The lymphoma and chronic lymphocytic leukemia (CLL) landscape in 2026 is defined by maturing long-term data, the movement of bispecific antibodies and targeted agents into earlier lines of treatment, and the arrival of all-oral, fixed duration treatment regimens. For diffuse large B-cell lymphoma, the five-year POLARIX update crystallizes both the benefit and the limits of polatuzumab vedotin. For follicular lymphoma, epcoritamab combinations lead to remarkable complete response rates but highlights the infection risk. In CLL, the AMPLIFY trial has paved the way for the first all-oral, fixed-duration frontline option.

Diffuse Large B-Cell Lymphoma: POLARIX at Five Years

What the Five-Year Data Tell Us

When POLARIX was first reported, it generated significant excitement as the first trial in over two decades to show a progression-free survival improvement over R-CHOP in diffuse large B-cell lymphoma. Five years later, that PFS benefit persists: pola-R-CHOP at 65% versus R-CHOP at 60%. It is modest but durable.

Although this long-term follow-up has not demonstrated an overall survival difference, this does not reflect upon the efficacy of polatuzumab. Instead, it is a reflection of the progress made in second-line options for patients with relapsed or refractory DLBCL. Patients who relapse after first-line treatment now have access to bispecific antibodies and CAR-T cell therapy, and these favorable efficacy of these second line plus treatment options likely obscure the OS benefit.

The subgroup analysis from POLARIX continues to guide clinical practice. The benefit is most concentrated in patients with IPI scores of three to five and in those with the ABC (non-GCB) molecular subtype. For double-hit and triple-hit lymphomas, pola-R-CHOP does not appear to provide meaningful additional benefit — dose-adjusted DA-EPOCH-R remains the preferred approach for those patients, and clinical trials are the most important option for this high-risk group.

Epcoritamab Monotherapy: Four-Year Follow-Up Changes the Story

The EPCORE NHL-1 trial — for which four-year follow-up data now available — shows the promise of bispecific antibodies in lymphoma. Epcoritamab monotherapy was given to a very high-risk population: approximately 60% were primary refractory to first-line therapy, and approximately 40% had already failed CAR-T cell therapy. These are patients with limited options and poor prognoses by conventional metrics.

Looking at the full cohort, median PFS was ~4 months and median OS ~18 months. However, most striking is looking at the ~40% of patients with a complete response. Of those CR patients, ~40% remained in CR four years later. The median duration of response for those who did respond was over three years. Four-year overall survival for CR patients approached 60%.

This data accomplishes two things. First, it establishes that for patients who respond to epcoritamab, responses can be remarkably durable, even in patients who have failed CAR-T. Second, it provides the biological rationale for combining epcoritamab with other agents to increase the proportion of patients reaching CR. That is exactly what the current generation of combination trials is attempting.

Epcoritamab in Combination With DA-EPOCH-R

A clinical trial currently open at Fred Hutch is evaluating the combination of epcoritamab with DA-EPOCH-R for patients with highly aggressive lymphomas, including double/triple-hit disease. This is based on the compelling long-term epcoritamab single-agent data from EPCORE NHL-1 and the hypothesis that adding a bispecific engager to DA-EPOCH-R may improve outcomes in a population where outcomes remain inadequate. Referrals are welcome for eligible patients.

Follicular Lymphoma: The EPCORE FL-1 Trial and Risk of Infectious Complications

Epcoritamab-R²

The EPCORE FL-1 trial evaluated epcoritamab added to R² (rituximab plus lenalidomide) for relapsed or refractory follicular lymphoma. The efficacy results are striking: complete response rate improved from 50% with R-squared to 83% with epcoritamab plus R-squared; overall response rate improved from ~80% to 95%. With a median follow-up of 15 months, the addition of epcoritamab reduced the risk of disease progression or death by 70% compared to R² alone. Additionally, there are early signals of a potential overall survival benefit, though this has not yet reached statistical significance.

This combination is now approved for relapsed/refractory follicular lymphoma, and it represents a real therapeutic advance. However, in risk-benefit discussions with patients, the risk of infectious complications needs to be seriously considered. Adding epcoritamab to R² increased the rate of grade three or higher infections and neutropenia. In current practice, epcoritamab-R² is reserved for fit patients where there may be less concern regarding potential neutropenia or infection complications.

Lenalidomide itself remains a drug with a challenging side effect profile in the lymphoma setting, with a significant discontinuation rate due to adverse effects. There is significant clinical interest in moving away from lenalidomide-containing regimens where possible.

Non-Lenalidomide Options: ROSEWOOD, Mosunetuzumab monotherapy, and the PROMOTE-FL Trial

ROSEWOOD trial (zanubrutinib plus obinutuzumab): Compared to obinutuzumab alone in third-line follicular lymphoma, the combination of zanubrutinib (a BTK inhibitor) plus obinutuzumab produced a PFS of approximately 22 months versus shorter with obinutuzumab alone in the 3rd line plus setting. This establishes the role of BTK inhibitors and a non-lenalidomide option, even in a heavily pre-treated population.

GO29781 – Mosunetuzumab monotherapy: In another study looking at third-line and beyond treatment strategies for follicular lymphoma, mosunetuzumab produced a ~60% complete response rate and ~80% overall response rate. Three-year PFS was ~40%; three-year OS was approximately ~80%. The median duration of complete response has not been reached. These are impressive and durable results for a single agent in a heavily pretreated population and highlight the role for bispecific antibodies for the treatment of follicular lymphoma.

PROMOTE-FL trial (pirtobrutinib plus mosunetuzumab): This is a trial that is open for enrollment at Fred Hutch that looks at the role of the combination of a BTK inhibitor and bispecific antibody without lenalidomide for the treatment of relapsed/refractory follicular lymphoma in the 3L+ setting. This treatment will be given for 1 year with the hope that this combination will continue to maximize efficiency while limiting the adverse effects profile. In fact, in the ROSEWOOD study, the combination zanu-obinu arm saw fewer infusions and less fever, and there is also data showing that BTK inhibitors can decrease CRS frequency and/or severity in combination with CAR T-cell therapy. Please reach out if there is a patient who would be interested in learning more about this trial.

CLL: AMPLIFY Delivers the First All-Oral Fixed-Duration Option

The Trial and Its Results

The AMPLIFY trial brought to reality an oral-fixed duration treatment option for patients with treatment-naïve CLL. It compared three arms: acalabrutinib plus venetoclax (AV), AV plus obinutuzumab (AVO), and chemoimmunotherapy with either FCR or BR and demonstrated that AV and AVO both demonstrated improved PFS over chemoimmunotherapy. However, only AV showed a superior OS benefit over chemoimmunotherapy, and this is reflected in an estimated 36-month OS of ~94% for AV, ~88% for AVO, and 86% for chemoimmunotherapy. The decrease in survival in the AVO arm was driven primarily by infection-related deaths, the large majority of which were COVID pneumonia, as this study conducted in the early days of the COVID-19 pandemic. This reflects obinutuzumab's potent B-cell depleting effect and its impact on immune defense.

AV is now FDA approved as the first all-oral, fixed-duration frontline option for previously untreated CLL. AVO is currently not approved, largely because of the survival signal driven by infectious deaths. However, it is reasonable to consider the addition of obinutuzumab in a fit patient with few concerns about infectious complications.

What's Coming Next in CLL

Looking ahead, the CELESTIAL-TNCLL-2 trial, a global phase III clinical trial, will compare two doublets: AV versus zanubrutinib plus sonrotoclax, a novel next-generation BCL-2 inhibitor. Initial data shows that the zanubrutinib and sonrotoclax combination may lead to improved undetectable MRD4 rates compared to AV, with > 90% uMRD4 rates in the target dose of zanubrutinib plus sonrotoclax 320mg cohort compared to the AMPLIFY AV arm, which saw an MRD rate of only 45%. This will help answer the question of which combination will lead to improved outcomes and without an increase in toxicities.

BTK degraders are a conceptually important emerging class. Rather than inhibiting BTK enzymatic activity, degraders lead to ubiquitination and proteasomal destruction of the BTK protein itself. This process not only inhibits BTK kinase activity but also blocks the scaffolding functions of BTK, which helps improve its therapeutic effects and overcome certain mechanisms of resistance. The degrader can then be recycled to be used to target additional BTK proteins for degradation.

Thus, based on the excitement of BTK degraders, we will also have a clinical trial under development that will open in a few months that will look at the combination of a BTK degrader (BGB-16673) with the 2<sup>nd</sup> generation BCL-2 inhibitor sonrotoclax. This combination will be given for 12 cycles after an initial 3 cycle ramp-up with the degrader for debulking of disease. If patients have detectable MRD at the end of these 15 total cycles, then they will continue this combination and add obinutuzumab. This later addition of obinutuzumab is due to the AMPLIFY data suggesting that the addition of obinutuzumab leads to increased infectious complications Thus, we are reserving the use of obinutuzumab for only those patients would benefit from the addition of another agent. This MRD-adaptive approach may represent the future of CLL treatment personalization.

Liso-Cel in CLL: Real-World Data Outperforms the Trial

CAR-T cell therapy with liso-cel was approved for CLL two years ago. Initial trial data from TRANSCEND showed a complete response rate of ~20% and an overall response rate of ~44%, leaving much room for potential improvement. Real-world data show substantially better outcomes: overall response rates approaching 90% and complete response rates around 66%. The improvement appears attributable to better disease control at the time of CAR-T infusion and more widespread use of BTK inhibitor bridging therapy, which may enhance T-cell fitness in this immunocompromised population.

Nemtabrutinib and Liso-cel

A clinical trial combining nemtabrutinib (a non-covalent BTK inhibitor) with liso-cel for CLL is opening at Fred Hutch to prospectively test this hypothesis. BTK inhibitors are also thought to improve CAR T-cell fitness and decrease CRS frequency and/or severity in combination with CAR T-cell therapy. Thus, our hope is that this combination with both improve the efficacy without increasing the adverse effects associated with CAR T-cell therapy.

For Patients

If you have follicular lymphoma or CLL, the options available today are substantially more effective than those of even five years ago. CAR T-cell therapy remains a highly effective treatment options for patients with relapsed or refractory disease, and bispecific antibodies have moved or are likely moving into earlier lines of therapy due to how well they have worked in patients who have not responded to or progressed on multiple treatment options. The treatment options for patients with CLL are also rapidly changing. An all-oral, time-limited treatment option now exists for patients with newly diagnosis CLL that does not require indefinite therapy or frequent clinic visits for infusions and there are many novel drugs in the pipeline that are either more effective itself or may improve how well treatments work when taken in combination with other treatment options.

Ask your oncologist about whether a clinical trial is right for your situation, and do not hesitate to seek a second opinion at a center with active clinical trial programs.

Key Takeaways

Pola-R-CHP for DLBCL continues to demonstrate a PFS benefit though there is difference in OS, likely due to the availability of effective treatment for relapsed/refractory disease
Bispecific antibody monotherapy in DLBCL continues to demonstrate that it can lead to a durable remission, especially for patients who had a complete response to therapy
Bispecific antibodies have moved into earlier lines of therapy in follicular lymphoma with the combination of epcoritamab and R<sup>2</sup>. However, the improvement in efficacy must also be balanced with the increase in grade 3+ neutropenia and infectious complications
Acalabrutinib and venetoclax is now approved as the first all-oral, fixed duration treatment option for patients with treatment-naïve CLL
Future directions:
- Studying the integration of specific antibodies into earlier lines of therapy, including the first-line setting
- Investigating the replacement of lenalidomide with other targeted agents such as bispecific antibodies and BTK inhibitors
- Exploring the potential for even more effective all-oral, fixed duration treatment regimens in CLL
- Numerous clinical trials open at Fred Hutch to bring the next generation of therapies to patients. Please reach out with any questions.

About the Author

Jennifer Huang, PhD, MD, is an Assistant Professor at Fred Hutchinson Cancer Center and the University of Washington School of Medicine in Seattle, Washington. She sees patients in the lymphoma, CLL, and immunotherapy/CAR-T programs and leads clinical and translational research on novel and combination therapies in lymphoma, with a focus on improving outcomes and understanding mechanisms of action for patients with B-cell malignancies.

References

Morschhauser F et. al. Five-Year Outcomes of the POLARIX Study Comparing Pola-R-CHP and R-CHOP in Patients With Diffuse Large B-Cell Lymphoma. J Clin Oncol . 2025 Dec 10;43(35):3698-3705. doi: 10.1200/JCO-25-00925.
Karimi Y et al. Sustained remissions beyond 4 years with epcoritamab monotherapy: Long term follow-up results from the pivotal EPCORE NHL-1 trial in patients with relapsed or refractory large B-cell lymphoma Presented at ASH 2025.
Falchi L. et al. Epcoritamab, lenalidomide, and rituximab versus lenalidomide and rituximab for relapsed or refractory follicular lymphoma (EPCORE FL-1): a global, open-label, randomised, phase 3 trial. Lancet . 2026 Jan 10;407(10524):161-173. doi: 10.1016/S0140-6736(25)02360-8.
Zinzani PL et al. Final Analysis of the Randomized Phase 2 ROSEWOOD Study of Zanubrutinib + Obinutuzumab vs Obinutuzumab Monotherapy in Patients With Relapsed/Refractory Follicular Lymphoma. Presented at ASH 2025.
Brown JR. Fixed-Duration Acalabrutinib Combinations in Untreated Chronic Lymphocytic Leukemia. N Engl J Med . 2025 Feb 20;392(8):748-762. doi: 10.1056/NEJMoa2409804.
Siddiq T et al. Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study. Lancet . 2023 Aug 19;402(10402):641-654. doi: 10.1016/S0140-6736(23)01052-8.
Huang JJ. "Updates in Lymphoma and CLL." Presented at the 2026 Alaska Hematology Oncology Conference, Anchorage, AK, May 2026.

Author

Jennifer Huang, PhD, MD

Fred Hutchinson Cancer Center and the University of Washington School of Medicine

Assistant Professor at at Fred Hutchinson Cancer Center and the University of Washington School of Medicine

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Bispecific Antibodies and Fixed-Duration CLL Therapy: The Lymphoma and CLL Landscape in 2026