ASH 2025: BTK Inhibitor Updates for High-Risk LBCL

Read a summary of updates that researchers presented at the 2025 American Society of Hematology (ASH) meeting about BTK inhibitor combinations as a first treatment for people with high-risk subtypes of large B-cell lymphoma (LBCL). 

Using acalabrutinib before chemotherapy 

Researchers from the National Cancer Institute studied the BTK inhibitor acalabrutinib (Calquence, AstraZeneca) given briefly before the standard first chemotherapy for people with newly diagnosed LBCL. This short “window” helped them see which LBCL cells were sensitive to the BTK inhibitor before chemotherapy started. 

Half of the patients experienced remission during the acalabrutinib window. Responses were seen across many LBCL subtypes. This is important because earlier studies suggested BTK inhibitors mainly worked in one subtype called activated B-cell (ABC) LBCL. The most common side effects from the combination were low blood counts and infections. These side effects were considered manageable for patients. 

Two years after the start of treatment, 84.8% of patients were alive without lymphoma progression. This study suggests acalabrutinib can be safely added to the first standard chemotherapy and that genetic testing may help identify which people with LBCL benefit the most. 

Read this abstract: Response-adapted Phase 2 study of acalabrutinib window prior to frontline chemotherapy in untreated large B-cell lymphoma: Molecular correlates of response to acalabrutinib

The impact of adding zanubrutinib to R-CHOP 

A study in China looked at zanubrutinib (Brukinsa, BeOne), a newer BTK inhibitor, combined with R-CHOP for newly diagnosed patients with certain subtypes of LBCL that were linked to poorer outcomes when chemotherapy was used by itself. 

The percentage of patients whose cancer was controlled by the combination was 91.4%. Three years after the start of treatment, 82.2% of patients were alive without lymphoma progression. People with the MCD LBCL subtype had especially strong results. 

Side effects were manageable, and notably, no heart rhythm problems were reported, which can be a concern with some BTK inhibitors. These findings suggest that adding zanubrutinib to chemotherapy may improve outcomes for people with certain subtypes of high-risk LBCL.  

Read this abstract: The phase II study of zanubrutinib combined with R-CHOP in previously untreated diffuse large B-cell lymphoma (DLBCL) patients with specific gene-expression

Ibrutinib with R-CHOP for LBCL

A study conducted in Italy focused on people with ABC LBCL. Researchers added ibrutinib (Imbruvica, Pharmacyclics/Johnson & Johnson), a first-generation BTK inhibitor, to R-CHOP and then continued ibrutinib as a maintenance therapy. The median age of patients was 57. 

At the end of treatment, 90.7% of patients had their cancer controlled by the treatment. Side effects were mostly manageable, and serious heart problems sometimes seen with ibrutinib were uncommon. 

These early results suggest this approach may improve outcomes for younger patients with ABC LBCL. Longer follow-up will show whether maintenance therapy with ibrutinib adds a lasting benefit.

Read this abstract: Ibrutinib plus R-CHOP followed by maintenance in untreated ABC-DLBCL patients with IPI≥2: A first analysis of phase II Study FIL RI-CHOP 

Zanubrutinib combination for LBCL found in the nervous system 

Primary central nervous system lymphoma (PCNSL) is a rare type of LBCL that affects the brain and spinal cord. Researchers from China tested zanubrutinib combined with rituximab and high-dose methotrexate as a first treatment. 

Nearly all patients experienced remission. Early results showed strong control of the lymphoma with manageable side effects, mainly low blood counts.

This matters because treatment options for PCNSL can be limited. Zanubrutinib’s ability to reach the central nervous system makes it a promising option that needs further research. 

Read this abstract: Zanubrutinib, rituximab, and high-dose methotrexate as first-line treatment in newly diagnosed primary central nervous system lymphoma zana: A prospective, single-arm study 

What this means for patients

Together, these studies show that BTK inhibitor combinations are becoming an important part of first treatment research for high-risk subtypes of LBCL. They highlight the growing role of genetic testing in guiding care and point toward more personalized treatment options in the future.

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