BTK Inhibitors Beyond CLL: Their Role in the Treatment of Select B-Cell Malignancies

Presenting a new way to learn with the JADPRO Clinical Case Series!

Here's how it works:

  1. Read these 3 case studies on the role of BTK inhibitors in the treatment of Waldenström macroglobulinemia, marginal zone lymphoma, and mantle cell lymphoma.
  2. Answer the poll next to each case to see how your colleagues are managing this patient population. You'll see results in real time.
  3. Continue your learning by watching a recording of a webinar presented by Laura J. Zitella, MS, RN, ACNP-BC, AOCN, as she delves deeper into the 3 cases and shares clinical pearls for advanced practitioners. Download the slides from the webinar for your reference.

Managing Hypertension With Ibrutinib for the Treatment of Waldenström Macroglobulinemia

Hypertension is common and can occur anytime during ibrutinib therapy.

Mr. Jones is a 71-year-old man who presents with early satiety. His past medical history is significant only for hypertension that is well-controlled with losartan. On physical exam, he is found to have splenomegaly, and his diagnostic bloodwork is significant for a hemoglobin of 10.3 g/dL and an SPEP showing monoclonal IgM of 3200 mg/dL. You perform a bone marrow biopsy and the results show 25% lymphoplasmacytic infiltration and is MYD88 mutation positive.

At his follow-up visit, the advanced practitioner (AP) and oncologist discuss with Mr. Jones that his results are consistent with a diagnosis of Waldenström macroglobulinemia (WM). Given that Mr. Jones is symptomatic, they recommend initiating therapy. After a discussion of first line treatment options, they elect to initiate ibrutinib plus rituximab, which can rapidly reduce the level of IgM and decrease risk of progression (as compared to single-agent rituximab). He is started on ibrutinib 420 mg daily and rituximab 375 mg/m2 on day 1 of weeks 1 through 4 and 17 through 20.

Mr. Jones is followed regularly for symptom and laboratory checks. He does well on therapy, and at his 6-month follow-up visit, the AP shares with him that he has had a very good partial response to treatment, as his splenomegaly has resolved and there is an improvement in his previously abnormal laboratory values (see table below). Therefore, he will continue treatment with oral ibrutinib therapy and will return for monthly visits.

Table. Laboratory Values for Mr. Jones at 6 Months

Laboratory Parameters Initial Values 6-mo Values
Hemoglobin 10.3 g/dL 12.1 g/dL

Monoclonal IgM 3200 mg/dL 214 mg/dL

At a follow-up visit 2.5 years after he began treatment, Mr. Jones reports that his home blood pressure readings have been increasing. He keeps a log of his blood pressures, and he shows the AP that they have recently ranged from 140–150 mmHg systolic and 80–90 mmHg diastolic. In the clinic, his blood pressure is 143/88 mmHg.

The AP explains to Mr. Jones that hypertension is a common side effect of BTK inhibitors such as ibrutinib, but it can typically be controlled with antihypertensive therapies. He is hesitant to adjust his blood pressure regimen, but the AP explains that although he is asymptomatic from his hypertension, good blood pressure control is important to prevent other cardiac adverse events. Mr. Jones is already taking 25 mg of losartan daily; the AP recommends that he increase his dose to 50 mg daily and encourages him to continue home monitoring. At his subsequent follow-up visits, his blood pressure is consistently less than 130/80 mmHg.

Managing Joint Pain With Ibrutinib for the Treatment of Marginal Zone Lymphoma

Most side effects can be managed with supportive care, but a dose reduction of ibrutinib may be warranted.

Ms. Brown is a 39-year-old woman with a diagnosis of stage IV extranodal marginal zone lymphoma (MZL) involving the breast, lymph nodes, and a presacral lesion. She initially presented to her primary care provider with a breast mass. Bilateral diagnostic mammogram demonstrated one 2.7 x 1 x 2.1 cm left breast mass and two right breast masses of 2 x 0.8 x 1.3 cm and 4.6 x 1 x 2 cm. Biopsies of the left breast mass and one of the right breast masses both showed B-cell lymphoma CD20+, negative for CD5, CD10, CD43, CD23, or Bcl1, kappa restricted, all of which are consistent with extranodal MZL. Neither API/MALT1 fusion nor t(11;18) was detected. PET/CT showed hypermetabolic disease in the left supraclavicular fossa, left submandibular glandular area, left breast, right breast, and a right presacral soft tissue lesion. There were no laboratory abnormalities.

Ms. Brown was initially treated with rituximab plus bendamustine and achieved a molecular complete response (mCR). However, after a 3-year remission, she presents to the clinic with relapsed disease. The AP and oncologist discuss treatment options and decide to initiate ibrutinib 560 mg daily.

At her 1-month assessment visit, Ms. Brown reports to the AP that she has been experiencing joint pain. She recalls from her pretreatment education that this was one of the known side effects of her medication. She works as a medical assistant, and the pain is interfering with her ability to get through her day at work. She skipped a few doses of ibrutinib, which provided some relief, but she is worried about compromising the efficacy of her therapy. She is also concerned that the treatment team will change her therapy based on this side effect.

The AP discusses with Ms. Brown the importance of not skipping a dose of ibrutinib, but that instead, her side effects could be managed with other approaches. For example, topical creams that include ingredients such as arnica, diclofenac gel, camphor, menthol, capsaicin, or lidocaine may be helpful. Over-the-counter analgesics, such as acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs), may be of benefit. However, the AP does note the potential for bleeding with NSAID administration, and therefore advises that the lowest possible dose should be used. She advises Ms. Brown that if these measures do not sufficiently reduce her joint pain, a short course of steroids could be considered.

After discussing these points with Ms. Brown and listening to her preferences, the AP recommends that she take acetaminophen and use topical arnica cream for joint pain. After approximately 1 week of this regimen, she calls the office to report that there has been no improvement in her pain. The AP recommends that she try ibuprofen 400 mg 3 times a day with food to prevent stomach upset and adequate hydration to prevent kidney injury. The AP also counsels her again that ibuprofen can increase the risk of bleeding or bruising. The AP asks her to call back if her pain does not resolve or if she has any bleeding.

At her follow-up visit the next week, Ms. Brown states that her joint pain still has not improved with ibuprofen. She is now having a hard time walking her dog and sleeping at night due to the discomfort. The AP prescribes her a short course of steroids consisting of 20 mg of prednisone daily for 5 days. Her symptoms resolve with the steroids, but they recur just a few weeks later. She is discouraged, but the AP advises her that arthralgias are fairly common, occurring in approximately 35% of patients, and that a dose reduction may resolve the joint pain without compromising the efficacy of therapy.1 The AP decreases her dose of ibrutinib to 420 mg daily, and her joint pain improves; it is ultimately resolved at her follow-up visit 2 months later.


  1. Rhodes JM, LoRe, VA, Mato AR 3rd, et al. Ibrutinib-associated arthralgias/myalgias in patients with chronic lymphocytic leukemia: incidence and impact on clinical outcomes. Clin Lymphoma Myleoma Leuk. 2020;20:483-444.e1.

Management of Diarrhea With Ibrutinib for the Treatment of Mantle Cell Lymphoma

Most side effects associated with ibrutinib can be successfully managed with supportive care.

Mrs. Davis is an 80-year-old woman who was diagnosed with stage IVA mantle cell lymphoma (MCL) at age 76. This diagnosis was made after she presented with rectal bleeding, rectal pain, abdominal cramping, and diarrhea with 8 to 10 bowel movements per day. A palpable mass was found during a rectal exam and biopsied during a colonoscopy. The mass demonstrated small- to medium-sized lymphocytes expressing CD20, CD5, bcl-1, and bcl-2. The Ki-67 was 40%. She underwent PET-CT, which showed hypermetabolic lymphadenopathy in the left hilum, bilateral axillary, left inguinal, and left external iliac lymph nodes. A staging bone marrow biopsy indicated MCL. Mrs. Davis was initially treated with rituximab plus bendamustine for 6 cycles, and she achieved a complete remission. She continued with rituximab maintenance for 2 years and was negative for minimal residual disease (MRD) by next-generation sequencing.

However, 9 months after Mrs. Davis completed rituximab maintenance therapy, the MRD slowly begins to rise. She is monitored closely, and at 14 months, after completing maintenance therapy, an epigastric mass is palpable on exam and a PET-CT scan confirms relapsed disease. She is initiated on 560 mg of ibrutinib daily in the second-line setting and experiences a decrease in the size of the palpable epigastric mass.

At her 3-month follow-up visit, Mrs. Davis reports that she has had 3 loose stools with mild abdominal cramping every morning for the past 2 weeks. She does not leave her house during the morning hours in anticipation of this because she needs to be close to the bathroom. After the morning episodes, she does not experience any additional diarrhea during the day. She asks the AP if there is anything she can do to prevent the morning diarrhea so that she can participate in her normal morning activities.

The AP initiates a workup to exclude infectious gastroenteritis, including a Clostridiales difficile and gastrointestinal polymerase chain reaction panel that detects Campylobacter, Escherichia coli, Salmonella, Shiga-like toxin–producing E. coli, Shigella, Vibrio cholerae, adenovirus, norovirus, and rotavirus. The results are negative.

The AP reiterates to Mrs. Davis that diarrhea is a common side effect, occurring in approximately 50% of patients, with the highest incidence in the first 6 months of therapy.1 She assures her that there are many strategies for management, which may include a low-residue diet and antidiarrheal medications such as loperamide, diphenoxylate/atropine, or cholestyramine. After this discussion, the AP prescribes 4 g of cholestyramine by mouth twice daily, and the dose of her ibrutinib is not adjusted. At a 1-week follow-up visit, Mrs. Davis reports that her diarrhea has resolved, and she has resumed her usual morning activities.


  1. Stephens DM, Byrd JC. How I manage ibrutinib intolerance and complications in patients with chronic lymphocytic leukemia. Blood. 2019;133:1298-1307.

Meet the Faculty

Laura J. Zitella

University of California San Francisco
San Francisco, CA

Laura J. Zitella, MS, RN, ACNP-BC, AOCN, is a hematology nurse practitioner in the UCSF Hematology, Blood and Marrow Transplant, and Cellular Therapy (HBC) Program and clinical associate professor at the University of California San Francisco (UCSF). She has practiced in the field for over 25 years and has delivered hundreds of educational presentations to national/international audiences, and authored numerous peer-reviewed publications, webcourses, and book chapters. Ms. Zitella also serves on planning committees for numerous educational conferences, the editorial board for the Journal of the Advanced Practitioner in Oncology, and national committees such as the ACCC Clinical Affairs committee, ACCC Community Oncology Research Institute (ACORI), and the APSHO Research and Quality Initiative Taskforce.

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