), and 13.8% (n=81) received CAR-T cell therapy (excluding subsequent relapses in de novo group). Syst (65.1%) & CNS (69.1%) responses (CR/PR) were higher before TT-ASCT compared to CAR-T cell (49.5% & 54.5%, respectively). After TT-ASCT, 52 pts (39.3%) relapsed, mainly in the CNS (n=30, 57.7%), with only 4 (7.7%) concomitant. After CAR-T, 48 pts (59.3%) relapsed: 15 (31.2%) isolated in CNS and 15 (31.2%) concomitant. 12-month cumulative incidence of relapse (with death as competing risk) was 21.1% after TT-ASCT and 55.8% after CAR-T. In 63 pts (5.4%), the first CNS event occurred >2 lines of Tx. With median follow-up of the entire cohort of 24.6 mos, median PFS and OS were 11 and 21 mos, respectively. mPFS and mOS were significantly better in pts with de novo SCNSL (13.4 & 47.4 mos) compared to SCNSL after 1L (10.4 & 14.2 mos) and >2 lines of Tx (6.5 & 9.7 mos); P<0.0001. Factors associated with significantly shorter OS in UVA across all presentations were age >60, male sex, GCB subtype, MYC-R, tLBCL, DE, TH, elevated LDH, ECOG PS ≥2, SCNSL after 1L (vs. de novo), and failure to achieve syst/CNS response to 1L. Of these, age >60, male sex, MYC-R, ECOG PS ≥2, and failure to achieve response to 1L remained significant in MVA. In de novo cases, age >60, DE, ECOG PS≥2, and failure to achieve syst/CNS response to 1L were associated with poorer OS; for pts with SCNSL after 1L, age >60, GCB subtype, and ECOG PS ≥2 were significant. Pts treated with HD-MTX-based regimens after 1L experienced longer OS than those treated with platinum regimens or high-dose cytarabine. In de novo cases, TT-ASCT was significantly associated with longer OS (HR=0.58; P=0.025) in MVA after adjusting for significant factors, 1L type, and response. For SCNSL at relapse, TT-ASCT (HR=0.34; P<.0001) and isolated SCNSL presentation (vs. concomitant HR=0.70, P=0.007) were associated with longer OS, adjusting for significant factors, type of second-line Tx, & site of CNS relapse. Conclusions: This study represents the largest analysis of SCNSL inclusive of all modes of presentation. Concomitant SCNSL at relapse was associated with poor outcomes, while TT-ASCT consolidation was associated with improved OS in de novo & relapsed disease. Despite advances in LBCL SCNSL remains an unmet therapeutic need.