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BTK Inhibitors in Lymphoma
The APP’s Guide to Patient-Centered BTK Inhibitor Therapy in Lymphoma

Released: November 10, 2025

Emily Patterson
Emily Patterson, AGACNP-BC
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Key Takeaways
  • Second-line therapy for relapsed/refractory CLL largely depends on the treatment prescribed to the patient in the first-line setting—whether acalabrutinib, zanubrutinib, or a venetoclax plus obinutuzumab combination.
  • BTK inhibitors are an option for first-line therapy in a patient who is diagnosed with MCL but who is deemed transplant ineligible.
  • Key adverse effects associated with BTK inhibitors include bleeding and cardiac arrhythmias, primarily atrial fibrillation, but effects are generally well-managed with proper education and monitoring.

Advanced practice providers aid in the management of patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), including those patients receiving BTK inhibitors, which are a standard-of-care therapeutic class. In CLL and MCL, the B-cell receptor is constitutively active, resulting in continuous BTK signaling and ultimately abnormal cell growth and survival. Multiple agents target and selectively inhibit BTK, stopping the cancer’s trajectory. The following commentary highlights 2 case scenarios of patients who will receive therapy with a BTK inhibitor.

Case 1: Relapsed/Refractory CLL
The following case describes Robert Green, a 72-year-old man diagnosed with CLL 5 years ago. He was initially treated with venetoclax and obinutuzumab and did well. He is currently on surveillance for his CLL.

Today, Mr Green presents to the clinic with increased fatigue, dyspnea on exertion, unintentional weight loss, and progressive lymphadenopathy. He has a history of hypertension and chronic kidney disease and is at low risk of cardiac adverse effects. The healthcare professional (HCP) examines Mr Green and notes multiple palpable lymph nodes in the cervical, axillary, and inguinal regions; he also has a mildly enlarged spleen.

Laboratory studies show a white blood cell count of 125,000 cells/µL and a hemoglobin concentration of 9.8 g/dL. More concerning is the decrease from a hemoglobin concentration of 11.2 g/dL. In addition, Mr Green’s platelets are down from 130,000/µL to 95,000/µL. His lactate dehydrogenase of 420 U/L is elevated beyond the upper limit of normal (210 U/L), and the elevation is a nonspecific marker for lymphoma. Mr Green has a previous diagnosis of CLL, and this increase indicates cell turnover. Mr Green also has CLL with a TP53 mutation.

Taken together, these data indicate relapsed CLL with a high-risk TP53 mutation. Chemotherapy-based options are unlikely to be effective with this relapse. Preferred options for this patient include a BTK inhibitor. BTK inhibitors are highly effective for patients with a TP53 mutation or 17p deletion, where traditional chemotherapy is often not effective.

Compared with ibrutinib, zanubrutinib and acalabrutinib are more selective for BTK, with fewer off-target effects, particularly regarding cardiac adverse effects like atrial fibrillation and bleeding complications. These complications can be of particular concern in older patients, individuals receiving anticoagulant medication, those at high risk for falls, and patients whose skin is more fragile. Ibrutinib is less favorable with these patients for those reasons.

How do you select treatment?
This patient has aggressive disease with a TP53 mutation, and the patient received obinutuzumab and venetoclax. Indeed, guidelines recommend that this patient could have received first-line obinutuzumab and venetoclax or a covalent BTK inhibitor. This initial decision is based on patient preference and comorbidities or concomitant medications. For example, a patient may prefer a time-limited therapy with obinutuzumab and venetoclax, or a patient may prefer to avoid receiving intravenous infusions and therefore use a BTK inhibitor.

In this case, Mr Green did not receive prior covalent BTK inhibitors. Therefore, acalabrutinib and zanubrutinib should be considered for second-line therapy. If he had relapsed or refractory disease and had received a prior covalent BTK inhibitor and BCL2 inhibitor, he could receive a third-generation BTK inhibitor, like pirtobrutinib, and/or CAR T-cell therapy.

Note that a patient with relapsed CLL or disease progression without cytopenias or bulky adenopathy does not require treatment. A watch-and-wait approach is feasible for these patients. Healthcare professionals can see them every 3 months to trend their complete blood cell counts and discuss their symptoms. If they remain stable over multiple 3-month visits, their treatment can be spaced out further, maybe 4 or 6 months, depending on how they are doing.

Case 2: MCL
The following case describes Joanne Simon, a 69-year-old woman. Her past medical history indicates atrial fibrillation, for which she was prescribed the β-blocker metoprolol succinate and the anticoagulant apixaban. Ms Simon also has hypertension, which is controlled with the angiotensin-converting enzyme inhibitor lisinopril; type 2 diabetes, which is controlled with metformin; and hyperlipidemia. She has a history of renal cell carcinoma, for which she underwent a left nephrectomy.

Today, Ms Simon wants to discuss treatment options for her newly diagnosed, previously untreated MCL. She presents to the clinic with pancytopenia because of bone marrow involvement of her MCL. She is experiencing fatigue, night sweats, and fevers. The infectious workup for Ms Simon is negative. Because of her age and comorbidities, she is deemed transplant ineligible. Upon examination, Ms Simon has no palpable lymphadenopathy or hepatosplenomegaly.

Laboratory studies show an elevated white blood cell count of 15,000 cells/µL, well above the normal limit of 11,000 cells/µL, and an abnormally low hemoglobin level of 8.6 g/dL. Also concerning is the number of platelets (72,000/µL), which is well below normal levels (400,000-150,000/µL). Her lymphocyte count is elevated beyond the upper limit of normal (11,000 cells/mL), consistent with her condition, as lymphocyte levels will abnormally fluctuate because of autoimmune disorders, infections, or leukemia.

A bone marrow biopsy is performed. Flow cytometry and immunohistochemistry (IHC) analysis of her biopsy confirm the CD20+, CD5+, and cyclin D1+ profile, characteristic of her diagnosis of MCL. IHC also shows a Ki-67 index of 60%, which indicates the aggressiveness of the lymphoma.

A PET scan with the radioactive tracer fluorodeoxyglucose (FDG) is performed. Imaging shows diffuse FDG avidity in the marrow, indicating the presence of hyperplastic bone marrow. The area is demonstrating increased metabolic activity, or increased cancer cells.

Molecular and genetic testing are also performed. The results show a cyclin D1 gene rearrangement. The hallmark of MCL is t(11;14)(q13;q32), which leads to overexpression of cyclin D1, and is essential for diagnosis. In addition, a TP53 mutation is present in the biopsied tissue. Testing for TP53 mutations is an important step in diagnosis because TP53 mutations are associated with a worse prognosis. Finally, the presence of an IGH/CCND1 fusion is detected. This genetic abnormality is present in nearly all cases of MCL.

How do you select treatment?
Ms Simon is seeking treatment for her newly diagnosed MCL. Given that Ms Simon has been deemed transplant ineligible because of her age and comorbidities, a BTK inhibitor is a good option for first-line therapy. Her history of atrial fibrillation on metoprolol succinate and well-controlled hypertension do not preclude her from treatment. However, she will require close monitoring for the development of rapid atrial fibrillation or worsening hypertension. Also given that she is receiving apixaban, the risk of bleeding is increased, and she will need to be monitored more closely, especially given her already-reduced platelet count. Zanubrutinib in combination with obinutuzumab and venetoclax is suitable induction therapy for this patient. Alternative regimens that are suitable for aggressive treatment would be a fixed duration with alternating rituximab plus cyclophosphamide/doxorubicin/vincristine/ prednisone in combination with a covalent BTK inhibitor/rituximab, dexamethasone, cytarabine, and a platinum chemotherapy drug. Because Ms Simon has a TP53 mutation, less aggressive drug regimens would not be appropriate.

Your Thoughts
What are you doing in your practice? Have you cared for patients receiving BTK inhibitors for newly diagnosed MCL? Please answer the polling question or leave a comment to join the discussion.

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