Relapsed and/or refractory follicular lymphoma (R/R FL) remains a therapeutic challenge due to its chronic relapsing course and increasingly complex treatment landscape. Novel therapies, including immunomodulatory combinations, bispecific antibodies (BsAbs), Bruton tyrosine kinase inhibitors, and chimeric antigen receptor (CAR) T-cell therapies, have expanded treatment options and increased the complexity of treatment selection and sequencing. The Canadian Hematology Consensus Group (CHCG) convened a national panel of lymphoma experts to develop evidence-informed consensus recommendations for the management of adults with R/R FL in the Canadian context. Clinical questions informed a structured literature review of studies published through February 2026, including randomized trials, phase II studies, observational data, conference proceedings, and relevant guidelines. Recommendations were developed using a modified Delphi consensus process and graded using a framework adapted from the British Committee for Standards in Haematology. Key recommendations include repeat biopsy to exclude histologic transformation at relapse, individualized treatment selection based on timing of relapse and patient-specific factors, preferential use of lenalidomide-rituximab (LenR)-based triplet combinations in most second-line settings, and incorporation of BsAb and CAR T-cell therapy in third-line and later disease. These recommendations aim to provide practical guidance for Canadian clinicians managing patients with R/R FL.

CD19 CAR T-cell therapy has significantly improved the survival of patients with relapsed or refractory large B cell lymphoma (R/R LBCL) and is considered standard of care for eligible patients in Canada. Axicabtagene ciloleucel (axi-cel) is an autologous CAR T-cell therapy, initially approved by Health Canada for adults with R/R LBCL after 2 or more lines of therapy. This multi-centre analysis, with registry data collected from CIBMTR, aims to present a Canadian perspective on the real-world experience of axi-cel in patients with R/R LBCL. With a median follow-up of 12.4 months, the best objective response rate (ORR) and complete response (CR) rate among all patients were 77% and 59%, respectively. At 12 months, estimated progression-free survival (PFS) and overall survival (OS) were 49% and 59%, respectively. Notably, the incidence and severity of adverse events were lower in this cohort compared to ZUMA-1 and other real-world reports, with CRS occurring in 77% (grade ≥ 3, 3%) and ICANS occurring in 38% (grade ≥ 3, 10%) of patients. Outcomes remained largely consistent across patient and disease characteristics. These findings demonstrate effectiveness and safety profiles comparable to international real-world studies and the ZUMA-1 trial, supporting the use of axi-cel as an effective treatment across broad Canadian populations.

Classic Hodgkin lymphoma (cHL) associated with Epstein-Barr virus (EBV) positivity as well as non-nodular sclerosis (non-NS) histologic subtypes have demonstrated poorer outcomes compared to EBV-negative and nodular sclerosis cases. We report a prespecified subset analysis of patients enrolled in the phase III SWOG S1826 trial to evaluate outcomes based on EBV status and histologic subtype in patients treated with nivolumab-AVD (N-AVD) or brentuximab vedotin (BV)-AVD. In the phase III SWOG S1826 trial, patients with stage III-IV cHL were randomized to N-AVD or BV-AVD. Of 970 eligible patients, 522 had known EBV status. N-AVD improved 3-year progression-free survival (PFS) in EBV-positive (91% v 70%; HR, 0.30; P = 0.01) and EBV-negative patients (90% v 84%; HR, 0.64; P = 0.09). Among 664 patients with slides available for histology review, 102 (15.4%) had non-NS subtypes. N-AVD prolonged 3-year PFS in patients with non-NS (86% v 63%; HR, 0.33; P = 0.006) and NS histologic subtype (93% v 86%; HR, 0.53; P = 0.01). Non-NS histology independently was associated with inferior outcomes (HR, 2.54; P < 0.0001) after adjusting for treatment in the entire cohort. However, N-AVD treatment still had favorable PFS within this high-risk group. In addition, patients with EBV positivity or non-NS histology cHL treated with BV-AVD had significantly worse PFS (HR, 1.97; P = 0.03 for EBV; and HR, 3.08; P < 0.0001 for histology). N-AVD substantially abrogated the historically poor prognosis associated with EBV positivity and non-NS histology in advanced-stage cHL. These results support N-AVD as frontline standard of care, particularly in high-risk biologic subgroups. (NCT03907488).

PURPOSE:S1826 was an international phase 3 randomized trial that demonstrated improved progression-free survival of nivolumab plus doxorubicin, vinblastine, and dacarbazine (N+AVD) over brentuximab vedotin plus AVD (BV+AVD) in newly diagnosed advanced stage classic Hodgkin lymphoma (cHL). Here we report results of enrolled participants with HIV. PARTICIPANTS AND METHODS:People with HIV (PWH) with a CD4+ T-cell above ≥200 cells/μL and on effective ART with an undetectable HIV viral load within 6 months prior to enrollment were eligible. Participants were randomly assigned in a 1:1 ratio to receive six 28-day cycles of either N+AVD or BV+AVD intravenously. The primary endpoint was progression-free survival. RESULTS:16 eligible PWH were enrolled, 11 received N+AVD and 5 received BV+AVD. The median follow-up duration was 32.7 months in the N+AVD arm and 26.7 months in the BV+AVD arm. The 2-year PFS rate was 77.9% in N+AVD arm and 75.0% in the BV+AVD arm. The 2-year OS was 85.7% in the N+AVD arm and 75.0% in the BV+AVD arm. Grade ≥ 3 adverse events were observed in 45% of participants in the N+AVD arm and 50% in the BV+AVD arm with more frequent febrile neutropenia, and severe infections observed in the BV+AVD arm. CONCLUSIONS:N+AVD is safe and effective in newly diagnosed HIV-associated advanced stage cHL. Clinicaltrials.gov number NCT03907488.

Introduction: The primary analysis of the randomized Phase 3 S1826 study in patients (pts) with previously untreated, advanced stage Hodgkin lymphoma (HL) showed a marked improvement in 1- and 2-year progression-free survival (PFS) with nivolumab, doxorubicin, vinblastine, dacarbazine (Nivo-AVD) compared to brentuximab vedotin (BV)-AVD (Herrera, NEJM, 2024). Multiple previous trials have explored the utility of interim (i) and end-of-treatment (EoT) PET scans in both early and advanced stage HL using the visual 5-point scale (5PS) score to predict outcomes and to escalate or de-escalate therapy. The Phase 3 ECHELON-1 study comparing BV-AVD to ABVD in advanced stage HL showed 5-yr PFS in the BV-AVD arm of 60.6% in pts with a positive iPET (5PS 4-5) compared to 84.9% in pts with a negative iPET (5PS 1-3) (Straus, Lancet Haematol 2021). In patients with relapsed HL receiving single agent PD-1 inhibitors, determining response using conventional PET response criteria has proved challenging due to persistent or new FDG-avid foci that may represent inflammation rather than active disease. The prognostic value of interim and EoT PET with the Nivo-AVD regimen has not been previously reported. Methods: Eligible pts ≥ age12 yrs with stage 3-4 HL were randomized to 6 cycles (C) of Nivo-AVD or BV-AVD. Response and disease progression were assessed by investigators for the primary endpoints using Lugano 2014 criteria. iPET following C2 was required for all participants enrolled through the Children's Oncology Group and was optional for all other participants. EoT PET was required for all pts within 4-8 weeks after C6D15. All scans were submitted for retrospective central imaging review performed by the NCI Imaging and Radiation Oncology Core. Both at interim and EoT, 5PS 1-3 was considered complete remission and 5PS 4-5 was partial remission or progressive disease based on comparison with baseline PET scan. Results: 994 pts were enrolled from 07/09/2019 to 10/05/2022 and randomized to N-AVD (n=496) or BV-AVD (n=498). 970 patients were eligible and comprised the intention to treat cohort. 742 (76%) pts had a centrally read iPET (368 N-AVD, 374 BV-AVD), 863 (89%) had a centrally read EoT PET (440 Nivo-AVD, 423 BV-AVD), and 693 (71%) had both. Landmark analyses from C3D1 and C6D28 comparing the entire study population to the subset with a centrally read PET showed a 3-yr PFS of 86% (C3D1all pts) and 87% (iPET subset) and 3-yr PFS 87% (C6D28 all pts) and 88% (EoT PET subset) confirming pts with centrally read PETs were representative of the entire study population. 3-yr landmark PFS was 89% (93% N-AVD, 85% BV-AVD) for iPET-neg, 77% (84% N-AVD, 73% BV-AVD) for iPET-pos (HR 2.31, P< 0.0001), 93% (94% N-AVD, 93% BV-AVD) for EoT PET-neg and 52% (68% N-AVD, 41% BV-AVD) for EoT PET-pos (HR 10.4, P <0.0001). Exploratory analyses showed no difference in 3-yr PFS for iPET 4 vs 5 but a difference in 3-yr PFS for EoT PET 4 (64%) vs 5 (29%), HR 2.93, P< 0.0001. There was no difference in 3-yr PFS for EOT PET 1-2 vs 3. Landmark 3-yr PFS, based on combined interim and EoT PET results, was 94% (iPET-neg, EoT PET-neg, n=527), 93% (iPET-pos, EoT PET-neg, n=75), 28% (iPET-neg, EoT PET-pos, n=35), and 60% (iPET-pos, EoT PET-pos, N=56). Landmark 3-yr PFS based on investigator-assessed PET response was 89% iPET-neg, 81% iPET-pos, 93% EoT PET-neg, 64% EoT PET-pos, all closely aligned with central read PFS analyses. 2% and 6% of iPETs and EoT PETs were read as indeterminate by local investigators. When comparing patient-level investigator and central 5PS scores among the overall population, discrepancies occurred in 20% of iPET reads and 12% of EoT reads; differences were similar in the Nivo and BV arms. Conclusions: Like prior studies in advanced stage HL, both iPET and EoT PET showed statistically significant differences in 3-year PFS for PET-neg vs. PET-pos, however EoT PET results were more clinically significant. Importantly, 84% of iPET-pos pts and 68% of EOT PET-pos pts treated with N-AVD remain progression-free at 3 yrs, suggesting significant limitations of PET Lugano criteria when applied to current therapies in HL and emphasizing the need to continue exploring new response assessment tools such as ctDNA. In pts treated with N-AVD, these results do not support altering therapy based on interim PET and suggest biopsy or close follow-up for most pts with an EoT positive PET.

Older patients with classic Hodgkin lymphoma (cHL) have inferior survival compared with younger patients. We report a subset analysis of older patients (60 years and older) enrolled in the phase three S1826 trial conducted by SWOG that randomly assigned patients with newly diagnosed advanced-stage (III-IV) cHL to six cycles of nivolumab (N)-AVD or brentuximab vedotin (BV)-AVD. Of 103 enrolled patients 60 years and older, 99 were eligible. At a median follow-up of 2.1 years, the 2-year progression-free survival was 89% after N-AVD (n = 50) and 64% after BV-AVD (n = 49, HR 0.24, 95%CI 0.09-0.63, 1-sided stratified log-rank P = .001). The 2-year OS was 96% with N-AVD versus 85% with BV-AVD (HR 0.16, 95%CI 0.03-0.75 stratified 1-sided log-rank P = .005). Six cycles were delivered without dose reduction in 69% on N-AVD and 26% on BV-AVD; 55% discontinued BV, and 14% discontinued nivolumab. The nonrelapse mortality was 16% with BV-AVD and 6% with N-AVD. Despite more neutropenia with N-AVD, febrile neutropenia, sepsis, and infections were higher with BV-AVD, as was peripheral neuropathy. Patient-reported outcomes of key adverse events confirmed the improved toxicity profile of N-AVD over BV-AVD. N-AVD was better tolerated and more effective than BV-AVD and is therefore a new standard of care for older patients with advanced-stage cHL fit for anthracycline-based combination therapy.

Introduction Patients (pts) with newly diagnosed, advanced-stage cHL are at risk for poor health-related quality of life (HRQoL) due to their underlying disease and its treatment. We assessed PROs in S1826, a trial showing that nivolumab plus doxorubicin, vinblastine, and dacarbazine (N+AVD) resulted in longer progression-free survival compared to brentuximab vedotin plus AVD (BV+AVD). Methods S1826 was a phase 3 multicenter, cross-network trial for pts >12 years old with stage III or IV newly diagnosed cHL. PROs assessment was required for pts able to complete questionnaires in English, Spanish, or French, and was obtained before registration (“baseline”) and at cycle 3, at 4-8 weeks after the end of treatment (EOT), and at 1 and 3 years (yrs) after randomization. The PROMIS-Fatigue 7a (or Ped PROMIS-Fatigue 10a), the FACT-GOG-Ntx, and the PROMIS-Global Health (Adult and Pediatric) scales were collected at each assessment. Two primary endpoints for fatigue (at EOT and 1 year) and two for neuropathy (at 1 and 3 yrs) were pre-specified, each tested using a two-sided alpha=.0125 test. Linear regression was used, adjusting for the baseline PRO score, age at randomization (12-17 vs 18-60 vs >60 yrs), the International Prognostic Score (IPS; 0-3 vs 4-7), and intent to use radiation (yes vs no). An effect size of 0.3 for both fatigue and neuropathy endpoints was targeted, corresponding to minimal clinically meaningful differences (MCID) of 3.6 points and 3.0 points, respectively. MCID, established separately for each questionnaire, characterizes the level at which a treatment tangibly affects a patient's daily life in terms of their well-being and HRQoL. We previously reported worse fatigue at cycle 3 and EOT for pts on the N+AVD arm, and worse neuropathy in the BV-AVD arm at the EOT and Year 1. In this update, we examine whether fatigue and neuropathy results differed by age group, using interaction tests, for mature data through 1 year (yr). We also report on the PROMIS-Global Health findings by arm and age group. Results The N=970 eligible pts included 236 (24.3%) aged 12-17 yrs, 639 (65.9%) aged 18-60 yrs, and 95 (9.8%) aged >60 yrs. Pts were predominantly male (56.1%); 11.8% identified as Black, and 32.0% had an IPS score of 4-7. PRO completion rates ranged from 98% at baseline to 70% at 1 yr post registration. For pre-specified primary endpoints, the adjusted PROMIS-Fatigue score was 1.7 (95% CI, -3.1 to -0.4, p=.01) points lower (i.e., more fatigue) for the N+AVD arm at EOT, although the difference did not exceed the MCID. At 1 year, there was no significant difference in fatigue from baseline (p=.83). While fatigue scores did not meaningfully differ by study arm (interaction p>.70 for all assessments), they did vary by participant age, with younger pts (12-17 yrs) and older pts (>60 yrs) reporting worse fatigue on treatment. In contrast, neuropathy scores at 1 yr were better for pts on the N+AVD arm, exceeding the MCID (3.0 points, 95% CI, 2.0-3.9, p<.001), and, secondarily, at EOT (5.6 points, 95% CI, 4.4-6.3, p<.001). However, the MCID in neuropathy at EOT and Yr 1 were only observed for pts aged 18-60 and >60 but not for pts 12-17 yrs (age interaction p<.05). Global health (HRQoL) scores were better for patients on the N+AVD arm among adults in both age groups (18-60 and >60 yrs through EOT; this pattern of improvement was not seen among adolescents, aged 12-17 yrs in the between-arm comparison. Conclusions Worse fatigue was found at the EOT, and less neuropathy was reported by yr 1, for pts on the N+AVD arm, results that were consistent across age groups. Worse neuropathy was found in the BV-AVD arm over time, specifically among pts aged 18 yrs and over. Global HRQoL was better for adult pts on the N+AVD arm through EOT, but did not differ by arm for adolescents. Trial results support the feasibility of serial collection of PROs, as indicated by high response rates, despite participants' advanced stage disease and broad institutional participation. Future analyses will address the planned 3-year outcomes as well as formal evaluation of missing data.

Abstract Introduction: The randomized phase 3 S1826 study demonstrated that, in adolescent and adult patients (pts) with previously untreated advanced stage (AS) classic Hodgkin lymphoma (cHL), PD-1 blockade with nivolumab in combination with doxorubicin, vinblastine, and dacarbazine (N-AVD) prolonged progression-free survival (PFS) compared with standard brentuximab vedotin (BV) combined with AVD at a median follow-up of 2 years. The PFS benefit was consistent across patient subgroups, N-AVD was better tolerated than BV-AVD, and radiation (RT) was rarely utilized. Herein, we evaluate durability of these results with a median follow-up of 3 years (y). Methods: Eligible pts were ≥12y with stage 3-4 cHL. Pts were randomized in a 1:1 ratio to receive either 6 cycles of N-AVD or BV-AVD. Pts were stratified by age, international prognostic score (IPS), and intent to use RT. G-CSF prophylaxis was mandatory with BV-AVD; it was optional with N-AVD. RT (30 Gy) to residually metabolically active lesions at the end of treatment was allowed according to pre-specified criteria. Pathology was centrally reviewed, patients without confirmation of cHL were ineligible for modified intent-to-treat (mITT) analysis. Response and disease progression were assessed by investigators using 2014 Lugano Classification. The primary endpoint was PFS; secondary endpoints included safety, event-free survival (EFS), patient-reported outcomes, and overall survival (OS). The database was locked for analysis on July 1, 2025. Results: 994 pts were enrolled from 7/9/19 to 10/5/22 and randomized to N-AVD (n=496) or BV-AVD (n=498). 970 (98%) were eligible and comprised the mITT cohort. Median age was 27y (range, 12-83y), 56% of pts were male, 76% were white, 12% were black, and 13% were Hispanic. 24% of pts were < 18y, 10% were > 60y, and 32% had IPS 4-7. Only 7 (0.7%) pts across arms received RT. With 3.1y of median follow-up (range, 0-5.5y), the PFS advantage with N-AVD was sustained (HR 0.48, 95%CI 0.34-0.69, one-sided p<0.0001), with 3y PFS of 91% after N-AVD compared to 82% after BV-AVD. As previously, the PFS benefit was significant across all age, stage, and IPS subgroups. Among pts ages 18-60y, 3y PFS in pts who received N-AVD was 91% compared to 85% in pts treated with BV-AVD (HR 0.61, 95% CI 0.38-0.96). Among adolescent pts ages 12-17y, 3y PFS in pts who received N-AVD was 93% vs 82% after BV-AVD (HR 0.36, 95% CI 0.17-0.79). In pts older than 60y, 3y PFS was 82% after N-AVD vs 58% after BV-AVD (HR 0.33, 95% CI 0.14 – 0.77). Pts with Stage IV cHL who received N-AVD had 3y PFS 89% compared to 80% after BV-AVD (HR 0.55, 95% CI 0.36-0.83), and had similar PFS to pts with stage III cHL who received N-AVD (3y PFS 93% vs 86% with BV-AVD, HR 0.42, 95% CI 0.22-0.81). Likewise, N-AVD led to improved PFS among pts with IPS scores of 4-7 (3y PFS 87% vs 77% with BV-AVD, HR 0.57, 95% CI 0.33-0.97). Pts with IPS 0-3 had longer PFS with N-AVD (3y PFS 92%) than with BV-AVD (3y PFS 84%, HR 0.45, 95% CI 0.28-0.72). EFS was also improved after N-AVD (HR 0.56, 95% CI 0.41-0.78, p=0.0004). There were 15 deaths observed after BV-AVD (3y OS 97%) compared to 8 after N-AVD (3y OS 98%, HR 0.48, 95% CI 0.20-1.15, p=0.092). No new safety signals were observed. Second cancers were observed in 6 (1.2%) pts after N-AVD (4 non-Hodgkin lymphomas [NHL], 1 skin cancer, 1 solid tumor) vs 11 (2.3%) pts after BV-AVD (3 NHL, 1 multiple myeloma, 7 solid tumors). Conclusions: The benefit of N-AVD compared to BV-AVD in adolescent and adult pts with AS cHL is sustained with 3y follow-up, including all pre-specified age, stage, and IPS risk subgroups. This update demonstrates the durability of remissions with N-AVD over time without any new safety signals, and enables benchmarking with other modern cHL trials. Follow-up will continue to evaluate for late toxicities, OS, and PROs. These results validate guidelines recommending N-AVD as a preferred frontline treatment regimen in patients with AS cHL, including high-risk patients.

Introduction: Classic Hodgkin lymphomas (cHL) have genetic bases for enhanced PD-1 signaling and the highest reported response rates to PD-1 blockade. In the S1826 phase III trial, patients (pts) with newly diagnosed advanced stage cHL who were treated with nivolumab (N)-AVD, vs brentuximab-vedotin (BV)-AVD, had improved progression-free survivals (PFS), establishing a new standard of care. We used our recently developed ctDNA assay to evaluate changes in molecular tumor burden (MTB) and compared ctDNA- and PET-assessed responses in S1826. Methods: The first 388 trial pts with baseline, cycle 3 day 1 (C3D1) and end-of-therapy (EOT) plasma samples (and germline DNAs) were analyzed with the targeted sequencing assay that captured recurrent single nucleotide variants, indels, somatic copy number alterations (SCNAs), structural variants, sites of physiologic and aberrant somatic hypermutation and EBV status. Low-pass whole genome sequencing provided an orthogonal assessment of SCNAs. A newly developed algorithm, MTB-Tracker, identified clustered variants and measured treatment (Tx)-related changes in MTB (log-fold changes in hGE/ml) that were compared to centrally reviewed PET scans (Deauville scores 1-3 [-] vs 4-5 [+]) at C3D1 (interim [i] PET) and EOT. Results: 375/388 (97%) pts with detectable clustered variants at baseline were included in the analysis. Clinical characteristics of these pts – median age 25y (range, 12-83y), 28% <18y, 10% >60y, 37% with IPS 4-7 – were comparable to the entire trial cohort; 3y PFS rates for the 191 N-AVD & 184 BV-AVD pts were 89% & 79%. Pts with detectable ctDNA at C3D1 had significantly inferior outcomes in the full 375 pt cohort (FC) and both Tx arms (3y PFS ctDNA+ vs ctDNA-: FC 61% vs 89%; N-AVD 71% vs 93%; BV-AVD 50% vs 84%; p<.0001 all comparisons). In the ctDNA cohort, iPET status was not significantly associated with PFS in univariate analysis (HR 1.75, p=.075) or a multivariable model (HR 1.7, p=.091) in all pts, or in the individual Tx arms. In contrast, ctDNA positivity at C3D1 remained independently prognostic (FC, HR 4.5, p<.0001; N-AVD, HR 6.0, p<.001; BV-AVD, HR 4.3, p<.0001). Among pts with detectable ctDNA at C3D1, the magnitude of decline in MTB from baseline further delineated risk groups. Pts with a major (≥ median log-fold) drop in MTB had 3y PFS rates in the FC, N-AVD and BV-AVD Tx arms of 83%, 88% and 77%. In contrast, those with only a minor (< median log-fold) drop in MTB had significantly poorer outcomes: 3y PFS in FC, N-AVD and BV-AVD pts of 38%, 52% and 25%. To assess the added value of ctDNA dynamics at C3D1, we compared a 2-group model (ctDNA+ vs ctDNA-) to a 3-group model that separated ctDNA+ pts into those with major vs minor drops in MTB. While the binary model was associated with outcome (HR 4.3; p<.0001), the 3-group model identified pts with only a minor drop in MTB as driving adverse prognosis (HR 8.9; p<.0001). In contrast, those with a major drop in MTB had outcomes similar to ctDNA- pts (HR 1.5, p=.424, relative to ctDNA- group). Model fit significantly improved with the 3-group approach (p<.0001), highlighting the value of capturing ctDNA dynamics at C3D1. Incorporating iPET into the 3-group ctDNA model did not improve outcome assessment. At EOT, pts with detectable ctDNA had significantly inferior 3y PFS in the FC and both Tx arms (ctDNA+vsctDNA-: FC 32% vs 89%; N-AVD 39% vs 91%; BV-AVD 27% vs 87%; p<.0001 all comparisons). PET positivity at EOT also correlated with worse outcomes in the FC and both Tx arms (PET+ vs PET-: FC 55% vs 90%; N-AVD 61% vs 90%; BV-AVD 50% vs 89%; p<.0001 all comparisons). Combining ctDNA and PET assessments further refined EOT risk stratification: ctDNA−&PET− pts had the most favorable 3y PFS (92% for FC, N-AVD and BV-AVD), whereas ctDNA+&PET+ pts had the poorest 3y PFS (FC 6%; N-AVD 14%; BV-AVD 0%), p<.0001 all comparisons. In EOT multivariable analysis, both ctDNA positivity (FC, HR 11.1; N-AVD, HR 11.8; BV-AVD, HR 11.4; p<.0001 all comparisons) and PET positivity (FC, HR 4.8, p<.0001; N-AVD, HR 3.5, p=.009; BV-AVD, HR 6.1, p<.0001) were independently associated with inferior outcomes, with ctDNA status having a stronger prognostic impact across the FC and both Tx arms. Conclusions: In S1826, ctDNA-guided analyses of MTB enabled early risk stratification at C3D1 and strongly outperformed PET assessments at EOT. Future prospective studies should incorporate ctDNA analyses of MTB to improve precision therapy in cHL.

Abstract Background The most widely used prognostication tool in classical Hodgkin lymphoma (cHL) historically has been the International Prognostic Score (IPS), developed to predict survival at 5 years (yrs) in patients (pts) with newly diagnosed advanced-stage (AS) HL. However, performance of the IPS has been suboptimal among contemporarily treated pts. The Hodgkin Lymphoma International Study for Individual Care (HoLISTIC) consortium developed a multivariable prediction model (the A-HIPI) for primarily ABVD-treated HL pts ages 18-65 yrs (Rodday. JCO 2023), utilizing continuous data values for 5 of 7 variables (ie, age, stage, albumin, hemoglobin and lymphocyte count). The A-HIPI demonstrated superior discrimination and calibration for progression-free survival (PFS) and overall survival (OS) versus the historic IPS. The c-statistics for 5-year PFS were 0.60 and 0.59 in the initial development (clinical trials) and validation (real world registries) cohorts, respectively, and 0.60-0.65 in subsequent validation analyses among Nordic and Brazilian external cohorts of AS HL pts treated with conventional chemotherapy regimens (Jørgensen. JCO Informatics 2024; Buccheri. BJHaem 2025). The phase 3 randomized SWOG S1826 study, the largest National Clinical Trials Network study of AS cHL, compared nivolumab with doxorubicin, vinblastine, and dacarbazine (N+AVD) with brentuximab vedotin with doxorubicin, vinblastine, and dacarbazine (BV+AVD) in pts 12 yrs or older with AS newly diagnosed cHL. N+AVD resulted in longer PFS than BV+AVD, resulting in a new standard of care incorporating novel checkpoint inhibitors. With the evolution of novel treatments, it is imperative to validate existing prognostic models against contemporary therapeutic outcomes for more precise clinical risk stratification. Thus, we sought to validate the A-HIPI as a clinical prognostic tool in the S1826 randomized trial, with a focus on adults aged ≥18 yrs. Methods S1826 was a phase 3, multicenter, open-label, randomized trial including pts 12 yrs of age or older with AS newly diagnosed cHL. The primary end point was PFS. Median follow up time is 3.1 yrs (range: 0 to 5.3 yrs). For the validation, all model parameters defining the A-HIPI were locked prior to S1826 application as previously defined. Hazard ratio (HR) estimation was conducted using Cox Regression and Harrell's index (C-index) was calculated for both IPS and A-HIPI models. Results A total of 731 pts 18 yrs or older were included with 367 receiving N+AVD and 364 receiving BV+AVD. Median age was 32 (range: 18-83) yrs; nodular sclerosis was the most common histology. The overall estimated 3-yr PFS is 86% (95% CI: 83%-88%) in this cohort. Using the A-HIPI, the predicted 3yr PFS by quartile (Q) of predicted risk was 92% for Q1 and Q2 (95%CI 86%-95%), 81% for Q3 (95%CI 74%-86%), and 79% for Q4 (73%-85%). Kaplan Meier plots stratified above and below median A-HIPI (n=365 and 366 pts) showed 3 yr PFS of 92% (95% CI 88%-94%) and 80% (95% CI 76%-84%), respectively, P<.001, and 3 yr PFS stratified by IPS 0-3 (n=509) versus 4-7 (n=222) were 88% (95% CI 84%-90%) & 82% (95% CI 76%-87%), respectively, P=.03. The c-statistic for the A-HIPI was .63 (95% CI .58-.68) and .59 for IPS-7 (95% CI .54 -.65); the difference was compared (P=.10, 95% CI .01-.07) using bootstrap resampling. The A-HIPI performed similarly in both treatment arms (c statistic: N+AVD .64 (95% CI .54-.72) and BV+AVD .62 (95% CI .54-.69)). Additionally, a multivariable Cox model with the A-HIPI and IPS showed superiority for the A-HIPI (A-HIPI HR 1.52 (95% CI 1.15-2.0) versus IPS HR 1.0 (95% CI .82-1.23)) with P=.003 and .97, respectively). Full analyses by treatment arm and calibration plots will be presented at the meeting. Conclusions The baseline A-HIPI clinical prediction tool performed well in the S1826 trial incorporating novel agents for adults with AS HL and was comparable to the original ABVD-treated cohort. Furthermore, the A-HIPI had superior prognostic performance compared to the IPS in S1826. Altogether, the A-HIPI is a treatment-agnostic prediction tool with superior capability at discriminating outcomes using both historical and novel targeted treatment strategies. This refined prediction model, which leverages continuous data values, is poised to serve as the new standard for risk stratification for adults with AS cHL. Funding NIH/NCI grant awards U10CA180888, U10CA180819, R01CA262265-04

The evolution of treatment for classical Hodgkin lymphoma (cHL) represents a great success in oncology, with disease outcomes evolving from universally fatal to vastly curable. However, not all patients benefit equally from modern therapies, which include response‑adapted regimens and the addition of novel, targeted agents to the front-line setting. Although patients older than 60 years account for the later peak in cHL’s characteristic bimodal age distribution and represent approximately 20–25% of all patients with cHL, their outcomes remain inferior compared to younger patients. A retrospective study including 401 patients >60 years treated in British Columbia between 2000 and 2019 revealed modest progression‑free survival (PFS) and disease-specific survival rates of 50% and 63%, respectively, with a median follow-up of nine years. While these outcomes have improved relative to cohorts treated prior to 2000, they nevertheless fall short of those experienced by younger patients. Furthermore, the gap in outcomes between young and older patients progressively worsens with each increasing age decile, with patients >70 years having a particularly poor prognosis. This shortfall has been attributed in part to patient-specific factors such as comorbidities and frailty, which may limit treatment tolerance, but also to differing disease biology, with negative prognostic features including advanced stage disease, Epstein-Barr virus positivity, and mixed cellularity histology often present in those with older age. Adding to the challenges in treating older patients is the fact that this group is frequently underrepresented in clinical trials, or excluded altogether, making their optimal treatment ill-defined.

Background Incorporating brentuximab vedotin into the treatment of advanced-stage classic Hodgkin's lymphoma improves outcomes in adult and pediatric patients. However, brentuximab vedotin increases the toxic effects of treatment in adults, more than half of pediatric patients who receive the drug undergo consolidative radiation, and relapse remains a challenge. Programmed death 1 blockade is effective in Hodgkin's lymphoma, including in preliminary studies involving previously untreated patients.Methods We conducted a phase 3, multicenter, open-label, randomized trial involving patients at least 12 years of age with stage III or IV newly diagnosed Hodgkin's lymphoma. Patients were randomly assigned to receive brentuximab vedotin with doxorubicin, vinblastine, and dacarbazine (BV+AVD) or nivolumab with doxorubicin, vinblastine, and dacarbazine (N+AVD). Prespecified patients could receive radiation therapy directed to residual metabolically active lesions. The primary end point was progression-free survival, defined as the time from randomization to the first observation of progressive disease or death from any cause.Results Of 994 patients who underwent randomization, 970 were included in the intention-to-treat population for efficacy analyses. At the second planned interim analysis, with a median follow-up of 12.1 months, the threshold for efficacy was crossed, indicating that N+AVD significantly improved progression-free survival as compared with BV+AVD (hazard ratio for disease progression or death, 0.48; 99% confidence interval [CI], 0.27 to 0.87; two-sided P=0.001). Owing to the short follow-up time, we repeated the analysis with longer follow-up; with a median follow-up of 2.1 years (range, 0 to 4.2 years), the 2-year progression-free survival was 92% (95% CI, 89 to 94) with N+AVD, as compared with 83% (95% CI, 79 to 86) with BV+AVD (hazard ratio for disease progression or death, 0.45; 95% CI, 0.30 to 0.65). Overall, 7 patients received radiation therapy. Immune-related adverse events were infrequent with nivolumab; brentuximab vedotin was associated with more treatment discontinuation.Conclusions N+AVD resulted in longer progression-free survival than BV+AVD in adolescents and adults with stage III or IV advanced-stage classic Hodgkin's lymphoma and had a better side-effect profile. (Funded by the National Cancer Institute of the National Institutes of Health and others; S1826 ClinicalTrials.gov number, NCT03907488.) In patients with advanced-stage Hodgkin's lymphoma, nivolumab added to chemotherapy resulted in greater 2-year progression-free survival than the addition of brentuximab vedotin to chemotherapy.

OBJECTIVES:Haematology patients are more likely to receive high intensity care near end of life (EOL) than patients with solid malignancy. Previous authors have suggested indicators of quality EOL for haematology patients, based on a solid oncology model. We conducted a retrospective chart review with the objectives of (1) determining our performance on these quality EOL indicators, (2) describing the timing of level of intervention (LOI) discussion and palliative care (PC) consultation prior to death and (3) evaluating whether goals of therapy (GOT), PC consultation and earlier LOI discussion are predictors of quality EOL. METHODS:We identified patients who died from haematological malignancies between April 2014 and March 2016 (n=319) at four participating McGill University hospitals and performed retrospective chart reviews. RESULTS:We found that 17% of patients were administered chemotherapy less than 14 days prior to death, 20% of patients were admitted to intensive care, 14% were intubated and 5% were resuscitated less than 30 days prior to death, 18% of patients received blood transfusion less than 7 days prior to death and 67% of patients died in an acute care setting. LOI discussion and PC consultation occurred a median of 22 days (IQR 7-103) and 9 days (IQR 3-19) before death. Patients with non-curative GOT, PC consultation or discussed LOI were significantly less likely to have high intensity EOL outcomes. CONCLUSIONS:In this study, we demonstrate that LOI discussions, PC consults and physician established GOT are associated with quality EOL outcomes for patients with haematological malignancies.

e13598 Background: Historically, accrual rates of AYA (aged 16-39) to cancer clinical trials have been low. This is suggested to contribute to lesser improvements in their outcomes compared with older and younger populations. We sought to describe the impact of collaborative initiatives launched by the Canadian Cancer Trials Group (CCTG), NCTN and C17 to address this. Methods: All CCTG trials open to accrual from 01/01/2004 to 31/12/2022 were evaluated. Trials with eligibility criteria limited to age > 39, or for which CCTG did not have access to individual patient data on age, were excluded. Accrual rates were assessed by age (<30, 30-39, >40 yrs), cancer type, and compared with 2022 Canadian Cancer Society (CCS) prevalence data. Results: 379 studies were open to accrual. 21 trials were excluded as they had no patients aged 16-39 within their inclusion criteria. 2 trials were excluded as they were either COVID related or a trial sub-study. 230 trials were excluded owing to patient age data being unavailable to CCTG. 126 CCTG and NCTN led trials were included. They involved the following disease sites: brain (3), breast (13), GI (12), GU (11), gynecology (6), head & neck (3), hematology (10), lung (11), melanoma (4), sarcoma (2) novel investigational agents (45) and symptom control (6) – the latter two spanned multiple tumor types. Patients aged 16-18 were excluded from many trials limiting accrual opportunities in this subgroup. AYA patients were recruited into trials at a higher level than expected by prevalence data except for brain, lung and head & neck patients. This may be due to younger, fitter patients being recruited onto trials. GU trials, hematology and sarcoma trials recruited better than expected as there were trials geared to diseases common in younger individuals (e.g. germ cell cancers) and incorporating intensive therapy e.g. stem cell transplantation in lymphoma. 3.5% of patients accrued on trials were <40 in 2004-2013 c.f. 8.7% of patients 2014-2022. Conclusions: Limited data is available on AYA aged 16-18 due to trial entry criteria. Currently, most CCTG trials include patients aged ≥14. Trial accrual in the AYA population was higher than predicted by CCS data indicating that clinical trials are acceptable to AYA patients. This supports ongoing efforts to improve trial access to AYA. [Table: see text]

Background: Survival rates in patients (pts) with classic Hodgkin lymphoma (HL) aged ≥60 years (y) are lower than younger pts. The difference is due to comorbidities, impaired performance status, decreased chemotherapy tolerance, and increased treatment-related toxicity and mortality. The frontline regimen Bv-AVD can be challenging to administer in older patients due to toxicities, particularly infection and neuropathy. The PD-1 pathway is central to pathogenesis of HL; PD-1 blockade is effective in HL. The randomized, phase 3 trial, S1826, was conducted by the National Clinical Trials Network to evaluate N-AVD vs Bv-AVD in pts with newly diagnosed advanced stage (AS) HL and enrolled 994 pts; 97 were eligible and aged ≥60y. Methods: In this subset analysis, eligible pts were ≥60y with stage 3-4 HL. Pts were randomized 1:1 to 6 cycles of N-AVD or Bv-AVD. G-CSF neutropenia prophylaxis was optional with N-AVD and required with Bv-AVD. Pre-specified pts could receive radiation therapy (RT) to residual lesions on end of treatment PET. Pts were stratified by age, international prognostic score (IPS), and intent to use RT. Response and progression were assessed by investigators using 2014 Lugano Classification. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), event-free survival (EFS), and detailed toxicity and safety events. EFS events were death without progression, progression/relapse, receipt of non-protocol systemic anti-lymphoma therapy without progression, or receipt of RT in a pt not declared eligible for RT at registration or who did not meet protocol-specified criteria for RT. Results: 97 pts aged ≥60y were enrolled from 7/9/19-10/5/22 and were randomized to N-AVD (n=48) or Bv-AVD (n=49). Median age was 66y (range, 60-83y), 62% were male, 86% were white, 3% were black, and 10% were Hispanic. 61% had stage IV disease and 47% had IPS 4-7. 69% of pts on N-AVD and 92% of pts on Bv-AVD received any G-CSF. No pts received RT per protocol. 95 pts were evaluable for safety analysis. While grade (gr) ≥3 hematologic toxicity occurred in 52% of pts on N-AVD and 38% on Bv-AVD (gr 3 neutropenia 48% vs 30%), febrile neutropenia, sepsis, and infections were lower for pts who received N-AVD vs Bv-AVD. (Table) Peripheral neuropathy was much less frequent with N-AVD than Bv-AVD in overall incidence (sensory: 31% vs 66% and motor: 8% vs 15%, respectively) and severity (grades ≥2, sensory: 10% vs 49% and motor: 0% vs 8%, respectively). (Table) The following adverse events, AEs (mainly <gr 3) were less frequent on N-AVD vs Bv-AVD: nausea (38% vs 62%), diarrhea (25% vs 45%), anorexia (15% vs 38%) and weight loss (4% vs 36%). Hypothyroidism (15% vs 0%), and rash (16% vs 2%, no gr ≥3) were more frequent on N-AVD than Bv-AVD; rates of other immune-related toxicities were similar between arms. In this subset analysis, median follow-up 12.1 months, PFS was superior in the N-AVD arm [HR 0.35 (95% CI 0.12-1.02) stratified one-sided logrank p=0.022]; 1-yr PFS was 93% (95% CI 79-98%) for N-AVD and 64% (95% CI 45-77%) for Bv-AVD. (Figure) 1-yr EFS was 93% (95% CI 79-98%) for N-AVD and 57% for Bv-AVD (95% CI 38-72%) [HR 0.19 (95% CI 0.06-0.61) stratified one-sided logrank p=0.0011]. 1-yr OS was 95% (95% CI 83-99%) for N-AVD and 83% (95% CI 67-92%) for Bv-AVD [HR 0.35 (95% CI 0.07-1.75) stratified one-sided logrank p=0.091]. On N-AVD, there were 2 deaths (due to infection/sepsis) and 3 progressions/relapses; on Bv-AVD, there were 7 deaths (5 due to infection/sepsis, 1 to pneumonitis, 1 unknown) and 8 progressions/relapses. Non-relapse mortality was 4% for N-AVD vs 14% for Bv-AVD. Treatment was discontinued early in 5 pts (10%) on N-AVD and 16 pts (33%) on Bv-AVD. N was discontinued early in 7 pts (15%) and Bv in 19 pts (39%). Reasons for discontinuation included (N vs Bv): AE (5 vs 14 pts), death (1 vs 3 pts), and disease progression (0 vs 1 pt). Conclusions: N-AVD improved PFS and EFS, and was better tolerated than Bv-AVD in pts aged ≥60 with AS HL. Substantially more pts discontinued Bv-AVD than N-AVD, primarily due to toxicity. Fewer deaths occurred on N-AVD than Bv-AVD. N-AVD is poised to become a standard of care for older AS HL pts fit for anthracycline-based combination therapy. Funding provided by the National Cancer Institute of the National Institutes of Health CA180888, CA180819, CA180821, CA180820, CA180863, CA189955 and funding/drug provided by BMS, drug provided by SeaGen for pts enrolled in Canada.

LBA4 Background: The addition of BV to initial chemotherapy improves overall survival (OS) in adults and PFS in pediatric patients (pts) with AS HL. However, frontline BV adds toxicity, most pediatric pts receive radiation therapy (RT), and 7-20% of pts still develop relapsed/refractory (RR) HL. The PD-1 pathway is central to the pathogenesis of HL and PD-1 blockade is effective in RR HL. The adult and pediatric cooperative groups of the National Clinical Trials Network (NCTN) conducted the randomized, phase 3 S1826 trial to evaluate N-AVD vs BV-AVD in pts with newly diagnosed AS HL. Methods: Eligible pts were ≥12 years (y) with stage 3-4 HL. Pts were randomized 1:1 to either 6 cycles of N-AVD or BV-AVD. Recipients of BV-AVD were required to receive G-CSF neutropenia prophylaxis vs optional with N-AVD. Pre-specified pts could receive RT to residually metabolically active lesions on end of treatment PET. Pts were stratified by age, international prognostic score (IPS), and intent to use RT. Response and disease progression were assessed by investigators using 2014 Lugano Classification. The primary endpoint was PFS; secondary endpoints included OS, event-free survival, patient-reported outcomes (PROs), and safety. Results: 994 pts were enrolled from 7/9/19 to 10/5/22; 976 were eligible and randomized to N-AVD (n=489) or BV-AVD (n=487). Median age was 27y (range, 12-83y), 56% of pts were male, 76% were white, 12% were black, and 13% were Hispanic. 24% of pts were < 18y, 10% were > 60y, and 32% had IPS 4-7. So far, < 1% of pts received RT. At the planned 2nd interim analysis (50% of total PFS events) the SWOG Data and Safety Monitoring Committee recommended to report the primary results because the primary PFS endpoint crossed the protocol-specified conservative statistical boundary. 30 PFS events occurred after N-AVD vs 58 events after BV-AVD. With a median follow-up of 12.1 months, PFS was superior in the N-AVD arm [HR 0.48, 99% CI 0.27-0.87, one-sided p=0.0005); 1y PFS: N-AVD, 94%, BV-AVD, 86%. 11 deaths (7 due to adverse events, AE) were observed after BV-AVD compared to 4 after N-AVD (3 due to AE). The rate of grade (gr) ≥ 3 hematologic AE was 48.4% (45.1% gr ≥ 3 neutropenia) after N-AVD compared to 30.5% (23.9% gr ≥ 3 neutropenia) after BV-AVD. Rates (any gr) of febrile neutropenia (5.6% N vs 6.4% BV), pneumonitis (2.0% N vs 3.2% BV), ALT elevation (30.7% N vs 39.8% BV), and colitis (1% N vs 1.3% BV) were similar. Hypo/hyperthyroidism was more frequent after N-AVD (7%/3% N vs <1% BV) while peripheral neuropathy (any gr) was more common after BV-AVD (sensory: 28.1% N vs 54.2% BV; motor: 4% N vs 6.8% BV). Conclusions: N-AVD improved PFS vs BV-AVD in pts with AS HL. Few immune AEs were observed and < 1% of pts received RT. Longer follow-up is needed to assess OS and PROs. S1826, the largest HL study in NCTN history, is a key step towards harmonizing the pediatric and adult treatment of AS HL. Funding provided by: National Cancer Institute of the National Institutes of Health U10CA180888 and U10CA180819 and Bristol-Myers Squibb. Clinical trial information: NCT03907488 .

Here, we report the first comparative analysis of patient-reported outcomes (PROs) with chimeric antigen receptor T-cell therapy vs standard-of-care (SOC) therapy in second-line relapsed/refractory large B-cell lymphoma (R/R LBCL) from the pivotal randomized phase 3 ZUMA-7 study of axicabtagene ciloleucel (axi-cel) vs SOC. PRO instruments were administered at baseline, day 50, day 100, day 150, month 9, and every 3 months from randomization until 24 months or an event-free survival event. The quality of life (QoL) analysis set comprised patients with a baseline and >= 1 follow-up PRO completion. Pre-specified hypotheses for Quality of Life Questionnaire-Core 30 (QLQ-C30) physical functioning, global health status/QoL, and EQ-5D-5L visual analog scale (VAS) were tested using mixed-effects models with repeated measures. Clinically meaningful changes were defined as 10 points for QLQ-C30 and 7 for EQ-5D-5L VAS. Among 359 patients, 296 (165 axi-cel, 131 SOC) met inclusion criteria for QoL analysis. At day 100, statistically significant and clinically meaningful differences in mean change of scores from baseline were observed favoring axi-cel over SOC for QLQ-C30 global health status/QoL (estimated difference 18.1 [95% confidence interval (CI), 12.3-23.9]), physical functioning (13.1 [95% CI, 8.0-18.2]), and EQ-5D-5L VAS (13.7 [95% CI, 8.5-18.8]; P < .0001 for all). At day 150, scores significantly favored axi-cel vs SOC for global health status/QoL (9.8 [95% CI, 2.6-17.0]; P = .0124) and EQ-5D-5L VAS (11.3 [95% CI, 5.4-17.1]; P = .0004). Axi-cel showed clinically meaningful improvements in QoL over SOC. Superior clinical outcomes and favorable patient experience with axi-cel should help inform treatment choices in second-line R/ R LBCL.