Introduction

Lymphoma and CLL data at the 2026 ASCO Annual Meeting spanned the treatment continuum, from frontline diffuse large B-cell lymphoma (DLBCL) to relapsed/refractory disease across several lymphoma subtypes, to a striking early combination in frontline CLL. Five studies stand out: frontMIND in frontline DLBCL, an early-phase CELMoD combination also in frontline DLBCL, SUNMO in relapsed/refractory DLBCL, fixed-duration glofitamab in relapsed/refractory mantle cell lymphoma, and a CLL combination achieving remarkably deep responses even in high-risk cytogenetics.

frontMIND: Tafasitamab Added to R-CHOP in Frontline DLBCL

More than 40% of patients with high-risk DLBCL are not cured with frontline R-CHOP. Tafasitamab, an anti-CD19 monoclonal antibody, combined with lenalidomide is already FDA-approved in relapsed/refractory DLBCL after demonstrating encouraging activity in that setting. frontMIND, a phase 3, global, multicenter, placebo-controlled, randomized study, tested tafasitamab plus lenalidomide added to R-CHOP (Tafa-Len-R-CHOP) against R-CHOP alone in untreated patients with high-intermediate or high-risk aggressive B-cell lymphoma.

Tafa-Len-R-CHOP significantly improved the primary endpoint of progression-free survival (HR, 0.75; 95% CI, 0.59–0.96; P=.0194), representing a 25% reduction in risk of progression, with 2-year PFS of 71.1% versus 62.9% and 3-year PFS of 67.3% versus 60.0% with R-CHOP. Event-free survival, a key secondary endpoint, was also significantly improved (HR, 0.79; 95% CI, 0.64–0.97; P=.0260). Interim overall survival showed a positive trend (HR, 0.85; 95% CI, 0.63–1.14) without reaching significance at this analysis, with 3-year OS of 81.1% versus 77.8%. The PFS benefit trended consistently favorable across most prespecified subgroups. The most common grade 3 or higher adverse events were cytopenia-related, and the rate of serious febrile neutropenia was modestly higher with Tafa-Len-R-CHOP (13.3% versus 9.8%), but delivery of the R-CHOP backbone itself was not compromised.

Cross-trial comparison is inherently limited, but relative to POLARIX (polatuzumab vedotin-R-CHP), frontMIND enrolled a higher-risk population and showed a PFS benefit that was, unlike POLARIX, independent of cell of origin. Tafa-Len-R-CHOP is a more complex regimen requiring weekly tafasitamab dosing, and whether tafasitamab exposure affects the efficacy of subsequent CD19-directed therapies (like CAR-T) is a real open question, though numbers so far are small. Tafa-Len-R-CHOP represents a new frontline treatment option for high-risk DLBCL and high-grade B-cell lymphoma, regardless of cell-of-origin subtype.

Golcadomide Plus Pola-R-CHP in Frontline Aggressive B-Cell Lymphoma

DLBCL is the most common aggressive lymphoma, with 30%–40% of patients not cured by frontline R-CHOP or Pola-R-CHP regimens. Golcadomide is a potential first-in-class, oral CELMoD (cereblon E3 ligase modulator), a more potent class of cereblon modulator than lenalidomide, inducing deeper conversion to the active, closed conformation and driving more rapid target degradation and immunomodulatory activity.

CC-220-DLBCL-001, an ongoing phase 1b dose-escalation and dose-expansion trial, tested golcadomide (at 0.2 mg or 0.4 mg) plus Pola-R-CHP in untreated aggressive B-cell lymphoma. At a median follow-up of 16.7 months, golcadomide 0.4 mg plus Pola-R-CHP resulted in high complete metabolic response rates at end of treatment, high MRD negativity rates by PhasED-Seq, and durable remissions in both the overall and high-risk populations, regardless of cell of origin. Safety was predictable and mainly hematologic (neutropenia the most common grade 3/4 event) and did not compromise delivery of chemotherapy, though neutropenia rates were substantially higher with golcadomide plus Pola-R-CHP than with Pola-R-CHP alone historically.

Golcadomide offers a superior approach to cereblon modulation compared with lenalidomide, with deeper substrate degradation and cell-of-origin-agnostic activity, and its high MRD negativity rates may predict durable outcomes as more data matures. The substantially higher neutropenia rate compared with Pola-R-CHP alone does raise real questions about feasibility in older or frailer patients, and this early-phase data may not yet be fully reflected in the ongoing phase 3 GOLSEEK-1 trial, which uses R-CHOP, not Pola-R-CHP, as its backbone.

SUNMO: Mosunetuzumab Plus Polatuzumab in Relapsed/Refractory DLBCL

For transplant-ineligible patients with relapsed/refractory large B-cell lymphoma, options beyond CAR-T remain limited. SUNMO, a phase 3 trial, tested mosunetuzumab plus polatuzumab vedotin (Mosun-Pola) against rituximab, gemcitabine, and oxaliplatin (R-GemOx) in transplant-ineligible relapsed/refractory large B-cell lymphoma, with this update focused on the 2L and 3L+ subgroups specifically.

At a median follow-up of 28.3 months, Mosun-Pola showed a durable PFS benefit in the intention-to-treat population (HR, 0.41; 95% CI, 0.28–0.61), with ORR 70.3% versus 41.4% and 2-year duration of complete response over 60% with Mosun-Pola, where more than 80% of complete responders remained in remission at 2 years. In the second-line subgroup specifically, median PFS was 17.6 versus 3.6 months (HR, 0.38), and in the 3L+ subgroup, treatment benefit was consistent (median PFS 8.6 versus 3.9 months). No new safety signals emerged, and CRS with Mosun-Pola was infrequent, early, and low-grade, notably lower in incidence than with many T-cell-engaging therapies.

SUNMO represents a significant advance for transplant-ineligible patients, offering among the most favorable CRS profiles of T-cell-engaging therapies in this space, with disease control comparable to CAR-T products, albeit against different comparators and populations. Its fixed-duration, outpatient-deliverable format makes it an attractive option for elderly, frail, or logistically constrained patients who are not CAR-T candidates.

Glofitamab Monotherapy in Relapsed/Refractory Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is challenging to treat, with limited duration of response to many therapies, particularly once patients progress on a Bruton's tyrosine kinase inhibitor (BTKi). The NP30179 phase I/II study evaluated fixed-duration glofitamab monotherapy in relapsed/refractory MCL, with this update reflecting a 3.5-year follow-up, in patients both with and without prior BTKi exposure.

Response rates were high in both the overall population and in the prior-BTKi subgroup: ORR 92.6% overall, with complete response rates of 70.6% in patients with prior BTKi exposure and 88.2% in BTKi-naive patients, and high, durable rates of complete response overall (77.9%). CRS was consistent with what's expected from CD20xCD3 bispecific therapies, generally manageable with standard supportive care, and notably lower in incidence and severity after the initial step-up dosing period. Durable, MRD-undetectable remissions at cycle 3 and end of treatment predicted durable PFS in landmark analyses.

Glofitamab represents a promising addition to relapsed/refractory MCL treatment, particularly in the post-BTKi setting where options remain limited, achieving a high complete response rate (70.6%) with durable, fixed-duration treatment and off-the-shelf availability, addressing real practical limitations of CAR-T therapy. Efficacy clearly exceeds ibrutinib and standard salvage therapy in the post-BTKi setting, though it does not yet match the PFS and OS achieved with brexucabtagene autoleucel (the currently approved CAR-T product in this setting). CRS rates in MCL are notably higher than glofitamab's rates in DLBCL, requiring experienced management, and the ongoing phase 3 GLOBRYTE trial should help define glofitamab's optimal position in the MCL treatment sequence.

Sonrotoclax Plus Zanubrutinib: Deep Responses Even in High-Risk CLL

Combinations of a BTK inhibitor and a BCL-2 inhibitor have already changed frontline CLL treatment, based on the AMPLIFY and SEQUOIA trials. This poster presentation reported updated results combining sonrotoclax (a next-generation BCL-2 inhibitor with a shorter half-life and lack of drug accumulation compared with venetoclax) with zanubrutinib as frontline treatment for CLL/SLL, including a look at patients with del(17p) or TP53 mutations, historically among the hardest-to-treat CLL subgroups.

Across 137 evaluable patients (51 in a 160-mg sonrotoclax cohort, 86 in a 320-mg cohort), objective response rate was 100% in both dose cohorts, with best undetectable MRD (uMRD4) rates reaching 87.3% for high-risk cytogenetics and unmutated IGHV genotype in the combined analysis. No cases of laboratory or clinical tumor lysis syndrome were observed, and the most common grade 3 or higher adverse event was neutropenia; low rates of treatment-emergent gastrointestinal toxicity were reported as well.

This combination's depth of MRD clearance, a 99% undetectable MRD4 rate even in patients with del(17p) or TP53 mutations, exceeds current standards, achieved despite no cases of tumor lysis syndrome, likely reflecting both sonrotoclax's enhanced BCL-2 potency and its shorter half-life and lack of drug accumulation relative to venetoclax. Ongoing phase 3 trials (CELESTIAL-TNCLL: sonrotoclax plus zanubrutinib versus zanubrutinib alone, and CELESTIAL-TNCLL-2: sonrotoclax plus zanubrutinib versus venetoclax plus obinutuzumab or acalabrutinib) will provide the randomized data needed to determine whether this combination should become a new standard of care.

For Patients

For people newly diagnosed with high-risk diffuse large B-cell lymphoma, two different combinations added to standard chemotherapy, tafasitamab plus lenalidomide (frontMIND) and an experimental drug called golcadomide (CC-220-DLBCL-001), both showed improved outcomes over standard treatment alone in clinical trials, offering potential new frontline options for higher-risk patients.

For people with relapsed large B-cell lymphoma who are not candidates for stem cell transplant, a combination of two antibody-based drugs, mosunetuzumab and polatuzumab vedotin, showed strong, durable responses with a favorable side-effect profile compared to older chemotherapy combinations, and can be given in an outpatient setting.

For people with relapsed mantle cell lymphoma, particularly those who have already tried a BTK inhibitor drug, a fixed-duration treatment with glofitamab (a bispecific antibody) produced high, durable response rates, offering an important option in a disease setting with historically limited treatment duration of benefit.

For people newly diagnosed with chronic lymphocytic leukemia (CLL), a combination of two oral targeted drugs, sonrotoclax and zanubrutinib, produced remarkably deep and clean responses, even in patients with high-risk genetic features that have historically predicted a poorer response to treatment.

Key Takeaways

  • frontMIND showed tafasitamab plus lenalidomide added to R-CHOP significantly improved PFS (25% risk reduction) in frontline high-risk DLBCL, independent of cell of origin.

  • Golcadomide plus Pola-R-CHP showed high complete metabolic response and MRD negativity rates in frontline aggressive B-cell lymphoma, though with substantially higher neutropenia than Pola-R-CHP alone.

  • SUNMO showed mosunetuzumab plus polatuzumab vedotin achieved a durable PFS benefit (HR, 0.41) over R-GemOx in transplant-ineligible relapsed/refractory large B-cell lymphoma, with one of the more favorable CRS profiles among T-cell-engaging therapies.

  • Fixed-duration glofitamab monotherapy achieved a 70.6% complete response rate in relapsed/refractory mantle cell lymphoma after prior BTKi exposure, though it has not yet matched CAR-T's PFS/OS in this setting.

  • Sonrotoclax plus zanubrutinib achieved 100% ORR and undetectable MRD in 87.3% of high-risk, unmutated-IGHV frontline CLL patients, with no tumor lysis syndrome observed; randomized phase 3 data are awaited.

References

  1. Lenz G, Balke-Want H, Bucher C, et al. frontMIND: phase 3 study of tafasitamab plus lenalidomide and R-CHOP for patients with newly diagnosed diffuse large B-cell lymphoma. Presented at: 2026 ASCO Annual Meeting.

  2. Hoffmann M, Nowakowski G, Michal Kwiatek, et al. Golcadomide, a potential first-in-class, oral CELMoD, plus Pola-R-CHP in patients with newly diagnosed aggressive B-cell lymphoma: safety and 12-month efficacy results. Presented at: 2026 ASCO Annual Meeting.

  3. Kim W, Westin J, Nastoupil L, et al. Mosunetuzumab plus polatuzumab vedotin versus rituximab, gemcitabine, and oxaliplatin in patients with relapsed/refractory large B-cell lymphoma (R-GemOx): updated efficacy and safety from the phase 3 SUNMO study, including 2L versus 3L+ subgroups. Presented at: 2026 ASCO Annual Meeting.

  4. Karimi YH, Martin Hutchings, Tycel Phillips, et al. Fixed-duration glofitamab monotherapy in relapsed/refractory mantle cell lymphoma with/without prior BTKi exposure: updated data with a median follow-up of 41.5 months. Presented at: 2026 ASCO Annual Meeting.

  5. Tam CS, Opat S, Lasica M, et al. First-line treatment of CLL/SLL with the all-oral combination of sonrotoclax and zanubrutinib achieves undetectable minimal residual disease rates of greater than 90%, including in patients with del(17p)/TP53. Abstract 7043. Presented at: 2026 ASCO Annual Meeting.