12  Novel Treatment Strategies in Aggressive Lymphoma

12.1 Session Overview

Session Details
Session Novel Treatment Strategies in Aggressive Lymphoma
Speakers Steven Park, MD; Eric Tse, MBBS, PhD
Affiliations Wake Forest University School of Medicine, Winston-Salem, NC, USA; The University of Hong Kong, Hong Kong
Time Day 2, 2:00–2:45 p.m.

Dr. Park and Dr. Tse present a case-based tour through aggressive B-cell lymphoma, built around three clinical vignettes that bracket the modern decision points: a primary-gastric DLBCL in an Asian patient with residual PET activity after R-CHOP (driving the discussion of ctDNA-MRD); an elderly GCB DLBCL patient eligible for Pola-R-CHP or bispecific-based frontline (driving the frail/unfit frontline discussion); and a multiply refractory young patient after R-EPOCH and R-ICE who needs CAR-T bridging (driving the R/R sequencing discussion) [slide p.1, p.13, p.25, p.38]. The learning objectives frame evidence-based treatment strategies, emerging approaches, and integration of new evidence into decision-making for aggressive B-cell lymphoma [slide p.3].

12.2 Speaker Spotlight

Steven Park, MD is a hematologist-oncologist at Wake Forest University School of Medicine specialising in aggressive B-cell lymphomas [slide p.1]. His contributions to ADC and bispecific antibody platforms have shaped the non-transplant R/R DLBCL armamentarium, and he anchors the session with three longitudinal cases from his own clinic.

Eric Tse, MBBS, PhD is a clinical haematologist at The University of Hong Kong with deep expertise in the Asian lymphoma landscape [slide p.1]. He frames the session in the regional epidemiology of lymphoid neoplasms, the access gap for novel agents in Asia-Pacific, and the practical consequences of those gaps for R/R DLBCL management.

12.3 Regional Epidemiology and Disease Context

Distribution of lymphoid neoplasms differs sharply across Asia-Pacific and the US [slide p.4]. DLBCL dominates the picture in China (~36%), Japan (~33%), and Korea (~30%) compared with 21% in the US—but the relative share of FL (~18% Japan vs ~9% US), CLL/SLL (~15% US vs <5% in Asia), ENKTL (~11% China, 4% Korea), and ATLL (~10% Japan) is strikingly different. The regional burden of aggressive B-cell disease is therefore proportionally higher in Asia, with distinct treatment-access constraints [slide p.4].

Aggressive B-cell lymphoma is a heterogeneous group united by brisk tumour cell proliferation requiring early treatment, now classified into more than 20 categories under the WHO HAEM5 and International Consensus Classification (ICC) based on morphology, immunophenotype, clinical presentation, and limited molecular features [slide p.5]. R-CHOP cures approximately 65% of DLBCL patients, but the remaining 35% relapse or develop primary progression and may become chemorefractory (Sehn LH, NEJM 2021) [slide p.6].

12.3.1 DLBCL molecular classification

Cell-of-origin (GCB vs ABC) classification by gene expression profiling dates back to Alizadeh (Nature 2000), and whole-exome sequencing has since layered on genetic subgroups: Schmitz et al. defined MCD, BN2, N1, EZB clusters (NEJM 2018), and Chapuy et al. defined C1–C5 clusters (Nat Med 2018) [slide p.7]. The integrated Sehn/LymphGen framework ties cell-of-origin to six molecular subtypes with distinct prognoses and genetic similarities to other lymphoma entities [slide p.8]:

LymphGen subtypes of DLBCL [slide p.8]
LymphGen Cluster Cell of origin Genetic hallmarks Biologic pathway Prognosis
EZB C3 GCB BCL2, EZH2, TNFSFR14, CREBBP, KMT2D (±MYC in DH/TH) Epigenetic, PI3K Favourable; poor if EZB-MYC+ or HGBCL-DH/TH
ST2 C4 GCB TET2, SGK1, DUSP2, ZFP36L1, ACTG1, ACTB, ITPKB, NFKBIA JAK/STAT Favourable
BN2 C1 Mixed BCL6, NOTCH2, TNFAIP3, DTX1 NOTCH2, immune evasion Intermediate
A53 C2 Mixed TP53, aneuploidy Genetic instability, immune evasion Poor / intermediate
N1 – ABC NOTCH1, IRF2BP2 NF-κB Unknown
MCD C5 ABC MYD88, CD79B, PIM1, HLA-B, BTG1, CDKN2A, ETV6, SPIB, OSBPL10 BCR + NF-κB Poor / intermediate

12.3.2 First-line treatment: “R-CHOP + X”

Two decades of “R-CHOP + X” trials (R-CHOP + rituximab maintenance, ASCT, mini-CEOP, R-CHOP-14, dose-adjusted EPOCH-R, enzastaurin, everolimus, lenalidomide, bortezomib, ibrutinib maintenance, ibritumomab, bevacizumab, obinutuzumab, ibrutinib, lenalidomide) consistently failed to improve outcomes—POLARIX (Pola-R-CHP) in 2022 was the only signal to emerge since R-CHOP’s own 2002 victory [slide p.9]. Dr. Park noted that in some Asian countries, Pola-R-CHP has already become standard for IPI ≥2/3 [slide p.9].

The current phase 3 landscape (Qualls D, Blood 2025;145:176–189) spans 16+ trials through 2031 [slide p.9]:

  • General/targeted: POLARIX (R-Pola-CHP), ENGINE1 (R-CHOP+enzastaurin), R-CHOP+tucidinostat, POLAR BEAR (Pola-R-mini-CHP), ESCALADE (R-CHOP+acalabrutinib), frontMIND (R-CHOP+Tafa-Len), SWOG 1918 (R-mini-CHOP+oral azacitidine), ZR2 in elderly, GUIDANCE-02 (R-CHOP+X)
  • Bispecific: BELIEVE-01 (R-CHOP+orelabrutinib), EPCORE DLBCL-2 (R-CHOP+epcoritamab), SKYGLO (R-Pola-CHP+glofitamab), OLYMPIA-3 (R-CHOP+odronextamab), GOLSEEK-1 (R-CHOP+golcadomide)
  • CAR-T: ZUMA-23 (axi-cel in 1L)
  • Elderly: ARCHED (R-mini-CHOP+acalabrutinib)

12.3.3 R/R DLBCL: an unmet need especially in Asia

The ORBIT study (Lim et al., ESMO Real World Data and Digital Oncology 2025) quantified the R/R DLBCL problem across Asia, where CAR-T access is limited [slide p.10]. Median OS dropped from 13.5 months at 1st relapse to 6.1 months at 2nd and 3rd relapse; 5-year OS fell from 29.8% → 17.0% → 11.8%. The time-to-relapse subgroup was even more sobering: median OS 6.2 months for <6-month relapse, 17.8 months for 6–12 months, and 34.2 months for >12 months (p=0.0004). Across lines, 32.8% received ICE-based salvage, and novel-agent use was <10% for most classes [slide p.10]. Early-relapsing DLBCL in Asia has median OS of just 6 months without CAR-T.

ZUMA-7 (Westin, NEJM 2023) and TRANSFORM established CAR-T as second-line standard for primary refractory or early-relapsing (≤12 months) DLBCL [slide p.11]:

  • Liso-cel (TRANSFORM, EHA 2024 update): 3-year PFS 51% vs 26% for standard of care.
  • Axi-cel (ZUMA-7, NEJM 2023): 4-year PFS 42% vs 24%; stratified HR 0.51 (95% CI 0.38–0.67); median PFS 14.7 vs 3.7 months.

Beyond CAR-T, bispecific T-cell engagers combined with chemotherapy are reshaping the R/R space. Glofit-GemOx vs R-GemOx (Abramson Lancet 2024; ICML 2025 update) showed [slide p.12]:

Glofit-GemOx vs R-GemOx in R/R DLBCL [slide p.12]
Outcome Glofit-GemOx (n=183) R-GemOx (n=91)
ORR 68.3% (CR 58.5%, PR 9.8%) 40.7% (CR 25.3%, PR 15.4%)
Median PFS 13.8 months 3.6 months
18-month PFS 46.5% 23%
Median OS Not estimable 13.5 months
24-month OS 54.4% 33.6%
HR (PFS) 0.41 (0.29–0.58), p<0.001 –

12.4 Case 1 — Residual PET, ctDNA-MRD, and the C2D1 landmark

12.4.1 Presentation

A 50-year-old man from Myanmar presents with black tarry stool and weight loss [slide p.13]. CT abdomen shows a diffuse gastric mass, extensive lymphadenopathy, and peritoneal carcinomatosis. Upper endoscopy and biopsy: atypical lymphoid cells CD20+, CD19+, CD10−, CD5−, BCL2+, BCL6+, MUM1−, Ki-67 90%, consistent with DLBCL, GCB subtype. H. pylori is positive; peritoneal fluid is positive for DLBCL; CSF is negative. FISH is negative for MYC and BCL2 rearrangements. IPI 4 (ECOG 2, LDH high, extranodal, stage IV).

He received 6 cycles of R-CHOP plus triple therapy for H. pylori and IT-MTX for CNS prophylaxis. End-of-treatment PET showed a residual right hilar node 2.2 × 1.5 cm with SUVmax 9.3 [slide p.14]. The session-audience question: which is the best predictor of outcome at EOT in DLBCL—IPI, LDH, PET response, or ctDNA MRD?

12.4.2 HOVON ctDNA-MRD cohort (Abstract #474, Steven Wang et al.)

Abstract #474 reported longitudinal ctDNA dynamics during and after first-line therapy in a Dutch HOVON national cohort of ~50 centres [slide p.15]. The study used PhasED-seq: phased variants (PVs) identified from FFPE (53%) or pretreatment plasma (47%) with buffy coat as paired normal, detected via the Foresight B-Cell Lymphoma Panel. Sample-level sensitivity depended on DNA input (plasma 3–6 mL) and analytical performance (median 120,000 informative molecules per sample) [slide p.16]. Cohort characteristics [slide p.17, p.18]:

  • 166 evaluable patients (median age 69, 65% male) with DLBCL (95%) or HGBL (5%); stage III–IV 79%; IPI 3–5 in 47%; R-CHOP 95% / DA-EPOCH-R 5%.
  • PVs were identified in 164/166 (99%) patients—near-universal trackability.
  • Median follow-up 33 months.
  • Blood collected in PAXgene ccfDNA tubes at C1D1–C4D1, EOT, and surveillance every 3 months in year 1, every 6 months in year 2.

12.4.3 Early MRD clearance at C2D1 identifies a no-relapse cohort

The central finding was that 30% of C2D1 samples were MRD-negative (n=44), and all of them remained relapse-free at the 3-year landmark [slide p.19]. Time to progression was dramatically different by C2D1 MRD status (HR 18.4, 95% CI 2.5–134.2; log-rank p<0.0001), and this was independently prognostic for TTP when controlled for IPI. This is arguably the strongest prognostic signal ever reported for an on-treatment biomarker in 1L DLBCL.

12.4.4 Surveillance MRD: positive, negative, and time-dependent meaning

Adding surveillance samples to the end-of-treatment assessment substantially improved relapse detection [slide p.20]:

  • EOT alone: 15/27 relapses detected (56%).
  • EOT + FU samples: 22/27 relapses detected (81%; +47% improvement).
  • Early relapses (≤1 year): 75% captured.
  • Late relapses (>1 year): 91% captured.

Crucially, the meaning of any single surveillance test is time-dependent. The probability of remaining relapse-free after a negative test [slide p.21]:

Months after negative test Non-relapse probability (95% CI)
6 99% (97–100)
12 97% (95–98)
24 91% (86–94)
30 86% (80–91)

Conversely, the probability of eventual relapse rises over time after a positive test, reflecting ctDNA’s biological lead time [slide p.22]:

Months after positive test Relapse probability (95% CI)
6 27% (15–42)
12 36% (22–52)
24 62% (44–78)
30 79% (61–81)

12.4.5 Clinical implications and Case 1 resolution

The HOVON authors’ conclusions [slide p.23]:

  • Early MRD clearance at C2D1 identifies a low-risk group suitable for future de-escalation trials.
  • Any negative surveillance test confers a very low short-term relapse risk; at 1 year, 97% remain relapse-free. Yearly MRD testing in patients in remission at EOT warrants prospective evaluation.
  • Risk after a positive test increases from 27% at 6 months to nearly 80% at 30 months—future trials should test whether early MRD-triggered intervention improves outcomes.

For Mr 1, endobronchial biopsy of the right hilar node showed granulomatous disease (no lymphoma, no TB, no fungi), repeat PET showed stable lymphadenopathy, MRD testing was negative at EOT and follow-up, and he has remained in remission for approximately 2 years [slide p.24]. Molecular response by ctDNA superseded the equivocal PET/CT—a preview of how MRD may substitute for invasive biopsy of equivocal EOT lesions [slide p.56].

Case 1 — Key Teaching Points
  1. Answer to the audience question: MRD status by ctDNA is now the strongest single predictor of outcome at EOT in DLBCL.
  2. C2D1 MRD negativity identifies a 30% subgroup with essentially zero relapses at 3 years (HR 18.4)—the first on-treatment biomarker that may license therapy de-escalation in DLBCL.
  3. EOT + surveillance MRD captures 81% of relapses (vs 56% with EOT alone), with ctDNA biological lead time of 6–12 months.
  4. Any negative test at any time point carries a 97% 1-year non-relapse probability; yearly MRD testing may replace routine imaging in remission.
  5. PhasED-seq / similar ultrasensitive technologies using clusters of mutations (vs single-point) will become the standard; MRD may complement or substitute for equivocal PET.

12.5 Case 2 — Frontline DLBCL in an unfit/frail patient

12.5.1 Presentation

A 65-year-old woman presents with worsening abdominal pain [slide p.25]. CT abdomen/pelvis shows extensive lymphadenopathy with the largest mesenteric nodal mass 9.9 × 6.6 cm; PET confirms hypermetabolic abdominal, retroperitoneal, and pelvic disease. Biopsy: CD20+, CD19+, CD10+, BCL2+, BCL6+, Ki-67 90%, DLBCL GCB subtype; FISH positive for BCL2 but negative for MYC. IPI 2 (age, ECOG 2).

Options: (1) R-CHOP × 3 + RT, (2) R-CHOP × 4–6 PET-directed, (3) Pola-R-CHP × 6, (4) R-EPOCH [slide p.26].

12.5.2 R-Pola-Glo (Abstract #61, Chapuy et al.): anthracycline-free frontline for elderly/frail

For elderly and unfit/frail patients, the phase II R-Pola-Glo chemolight trial (ASH 2025 Abstract #61) offers an anthracycline-free alternative [slide p.27]. The rationale: combine three biologically active anti-lymphoma agents—rituximab (anti-CD20), polatuzumab vedotin (anti-CD79b ADC), and glofitamab (CD20×CD3 bispecific)—to replace the CHOP backbone entirely [slide p.28].

Study design [slide p.29]:

  • One-arm, multicentre phase II, 30 centres in Germany and Austria, 80 patients untreated LBCL >60 years, non-eligible for full-dose R-CHOP.
  • Prephase → Cycle 1 step-up (O + Pola + Glo + Glo) → Cycles 2–6 target dose (R-Pola-Glo) → Cycles 7–12 glofitamab consolidation.
  • C1–C6 mandatory inpatient; mandatory CRS prophylaxis.
  • Primary endpoint: 1-year PFS rate.

Patient characteristics [slide p.30]:

  • Median age 80 years (range 66–92), 19% >85 years.
  • Advanced stage III/IV 63%, ECOG 2 28%, LDH>ULN 63%, IPI 3–5 64%.
  • By simplified geriatric assessment (sGA): 91.3% medically unfit or frail (fit 7.6%, unfit 35.4%, frail 19% <80y + 38% ≥80y).

Response rates [slide p.31]:

R-Pola-Glo response [slide p.31]
Timepoint ORR (95% CI) CMR
Post-C2 96% (89–99) 58%
Post-C6 94% (86–98) 75%
Post-C12 (EOT) 90% (81–96) 81%

CMR conversions were observed after C6, highlighting the role of glofitamab consolidation in deepening responses [slide p.31].

Safety [slide p.32, p.33, p.34]:

  • 80% completed treatment as planned; 34% finished without any grade 3–5 AE in any cycle; grade 5 AE 4% (n=3: COVID, COVID+RSV, unknown).
  • CRS 31% (all grades), grade 3 only 1%, no grade 4/5; concentrated in C1.
  • ICANs 4% (n=3; 2 grade 2, 1 grade 3), infrequent.
  • Infections 66% any grade, grade 3 19%, grade 4 3%, grade 5 4%.

Outcome [slide p.35]:

  • Median follow-up 15 months.
  • 1-year PFS 84.6% (95% CI 77.0–93.0).
  • 1-year OS 89.7% (95% CI 83.2–96.7).
  • At analysis (July 2025), 89% (71/80) alive.

Conclusion: R-Pola-Glo achieves high and durable CMR rates with manageable safety in a truly frail population, and demonstrates that an anthracycline-free regimen can induce durable remissions in patients otherwise ineligible for standard approaches [slide p.36].

12.5.3 Case 2 resolution and frontline landscape

Case 2’s patient enrolled in a phase 3 trial of glofitamab + Pola-R-CHP vs Pola-R-CHP (SKYGLO), was randomised to the experimental arm, tolerated treatment well with only grade 1 peripheral neuropathy and no CRS/ICANS, achieved Deauville 1 CR, and has been in remission for ~1 year [slide p.37].

Case 2 — Key Teaching Points
  1. Pola-R-CHP remains standard for IPI ≥3, ABC subtype, double-expressor, and BCL6-rearranged DLBCL; R-CHOP and R-EPOCH (for double-hit) remain alternatives [slide p.57].
  2. R-Pola-Glo (phase II, 80 patients, 91% unfit/frail) achieved 1y PFS 84.6% / 1y OS 89.7% with an anthracycline-free regimen—a real option for elderly patients where standard approaches are off the table.
  3. Multiple bispecific-based frontline phase 3 trials are in flight: SKYGLO (glofit+Pola-R-CHP), EPCORE DLBCL-2 (epcoritamab+R-CHOP), OLYMPIA-3 (odronextamab-CHOP), ZUMA-23 (axi-cel in 1L), frontMIND (Tafa-Len-CHOP), ESCALADE (acalabrutinib-R-CHOP), GOLSEEK-1 (golcadomide+R-CHOP) [slide p.57].
  4. Emerging elderly regimens include R-Pola-Glo and Epcor-R-mini-CHOP [slide p.57].

12.6 Case 3 — Multiply refractory DLBCL and the CAR-T decision

12.6.1 Presentation

A 46-year-old man initially presented at an outside hospital with worsening shortness of breath and fatigue [slide p.38]. CT showed extensive lymphadenopathy, pleural effusion, and osseous lesions. CT-guided biopsy of a retroperitoneal node: DLBCL (CD20+, CD30+, CD10−, CyclinD1−, EBV−; FISH not available). He received 6 cycles of R-EPOCH with primary refractory disease on repeat PET, then 4 cycles of R-ICE and was lost to follow-up for a few months.

He presented to Dr. Park’s clinic to establish care: PET showed extensive hypermetabolic lymphadenopathy, osseous lesions, and a right pleural-based lesion. Biopsy of the left axillary lymph node: CD20+, CD19+, CD10+, BCL2+, BCL6+, Ki-67 60%, DLBCL GCB subtype.

Options: (1) salvage chemotherapy + ASCT, (2) bispecific antibody, (3) bridging therapy + CAR-T, (4) allogeneic SCT [slide p.39].

12.6.2 Mosun-Pola 2-year follow-up (Abstract #1020, Ghosh et al.)

For patients not eligible for transplant or CAR-T, fixed-duration subcutaneous mosunetuzumab + polatuzumab vedotin is emerging as a clinically meaningful non-transplant option. Abstract #1020 reports the >2-year update of the Phase Ib/II randomised cohort (NCT03671018) comparing Mosun(SC)-Pola vs R-Pola in R/R LBCL [slide p.40, p.41].

Design [slide p.42]:

  • Confirmed LBCL (DLBCL, HGBCL, FL grade 3b, trFL), ≥1 prior line including anti-CD20.
  • Mosun SC step-up C1, total 8 cycles; Pola 1.8 mg/kg IV D1 C1–6; rituximab 375 mg/m² IV D1 C1–8.
  • No mandatory hospitalisation; mandatory corticosteroid CRS premedication at C1 only.
  • Retreatment permitted in CR patients with later PD; R-Pola patients with PD or SD at EOT could cross over to Mosun-Pola.
  • Median follow-up: 25.7 months (Mosun-Pola) vs 27.2 months (R-Pola).

Baseline characteristics [slide p.43]:

  • Median age 71.5 vs 67.5; 62.5% male; primary US cohort.
  • Ann Arbor III/IV 77.5% vs 85%; GCB 59.5% vs 64.1%.
  • Double/triple-hit 21.6% vs 7.7%; bulky disease 20% vs 25%.
  • Prior CAR-T 35% vs 37.5%; refractory to CAR-T 71.4% vs 80%; primary refractory/early relapse 62.5% vs 70%.
  • Median cycles: Mosun 8, Pola 6 (Mosun arm); R 4, Pola 4 (R arm).

Response and safety [slide p.44]:

Mosun-Pola vs R-Pola in R/R LBCL [slide p.44]
Outcome Mosun(SC)-Pola (n=40) R-Pola (n=40)
ORR 77.5% 50%
CR 55% 35%
PR 22.5% 15%
ICANS (any grade) 0 0
Febrile neutropenia 2.5% 0
Peripheral neuropathy (any) 10% 5.1%
Infections (any) 45% 33.3%
Infections grade 5 5% 0
Neutropenia grade 3–4 32.5% 23.1%

PFS and OS [slide p.45]:

  • Median PFS 25.4 vs 6.4 months (HR 0.47, 95% CI 0.24–0.94, p=0.0287)—a nearly four-fold improvement.
  • Median OS NR vs 25.5 months (HR 0.78, p=0.47; OS underpowered by crossover).
  • 18-month event-free rate 54.2% vs 32.0%; 24-month 54.2% vs 25.6%.

In early-relapse/refractory patients, Mosun-Pola delivered ORR 68% vs 39.3% for R-Pola [slide p.46]. Low-grade CRS events were limited to C1D1; no new safety signals emerged. Consistent efficacy has been observed in the global phase 3 SUNMO study [slide p.46].

12.6.3 Mosun-Pola-Axi-cel “total therapy” (Abstract #63, Spiegel et al.)

For CAR-T–eligible patients, Abstract #63 tested a “total therapy” combining mosunetuzumab and polatuzumab with axicabtagene ciloleucel to address four causes of CAR-T failure: CD19 antigen loss, T-cell exhaustion, unreliable manufacturing, and the optimal CAR-T cell question [slide p.47, p.48].

Protocol [slide p.49]:

  • Bridging: D-36 apheresis; Mosun 1 mg IV D-35; Mosun 2 mg IV D-28; Mosun 60 mg + Pola 1.8 mg/kg IV D-21.
  • CAR-T: Flu 30 mg/m² + Cy 500 mg/m² D-5/-4/-3; Axi-cel D0; Mosun 30 mg IV D+14.
  • Consolidation (SD/PR/CR): Mosun 30 mg + Pola 1.8 mg/kg IV D+35, D+56, D+77.
  • Key inclusion: age ≥18, DLBCL NOS/PMBCL/TFL/HGBL/FL grade 3b, ≥1 prior line, ECOG 0–2, CrCl ≥30, LVEF ≥45%.
  • Primary endpoint: CR at D90 post CAR-T.

Patient baseline (N=25) [slide p.50]:

  • Median age 63 (26–83), 56% ≥65, 48% male, ECOG 0–1 in 84%.
  • DLBCL NOS 52%, HGBCL 20%, TFL 20%, TMZL 8%; stage III/IV 64%; IPI 3–5 48%.
  • Primary refractory 44%, early relapse within 1 year 24%, relapsed 32%; ≥2 prior lines 60%.
  • Prior ASCT 16%; bulky disease (≥10 cm) 20%.

Efficacy [slide p.51, p.52]:

  • D28 CR rate: 67% (no PD); 83% received D+14 mosunetuzumab.
  • D90 CR rate: 92% (CR+PR 92%, SD 0%, PD 8%); 5 total deaths (1 NRM, 4 PD).
  • 12-month OS 79% (95% CI 56–91); 12-month PFS 79% (95% CI 57–91); median follow-up 22.7 months.

Safety [slide p.53]:

  • CRS 96%, all grade 1–2 (67% grade 1, 29% grade 2).
  • ICANS 58% (12% grade 1, 17% grade 2, 29% grade 3, no grade 4); 1 recurrent ICANs after D+14 Mosun.
  • No CRS/ICANS with consolidation mosunetuzumab/polatuzumab—the post-CAR-T consolidation phase was remarkably clean.
  • Prolonged neutropenia was the main additional toxicity beyond standard CAR-T.

The authors plan a randomised phase 2 trial against SOC CAR-T approaches to better assess the combination [slide p.54].

12.6.4 Case 3 resolution

Case 3’s patient received R-GemOx × 3 cycles as bridging followed by liso-cel CAR-T, achieving a Deauville 1 CR [slide p.55]. He consented to SWOG 2114—a randomised phase 2 study of mosunetuzumab plus polatuzumab vs controls for consolidation post CAR-T in R/R aggressive B-NHL—but eventually decided not to enrol. He remains in remission ~1 year later.

Case 3 — Key Teaching Points
  1. CAR-T is standard second-line for primary refractory or early-relapsing (≤12 months) DLBCL based on ZUMA-7 (axi-cel 4y PFS 42% vs 24%) and TRANSFORM (liso-cel 3y PFS 51% vs 26%) [slide p.11, p.58].
  2. Chemotherapy + ASCT remains standard for late (>1-year) relapse [slide p.58].
  3. For patients not eligible for transplant or CAR-T, non-transplant options include Mosun+Pola, Glofit+GemOx, Epcor+GemOx, Pola-R-GemOx, Tafasitamab+Lenalidomide, and Pola-BR [slide p.58].
  4. Mosun(SC)-Pola (Abstract #1020, 25-month FU) delivered 4× PFS benefit vs R-Pola (25.4 vs 6.4 months) with an outpatient, fixed-duration schedule.
  5. Mosun-Pola-Axi-cel “total therapy” (Abstract #63) achieved a D90 CR of 92% and 12-month PFS of 79%, with CRS limited to grade 1–2 and clean consolidation—early signal that bispecific-enhanced CAR-T bridging and consolidation may rescue a substantial fraction of primary refractory patients.

12.7 Session Synthesis

Ten Take-Home Points from “Novel Treatment Strategies in Aggressive Lymphoma”
  1. DLBCL dominates aggressive lymphoma in Asia-Pacific (30–36% vs 21% in the US), and CAR-T access gaps make R/R outcomes especially poor (ORBIT median OS 6 months at early relapse) [slide p.4, p.10].
  2. R-CHOP cures ~65% of DLBCL; the remaining 35% remain the therapeutic battleground [slide p.6].
  3. POLARIX (Pola-R-CHP) is the only “R-CHOP + X” winner in 20 years; 16+ ongoing phase 3 frontline trials may reshape the landscape by 2031 [slide p.9].
  4. ctDNA-MRD at C2D1 is the strongest on-treatment prognostic biomarker ever reported in DLBCL (HOVON: HR 18.4, no relapses at 3-year landmark in MRD-negative patients) [slide p.19].
  5. EOT + surveillance MRD captures 81% of relapses vs 56% with EOT alone; interpretation is time-dependent—negative tests confer 97% 1-year non-relapse, positive tests carry 27% → 80% relapse risk over 6–30 months [slide p.20, p.21, p.22].
  6. R-Pola-Glo (Abstract #61) demonstrates that an anthracycline-free regimen can deliver 1y PFS 84.6% / 1y OS 89.7% in a 91% unfit/frail elderly cohort [slide p.35].
  7. CAR-T is second-line standard for primary refractory or early-relapse DLBCL (ZUMA-7 4y PFS 42% vs 24%; TRANSFORM 3y PFS 51% vs 26%) [slide p.11].
  8. Mosun(SC)-Pola (Abstract #1020) achieves median PFS 25.4 vs 6.4 months vs R-Pola (HR 0.47) with outpatient administration—a leading non-transplant, non-CAR-T option [slide p.45].
  9. Mosun-Pola + Axi-cel (Abstract #63) achieves 92% D90 CR and 79% 12-month PFS, with clean post-CAR-T consolidation—a signal that bispecific-enhanced CAR-T may rescue primary refractory disease [slide p.51, p.52, p.53].
  10. Glofit-GemOx (Abramson Lancet 2024) achieves 18-month PFS 46.5% vs 23% for R-GemOx, 24-month OS 54.4% vs 33.6%—solidifying bispecific + chemotherapy combinations in R/R DLBCL [slide p.12].
Asia-Pacific Perspective

Eric Tse’s contribution throughout the session frames the access problem: DLBCL is proportionally more common in Asia, yet CAR-T access is constrained in the 2nd-line setting across much of the region [slide p.11]. In the ORBIT Asian R/R DLBCL cohort (excluding CAR-T–treated patients), median OS drops to 6 months for early relapse and <18 months even for late relapse [slide p.10]. Bispecific antibodies and off-the-shelf combinations (Mosun-Pola, Glofit-GemOx, Pola-R-GemOx, Tafa-Len, Pola-BR) are therefore not just conveniences but essential alternatives when CAR-T is unavailable. Frontline trials of bispecific + CHOP (SKYGLO, EPCORE DLBCL-2, OLYMPIA-3) and elderly-focused regimens (R-Pola-Glo, Epcor-R-mini-CHOP) may disproportionately benefit Asian patients if they become available at scale.

12.8 Key References

  1. Park S, Tse E. Novel Treatment Strategies in Aggressive Lymphoma. Highlights of ASH Asia-Pacific 2026 [slide deck p.1–p.59].
  2. Sehn LH, Salles G. Diffuse large B-cell lymphoma. N Engl J Med. 2021;384:842–858 [slide p.6, p.8].
  3. Schmitz R, Wright GW, Huang DW, et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med. 2018;378:1396–1407 [slide p.7].
  4. Chapuy B, Stewart C, Dunford AJ, et al. Molecular subtypes of diffuse large B-cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med. 2018;24(5):679–690 [slide p.7].
  5. Tilly H, Morschhauser F, Sehn LH, et al. Polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma (POLARIX). N Engl J Med. 2022;386:351–363 [slide p.9].
  6. Palmer AC, et al. Clinical progression in DLBCL frontline trials. N Engl J Med. 2023;389:764–766 [slide p.9].
  7. Qualls D, et al. The frontline DLBCL trial landscape. Blood. 2025;145:176–189 [slide p.9].
  8. Lim NA, et al. ORBIT: outcomes in Asian R/R DLBCL. ESMO Real World Data and Digital Oncology. 2025;10:100195 [slide p.10].
  9. Westin JR, Oluwole OO, Kersten MJ, et al. Survival with axicabtagene ciloleucel in large B-cell lymphoma (ZUMA-7). N Engl J Med. 2023;389:148–157 [slide p.11].
  10. Abramson JS, et al. TRANSFORM 3-year follow-up: liso-cel in 2L DLBCL. Proc EHA. 2024 [slide p.11].
  11. Abramson JS, et al. Glofit-GemOx vs R-GemOx in R/R DLBCL. Lancet. 2024; ICML 2025 update [slide p.12].
  12. Wang S, Nijland M, Bilgin YM, et al. Longitudinal ctDNA dynamics during & after first-line therapy in large B-cell lymphoma (HOVON). ASH 2025 Abstract #474 [slide p.15–p.23].
  13. Chapuy B, Wurm-Kuczera R, Michael R, et al. Phase II frontline chemolight R-Pola-Glo trial in elderly/unfit/frail aggressive B-cell lymphoma. ASH 2025 Abstract #61 [slide p.27–p.36].
  14. Ghosh N, Chavez JC, Bastos-Oreiro M, et al. Long-term follow-up of SC mosunetuzumab + polatuzumab vs rituximab + polatuzumab in R/R B-NHL. ASH 2025 Abstract #1020 [slide p.40–p.46].
  15. Budde LE, et al. Mosun-Pola initial reports. Nat Med. 2024;30:229–239; J Clin Oncol. 2025 doi:10.1200/JCO-25-01957 [slide p.41].
  16. Spiegel JY, Alderuccio JP, Beitinjaneh A, et al. Mosunetuzumab and polatuzumab combined with axicabtagene ciloleucel induce high CR at D+90 in R/R large B-cell lymphoma. ASH 2025 Abstract #63 [slide p.47–p.54].
  17. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403:503–511 [slide p.7].
  18. Tse E, Kwong YL. Management of extranodal NK/T-cell lymphoma: current and emerging strategies. Lancet Haematol. 2023;10(4):e306–e316.