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How I Manage Mantle Cell Lymphoma Using BTK Inhibitors: A Case Study From My Practice

Christopher R. Flowers, MD, MS

Department Chair, Department of Lymphoma/Myeloma
Division of Cancer Medicine
University of Texas MD Anderson Cancer Center
Houston, Texas

Christopher R. Flowers, MD, MS, has disclosed that he has received consulting fees from AbbVie, Bayer, BeiGene, Celgene, Denovo Biopharma, Genentech/Roche, Genmab, Gilead Sciences, Janssen, Karyopharm, Pharmacyclics, Seattle Genetics, and Spectrum and funds for research support from 4D, AbbVie, Acerta, Adaptimmune, Allogene, Amgen, Bayer, Celgene, Cellectis, EMD, Genentech/Roche, Gilead Sciences, Guardant, Iovance, Janssen, Kite, Morphosys, Nektar, Novartis, Pfizer, Pharmacyclics, Sanofi, Takeda, TG Therapeutics, Xencor, and Ziopharm.

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Released: March 7, 2022

Three Bruton tyrosine kinase (BTK) inhibitors—acalabrutinib, ibrutinib, and zanubrutinib—are approved to treat B-cell lymphomas, including mantle cell lymphoma (MCL), chronic lymphocytic lymphoma, and small lymphocytic lymphoma. As the use of these agents becomes more commonplace in the community setting, it is important for healthcare professionals to be aware of differences in safety profiles so they can select the most appropriate therapy for each patient. In this commentary, Christopher R. Flowers, MD, MS, will walk through a case presentation of MCL and discuss the use of available BTK inhibitors for treatment, as well as the implications of adverse event (AE) profiles on treatment choice.

Patient Case
The patient in this case is a 77‑year‑old man who, at initial diagnosis, had relatively indolent-behaving disease and was monitored for approximately 9 months. As is common for patients with MCL, before treatment he had an endoscopy, and on colonoscopy he was noted to have bowel involvement on blind biopsies. Ultimately, we noted an increased lymph node size in his axilla and neck. We subsequently treated him with bendamustine and rituximab for 6 cycles, followed by 9 months of observation with no maintenance therapy, which he tolerated well.

Approximately 2.5 years after initial treatment, the patient experienced recurrence of large lymph nodes in his bilateral neck region that were quite uncomfortable, smaller lymph nodes in his axillary region, and notable nodes on PET/CT in his mesenteric region and chest. At the time of relapse, the patient had an elevated lactate dehydrogenase of >400 units/L, compared with the upper limit of normal in the lab of approximately 200 units/L. The patient did not have any major medical comorbidities. He had some evidence of hypertension but was not regularly receiving medication for this issue. However, he was taking 81 mg/day of aspirin for management of potential cardiovascular disease, as recommended by his primary care physician. 

To treat relapsed disease, we started this patient on acalabrutinib. His initial response, after approximately 3 months of therapy, was improvement of his symptoms and resolution of some fatigue he experienced before therapy. In addition, the uncomfortable lymphadenopathy in his neck resolved, and other lymph nodes improved to achieve a partial response. He had minimal bruising with the acalabrutinib but continued therapy without any difficulty.

Selecting a BTK Inhibitor
When starting this patient and others on BTK inhibitors, there is always the question of which agent to choose. Currently, ibrutinib, acalabrutinib, and zanubrutinib all would be approved agents for relapsed MCL, but when this patient started therapy, zanubrutinib clinical trials were still ongoing. Because of the tolerability, acalabrutinib was selected as the preferred agent for this patient.

For me, the patient’s daily aspirin regimen was not a major decision factor in terms of which BTK inhibitor to select. For patients who are taking anticoagulants, particularly coumadin, I would not select ibrutinib for treatment. Earlier trials with ibrutinib showed an increased risk of major hemorrhage for patients concurrently receiving ibrutinib and anticoagulants. I also typically would not start patients with known atrial fibrillation on ibrutinib because of the risk of serious cardiac arrhythmias and cardiac failure. However, there are variations between my practice and many other practices. Some experts in MCL do prescribe ibrutinib for patients with atrial fibrillation or patients taking anticoagulants.

BTK Inhibitor Toxicities
This patient was aware that bruising was a possible complication with acalabrutinib treatment. When he experienced minimal to modest bruising, he elected to hold acalabrutinib on his own for a few days and then called to tell us about the bruising. At that time, he was immediately restarted on acalabrutinib. 

Occasionally we see thrombocytopenia with BTK inhibitors. For grade ≥3 thrombocytopenia with bleeding, I would consider stopping acalabrutinib and then restarting at the same dose (100 mg twice daily) once the bleeding and thrombocytopenia have resolved to grade 1 or baseline. If grade ≥3 thrombocytopenia happens on >1 occasion, I consider reducing the acalabrutinib dose to 100 mg once daily.

With BTK inhibitors, patients sometimes develop neutropenia that lasts longer than 7 days, and that happened with this patient later in his therapy. In those cases, interrupting acalabrutinib treatment until resolution makes sense. In addition, if the neutropenia occurs more than twice, I consider reducing the acalabrutinib dose.

Grade 1 or 2 headache also is common with acalabrutinib at the start of therapy, occurring in 20% to 40% of people. When that happens, giving caffeine is a trick that can help. Holding the acalabrutinib and restarting after some interruption is another approach.

Another AE that can be common with acalabrutinib is diarrhea, which occurs in approximately one third of patients. Diarrhea can be managed by interrupting the treatment and restarting upon resolution. It also is important to look for causes of diarrhea that are unrelated to the medication.

Myalgia―a soreness or stiffness of the muscles or muscle aches and pains―is more common with ibrutinib but also occurs with acalabrutinib and the other BTK inhibitors. Myalgia can be managed by interrupting the BTK inhibitor treatment, giving symptomatic treatments, and restarting the treatment after some break.

Healthcare professionals in the community are becoming familiar and comfortable with the use of BTK inhibitors in the relapse and frontline settings for chronic lymphocytic leukemia. By and large, acalabrutinib and other BTK inhibitors are reasonably well tolerated and produce meaningful response in most patients. However, there is an ongoing need for education around the management of AEs, especially the more subtle AEs. This information may not have completely made it to all community providers.

Your Thoughts?
In your clinical practice, which AE associated with BTK inhibitors is most challenging to manage? Take the poll and share your comments below.

Do you want to learn more about the use of BTK inhibitors for patients with chronic lymphocytic leukemia and MCL? Sign up here to attend the live webinar “Addressing Evolving Educational Needs on BTK Inhibitor Therapies in CLL/SLL and MCL” on Monday, March 7, 2022, at 4:00 PM ET with experts Jeff P. Sharman, MD; Matthew S. Davids, MD, MMSc; and Anthony Mato, MD, MSCE, where they will discuss current best practices with and emerging uses of BTK inhibitors in a virtual talk show format.

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