Key Ideas

Bruton's tyrosine kinase (BTK) inhibitor combinations now anchor frontline mantle cell lymphoma treatment across age and fitness categories, including chemotherapy-free regimens for older patients and TP53-mutated disease. Two new immunotherapy agents, tafasitamab and epcoritamab, expand FDA-approved second-line options in follicular lymphoma. Meanwhile, measurable residual disease (MRD) testing, initially a research tool, is beginning to guide treatment intensity in mantle cell lymphoma, Hodgkin lymphoma, and diffuse large B-cell lymphoma. The following reviews recent frontline mantle cell lymphoma data, new second-line options in follicular lymphoma, and where MRD-adapted strategies are headed next.

Frontline Mantle Cell Lymphoma Treatment Shifts Toward BTK Inhibitor Combinations

Younger, Transplant-Eligible Patients

The phase 3 TRIANGLE trial established a new standard of care for patients aged 18 to 65 with mantle cell lymphoma who are eligible for autologous stem cell transplant (ASCT). Adding ibrutinib to induction chemoimmunotherapy, with two years of BTK/rituximab maintenance, improved overall survival across arms. The inclusion of ASCT in first remission did not improve failure-free survival as compared to BTK/chemoimmunotherapy without transplant. BTK-containing induction and BTK/rituximab maintenance, without ASCT, should now be considered a standard of care for younger, fit patients.

Fit Older Patients

For patients over 65, the phase 3 ECHO trial randomized 598 previously untreated patients to bendamustine-rituximab (BR) with or without acalabrutinib. At a median follow-up of 45 months, median progression-free survival was 66.4 months including acalabrutinib compared with 49.6 months with BR alone, a 27% reduction in the risk of progression or death. This mirrors earlier findings from the SHINE trial, which paired ibrutinib with BR, although ECHO demonstrated a potentially more favorable safety profile including lower rates of atrial fibrillation.

Chemotherapy-free Approaches Older Patients

For patients not suited to chemoimmunotherapy, the ENRICH trial compared ibrutinib-rituximab against clinician's choice of R-chemo (BR or R-CHOP) in patients 60 and older. At a median follow-up of nearly four years, ibrutinib-rituximab significantly improved progression-free survival over R-chemo overall, an effect driven primarily by outperforming R-CHOP; outcomes with ibrutinib-rituximab were comparable to BR alone. Taken together with ECHO, this suggests ibrutinib-rituximab is a reasonable chemotherapy-free option for less fit patients, while BR plus acalabrutinib remains an option for more fit older patients. The second generation BTK inhibitors acalabrutinib and zanubrutinib have been evaluated in chemotherapy-free doublets in smaller single-arm studies, with similarly excellent results. 

TP53-Mutated Mantle Cell Lymphoma

TP53 mutations mark a distinct, chemotherapy-resistant subset of mantle cell lymphoma with little benefit from transplant. The BOVen regimen (zanubrutinib, obinutuzumab, and venetoclax) produced an overall response rate of 96% and a complete response rate of 88% in untreated TP53-mutated disease, with a 2-year progression-free survival of 72%, and has been incorporated into NCCN guidelines as a frontline option for TP53-mutated mantle cell lymphoma. Several similar chemotherapy-free triplets such as acalabrutinib-venetoclax-rituximab (AVR) have shown encouraging early results in broader populations without TP53 mutations, though longer follow-up is still needed.

New Options Expand Second-Line Follicular Lymphoma Treatment

Lenalidomide plus rituximab (R2) has long served as a chemotherapy-free backbone for follicular lymphoma. Two recent phase 3 trials tested the addition of newer immunotherapies to this backbone in the relapsed/refractory setting.

Tafasitamab Plus R2: The inMIND Trial

The phase 3 inMIND trial added tafasitamab, a CD19-targeted monoclonal antibody, to R2 in patients with relapsed or refractory follicular lymphoma. Median progression-free survival improved from 13.9 months with placebo plus R2 to 22.4 months with tafasitamab plus R2, a 57% reduction in the risk of progression, relapse, or death (hazard ratio 0.43). Overall response rate rose from 72% to 84%. Rates of neutropenia and other cytopenias were similar between arms, and treatment discontinuation was only modestly higher with tafasitamab, confirming this regimen as an attractive FDA-approved second line option in FL.

Epcoritamab Plus R2: The EPCORE FL-1 Trial

The phase 3 EPCORE FL-1 trial paired epcoritamab, a CD3xCD20 bispecific antibody, with R2 in a similar relapsed or refractory follicular lymphoma population. The novel combination yielded a 79% reduction in the risk of progression or death compared with R2 alone (hazard ratio 0.21), with median progression-free survival not yet reached in the epcoritamab. This benefit came with a toxicity tradeoff, including higher rates of grade 3 or higher infections, though cytokine release syndrome was generally low grade. This combination is now FDA-approved, appears highly effective, and may be most promising for fit patients or those with aggressive disease biology, including early progression after frontline therapy.

Measurable Residual Disease Testing Begins to Guide Treatment Intensity

Mantle Cell Lymphoma: EA4151 Questions Transplant's Role in Deep First Remission

The phase 3 EA4151 trial enrolled patients with mantle cell lymphoma in first radiographic complete remission, utilizing the ClonoSEQ immunosequencing assay to identify those with undetectable MRD after investigator’s choice of induction. These patients were randomized to consolidative ASCT plus maintenance rituximab versus maintenance rituximab alone. There was no difference in overall or progression-free survival between the two groups, including in the subset who completed transplant as assigned. The rate of frontline BTK utilization was low at 7.2%, so contemporary patients will likely receive different induction regimens than those administered in EA4151. However, for patients who achieve MRD-undetectable remission after any induction strategy, the role of consolidative transplant now appears very limited.

Hodgkin Lymphoma: Building Toward De-Escalation

The phase III S1826 trial established nivolumab-AVD as a new frontline standard for advanced-stage classic Hodgkin lymphoma, with a particular benefit in older patients, including improved overall survival and lower rates of treatment discontinuation compared with brentuximab vedotin-AVD. With high contemporary response rates, an open question is whether therapy can be de-escalated in responding patients. Traditional interim PET-based de-escalation appears less reliable with checkpoint inhibitor-containing regimens, with higher rates of interim PET positivity than would be expected given low rates of subsequent relapse. Many interim PET-positive patients are MRD-negative by circulating tumor DNA testing and do not go on to relapse. The PRECISE-HL trial is now testing MRD-based de-escalation of the nivolumab-AVD regimen: patients with undetectable ctDNA after two cycles of nivolumab-AVD have chemotherapy omitted from the final two cycles while continuing nivolumab, while ctDNA-positive patients continue standard therapy.

Diffuse Large B-Cell Lymphoma: Acting on Molecular Residual Disease

End-of-treatment MRD positivity in DLBCL is highly prognostic, and appears to outperform both the International Prognostic Index and end-of-treatment PET-CT. Even patients in complete metabolic response by PET have markedly different outcomes depending on MRD status: roughly 89% three-year progression-free survival if MRD-negative versus roughly 36% if MRD-positive. This gap has driven interest in early, MRD-directed consolidation for patients in radiographic complete response with detectable molecular disease. The randomized phase III ALPHA3 trial is testing this approach directly, randomizing MRD-positive patients after first-line chemoimmunotherapy to observation or allogeneic CD19-directed CART. Investigator-initiated trials using ctDNA-directed early consolidation are also opening at academic centers, reflecting a broader shift toward treating molecular relapse before it becomes clinically apparent.

For Patients

Several updates from this year point towards a more personalized future for lymphoma care. For mantle cell lymphoma, BTK inhibitors are increasingly replacing or reducing the need for intensive chemotherapy and stem cell transplant, across both younger and older patients. Chemotherapy-free treatment appears particularly promising for patients whose tumors carry a TP53 mutation, a feature that historically predicted poor responses to standard treatment. For follicular lymphoma that has returned after treatment, two new immunotherapy combinations, one adding tafasitamab and another adding epcoritamab to standard therapy with lenalidomide and rituximab, both meaningfully delay progression. A broader theme is the growing use of extremely sensitive blood tests that detect tiny amounts of remaining lymphoma, even when scans look clear. These tests are beginning to help decide who truly needs a stem cell transplant, who might safely receive less chemotherapy, and who might benefit from earlier treatment to prevent a relapse before it shows up on a scan.

Key Takeaways

  • The TRIANGLE trial supports BTK-containing induction and maintenance, without autologous transplant, as a new standard for younger, transplant-eligible mantle cell lymphoma patients.

  • The ECHO and ENRICH trials both support BTK inhibitor-based, chemotherapy-light or chemotherapy-free regimens for older mantle cell lymphoma patients, based on fitness.

  • The BOVen regimen (zanubrutinib, obinutuzumab, venetoclax) is now an NCCN-listed frontline option for TP53-mutated mantle cell lymphoma.

  • Adding tafasitamab (inMIND trial) or epcoritamab (EPCORE FL-1 trial) to lenalidomide-rituximab significantly improves progression-free survival in relapsed or refractory follicular lymphoma.

  • Measurable residual disease testing is increasingly guiding treatment intensity decisions in mantle cell lymphoma (EA4151), with trials underway in Hodgkin lymphoma (PRECISE-HL) and diffuse large B-cell lymphoma (ALPHA3) testing both de-escalation and early consolidation based on molecular, rather than radiographic, response.

References

  1. Dreyling M, Doorduijn JK, Gine E, et al. Addition of autologous stem-cell transplantation to an ibrutinib-containing first-line treatment in patients aged 18-65 years with mantle cell lymphoma (TRIANGLE): 4.5-year follow-up of a three-arm, randomised, open-label, phase 3 superiority trial. Lancet. 2026.

  2. Wang ML, Jurczak W, Dreyling M, et al. Acalabrutinib plus bendamustine and rituximab in untreated mantle cell lymphoma (ECHO trial). J Clin Oncol. 2026.

  3. Lewis DJ, Jerkeman M, Sorrell L, et al. Ibrutinib and rituximab versus immunochemotherapy in patients with previously untreated mantle cell lymphoma (ENRICH): a randomised, open-label, phase 2/3 superiority trial. Lancet. 2025.

  4. Kumar A, Soumerai J, Abramson JS, et al. Zanubrutinib, obinutuzumab, and venetoclax for first-line treatment of mantle cell lymphoma with a TP53 mutation (BOVen). Blood. 2025;145(5):497-507.

  5. Trneny M, Sehn LH, et al. Tafasitamab, lenalidomide, and rituximab in relapsed or refractory follicular lymphoma (inMIND): a global, phase 3, randomised controlled trial. Lancet. 2025.

  6. 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. 2025.

  7. Fenske TS, Wang XV, Till BG, et al. Lack of benefit of autologous hematopoietic cell transplantation in mantle cell lymphoma patients in first complete remission with undetectable minimal residual disease: initial report from the ECOG-ACRIN EA4151 phase 3 randomized trial. Blood. 2024;144(Suppl 2):LBA-6.

  8. Rutherford SC, Herrera AF, LeBlanc M, et al. Nivolumab-AVD versus brentuximab vedotin-AVD in patients with advanced-stage classic Hodgkin lymphoma: results of SWOG S1826. J Clin Oncol. 2025.

  9. Lynch R, Russler-Germain D, Schroers-Martin J, et al. PRECISE-HL trial: personalized reduction of chemotherapy intensity through ctDNA evaluation in advanced Hodgkin lymphoma. Blood. 2025;146(Suppl 1):5408.