11  Updates in Management of Indolent Lymphoma and CLL

11.1 Session Overview

Session Details
Session Updates in Management of Indolent Lymphoma and Chronic Lymphocytic Leukemia [slide p.1]
Speaker Jia Ruan, MD, PhD [slide p.1]
Affiliation Weill Cornell Medicine, New York, NY [slide p.1]
Disclosures Consultancy: AstraZeneca, BMS, Ipsen, Pfizer. Research Funding: AstraZeneca, BMS, Daiichi Sankyo, Genentech. Off-label discussion: pirtobrutinib, zanubrutinib, obinutuzumab [slide p.2]

Dr. Ruan organises the session around three disease areas — chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and follicular lymphoma (FL) — and uses six ASH 2025 abstracts to benchmark where the field is moving [slide p.1]. The learning objectives are to evaluate recent frontline and relapsed/refractory advances, analyse evolving sequencing strategies based on molecular risk and patient factors, and assess the clinical implications of emerging therapies [slide p.3]. Headline datasets include the randomised CLL17 trial of fixed-duration venetoclax combinations versus continuous ibrutinib, BRUIN CLL-314 and CLL-313 comparing non-covalent pirtobrutinib against ibrutinib and bendamustine-rituximab (BendaR), the BOVen and TrAVeRse triplets in frontline MCL, sonrotoclax in BTKi-pretreated MCL, and EPCORE FL-1 adding epcoritamab to R-squared in relapsed FL, complemented by long-term CAR-T readouts from TRANSCEND FL and ELARA [slide p.5–58].

11.2 Speaker Spotlight

Jia Ruan, MD, PhD is an attending physician and lymphoma specialist at Weill Cornell Medicine in New York. Her clinical and translational research focuses on novel therapeutic strategies for indolent B-cell lymphomas, with particular expertise in optimizing targeted therapy sequencing and combination approaches. She has contributed to pivotal trials evaluating bispecific antibodies and targeted agents in follicular lymphoma and has been a leader in integrating biomarker-driven treatment selection into clinical practice for low-grade lymphoid malignancies.

11.3 What’s New in 2025–2026

11.3.1 CLL Frontline: CLL17 Reframes Fixed-Duration vs Continuous Therapy

The randomised phase 3 CLL17 trial (Al-Sawaf et al., ASH 2025 Abstract #1) screened 976 previously untreated CLL patients at 174 sites across 13 countries and randomised them 1:1:1 to continuous ibrutinib (I), fixed-duration venetoclax + obinutuzumab (VO), or fixed-duration venetoclax + ibrutinib (VI), stratified by fitness, del(17p)/TP53, and IGHV status [slide p.6]. At a median observation of 34.2 months, 3-year PFS was essentially overlapping across arms — 81.0% for ibrutinib, 79.4% for VI, and 81.1% for VO (VI vs I HR 0.84, type-I-error adjusted 98.0% CI 0.53–1.32; VO vs I HR 0.87, 98.3% CI 0.54–1.41) [slide p.7], confirming non-inferiority of the two fixed-duration arms to continuous ibrutinib.

Subgroup signals nonetheless matter. In TP53del/mut patients, 3-year PFS was numerically lower with fixed-duration combinations (VI 69.0%, VO 62.0%) than with continuous ibrutinib (79.4%), with wide confidence intervals reflecting the small subgroup (n ~21–25 per arm) [slide p.8]. In unfit patients (CIRS >6 and/or GFR <70 mL/min), VO outperformed ibrutinib (3-year PFS 79.6% vs 70.4%; HR 0.58, 95% CI 0.34–0.99), whereas fit patients did similarly well across arms (I 88.7%, VI 82.7%, VO 82.1%) [slide p.9]. Dr. Ruan’s synthesis: most treatment-naïve CLL patients can reasonably consider a fixed-duration option as a primary choice, longer follow-up is needed for the TP53-aberrant subgroup, and the relevance of ibrutinib as a comparator in an era of second-generation covalent BTKis (acalabrutinib, zanubrutinib) is questionable [slide p.20].

11.3.2 CLL Frontline: Pirtobrutinib vs Ibrutinib and vs BendaR

Two randomised phase 3 trials introduce non-covalent BTKi into the frontline conversation. BRUIN CLL-314 (Woyach et al., ASH 2025 Abstract #683) randomised 662 BTKi-naïve CLL/SLL patients (34% treatment-naïve, 66% R/R) 1:1 to pirtobrutinib 200 mg QD vs ibrutinib 420 mg QD, with co-primary endpoints of non-inferior ORR and superior PFS in the ITT and R/R populations [slide p.10–11]. Pirtobrutinib was non-inferior and numerically higher for ORR in the ITT population (87.0% vs 78.5%, nominal p = 0.0035; ORR ratio 1.108, 95% CI 1.034–1.187, p for NI <0.0001) [slide p.12]. PFS in the ITT population favoured pirtobrutinib with a 43% reduction in risk (HR 0.569, 95% CI 0.388–0.834, nominal p = 0.0034; 18-month PFS 86.9% vs 82.3%) [slide p.13]. Safety favoured pirtobrutinib: grade ≥3 hypertension 3.3% vs 4.9%, atrial fibrillation any-grade 2.4% vs 12.6%, and fewer dose reductions (7.9% vs 18.2%) and discontinuations (9.4% vs 10.8%) [slide p.14]. One patient on pirtobrutinib and four on ibrutinib developed Richter transformation over a median 20.5 and 19.3 months on treatment, respectively [slide p.14].

BRUIN CLL-313 (Jurczak et al., ASH 2025 LBA-3) randomised 282 untreated CLL/SLL patients without del(17p) 1:1 to pirtobrutinib vs bendamustine + rituximab (BendaR), with optional crossover on IRC-confirmed progression [slide p.15–16]. Pirtobrutinib produced an 80% reduction in risk of progression or death (24-month PFS 93.4% vs 70.7%; HR 0.20, 95% CI 0.11–0.37, p <0.0001) [slide p.17], and an early OS trend favoured pirtobrutinib (HR 0.26, 95% CI 0.07–0.93) despite 52.9% effective crossover [slide p.18]. Grade ≥3 infections were comparable (13.6% vs 8.3%), but the pirtobrutinib arm had more all-grade bleeding (25.7% vs 1.5%) and lower rates of neutropenia and atrial fibrillation/flutter [slide p.19]. Dr. Ruan’s bottom line: pirtobrutinib is a viable non-chemotherapy 1L option especially for older patients, but the trials do not yet justify placing a non-covalent BTKi before a covalent BTKi in treatment-naïve disease [slide p.20].

Relevance of Ibrutinib as Comparator

Across both CLL17 and BRUIN CLL-314, Dr. Ruan repeatedly flags that ibrutinib is no longer the appropriate benchmark in 2025–2026 because acalabrutinib and zanubrutinib already provide superior cardiovascular safety and at least comparable efficacy [slide p.20]. Interpreting head-to-head results should therefore factor in the evolving standard of covalent BTKi [slide p.20].

11.3.3 MCL Frontline: BOVen and TrAVeRse Push Chemotherapy-Free, MRD-Guided Triplets

BOVen (zanubrutinib + obinutuzumab + venetoclax; Kumar et al., ASH 2025 Abstract #888) enrolled 50 previously untreated MCL patients aged ≥65 years or ineligible for autologous transplant [slide p.22–23]. Zanubrutinib 160 mg BID ran continuously, obinutuzumab 1000 mg was given cycles 1–8, and venetoclax was ramped up starting cycle 3 to 400 mg daily; after 24 cycles the protocol permitted treatment discontinuation in patients achieving CR with uMRD at 10-6 by ClonoSEQ, with others continuing zanubrutinib plus venetoclax [slide p.23]. MRD was evaluable in 98% (49/50), and peripheral-blood uMRD6 rates climbed from 28% at cycle 3 to 87% at cycle 13 and 93% at cycle 24/end of treatment [slide p.26]. With a median follow-up of 25 months, 2-year PFS was 86% (95% CI 77–97) and 2-year OS was 92% (95% CI 84–100), median PFS not reached [slide p.27]. Any-grade treatment-related AEs affected 94% of patients, grade ≥3 events 42%, infections 76%, and 44% experienced a serious AE; two deaths were considered possibly related (viral encephalitis and sudden death in a patient receiving venetoclax), alongside 2 TLS events after C1D1 of obinutuzumab [slide p.25]. Dr. Ruan highlights BOVen as a benchmark for deep molecular responses and the basis for the upcoming BOSON MRD-guided triplet trial [slide p.34].

TrAVeRse (Hawkes et al., ASH 2025 Abstract #884) is a global phase 2 study of acalabrutinib + venetoclax + rituximab (AVR) induction in 108 untreated MCL patients ≥18 years with Ann Arbor stage II–IV disease [slide p.28–29]. After 13 cycles of AVR induction, patients in MRD-negative CR by NGS (10-5 ClonoSEQ) are randomised to continuing acalabrutinib vs observation with acalabrutinib retreatment on progression, whereas MRD-positive/non-CR patients continue acalabrutinib maintenance [slide p.29]. The primary endpoint of MRD-negative CR at end of induction was 82% (89/108) in the ITT population and 93% (87/94) in patients evaluable at cycle 14 [slide p.30]. PFS rates at 12 months were 95.2% overall and 88.2% in TP53-mutated patients (n = 17), suggesting benefit is preserved in this traditionally high-risk subgroup at a median follow-up of 14.9 months [slide p.31]. Toxicity was manageable: any-grade neutropenia 48.1% (grade ≥3 34.3%), cardiac events 14.8% (grade ≥3 1.9%, including 4 atrial fibrillation/flutter), hepatotoxicity 16.7%, infections 65.7% (grade ≥3 16.7%), second primary malignancies 10.2%, and only 1 TLS event [slide p.32].

11.3.4 MCL R/R: Sonrotoclax Monotherapy After BTKi

Sonrotoclax (BGB-11417), a next-generation BCL2 inhibitor, was evaluated as monotherapy in 115 BTKi-pretreated R/R MCL patients in the BGB-11417-201 phase 1/2 study (Wang et al., ASH 2025 Abstract #663) [slide p.33–35]. The recommended phase 2 dose was 320 mg QD, achieved after a ~4-week ramp-up that did not require hospitalisation or 12/24-hour post-dose monitoring [slide p.35]. Among the 103 part-2 patients, IRC-assessed ORR was 52.4% (95% CI 42.4–62.4) with a CR rate of 15.5%, and investigator-assessed ORR was 47.6% with a 22.3% CR rate — meeting the primary endpoint relative to a 30% historical control [slide p.37]. Responses deepened over time: median DOR by IRC was 15.8 months (95% CI 7.4–NE), median PFS 6.5 months, and median OS was not reached [slide p.38]. Grade ≥3 TEAEs occurred in 52.2%; 27% had temporary treatment interruption and only 0.9% required dose reduction [slide p.36]. Phase 3 CELESTIAL is evaluating sonrotoclax plus zanubrutinib [slide p.39].

11.3.5 FL R/R: EPCORE FL-1 Establishes Epcoritamab + R-Squared as New Standard

EPCORE FL-1 (Falchi et al., ASH 2025 Abstract #466) is a global randomised phase 3 trial comparing 12 cycles of epcoritamab 48 mg SC plus rituximab + lenalidomide (R2) against R2 alone in 488 R/R FL patients after ≥1 prior anti-CD20–containing therapy [slide p.41–42]. At a median follow-up of 14.8 months, epcoritamab + R2 produced a 79% reduction in the risk of progression or death (HR 0.21, 95% CI 0.14–0.31, p <0.0001; 16-month PFS 85.5% vs 40.2%; median PFS not reached vs 11.7 months) [slide p.43]. Time to next antilymphoma treatment was dramatically prolonged (HR 0.15, 95% CI 0.09–0.27; 16-month event-free 92.8% vs 64.9%) [slide p.44], and overall survival trended in favour of epcoritamab + R2 (HR 0.38, 95% CI 0.18–0.80; 16-month OS 95.8% vs 88.8%) [slide p.45]. Grade ≥3 adverse events occurred in 90% vs 68%, with manageable grade ≥3 neutropenia (69% vs 42%) and infections (33% vs 16%); fatal AEs were rare (2% vs 4%) [slide p.46]. Cytokine release syndrome was low grade and predictable with the 3-step-up dosing (3-SUD) regimen (CRS any-grade 26%, only 5% grade 2; one grade 1 ICANS; no CRS/ICANS discontinuations) [slide p.47]. Dr. Ruan frames epcoritamab + R2 as a novel chemotherapy-free, outpatient, fixed-duration standard of care in R/R FL [slide p.58].

11.3.6 FL R/R: ROSEWOOD Final Analysis Supports BTKi-Based Doublets

The final analysis of the randomised phase 2 ROSEWOOD study (Zinzani et al., ASH 2025 Abstract #227) tested zanubrutinib + obinutuzumab (ZO) vs obinutuzumab (O) monotherapy in 217 R/R FL patients with ≥2 prior lines (2:1 randomisation; no prior BTKi; crossover permitted) [slide p.49]. ORR by IRC was 70.3% with ZO vs 44.4% with O (risk difference 25.5%, p = 0.0003), CR rate 42.1% vs 19.4% (p = 0.0009) [slide p.50]. Median PFS was 22.1 months (95% CI 16.1–34.0) vs 10.3 months with obinutuzumab alone (HR 0.54, 95% CI 0.37–0.79, p = 0.0012) at a median follow-up of ~44 months [slide p.51], and median time to next anticancer therapy was 51.7 vs 12.1 months (HR 0.37, 95% CI 0.25–0.55, p <0.0001) [slide p.52]. The results support ZO as a chemotherapy-free doublet option while the phase 3 MAHOGANY study is ongoing [slide p.58].

11.3.7 FL R/R: Long-Term CAR-T Data Mature

Two long-term CAR-T readouts confirm durability in heavily pretreated FL. The TRANSCEND FL 3-year update for lisocabtagene maraleucel (liso-cel) in 103 patients with 3L+ FL reported an ORR of 97% with a 94% CR rate [slide p.53]; median DOR, PFS, TTNT, and OS remained not reached, with 36-month rates of 70%, 68%, 75%, and 86%, respectively, at a median follow-up of 35–42 months [slide p.54]. The ELARA 5-year update for tisagenlecleucel in 94 R/R FL patients showed a median PFS of 53.2 months with a 46% 60-month PFS rate (59.8% among CR patients) and no relapses reported beyond 36 months [slide p.55]; PFS benefit persisted in POD24 (41.1%), high-FLIPI (35.5%), bulky (45.1%), and double-refractory (50.5%) subgroups [slide p.56]. Dr. Ruan concludes that both products deliver deep and durable responses even in double-refractory or POD24 disease and can be safely delivered with relatively low infection rates [slide p.58].

11.4 Clinical Pearls

Five Key Takeaways
  1. Fixed-duration wins for most frontline CLL. CLL17 confirms non-inferior 3-year PFS for VO and VI versus continuous ibrutinib (all ~80%), so most treatment-naïve CLL patients can select a fixed-duration option as a primary strategy [slide p.7, p.20]. Longer follow-up is still required in TP53-aberrant disease, where fixed-duration arms trend lower (62–69%) [slide p.8].
  2. Non-covalent BTKi is climbing the line, but not ahead of covalent. Pirtobrutinib beat ibrutinib (HR 0.569) in BRUIN CLL-314 and crushed BendaR (HR 0.20) in BRUIN CLL-313, with better AF and hypertension profiles [slide p.13, p.17, p.19]. Neither trial, however, used acalabrutinib or zanubrutinib as comparator, so pirtobrutinib does not yet displace second-generation covalent BTKi in 1L [slide p.20].
  3. MRD-guided triplets redefine frontline MCL. BOVen and TrAVeRse deliver uMRD6/MRD-negative CR rates of 82–93% with 2-year PFS of 86% and 95%, preserving benefit even in TP53-mutated patients and enabling treatment discontinuation in selected responders [slide p.26, p.27, p.30, p.31]. BOVen is the basis for the upcoming BOSON trial [slide p.34].
  4. Sonrotoclax extends BCL2 activity after BTKi failure. In BTKi-pretreated R/R MCL, sonrotoclax monotherapy achieved a 52% ORR with a median DOR of 15.8 months, low TLS incidence, and a simplified ramp-up; phase 3 CELESTIAL will pair it with zanubrutinib [slide p.37, p.38, p.39].
  5. Epcoritamab + R2 is the new chemo-free standard for R/R FL. EPCORE FL-1 delivered a 79% reduction in PFS risk, dramatically longer TTNT (HR 0.15), and an early OS trend (HR 0.38), with manageable CRS using 3-step-up dosing [slide p.43, p.44, p.45, p.47]. ROSEWOOD (ZO) and mature CAR-T datasets (TRANSCEND FL, ELARA) provide complementary non-chemotherapy options across the FL continuum [slide p.50, p.51, p.53, p.55].

11.5 Key References

  1. Al-Sawaf O, Stumpf J, Zhang C, et al. Fixed-duration versus continuous targeted treatment for previously untreated chronic lymphocytic leukemia: results from the randomized CLL17 trial. ASH Annual Meeting. 2025. Abstract #1 [slide p.5].
  2. Woyach JA, Qiu L, Grosicki S, et al. Pirtobrutinib vs ibrutinib in treatment-naïve and relapsed/refractory CLL/SLL: results from BRUIN CLL-314. ASH Annual Meeting. 2025. Abstract #683 [slide p.10].
  3. Jurczak W, Kwiatek M, Czyz J, et al. Pirtobrutinib vs bendamustine plus rituximab (BendaR) in patients with CLL/SLL: first results from BRUIN CLL-313. ASH Annual Meeting. 2025. LBA-3 [slide p.15].
  4. Kumar A, Soumerai J, Karmali R, et al. Preliminary safety and efficacy of BOVen (zanubrutinib, obinutuzumab, and venetoclax) as frontline therapy for older patients with mantle cell lymphoma. ASH Annual Meeting. 2025. Abstract #888 [slide p.22].
  5. Hawkes EA, Romejko-Jarosinska J, Jurczak W, et al. Acalabrutinib plus venetoclax and rituximab in patients with treatment-naive mantle cell lymphoma: results from the phase 2 TrAVeRse study. ASH Annual Meeting. 2025. Abstract #884 [slide p.28].
  6. Wang M, Song Y, Hermine O, et al. Sonrotoclax (BGB-11417) monotherapy in patients with R/R MCL previously treated with a BTK inhibitor: results from a phase 1/2 study. ASH Annual Meeting. 2025. Abstract #663 [slide p.33].
  7. Falchi L, Nijland M, Huang H, et al. Primary phase 3 results from the EPCORE FL-1 trial of epcoritamab with rituximab and lenalidomide (R2) versus R2 for relapsed or refractory follicular lymphoma. ASH Annual Meeting. 2025. Abstract #466 [slide p.41].
  8. Zinzani PL, Mayer J, Flowers CR, et al. Final analysis of the randomized phase 2 ROSEWOOD study of zanubrutinib + obinutuzumab vs obinutuzumab monotherapy in patients with R/R follicular lymphoma. ASH Annual Meeting. 2025. Abstract #227 [slide p.48].
  9. Ahmed S, Martín García-Sancho A, Reguera Ortega JL, et al. Three-year efficacy and longitudinal safety of lisocabtagene maraleucel in patients with third-line or later follicular lymphoma from TRANSCEND FL. ASH Annual Meeting. 2025. Abstract #467 [slide p.53].
  10. Schuster SJ, Thieblemont C, Dickinson M, et al. Clinical outcomes of tisagenlecleucel in patients with relapsed/refractory follicular lymphoma: phase 2 ELARA 5-year update. ASH Annual Meeting. 2025. Abstract #468 [slide p.55].