Abstract Hodgkin lymphoma (HL) is a B‐cell‐derived malignancy often affecting young adults. Allocation into risk groups is based on staging with positron emission tomography and computed tomography (PET/CT) and the presence or absence of risk factors. Standard treatment for early‐stage favorable classic HL (cHL) consists of two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), followed by 20 Gy involved‐site radiotherapy (IS‐RT). Two cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) or a procarbazine‐free eBEACOPP variant plus two cycles of ABVD, followed by 30 Gy IS‐RT in the case of PET/CT positivity and no further treatment in the case of PET/CT negativity after chemotherapy should be considered in patients with early‐stage unfavorable cHL ≤ 60 years. If a less intensive approach is preferred and in individuals > 60 years, four cycles of A(B)VD followed by 30 Gy IS‐RT can be given. In advanced cHL, brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD) for four (in the case of PET/CT negativity after two cycles) or six cycles (in the case of PET/CT positivity after two cycles), followed by PET/CT‐guided 30 Gy IS‐RT should be considered in patients ≤ 60 years. Six cycles of nivolumab and AVD (N‐AVD) followed by PET/CT‐guided 30 Gy IS‐RT represents a less intensive alternative for younger patients and the preferred approach for patients > 60 years. Patients with cHL recurrence should receive checkpoint inhibitor‐containing salvage treatment followed by high‐dose chemotherapy and autologous stem cell transplantation if eligible. Treatment of nodular lymphocyte‐predominant HL differs from cHL in some situations and may contain an anti‐CD20 antibody. This guideline aims at providing recommendations for diagnosis, staging, treatment, and follow‐up of HL.

Zamtocabtagene autoleucel is an autologous, non-cryopreserved tandem CD20-CD19 directed CAR-T cell therapy produced on the fully automated CliniMACS® Prodigy System in 12 d and showed promising efficacy and safety in a Phase II trial in r/r DLBCL. We report primary analysis results of the pivotal DALY 2-EU trial (NCT04844866), which compares zamto-cel vs standard of care (SoC) as second-line (2L) therapy for r/r LBCL in non-transplant eligible (NTE) pts in a randomized, multicenter study.Adult NTE pts with r/r (≤ 24 m after start of first-line [1L] therapy) LBCL were assigned to receive zamto-cel or SoC (R-GemOx, n=78 or Pola-BR, n=8). Key inclusion criteria were LBCL, ECOG ≤ 2 or one NTE criterion. Pts in the zamto-cel arm started lymphodepletion (fludarabine + cyclophosphamide) during manufacturing, followed by infusion of zamto-cel, target dose 2.5 × 106 CAR-T cells/kg body weight. No chemoimmunotherapy bridging except steroids was allowed. The primary endpoint was event free survival (EFS) by blinded independent review committee comparing zamto-cel vs R-GemOx. Key secondary endpoints included remission rates, progression-free survival (PFS) and overall survival.In total, 168 pts were randomized (N=82 zamto-cel, N=86 SoC). Key baseline characteristics were balanced: 63% male pts, median age 74 y (range 19-87), 85% DLBCL, 57% refractory to 1L therapy, 57% IPI 3-5 pts and 66% stage III-IV. 76 pts (93%) received zamto-cel. Six pts did not receive zamto-cel (2 withdrawals, coronary artery stenosis, pneumonia, worsening condition, progressive disease). Median vein-to-vein time was 15 d (range 14-16). With a median follow-up of 17 m, median EFS was 6.2 m (95% CI 3.8-13.8) for zamto-cel and 2.5 m (95% CI 2.0-3.3) for R-GemOx (HR 0.39; 95% CI 0.27-0.58; p<0.0001) in the ITT population. Median PFS was significantly longer with zamto-cel vs R-GemOx (8.5 m [95% CI 3.8-16.8] vs 3.3 m [95% CI 2.0-3.8]; HR 0.43 [95% CI 0.28-0.65]; p<0.0001). ORR was 72% (61-81%) with a CR rate of 54% for zamto-cel vs 45% (34-57%) ORR and 14% CR rate for R-GemOx. Among all patients treated with zamto-cel in the experimental arm, ORR was 78%, with 58% achieving CR. In the zamto-cel arm, CRS Grade (G) ≥3 was reported in 4 pts (5.3%; 2 pts G3, 1 pt G4, 1 pt G5). Median time to onset of CRS was 2 d (1-14), median duration was 3 d (1-24). One pt (1.3%) had ICANS G3, no G4/5. For CRS, 29 (38%) pts received tocilizumab, 14 (18%) corticosteroids. Persisting neutropenia (≥ 28 d) of G4 was reported in 7 pts (9%). Within 90 d after start of treatment, 8 pts died in each arm; main reason was progression in 4 (50% zamto-cel) and 5 (63% R-GemOx) pts.Zamto-cel demonstrated significant and clinically meaningful superiority over R-GemOx in NTE pts. Zamto-cel was well tolerated in this vulnerable elderly population with low rates of severe CRS/ICANS. This favorable risk/benefit profile suggests the use of zamto-cel as preferred treatment option in 2L NTE pts with r/r LBCL.

BACKGROUND:In early-stage favorable Hodgkin lymphoma (ES-HL), lymph node involvement patterns (NIP) have not been investigated until now. Adding finer granularity to the current disease classification system evaluated through systematically incorporating NIP alongside established clinical variables may help to identify distinct patient subgroups and improve the understanding of ES-HL. METHODS:A total of 3715 patients with ES-HL treated within the German Hodgkin Study Group HD10, HD13, and HD16 studies was retrospectively analyzed (stage I/II without risk factors). Involved lymph node regions were categorized into predefined anatomical areas, and the distribution patterns of affected lymph node regions were explored. Associations of patterns with baseline characteristics, histology, and 5-year progression-free survival (PFS) were analyzed using univariate and multivariable models. RESULTS:Despite 22 possible combinations, 91.6% of patients presented with one of the six most common NIP. They differed in terms of age, sex distribution, weight, hemoglobin levels, and histologic subtype composition. For example, the combination of cervical and mediastinal involvement was more frequent in younger patients, females, enriched for nodular sclerosis histology, and associated with superior 5-year PFS compared to other patterns (95.1% vs 91.9%, p < .001). Conversely, the combination of cervical and axillary involvement was associated with decreased 5-year PFS (85.3% vs 93.4%, p < .001) and was enriched for male sex and nodular lymphocyte-predominant Hodgkin lymphoma. CONCLUSIONS:Different presentation phenotypes exhibit distinct clinicopathologic characteristics and have prognostic impact in ES-HL. Further studies integrating molecular profiling are warranted to elucidate root mechanisms and possibly refine risk group allocation.

The MK-4280-003 study evaluated favezelimab plus pembrolizumab in hematologic malignancies. We report results for anti-programmed cell death protein 1 (PD-1)-refractory classic Hodgkin lymphoma (cHL; cohort 2). Participants in the safety lead-in had relapsed or refractory (R/R) cHL, diffuse large B-cell lymphoma, or indolent B-cell lymphoma. Participants in cohort 2 had R/R cHL, had undergone or were ineligible for autologous stem cell transplantation, and had disease progression after ≥2 doses of anti-PD-1 therapy and within 12 weeks of last dose. Primary end points were safety and the recommended phase 2 dose (RP2D) of favezelimab plus pembrolizumab. Objective response rate (ORR) was secondary. Duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were exploratory. In the safety lead-in, 1 of 21 participants experienced a dose-limiting toxicity (grade 4 autoimmune hepatitis). The RP2D was favezelimab 800 mg plus pembrolizumab 200 mg IV every 3 weeks. Cohort 2 included 34 participants. Treatment-related adverse events (AEs) occurred in 28 participants (82%; grade 3 or 4 in 6 participants [18%]; no grade 5 AEs). Immune-mediated AEs and infusion reactions occurred in 17 participants (50%; grade 3 or 4 in 3 participants [9%]; no grade 5 AEs). ORR was 29% (95% confidence interval [CI], 15-48). Median DOR was 21.9 months (range, 0.0+ to 26.1+). Median PFS was 9.7 months (95% CI, 5.1-14.7); 24-month PFS was 21%. Median OS was not reached (NR; 95% CI, 27.9 to NR); 24-month OS was 76%. Favezelimab plus pembrolizumab showed manageable safety and antitumor activity in heavily pretreated anti-PD-1-refractory cHL. This trial was registered at www.clinicaltrials.gov as NCT03598608.

BACKGROUND:Effective treatments with deep and durable responses for relapsed or refractory marginal zone lymphoma (MZL) are lacking. The objective of the primary analysis from the MZL cohort of TRANSCEND FL was to evaluate the efficacy and safety of the CD19-directed chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel. METHODS:In this phase 2, single-arm, multicohort study, patients from 30 sites in the USA, Canada, Europe, and Japan with relapsed or refractory MZL who had at least two previous lines of systemic therapy were eligible to receive lisocabtagene maraleucel (100 × 106 CAR+ T cells). Bridging therapy was allowed. The primary endpoint was overall response rate per independent review committee by CT by use of Lugano 2014 criteria (null hypothesis ≤50%). This study is registered with ClinicalTrials.gov, NCT04245839, and is ongoing. FINDINGS:Of 77 leukapheresed patients recruited between November 11, 2020, and August 24, 2023, 67 received lisocabtagene maraleucel and 66 were efficacy evaluable. MZL subtypes included nodal (n=32 [48%]), splenic (n=18 [27%]), and extranodal-mucosa-associated lymphoid tissue (n=17 [25%]). Median (IQR) previous lines of systemic therapy was 3 (2-4). Median on-study follow-up was 24·1 months. The primary endpoint was met, with an overall response rate of 95% (n=63; 95% CI, 87·3-99·1; one-sided p<0·0001). All patients experienced a treatment-related adverse event. Grade 3 cytokine release syndrome or neurological events occurred in three (4%) patients each (no grade 4-5 events). 11 (16%) patients had grade ≥3 infections: six (9%) patients during the 90-day treatment-emergent period and seven (10%) during the post-treatment-emergent period. INTERPRETATION:In patients with relapsed or refractory MZL, lisocabtagene maraleucel showed high rates of durable responses. The safety profile was manageable, with no new safety signals. These results support lisocabtagene maraleucel as a new treatment option for patients with relapsed or refractory MZL. FUNDING:Celgene, a Bristol-Myers Squibb Company.

In relapsed/refractory classic Hodgkin lymphoma (r/r cHL), salvage followed by high-dose chemotherapy and autologous stem cell transplantation (HD-ASCT) yields suboptimal outcomes. PD-1 inhibitor-based salvage regimens have shown superior complete response (CR) rates of up to 95% (for P-GVD) with unprecedented PFS after HD-ASCT. However, immune checkpoint inhibitors are not EMA-approved in 2nd line, and European data remain sparse. This retrospective, multicentric analysis included r/r cHL patients who received salvage with intent to consolidation. Response before and after SCT consolidation, and PFS and OS were assessed. 47 patients were included (median prior lines: 2). Salvage regimens were PD-1 monotherapy (n=10), PD-1 + chemotherapy [P-ICE/ N-ICE /P-GVD] (n=34), or PD-1 + BV (brentuximab vedotin) (n=3). Overall response (OR)/CR were 90.9%/47.7%. OR/CR rates by salvage regimen were: PD-1 monotherapy 80/10%; PD-1 + chemotherapy, 93.6/61.3%; PD-1 + BV, 100/33.3%. With median follow-up of 16 months, 1- year PFS was 83.9% and OS was 95.6%. In the subgroup of patients with one prior line (n=22), 1-year PFS was 100%. In this real-world cohort, previously reported high CR rates were not reached. However, with the restriction of a limited follow-up, outcomes after HDASCT were excellent, supporting the role of PD-1 inhibitor-based salvage followed by consolidative HD-ASCT for r/r cHL.

The benefit of antibiotic prophylaxis (ABP) during chemotherapy for cancer remains controversial. The growing resistance to fluoroquinolones in hematological patients (Gupta et al., Lancet Oncology, 2025) and concerns about adverse events challenge its widespread use. In the GHSG HD21 trial for advanced-stage classic Hodgkin lymphoma (AS-cHL), patients received polychemotherapy regimens (eBEACOPP [bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone] or BrECADD [brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone]) with a risk to develop febrile neutropenia (FN) and/or infections. Here, we investigate the impact of ABP and Granulocyte colony-stimulating factor (G-CSF) formulation (pegylated vs. non-pegylated) on FN and infection rates. HD21 is an international, prospective, open-label, randomized trial of individualized PET2-guided treatment of AS-cHL with either eBEACOPP or BrECADD. In this post-hoc analysis patients, who received at least one cycle of treatment, were included. ABP was recommended per protocol but not mandatory. G-CSF support was mandated. Associations between ABP use and patient, center and treatment characteristics were tested via χ²/Fisher's exact and unequal-variance t-tests. Rates of FN and CTCAE Grade (G) ≥3 infections were compared per cycle. The effects of ABP and pegylated (peg) vs non-peg G-CSF were analyzed separately over all cycles available. Due to high overall survival rates for both regimens, we were not able to assess the effects of ABP on mortality. 1.500 patients were enrolled into the HD21 trial, of whom 1470 patients (with N=6955 cycles) received at least one cycle of treatment (ITT-TRMB). Of these patients, 984 (67 %) received ABP in at least one cycle. Per cycle, usage of fluoroquinolone ABP ranged between 97.1% and 98.1%. ABP was more commonly used in female than male patients (71.1 % vs. 63.6 %, p=0.0026) and at academic sites and outpatient clinics than in non-academic hospitals (71.0% vs. 82.9 % vs. 61.9 %, p<0.0001). The proportion of patients experiencing FN or infection ≥ G3 was higher in the first (15.9%; 9.2%) than in subsequent cycles (4.7-7.6%; 4.1-5.7%) and in this cycle especially high for patients ≥40 years (18.4%; 12.3%) vs <40 years (15.0%; 8.0%). We found a benefit for the use of ABP with BrECADD: The rate of FN was 9.8 % without ABP and 7.5 % with ABP (p = 0.019), and for ≥ G3 infections 6.7 % and 4.5 % (p = 0.0065), respectively. With eBEACOPP, there were no significant differences (FN: 6.8 % vs 6.3 %, p = 0.54; ≥ G3 infections: 5.6 % vs 4.9 %, p = 0.40). Focusing on the first cycle, reduction was present with ABP in both arms: With eBEACOPP (n=732), FN occurred in 16.1 % vs 9.7 % and ≥ G3 infections in 9.7 % vs 6.5 %; with BrECADD (n=738), occurrence of FN was 22.0 % vs 16.6 % and ≥ G3 infections 14.0% vs 7.1 %. Non-peg G-CSF was used in 599 (8.7 %) of 6905 cycles. With BrECADD, the incidence of FN (8.3% vs. 13.8%, p = 0.0051) was significantly lower with peg G-CSF vs non-peg G-CSF, whereas no such difference was observed with eBEACOPP (6.4% vs. 8.4%, p = 0.17). This comprehensive analysis of the HD21 trial demonstrates the efficacy of ABP and peg G-CSF in the treatment of AS-cHL in preventing FN and higher-grade infections. This effect is most pronounced in the first cycle and in patients receiving BrECADD. Based on these results, we recommend the use of ABP during the first cycle of the BrECADD regimen, at least.

Abstract The Lugano Imaging Committee recently refined the Deauville score (DS), subdividing DS5 into DS5a (>2× liver uptake without new lesions) and DS5b (new lesions). We investigated whether this improves prognostic discrimination at interim positron emission tomography (PET) after 2 cycles (PET-2) in patients with advanced-stage classical Hodgkin lymphoma (AS-cHL) treated in recent German Hodgkin Study Group randomized phase 3 trials. The primary analysis cohort was HD18 postamendment standard arms (uniform treatment with 6 cycles of escalated doses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone [eBEACOPP]); sensitivity cohorts were HD18 intention-to-treat and HD21 eBEACOPP and brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone arms. Progression-free survival (PFS) was analyzed by landmark Cox models starting at PET-2. DS5a was infrequent (4%-6% across cohorts; 39/639, 67/1745, 33/568, and 29/560). In the primary cohort, DS5 was associated with inferior PFS vs DS1 to DS3 (hazard ratio [HR], 3.00; 95% confidence interval [CI], 1.25-7.23) and vs DS1 to DS4 (HR, 2.35; 95% CI, 1.01-5.50). Across sensitivity cohorts, DS5a remained adverse compared with DS1 to DS4 (HR range, 2.57-5.47), whereas DS4 according to the new definition did not consistently separate from DS1 to DS3, which is likely a result of PET-adapted treatment. Overall survival trends were concordant, but interpretation is limited by few events. To our knowledge, this is the first prognostic validation of the refined DS in prospectively randomized trial populations. The newly introduced DS5a isolates a small high-risk AS-cHL, which further supports risk assessment and adaptation using quantitative biomarkers from PET. The HD18 and HD21 trials were registered at www.clinicaltrials.gov as NCT00515554 and NCT02661503, respectively.

In TRANSCEND FL, lisocabtagene maraleucel (liso-cel) demonstrated strong efficacy, with 97% overall response rate (ORR) and 94% complete response (CR) rate in third-line or later (3 L+) follicular lymphoma (FL). Here, we compared efficacy and safety of liso-cel from TRANSCEND FL to standard-of-care (SOC [excluding T-cell-engaging therapies]) by constructing an external control arm (ECA) of patients from historical clinical trials and real-world practice. Using inverse probability of treatment weighting (IPTW), ECA cohort was balanced to match TRANSCEND FL. After IPTW, liso-cel-treated patients had significantly higher ORR (relative risk: 1.4; 95% confidence interval [CI]: 1.3-1.6) and CR rate (2.4; 2.1-2.7) than SOC. Adjusted hazard ratios (95% CI) for duration of response (0.26; 0.15-0.46), time to next treatment (0.24; 0.13-0.44), progression-free survival (0.28; 0.17-0.48), and overall survival (0.40; 0.19-0.84) significantly favored liso-cel, demonstrating meaningful efficacy improvement with liso-cel over SOC, solidifying liso-cel as a treatment option for patients with 3 L + FL.

7003 Background: The epigenetic enzyme protein arginine methyltransferase 5 (PRMT5) plays a critical role in cell proliferation and differentiation; PRMT5 dysregulation is associated with cancer development. Methylthioadenosine (MTA) is an endogenous partial inhibitor of PRMT5 that accumulates in cancer cells deficient in MTA phosphorylase (MTAP). In classic Hodgkin lymphoma (cHL), we previously reported that >80% of primary patient (pt) tumor samples are MTAP deficient (Urosevic J, ASH 2023). The MTA-cooperative PRMT5 inhibitor AZD3470 preferentially binds to the MTA-bound state of PRMT5, increasing its target engagement to MTAP-deficient cancer cells. Here, we present safety and preliminary efficacy of AZD3470 from a first-in-human Phase 1 study in relapsed/refractory (r/r) cHL (NCT06137144). Methods: Eligible pts were ≥18 years with r/r cHL after ≥3 prior lines of therapy (including brentuximab vedotin (BV) and anti-PD-1). In dose escalation, pts received oral AZD3470 monotherapy QD in ascending dose levels (DLs) using an mTPI-2 design. Primary endpoints were incidence and severity of treatment-emergent adverse events (TEAEs) and dose-limiting toxicity (DLT). Secondary endpoints were overall response rate (ORR) and complete response rate (CRR) per Lugano 2014 criteria. Results: As of Nov 25, 2025, 39 pts had received AZD3470 at DLs ranging from 1 to 8. Most pts were male (62%) with stage IV disease (77%) and a median age of 42 (range 25–78) years. Pts had received a median of 6 prior lines of anticancer therapy (range 3–14); all had had prior BV and anti-PD1 treatments, and 20 (51%) and 5 (13%) pts had had prior autologous and allogeneic hematopoietic stem cell transplantation, respectively. All patients evaluable for MTAP protein expression were MTAP deficient. Median duration of exposure was 15 weeks (range 0.1–45.1), with treatment ongoing in 16 pts (41%). TEAEs occurred in 85% of pts, predominantly grades 1 or 2. The most common TEAEs (any grade) were anemia (28%) and nausea (15%), followed by asthenia, constipation, fatigue, and neutropenia (13% each). Grade ≥3 TEAEs occurred in 28% of pts, most commonly neutropenia (related) and hypokalemia (n=2 each). Serious TEAEs occurred in 5 (13%) pts. Two pts had dose reductions due to TEAEs (grade 4 hypertriglyceridemia and grade 3 esophagitis). No DLTs, treatment discontinuations nor deaths due to TEAEs were reported. Of the 31 pts evaluable for efficacy, 14 had an objective response, with responses at doses ≥DL4. The highest response rate was observed at doses ≥DL7 (n=10) with an ORR of 80% and CRR of 50%. Conclusions: AZD3470 monotherapy was well tolerated up to DL8, with no DLTs and mainly low-grade AEs. Incidences of grade ≥3 AEs and SAEs were low. Importantly, both the ORR and CRR were dose-dependent and notably high in this heavily pretreated cHL population. Dose optimization is ongoing and further safety and efficacy will be reported. Clinical trial information: NCT06137144 .

The LP-IPS including four (age, stage, splenic involvement, hemoglobin; 1 point for each factor) and the GHSG score comprising three (sex, albumin, variant histopathological growth pattern (GP); 2 points for sex, 1 point for albumin and variant GP) risk factors represent prognostic tools for nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). A comparison of the scores has not been conducted until now. We thus performed an analysis comprising 583 NLPHL patients treated within GHSG studies. In addition to the LP-IPS and the original GHSG score, a modified GHSG score (GP DE replacing GP CDEF as risk factor variant GP) was also investigated. Low-risk vs high-risk groups were defined as 0-1 vs 2-4 points for the LP-IPS and 0-2 vs 3-4 points for the GHSG scores. Regarding progression-free survival (PFS) and overall survival (OS), Cox regression analyses revealed hazard ratios (HR) for the high-risk vs low-risk groups of 2.71 (95%-CI: 1.76-4.18) and 8.24 (95%-CI: 3.7-18.34) for the LP-IPS, 1.59 (95%-CI: 1.04-2.45) and 2.45 (95%-CI: 1.1-5.45) for the original and 1.97 (95%-CI: 1.25-3.09) and 4.15 (95%-CI: 1.86-9.23) for the modified GHSG score. The combination of the LP-IPS and the modified GHSG score (low-risk/low-risk vs high-risk/high-risk) resulted in high HR for the high-risk/high-risk group in terms of both PFS (HR: 3.74; 95%-CI: 2.09-6.7) and OS (HR: 13.52; 95%-CI: 5.03-36.35). Thus, the LP-IPS represents the most reliable standalone risk score for NLPHL. The combination of the LP-IPS and the modified GHSG score may help to further characterize specific risk groups.

Abstract We evaluated outcomes by management type for patients with stage IA nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) in the Global NLPHL One Working Group retrospective database of 2243 patients with stages I to IV disease diagnosed from 1992 to 2021 at 38 international institutions. A total of 779 patients had stage IA disease with median age of 35 years (range, 3-89) and median follow-up of 6.1 years. The 6-year progression-free survival (PFS) and overall survival were 86.3% and 97.7%, respectively. Outcomes were analyzed for the 2 groups: complete resection and unresected disease. Patients with a complete resection and observation alone (n = 99) had a 6-year PFS of 65.5% vs 90.5% for those who received radiotherapy (RT) (n = 53). Patients with unresected disease (n = 627; 80.5%) had a 6-year PFS of 62.0% for rituximab alone (n = 31), 89.6% for RT alone (n = 325), 76.8% for ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) alone (n = 40), and 94.3% for ABVD plus RT (n = 130). A total of 127 patients relapsed (16.3%), of which 25 (19.7%) had transformation. Our analysis suggests the following: (1) RT improves the PFS in patients with completely resected disease; (2) rituximab or ABVD alone does not appear to achieve a durable response; and (3) chemotherapy was not observed to add additional PFS benefit when used in combination with RT. Thus, for stage IA NLPHL, RT alone is likely sufficient for definitive treatment.

Emerging long-term data indicates relapse rates of over 50% after CD19 redirected chimeric antigen receptor (CAR) T cell therapy in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). To reduce selective pressure on the CD19 antigen we conducted a first-in-human phase I clinical trial of zamtocabtagene autoleucel (zamto-cel) - a non-cryopreserved tandem CD20-CD19-directed CAR-T cell therapy. Two predefined dose levels (DL1=1x106 and DL2=2.5x106 CAR+ T cells/kg body) were applied. The primary endpoint (EP) was the maximum tolerated dose (MTD). Secondary EPs included adverse events (AEs), best overall response (BOR) and biomarker assessments. A total of 12 patients, 6 per dose level were treated. No DLT and no cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) grade ≥3 were observed. Thus, MTD was not reached. The BOR by investigator assessment was 75% with 5/12 patients (42%) achieving complete remission (CR) until month 12 with no relapse in clinical evaluation up to 5 years after infusion. CR was associated with higher mean Cmax and detection of zamto-cel beyond month 6. Additional product characterization revealed increased expression of CD27 and CD127 along with increased expansion of CAR+ TCM cells in patients with CR, thus facilitating persistence and improved outcomes in r/r B-NHL treated with zamto-cel. Based on the promising risk-to-benefit ratio, evaluation of zamto-cel at DL2 is ongoing in pivotal Phase II clinical trials for patients with r/r aggressive B-NHL. This trial was registered at www.clinicaltrials.gov as #NCT03870945.

ABSTRACT:Beyond cure, major goals in patients with Hodgkin lymphoma (HL) are tailoring treatment to a patient's individual risk for relapse to reduce acute and late toxicities, identifying candidates for early incorporation of novel agents, and making treatment affordable on a global level. Minimal residual disease (MRD) assessment by circulating tumor DNA (ctDNA) sequencing emerged as a promising strategy to achieve these goals; however, previous studies differed in sampling time points, assay validation, and definitions for MRD negativity. Here, we applied LymphoVista, a validated ctDNA sequencing assay for genotyping and MRD monitoring in lymphoma, to samples obtained from the German Hodgkin Study Group (GHSG) HD21 trial after 2 cycles of treatment (MRD-2) using a case-cohort design. Patients with positive MRD-2 result were at higher risk for relapse, progression, or death compared with MRD-2-negative patients (4-year progression-free survival [PFS], 36.7% vs 82.2%; hazard ratio, 5.3; 95% confidence interval, 2.0-13.8; P = .0008). After inverse probability weighting accounting for the number of events in the full reference set, patients with positive and negative MRD-2 results had 4-year PFS rates of 72.2% vs 95.3%. Combining MRD-2 with positron emission tomography after 2 cycles of BrECADD/eBEACOPP (PET-2) can identify patients at very low and patients at very high risk of relapse, progression, or death. In summary, these results suggest that MRD-2 assessment by LymphoVista allows for early outcome prognostication in patients with HL and could be used as a tool to improve treatment guidance on its own or in conjunction with PET-2.

ABSTRACT:In 82 patients with classic Hodgkin lymphoma, stable gonadal hormone levels were observed up to 24 months after nivolumab in combination with doxorubicin, vinblastine, and dacarbazine (N-AVD) first-line treatment. These findings suggest preserved gonadal function and fertility after 4×N-AVD. The trial was registered at www.clinicaltrials.gov as NCT03004833.

Background Curative first-line treatment of advanced-stage classical Hodgkin lymphoma (cHL) has historically been defined by ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine ) and escalated BEACOPP (eBEACOPP; bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). Positron-emission tomography (PET)-adapted strategies enabled response-guided escalation and deescalation, while antibody-based regimens have again shifted the risk-benefit profile. Nivolumab-AVD (N-AVD; nivolumab, doxorubicin, vinblastine, dacarbazine) and brentuximab-ECADD (BrECADD; brentuximab-vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) are two effective contemporary approaches that may serve as new standards for patients with advanced cHL, depending on regional practice patterns. Objective This work aims to position N-AVD and BrECADD based on the SWOG S1826 and German Hodgkin Study Group (GHSG) HD21 trials, discuss practical treatment selection, and outline GHSG-driven future concepts integrating PET and circulating tumor DNA (ctDNA). Materials and methods We performed a narrative review of pivotal randomized trials and relevant subgroup/biomarker data (PET, ctDNA) in advanced-stage cHL. Results and conclusion Compared to earlier regimens, N-AVD and BrECADD combine higher efficacy with a favorable side effects profile. In the phase III S1826 trial, N-AVD improved progression-free survival versus brentuximab-AVD (BV-AVD; brentuximab-vedotin, nivolumab, doxorubicin, vinblastine, dacarbazine), with tendential benefits in several subgroups, including older patients. However, the PET-based response evaluation under PD-1 inhibition is limited, and long-term tolerability assessment requires structured surveillance for immune-related adverse events. In the phase III HD21 trial, PET-guided BrECADD reduced treatment-related morbidity compared with eBEACOPP and achieved excellent PFS; fertility recovery and patient-reported outcomes further support a favorable patient-centered profile. Ongoing GHSG programs (Pembro-FLASH, QUANTIFY) and integrated ctDNA/quantitative PET approaches may refine risk stratification, enable safe de-intensification, and support step-up strategies reserving intensified chemotherapy for patients who truly need it.

Introduction In the primary analysis of TRANSCEND FL (NCT04245839), an open-label, pivotal study, liso-cel showed high response rates and favorable safety in patients with R/R FL. Objectives To report 3-y follow-up (FU) results in patients with 3L+ FL, including efficacy, safety, and longitudinal safety analyses for key AEs. Methods Eligible patients had R/R FL after ≥ 2 prior lines of combination systemic therapy, including an anti-CD20 antibody and an alkylator. Patients received liso-cel after lymphodepleting chemotherapy (LDC). Bridging therapy was allowed with reconfirmation of PET-positive disease before LDC. The primary endpoint was ORR per independent review committee by PET/CT using Lugano 2014 criteria. Secondary endpoints included CR rate, duration of response, PFS, OS, and safety. Additional post hoc analyses included time to next treatment and efficacy by progression of disease ≤ 24 mo from first-line chemoimmunotherapy (POD24) status (yes vs no) and by prior bendamustine exposure before leukapheresis (yes vs no). Incidences of infections, second primary malignancies (SPM), hypogammaglobulinemia, and grade ≥ 3 cytopenia (overall and by lineage) were assessed over time from Days 1–30, at 3-mo intervals until Month 12, at 6-mo intervals until Month 36, and from Month 36 until end of study. Results At data cutoff (03/31/2025), 107 patients with 3L+ FL received liso-cel and were evaluable for safety; 103 were efficacy evaluable. Median (range) age was 62 y (23–80); 95 (89%) had Ann Arbor stage III/IV disease; 61 (57%) were high risk per FL International Prognostic Index. Fifty-nine patients (55%) had POD24; 69 (64%) were double refractory to anti-CD20 antibody and an alkylator; 65 (61%) had prior bendamustine exposure.Median (range) on-study FU was 41.5 mo (0.3–54.0). Response rates were high overall and regardless of POD24 status or prior bendamustine exposure (Table 1).Treatment-emergent (TE) AE rates were consistent with the primary and 2-y FU analyses. Grade 3 cytokine release syndrome was reported in 1% (no grade 4/5) and grade 3 neurological events in 2% (no grade 4/5). SPMs were reported in 11 patients (10%; 4 additional patients since the 2-y FU analysis; no secondary T-cell malignancies). Grade ≥ 3 infections were reported in 13 (12%) patients, including 7 (7%) in the TE period (≤ 90 d after infusion) and 8 (7%) in the post-TE period (3 more patients since the 2-y analysis). AE incidences over time are shown in Table 2. Conclusion In patients with 3L+ FL, a single infusion of liso-cel demonstrated remarkable efficacy, with durable responses and high 3-y survival rates, regardless of POD24 status or prior bendamustine exposure. No new safety signals were identified. Grade ≥ 3 neutropenia and hypogammaglobulinemia decreased over time and severe infections remained low, further underscoring the favorable long-term safety profile of liso-cel in patients with 3L+ FL.