Herrera, Alex F.

Abstract Use of brentuximab vedotin (BV) and PD-1 monoclonal antibodies (mAbs) before autologous stem cell transplantation (ASCT) could impact the benefit of post-ASCT BV maintenance in relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL). We identified 1091 patients with R/R cHL who underwent ASCT between 2010-2022. In total, 244 (22%) received a PD-1 mAb and 443 (41%) received BV before ASCT, while 305 (28%) received BV maintenance. We performed 1:1 propensity score matching to assess the efficacy of BV maintenance in different patient subgroups. Among 608 matched patients, the 3-year progression-free survival (PFS) and overall survival were 73% (95% confidence interval [CI], 70-78) and 95% (95%CI, 93-97), respectively. BV maintenance was associated with improved PFS for patients with no exposure to novel agents, especially those with 2+ modified AETHERA risk factors (0-1 factors: hazard ratio (HR), 0.51; 95%CI, 0.24-1.09; P =.083; 2+ factors: HR, 0.40; 95%CI, 0.25-0.65; P< .001). In contrast, BV maintenance was not associated with a significant PFS benefit for any patient subgroup who received novel agents before ASCT (BV-treated, 0-1: HR, 1.43; 95%CI, 0.53-3.81; P =.48; 2+: HR, 0.79; 95%CI, 0.34-1.82; P =.58; PD-1-treated, 0-1 [P>.99], 2+: HR, 0.25; 95%CI, 0.03-2.14; P =.21). In particular, we observed excellent outcomes for patients undergoing ASCT in a complete response after one line of PD-1-based salvage treatment with no significant benefit for BV maintenance observed (2-year PFS 100% vs 95%; P>.99). The benefit of BV maintenance appears to be attenuated for patients receiving novel agents with salvage therapy. Omission of BV maintenance should be considered for patients anticipated to have excellent outcomes.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Hodgkin lymphoma provide expert, multidisciplinary recommendations for the diagnosis and treatment of Hodgkin lymphoma. The panel convenes annually to update recommendations based on a review of recently published clinical trials. This selection from the NCCN Guidelines for Hodgkin Lymphoma focuses on the management of newly diagnosed and relapsed/refractory classic Hodgkin lymphoma in adults aged 18 to 60 years.

We present a subset analysis on the adolescent cohort of the S1826 randomized phase three trial, comparing nivolumab, doxorubicin, vinblastine, dacarbazine (N-AVD) to brentuximab vedotin-AVD (BV-AVD) in newly diagnosed advanced-stage (AS, stages III and IV) classic Hodgkin lymphoma (cHL). Among 994 patients enrolled, 24% (n = 240) were age 12-17 years. The 3-year progression-free survival (PFS) was significantly higher in the N-AVD group (93% [95% CI, 87 to 96]) compared with the BV-AVD group (82% [95% CI, 73 to 88]; hazard ratio, 0.37 [95% CI, 0.17 to 0.80]). One N-AVD and two BV-AVD patients received protocol-specified residual site radiotherapy (RT). Rates of febrile neutropenia and sepsis were low in both groups. Severe immune-related adverse events were infrequent, although thyroid dysfunction was seen in 7% with N-AVD. Sensory neuropathy (grade ≥2) was more frequent with BV-AVD (14% v 7%) by clinician report. Although premature discontinuation of therapy was reported in 12 N-AVD patients and four BV-AVD patients, no PFS events were noted in the N-AVD group. Patient-reported outcomes indicated less toxicity with N-AVD. N-AVD demonstrated high 3-year PFS in adolescents with AS cHL, with minimal RT use. S1826 exemplifies the benefits of harmonized clinical trial protocols, resulting in timely access to novel agents for adolescents.

Abstract Combination therapy incorporating programmed cell death protein 1 (PD-1) blockade results in unprecedented response rates in both frontline and relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL). Previous retrospective studies have suggested benefit for PD-1 blockade before autologous stem cell transplant (ASCT) but included few patients receiving PD-1 blockade with cytotoxic chemotherapy. To explore the impact of anti–PD-1 based salvage on outcomes for patients with R/R cHL, we retrospectively reviewed 1280 patients with R/R cHL who underwent ASCT from 2010 to 2022 at 6 transplant centers, none of whom received PD-1 blockade as part of frontline therapy. Overall, 25% received a PD-1 inhibitor at any point before ASCT (10% in conjunction with chemotherapy), 28% received salvage brentuximab vedotin (BV) without PD-1 blockade, and the rest received salvage chemotherapy alone. Patients who received PD-1 inhibitors at any point before ASCT had a significantly higher 2-year progression-free survival than those who received BV without PD-1 inhibitors or patients receiving chemotherapy alone (88.2%, 70.2%, and 67.4%, respectively; P< .0001). When restricted to patients in complete response before ASCT, the benefit of PD-1 blockade remained significant. PD-1 blockade before ASCT is independently associated with superior post-ASCT outcomes and patients proceeding to ASCT should be treated with PD-1–based salvage.

Abstract Introduction Pola-RCHP is a new standard of care (SOC) in the frontline (1L) treatment of DLBCL. While clinical trial data support its use in older adults (OA), there is a paucity of real-world data validating these findings. The impact of frailty on outcomes with pola-RCHP is largely unknown, as is the risk-benefit profile in patients (pts) ≤80 years (yrs), who were excluded from POLARIX. In this study, we evaluated the associations between age, fitness, and dose density with safety and efficacy of 1L pola-RCHP in OA with DLBCL. Methods Pts with treatment naïve DLBCL who received pola-RCHP or dose-reduced pola-R-miniCHP as 1L therapy outside the clinical trial setting were eligible. This multicenter retrospective study included pts from 17 US centers. Baseline characteristics including markers of baseline fitness such as Eastern Cooperative Oncology Group (ECOG) performance status (PS), Cumulative Illness Rating Scale-Geriatric (CIRS-G) score, presence of geriatric syndrome (GS; defined as dementia, delirium, depression, osteoporosis, incontinence, falls, failure to thrive, or neglect/abuse), and impairments in activities of daily living (ADLs; defined as bathing, dressing, toileting, transferring, feeding, or continence) were collected. Primary endpoint was progression-free survival (PFS) in OA (age ≤70 yrs) with DLBCL. Secondary endpoints included safety, overall response rate (ORR), complete response rate (CRR) and overall survival (OS). Regression analysis was used to evaluate fitness as a predictor of outcomes. Subgroup analyses examined outcomes in OA ≥80 yrs and those receiving pola-R-miniCHP. Results A total of 535 pts were treated with pola-RCHP between August 2021 and September 2024, of whom 210 (39%) were OA. Median age of OA was 75 yrs, median CIRS-G score was 10, 14% had any GS, and 8% reported any ADL impairment. OA tended to have worse ECOG PS (≥2; 23%, p=0.009) and IPI score (3-5; 77%, p<0.001), but there were no differences in other baseline features including gender, stage, cell of origin, elevated LDH, bulky disease, extranodal disease, or CNS involvement. OA received pola-R-miniCHP more frequently (18% vs 1.5%, p<0.0001) and had similar rates of treatment completion (85%, p=0.2) as pts <70 yrs. Median follow up was 11.3 months. ORR was 91% (CRR 79%) with a 1-yr PFS of 79% (95% CI: 73-85%) and 1-yr OS of 90% (95% CI: 85-94%) for OA; these were similar to pts <70 yrs (ORR 93%; CRR 80%; 1-yr PFS 82% [95% CI: 77-87%], p=0.18; 1-yr OS 91% [95% CI: 88-95%], p=0.53]. OA had higher rates of cardiomyopathy (6.2% vs. 1.5%, p=0.004), grade 3+ (G3+) neutropenia (38% vs. 27%, p=0.013), G3+ thrombocytopenia (22% vs. 11%, p<0.001) and hospitalization (38% vs 26%, p=0.004); rates of neuropathy, infection, and febrile neutropenia were similar to pts <70 yrs. Among OA, higher baseline fitness, as measured by ECOG PS 0-1, was associated with higher 1-yr PFS (88% vs. 63%, p<0.0001) and 1-yr OS (96% vs. 74%, p<0.0001) and a lower rate of hospitalization (30% vs. 65%, p<0.001). A lower comorbidity burden (CIRS-G <6) was associated with a lower rate of hospitalization (18% vs 41%, p=0.041), but did not impact PFS or OS. Impairments in ADLs were also associated with lower OS (78% vs 91%, p=0.03). OA receiving pola-R-miniCHP (n=38) were older (79 yrs vs. 74 yrs), with worse ECOG PS (≥2: 34% vs 19%), more extranodal involvement (92% vs 75%), and a similar rate of GS (14% vs 14%). The rate of hospitalization was higher (45% vs. 36%, p<0.05) but ORR (84% vs. 93%), CRR (79% vs. 79%), 1-yr PFS (85% vs. 78%), and 1-yr OS (87% vs. 90%) were similar. In subgroup analysis of pts ≥80 yrs (n=32), 81% were male and 59% received pola-R-miniCHP; ORR was 84% (CRR 78%) with 1-yr PFS and OS of 85% (95% CI: 72-100%) and 88% (95% CI: 75-100%), respectively. Pts ≥80 yrs had a higher rate of any grade neuropathy (23%, p=0.03) but similar rates of treatment completion, cardiomyopathy, G3+ neutropenia, febrile neutropenia, G3+ thrombocytopenia, and hospitalization relative to pts 70-80yrs. Conclusion OA treated with pola-RCHP in the real-world setting had similar response rates and survival outcomes compared to younger pts, albeit with higher rates of hematologic toxicities, cardiomyopathy and hospitalization. Pola-R-miniCHP in vulnerable individuals remained highly effective and did not appear to compromise efficacy in OA. Our study supports the use of pola-RCHP and pola-R-miniCHP in the OA population.

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 CAR T cell treatment is the standard of care for patients (pts) with primary refractory and relapsed large B-cell lymphoma (LBCL) within the first 12 months of chemoimmunotherapy, or for those unfit for autologous stem cell transplant (ASCT) regardless of timing of relapse. Consequently, the role of ASCT is limited to pts with late relapse (>12 months) who achieve a complete or partial response (CR or PR) to salvage therapy and are deemed eligible for ASCT based on comorbidities and performance status. In this report, we evaluated post-ASCT outcomes in this population of pts. Methods We conducted a retrospective cohort study using publicly available data from the Center for International Blood and Marrow Transplant Research (CIBMTR). Adult pts (age ≥18 years) with DLBCL, NOS, and high-grade large B-cell lymphomas (HGBL) who relapsed after having responded to initial treatment and who remained on response for at least 12 months since diagnosis were selected. We considered for this analysis only pts who achieved a CR or PR after salvage treatment at the time of relapse, documented on pre-ASCT CT or PET scan (per the 2014 Lugano definition). CIBMTR databases used for this study included pts who received ASCT from 2013 to 2021. We compared baseline characteristics between ASCT in CR vs PR using the Wilcoxon rank sum test for continuous variables and the Pearson's χ2 test for categorical variables after ignoring missing data. Primary endpoints included Progression-free survival (PFS) and overall survival (OS). Non-relapse mortality (NRM) and relapse rate were among the secondary endpoints. Results 182 were included in the analysis: 100 were in CR and 82 in PR before ASCT. The median age at ASCT was 60 years (range, 26-79). Race distribution was similar across CR and PR pts. Advanced-stage disease at diagnosis (stage III–IV) was seen in 61% of CR pts and 55% of PR pts. High-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements was similar in the CR and PR groups (7% vs 4%). The median number of lines of treatment before ASCT were identical in CR and PR pts (N=2). BEAM was the most frequently used transplant conditioning regimen in both groups (80%). Median follow-up after ASCT was 34 months (range, 1–95): it was 37 months (range 1-95) in the CR group and 26 months (range 1-79) in the PR group For the entire cohort, OS at 3 years was 67.6% and PFS was 50.6%. NRM was 1.7% at 100 days and 3.4% at 1 year. Cumulative incidence of relapse at 3 years was 43.9%. The NRM analysis showed no statistically significant difference between pts in CR and PR. The 3-year OS for CR pts was 73.9%% compared to 59.4% for PR pts (95% CI, 0.334-0.99; p=.044). The 3-year PFS for CR pts was 59.8%, compared to 38.6% for PR pts (95% CI, 0.321-0.784; p=.001). The median PFS for CR pts was 52.01 months, compared to 14.05 months for PR pts. The cumulative incidence of relapse at 3 years in CR and PR pts was 35.2% vs 55.7%, respectively (95% CI, 0.311-0.811; p=.003.). Higher age (HR 1.03; p=.026) and number of previous lines of treatment (HR 1.43; p=.002) were associated with inferior OS. For PFS, no variables showed any significant impact in univariable analysis. The stepwise multivariable analysis showed that only the number of previous treatments had a significant impact on the OS (p=.009), while undergoing ASCT on a PR was the only factor significantly associated with shorter PFS (HR 1.41; 95% CI, 1.09-1.82; p=.029). Conclusion This dataset supports that ASCT provides high efficacy in pts experiencing late relapses (after 12 months) achieving CR following pre-transplant savage and validates the value of achieving CR. Outcomes for PR are inferior, and this analysis provides a benchmark for future investigations. At this time, until convincing on other non-transplant treatment show superior outcomes in this setting, ASCT remains a standard of care for fit pts with chemo-sensitive late relapsed DLBCL. In this group of patients, who have a better prognosis compared to patients who relapse within a year the major hurdle is achieving a remission pre-ASCT.

Abstract Introduction: Axi-cel, an autologous anti-CD19 CAR T-cell therapy has shown high and durable response rates and a manageable safety profile among R/R FL pts in the ZUMA-5 trial (Jacobson et al. 2022; Neelapu et al. 2024). Evidence from real-world data showed favorable early outcomes in a broader population using CIBMTR data, with comparable outcomes by ZUMA-5 eligibility, age, lines of therapy (LOT), and prior bendamustine (benda) use (Jacobson et al. 2023). This study investigated long-term outcomes and the association between age, performance status, comorbidities, and therapies given prior to infusion among R/R FL pts treated with axi-cel. Methods: Pts with R/R FL who received commercial axi-cel between 03/2021–10/2023 in the US were identified from the CIBMTR® registry; pts without consent, with prior non-transplant cellular therapy, and FL grade 3B or 3A/3B unspecified or unknown were excluded. Descriptive analyses were done among all pts and by age at infusion (<65 vs ≥65 y), Karnofsky performance score (KPS), presence of hepatic, cardiovascular (CV), or moderate to severe pulmonary comorbidities, prior treatments (benda pre-leukapheresis, autologous hematopoietic stem cell transplant [autoHSCT]), and lymphodepletion (LD) therapy. Multivariable (MV) Cox and logistic regression were used to adjust for confounders. Results: In total, 238 pts from 68 centers were included (data cut-off October 2024). Median age at infusion was 61 yr (range, 29-83; ≥65 yr, 38%), and 79% were non-Hispanic White. KPS of pts was ≤70% (11%), 80% (35%), or 90-100% (54%); 2% had ECOG ≥2. Most (75%) had ≥1 clinically significant comorbidity (hepatic, 6%; CV, 15%; pulmonary, 18%). Median (min, max) prior LOT was 4 (1,13); 74% received benda pre-leukapheresis, and 6% had benda LD therapy. At a median follow-up of 24.1 months, objective response rate (ORR) was 96% (complete response [CR] rate, 91%). The 2-yr (95% CI) DOR, PFS, and OS were 70% (63-77), 64% (57-71), and 84% (78-89) respectively. Grade ≥3 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 4% and 18% of pts (any grade, 74% and 42%), respectively. Prolonged cytopenias by day 30 occurred in 14% of pts (neutropenia [10%] and thrombocytopenia [8%]) while 29% had clinically significant infections at 6 months. Second primary malignancies occurred in 16 pts (7%), with 7 (2%) being therapy-related myeloid neoplasm. The leading primary causes of death (n=34) were relapse/progression (10; 29%), organ failure (7; 21%), and infection 5 (15%). Cumulative incidence of non-relapse mortality at 2-yr was 9%. Outcomes were generally comparable among age, autoHSCT, and comorbidity subgroups. However, effectiveness outcomes differed by prior benda use (Yes vs No): ORR (95% vs 98%); CR (88% vs 98%); DOR (65% vs 89%), PFS (58% vs 84%), and OS (82% vs 91%) at 2 years. By LD therapy (single agent benda vs cyclophosphamide + fludarabine [Cy + Flu]): the ORR was 93% vs 96%; CR rate was 57% vs 93%. On MV analysis, prior benda use was associated with (OR/HR [95% CI]): worse CR (0.02 [<0.01-0.43]), DOR (3.69 [1.51-9.02], and PFS (2.21 [1.12-4.38]). Pts given benda LD therapy had (OR/HR [95% CI]): worse CR rate (0.02 [<0.01-0.16]), DOR (7.59 [2.33-24.72]), and PFS (4.89 [1.79-13.39]) compared to those who received Cy + Flu. CRS and ICANS were lower among those with prior benda use (Yes vs No): any-grade CRS (70% vs 87%); Grade ≥3 CRS (3% vs 8%); any-grade ICANS (36% vs 61%); and grade ≥3 ICANS (17% vs 25%). By LD therapy (single agent benda vs Cy + Flu): the Grade ≥3 CRS and ≥3 ICANS were 0% vs 5% and 7% vs 19% respectively. Any-grade ICANS was higher among those aged ≥ 65 yr vs <65 yr (53% vs 35%). On MV analysis, pts who had prior benda use were less likely to have any-grade CRS (0.30 [0.12-0.75]), and any-grade ICANS (0.23 [0.11-0.50]. Pts ≥ 65 yr had higher any-grade ICANS (2.31 [1.18 – 4.50]). Summary/Conclusion: This long-term follow up of axi-cel in R/R FL shows durable responses and manageable safety similar to ZUMA-5. Outcomes among the elderly and those with comorbidities were generally comparable to the overall R/R FL population. Although benda use pre-leukapheresis was associated with less durable responses, we were unable to determine whether this association is limited to use close to axi-cel infusion, as data on timing of use was unavailable. The associations for benda LD should be interpreted with caution given the small sample size.

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.