Citations

The treatment landscape for soft tissue sarcomas (STS) is evolving constantly. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for STS specific to surgical management and systemic therapy recommendations for various subtypes.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cervical Cancer provide diagnostic workup, staging, and various treatment recommendations for cervical cancer based on clinical and surgical staging. This selection from the NCCN Guidelines for cervical cancer specifically focuses on diagnosis and workup, principles of staging and surgery, and primary treatment recommendations for early-stage and advanced disease and provides a detailed overview of systemic therapy recommendations for cervical cancer.

PURPOSE To compare patient-reported and clinical outcomes between radical cystectomy (RC) and bladder-sparing therapy (BST) in patients with recurrent high-grade non–muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS This pragmatic, prospective observational cohort study was designed with patients, who selected and prioritized outcomes. Eligible adults were candidates for both RC or BST, had previous induction Bacillus Calmette-Guérin (BCG), and received their last treatment within 12 months. The primary outcome was the EORTC-QLQ-C30 physical function scale at 12 months. Secondary outcomes included other EORTC-QLQ-C30 scales, depression, anxiety, bladder cancer–specific quality of life (QOL), financial burden, and cancer-specific outcomes. Targeted maximum likelihood estimation (TMLE) was used to calculate average treatment effect (ATE) estimates between arms. Inverse probability weighted risk ratios (wRR) were calculated using quasi-Poisson regression. RESULTS Of 570 participants (mean age 71.4 years; 21% female), 371 selected BST and 199 selected RC. Physical function was significantly worse in the RC arm at 3 months; by 9 months, there was no difference between arms, and at 12 months, physical function did not differ (ATE, 0.9; 95% CI, –0.6 to 2.4; P = .22). RC was associated with better emotional function, generic health-related QOL, and financial burden, and lower depression and anxiety, while BST was associated with better bowel and sexual health. Cancer-specific survival was 99% for BST versus 96% for RC (wRR, 0.99; 95% CI, 0.97 to 1.01). RC was associated with a higher risk of adverse events and serious adverse events, including a 90-day mortality rate of 2.5%. CONCLUSION Most patient-prioritized outcomes were similar or better among participants who chose RC compared with BST. These findings support the continued role of RC in managing recurrent high-grade NMIBC.

ABSTRACT Background Electrical storm (ES) is a life‐threatening manifestation of recurrent ventricular arrhythmia. While anti‐arrhythmic drugs (AADs) have historically been the first‐line treatment, the role of catheter ablation (CA) as an initial therapy in ES remains incompletely defined. This meta‐analysis evaluates the efficacy and safety of radiofrequency CA compared to escalating medical therapy in patients with ES. Methods A systematic search of PubMed, Science Direct, and Cochrane databases was conducted for studies published from 2010 to 2025 that compared CA with medical therapy as first‐line treatment for ES. Outcomes of interest included ES recurrence, ventricular arrhythmia recurrence, in‐hospital mortality, procedural complications, and follow‐up survival. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random‐effects models. Results Six studies encompassing 963 patients (473 CA, 490 medical therapy) were included. The mean age was 67.8 years, and 87.7% were male. The mean left ventricular ejection fraction was 33%, and ischemic cardiomyopathy was present in 77.5% of CA and 72.1% of MT patients. CA reduced the risk of ES recurrence by 71% compared to medical therapy (OR: 0.29; 95% CI: 0.15–0.53; p < 0.001; I ² = 53%). Recurrence of any ventricular arrhythmia, in‐hospital mortality, and long‐term survival were also significantly improved with CA. Conclusion This meta‐analysis suggests that CA is associated with lower ES and VA recurrence and in‐hospital mortality and improved survival compared to medical therapy alone. These findings support consideration of catheter ablation as a first‐line strategy. Larger prospective trials are needed to confirm these findings and guide patient selection.

Abstract Wiskott-Aldrich syndrome (WAS), an X-linked disorder characterized by immunodeficiency, thrombocytopenia, autoimmunity, and malignancy, can be effectively treated with allogeneic hematopoietic cell transplantation (HCT). Older age at HCT and mismatched donors are known to affect overall survival (OS). However, the influence of specific clinical manifestations or WAS variant class on OS and factors associated with event-free survival (EFS) remain incompletely defined. We analyzed outcomes of 308 patients with WAS who underwent HCT at 37 institutions of the Primary Immune Deficiency Treatment Consortium from 1990 to 2018. With a median follow-up of 5.3 years, the 5-year OS and EFS were 87.2% and 79.7%, respectively. Age ≥5 years, donor type, and a pre-HCT history of severe infection had a negative impact on OS and EFS, whereas pre-HCT autoimmunity had no impact. Reduced-intensity regimens were associated with lower T-cell and myeloid donor chimerism, particularly when non–busulfan-based regimens were used. Low myeloid donor chimerism was associated with lower platelet counts. Mixed chimerism was not consistently associated with post-HCT autoimmunity. Patients with class I (exon 1-2 missense and intron 5 hot spot variants) and class II variants (all others) had similar pre-HCT clinical symptom severity and no difference in OS, EFS, or platelet recovery post-HCT. In conclusion, our study showed excellent long-term OS and EFS after HCT for WAS, highlighting the importance of early HCT, before the development of severe infections. We confirmed that HCT using busulfan-based conditioning was associated with improved donor chimerism and platelet recovery. This trial was registered at www.clinicaltrials.gov as NCT02064933.

Abstract Background Several BsAbs with different treatment (Tx) approaches have been approved by the FDA for Tx of lymphoma, including: fixed-duration and less frequently dosed mosunetuzumab (mosun) and glofitamab (glofit) (Option 1 Tx approach); and treat to progression and more frequently dosed epcoritamab (epcor) (Option 2 Tx approach). Differences in Tx approaches have implications for time spent receiving care, known as “time toxicity”. We previously reported that mosun and glofit were associated with about 2 weeks lower time toxicity vs epcor over the first year in R/R FL and DLBCL, based on registrational trial protocols (Torka et al. Blood 2024; Ma et al. Value in Health 2025). In this study, we assessed time toxicity from the perspective of patients (pts) receiving BsAbs for R/R FL or DLBCL. Methods An online survey was conducted aiming for input from 120 pts with R/R FL or DLBCL, who have received BsAb for ≥1 month in the US. Time toxicity was measured by pts recalling time spent on healthcare contacts related to BsAb Tx, cancer management, and any other reasons in the past 30 days. Pts' preferences were assessed through direct elicitation of choice between 2 hypothetical Tx profiles with different Tx approaches and time toxicity, assuming the same efficacy and safety. The survey was pre-tested and refined based on input from 3 BsAb pts with R/R DLBCL to ensure relevance and comprehension. Descriptive analyses were performed on pts characteristics, mean and standard deviation (SD) of time spent per pt per month, and the proportion of pts preferring the convenience of different Tx profiles. Results At this interim analysis, 101 pts receiving BsAbs responded to the survey: 48 pts with R/R FL (mosun n=28; epcor n=20) and 53 pts with R/R DLBCL (glofit n=32; epcor n=21). Most pts with R/R FL lived in urban/suburban areas (87.5% vs 12.5% in rural areas) and had a shorter one-way travel time to receive care vs pts in rural areas (mean±SD: 28.2±13.5 vs 60.3±30.2 minutes). The median age was 58 years for both mosun and epcor. Mean±SD Tx duration was 6.2±1.8 months for mosun vs 4.5±1.3 months for epcor. In the past 30 days, pts on mosun had fewer BsAb Tx visits vs epcor (mean±SD: 1.0±0.2 vs 2.0±1.2), and fewer all-cause healthcare contacts vs epcor (mean±SD: 1.7±0.8 vs 3.5±2.0). The mean±SD time spent per BsAb Tx visit was 5.0±1.4 hours for mosun vs 3.8±1.8 hours for epcor. Less time was spent per pt per month on recovery at home after Tx visit for mosun vs epcor (22.7±16.5 vs 43.2±47.6 hours). Less time was spent per pt per month on Tx and cancer management for mosun vs epcor (mean±SD: 30.5±16.9 vs 56.9±59.3 hours). Most pts with R/R DLBCL lived in urban/suburban areas (88.7% vs 11.5% in rural areas) and had a shorter one-way travel time to receive care vs pts in rural areas (mean±SD: 31.4±14.1 vs 103.3±19.4 minutes). The median age was 67 years for glofit and 66 years for epcor. The mean±SD Tx duration was 6.1±2.0 months for glofit vs 5.9±1.8 months for epcor. In the last 30 days, pts on glofit had fewer BsAb Tx visits vs epcor (mean±SD: 1.1±0.2 vs 1.7±0.5), and fewer all-cause healthcare contacts vs epcor (mean±SD: 2.2±1.3 vs 3.0±1.1). Irrespective of the route of administration, the time spent per BsAb Tx visit was similar (mean±SD: 5.1±1.6 hours for mosun; 5.6±1.2 hours for epcor). Less time was spent per pt per month on recovery at home after Tx visit for glofit vs epcor (mean±SD: 34.3±23.8 vs 69.3±39.4 hours). Less time was spent per pt per month on Tx visits and cancer management for glofit vs epcor (mean±SD: 43.0±25.9 vs 85.0±44.2 hours). Regardless of which BsAb pts received, most pts (93%) preferred the convenience of Option 1 Tx approach with less time required over Option 2 Tx approach with more time required. Conclusions This is the first study to directly measure pt-reported time toxicity from pts with R/R FL and DLBCL receiving BsAbs in a real-world setting. Fixed-duration less frequently dosed mosun and glofit (Option 1 Tx approach) had less pt-reported time toxicity, with less healthcare contact and less time spent per pt per month vs treat to progression more frequently dosed epcor (Option 2 Tx approach). Over 90% of pts preferred the convenience of a fixed-duration, less frequently dosed, and less time required Tx option, suggesting that time toxicity is a significant factor in shared Tx decision-making for pts with R/R FL and DLBCL. Analysis is ongoing to comprehensively measure pt-reported time toxicity.

Abstract Introduction: Cilta-cel is a BCMA-directed CAR T-cell therapy that has shown remarkable efficacy in patients with RRMM. As real-world (RW) experience with cilta-cel continues to expand, and with the recent FDA guidance reducing the recommended proximity to the CAR T center from four to two weeks post-infusion, there is growing interest in identifying patients at low risk for severe early complications who may be safely managed in the outpatient setting and potentially ‘discharged’ home earlier. Methods Data were collected from 769 patients with RRMM treated with cilta-cel at 15 institutions in the U.S. via the Multiple Myeloma Immunotherapy Consortium.Logistic regression was used to identify predictors of patients who could be managed in the outpatient setting (low-risk group). Based on expert consensus within the Consortium, low-risk patients were defined as: grade ≤1 CRS, no ICANS, and no IEC-HS. The remaining patients were categorized as high-risk. We evaluated baseline characteristics with missingness &lt; 20% as predictors, including age, sex, race, and ethnicity, ECOG performance status (PS) at time of lymphodepletion (LD), extramedullary disease, bone marrow plasma cell (BMPC) percentage, high-risk cytogenetics, bridging therapy including response, penta-refractory status, number of prior lines of therapy, prior anti-BCMA therapy, baseline C-reactive protein (CRP), and baseline ferritin. The cohort was restricted to patients with complete data on all predictors (n=455) and split into a training and testing cohort (80/20 split, n=364/91). Bidirectional stepwise regression was used to build the predictive model using variables with significance of p&lt;0.15 selected for entry. The best model was selected based on the AIC (Akaike Information Criterion) and a significance level of p&lt;0.05. Results Among the 455 patients with complete data included in the final model, 290 (64%) were categorized as low-risk and 165 (36%) as high-risk. Compared to the low-risk group, high-risk patients were more likely to have an ECOG PS ≥2 at time of LD (20% vs 9%, p&lt;0.001), high-risk cytogenetics (47% vs 35%, p=0.009), and penta-refractory disease status (34% vs 24%, p=0.031). High-risk patients also had a higher median BMPC percentage (15% vs 5%, p&lt;0.001), and higher baseline pre-LD CRP and ferritin. Overall response rates were high, at 95% vs 90% (p=0.047) for the low vs high risk groups, with complete response or better achieved in 73% vs 66% of patients, respectively (p=0.14). With a median follow-up of approximately 11 months, median progression-free survival was not reached (95% CI: 27-NA) in the low-risk group and 18.2 months (95% CI: 13.1-NA) in the high-risk group. In terms of safety, non-ICANS neurotoxicity (NINT) occurred less frequently in the low-risk group (6.6% vs 13%, p=0.015). Specifically, Parkinsonism was observed in 1.7% vs 6.1% (p=0.013), and cranial nerve palsy in 4.5% vs 5.5% (p=0.7), respectively. Non-relapse mortality (NRM) was lower in the low-risk group (4.2%) compared to the high-risk group (14%; p &lt; 0.001). The most common causes of NRM in the low- and high-risk groups were acute toxicities (0% vs 36%, including CRS, IEC-HS, and ICANS), delayed toxicities (0% vs 8%, including colitis, NINT, and Parkinsonism), infections (50% vs 48%), and other unrelated causes (50% vs 8%). The best model to predict low-risk patients that could be managed in the outpatient settingincluded BMPC percentage and ECOG PS at LD. In the training cohort, patients with a higher pre-LD BMPC percentage and an ECOG PS ³2 were less likely to be in the low-risk group(OR per 1-unit change in BMPC percentage = 0.99, 95% CI=0.98-0.99, p&lt;0.001 and OR for ECOG PS 2-4 = 0.38, 95% CI=0.20-0.72, p=0.003). The AUC for this model was 0.663 in the training cohort and 0.659 in the testing cohort. Conclusion In this large, multi-institutional cohort of patients with RRMM treated with cilta-cel, we identified clinical factors associated with lower risk for early severe toxicities, supporting outpatient administration and the potential for earlier discharge in selected patients, particularly those who are fit and have low disease burden. Our findings provide a practical framework to guide risk stratification and outpatient CAR T management strategies, particularly in light of evolving regulatory guidance and growing RW experience with cilta-cel.

Abstract Introduction: First-line therapy for mantle cell lymphoma (MCL) represents a critical opportunity for clinical benefit via sustained complete response. Multitargeted combinations, including optimized chemotherapy with novel agents targeted to MCL, may best address the biologic heterogeneity of this disease. Building on prior experience using modified VR-CAP and R-cytarabine, we enhanced this regimen by adding acalabrutinib while reducing cytarabine, aiming for improved efficacy and safety without impeding stem cell collection. To evaluate this regimen, we conducted a phase 2 multicenter trial at four centers in the Academic and Community Cancer Research United (ACCRU) network. Methods: CARiBOU (ACCRU-LY-1804) employs alternating VR-CAP and R-cytarabine with continuous acalabrutinib, in six 21-day cycles, for previously untreated MCL. Eligible patients (pts) were at least 18 years old with adequate organ function, measurable disease, no CNS involvement; and were ASCT-eligible per investigator. VR-CAP (cycles 1, 3, and 5) employed bortezomib 1.3 mg/m² subcutaneously days 1,8, and 15; rituximab 375 mg/m² day 1; cyclophosphamide 750 mg/m² day 1; doxorubicin 50 mg/m2 day 1; and prednisone 100 mg PO days 1-5. Cycles 2,4, and 6 used outpatient rituximab with cytarabine at 3 g/m² x 2 daily doses in the first 5 pts, after which the dose was reduced to 2 gm/m2 x 2 daily doses due to thrombocytopenia. Acalabrutinib 100 mg p.o. twice daily was given continuously but held for grade 4 thrombocytopenia or clinically significant toxicity. Growth factors and prophylactic antimicrobials were required. Responses were assessed after six cycles using FDG PET/CT, bone marrow aspirate/biopsy (BM Bx), and endoscopy when indicated (Lugano 2014). The primary endpoint was complete metabolic response (CMR) rate at end of treatment (EOT). Secondary endpoints included safety, feasibility of stem cell collection, proportion proceeding to ASCT, and progression-free (PFS) and overall survival (OS). Peripheral blood measurable residual disease (MRD) was evaluated using the ClonoSEQ assay (Adaptive Biotechnologies). A Simon two-stage design was used, targeting a CMR rate ≥ 70% versus a null rate of 50%, with a total sample size of 39 evaluable pts. Results: 41 pts were accrued from October 2021 through May 2025, 37 of whom completed all 6 cycles and are evaluable for response; two are still on therapy, and two discontinued therapy early for toxicity. Median age was 63 years (range 41-73), 22% were female, and 85% were White. MIPI risk groups were low (44%), intermediate (39%), and high (17%), and Ki-67 was ≥ 30% in 54% of pts. Three pts (7%) had known TP53 mutations by sequencing. At EOT, the CMR rate was 85.3% among all pts (35/41; 95% CI 67.9%-92.9%), or 94.5% among evaluable pts (35/37). BM Bx was performed in 31 pts at EOT, 30 of which (96.8%) were negative for MCL. Undetectable peripheral blood MRD using a 10^6 threshold (uMRD6) was achieved at EOT in 78.1% (25/32) of tested pts, and 93.8% (30/32) achieved uMRD5. Nine of 41 pts underwent ASCT; no patient failed stem cell collection. Maintenance therapy was not protocol-defined but included rituximab in 91.9% of pts and a BTK inhibitor in 21.6% of pts. With a median follow-up of 16.7 months, PFS and OS rates at 18 months were 76.7% (95% CI: 60.7%-96.9%) and 95.5% (95% CI: 87.1%-100%). Toxicities were primarily hematologic. Grade 3+ toxicities included thrombocytopenia (66.6%), neutropenia (28.2%), and anemia (25.6%). Grade 3+ febrile neutropenia was observed in 10.2% of pts. Peripheral neuropathy was seen in 20.5% of pts and all grade 1-2. Bleeding events included purpura in 2 pts (5.2%) and epistaxis in 1 patient (2.6%). One case of atrial fibrillation was observed. Eighteen pts required temporary dose hold of acalabrutinib for toxicity (mainly thrombocytopenia), and 2 had acalabrutinib dose reductions. Serious adverse events occurred in 6 pts, and no treatment-related deaths occurred. Conclusions: CARiBOU is an efficient, highly effective outpatient regimen for 1st line MCL, employing intermediate dose cytarabine with continuous acalabrutinib. With supportive care and platelet monitoring, this approach safely yielded high rates of CMR and uMRD6, supporting multitargeted induction therapy for appropriate pts with untreated MCL.

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&lt;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&lt;0.0001) and had similar rates of treatment completion (85%, p=0.2) as pts &lt;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 &lt;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&lt;0.001) and hospitalization (38% vs 26%, p=0.004); rates of neuropathy, infection, and febrile neutropenia were similar to pts &lt;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&lt;0.0001) and 1-yr OS (96% vs. 74%, p&lt;0.0001) and a lower rate of hospitalization (30% vs. 65%, p&lt;0.001). A lower comorbidity burden (CIRS-G &lt;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&lt;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 (&gt;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 &lt;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 &lt;60 yrs (p=0.044). 1-yr OS was 97.5% (95% CI: 94.1-100%) and not evaluable in pts &lt;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 &lt;60 yrs. Our data reinforces the use of NAVD as the preferred 1L option for OAs with advanced stage cHL.