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Managing BTK Inhibitor Toxicities

CE / CME

Optimizing the Use of BTK Inhibitors in B-Cell Malignancies: Addressing BTK Inhibitor Toxicities

Pharmacists: 1.00 contact hour (0.1 CEUs)

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Nurses: 1.00 Nursing contact hour

Released: September 29, 2021

Expiration: September 28, 2022

Christopher R. Flowers
Christopher R. Flowers, MD, MS
CME/CE Information

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Dosing Guidance for Ibrutinib

The algorithms for dose reduction and discontinuation for BTK inhibitors are straightforward. For ibrutinib, the drug should be held for the first occurrence of grade ≥3 nonhematologic AEs, grade 3 neutropenia with fever or infection, and grade 4 hematologic AEs.9 Once the event resolves to grade 1 or better, ibrutinib can be restarted at the starting dose. For the second occurrence of the event, the drug should be held until resolution to grade ≥1 and restarted at a dose 140 mg lower than the previous dose. The same approach should be followed for the third occurrence of the AE. For the fourth occurrence, ibrutinib should be permanently discontinued.

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Dosing Guidance for Acalabrutinib

For acalabrutinib, dose modifications apply for any grade ≥3 nonhematologic AEs, grade 3 thrombocytopenia with bleeding, grade 4 thrombocytopenia, and any occurrence of grade 4 neutropenia that lasts >7 days.10 For the first and second occurrences of these AEs, acalabrutinib should be held until the event resolves to grade 1 or better. Once resolved, acalabrutinib can be resumed at its original dose of 100 mg twice daily. For the third occurrence, acalabrutinib should be held until resolution to grade 1 or better and then resumed at 100 mg once daily. For the fourth occurrence, acalabrutinib should be permanently discontinued.

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Dosing Guidance for Zanubrutinib

Patients receiving zanubrutinib will need dose modifications if they experience grade ≥3 nonhematologic AEs, grade 3 febrile neutropenia or thrombocytopenia with significant bleeding, or grade 4 neutropenia or thrombocytopenia lasting ≥10 days.11 Upon the first occurrence of 1 of these events, zanubrutinib should be held until the event resolves to grade 1 or better and then resumed at the starting dose. For the second occurrence, zanubrutinib also should be held until the event resolves to grade 1 or better. However, upon resolution, the dose should be reduced to 80 mg twice daily or 160 mg once daily, depending on the original starting dose. Upon the third occurrence, zanubrutinib should be held until resolution to grade 1 or better and then resumed at 80 mg once daily, regardless of the starting dose. Like the other BTK inhibitors, upon the fourth occurrence, zanubrutinib should be permanently discontinued.

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A 74-year-old man with hypertension, hypercholesterolemia, and mild renal insufficiency (creatinine 1.9 mg/dL; glomerular filtration rate [GFR] 50 mL/min) was diagnosed with CLL. His laboratory values are as follows: white blood cell (WBC) count 75,000/mm3; hemoglobin (Hb) 10 g/dL; del(17p) by FISH. The patient started on ibrutinib 420 mg QD. The pretreatment WBC of 75,000/mm3 rises to 200,000/mm3 but by 3 months has dropped to 37,000/mm3. His Hb initially drops to 9.3 g/dL but then normalizes, as does lactate dehydrogenase (LDH). At Month 3, the patient complains of moderate to severe joint stiffness and pain that has limited his ability to walk his dog, do any heavy lifting, or open jars or cans.

In your current practice, which of the following would you recommend for managing this patient’s grade 3 arthralgias?
An Interactive Algorithm Tool: Assessment and Management of BTK Inhibitor AEs

How should we approach managing this patient’s grade 3 arthralgias associated with ibrutinib therapy for CLL? Clinical Care Options has worked with a panel of 5 experts to develop an Interactive Decision Support Tool offering consensus recommendations for management of BTK inhibitor–associated AEs based on important patient factors. The expert panel includes myself and my colleagues, Farrukh T. Awan, MD; Nicole Lamanna, MD; John P. Leonard, MD; and Julie M. Vose, MD, MBA.

For this patient, our consensus recommendation for managing the first occurrence of grade ≥3 arthralgias is to withhold ibrutinib until the patient’s symptoms resolve, then resume at the same dose of ibrutinib. Some of the panel also would recommend over-the-counter analgesics, potentially escalating to more potent analgesics and/or corticosteroids for symptom relief.

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Recommendations to Reduce Drug–Food Interactions With BTK Inhibitors

To minimize the risk of toxicity and optimize adherence, it is important to consider drug–food interactions that can occur with BTK inhibitors. As with drug–drug interactions, which we will discuss shortly, patient counseling by nurses and pharmacists is vital to minimizing the risks of these interactions.

Acalabrutinib is a 100-mg capsule taken twice daily.10 It can be taken with or without food, and patients should swallow that capsule whole with water.

Ibrutinib comes in capsule or tablet form with different doses.9 Patients should swallow the capsule whole with water and should not cut, crush, or chew the tablets. Taking ibrutinib with a high-fat or high-caloric meal can increase the expected Cmax and AUC—values indicating the peak serum concentration of the drug and total exposure, respectively—with ibrutinib compared with overnight fasting.

Zanubrutinib is available as 80-mg capsules and should be given at either 160 mg twice daily or 320 mg once daily.11 The capsules can be taken with or without food, and patients should swallow the whole capsules with water.

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BTK Inhibitor Drug–Drug Interactions

The CYP450 enzymes are integral to drug metabolism, with many drugs and other exogenous chemicals being largely metabolized by CYP3A4.33 The BTK inhibitors are no exception and are largely metabolized by CYP3A enzymes—raising the potential for interactions with other drugs also metabolized by these enzymes.9-11 Agents that act as CYP3A inducers thus increase the plasma concentration of BTK inhibitors; a common example of a CYP3A inducer is St. John’s wort.33,34 By contrast, CYP3A inhibitors lower the plasma concentration of BTK inhibitors; common examples include grapefruit juice and Seville oranges.

The table shown here outlines dosing recommendations for some important drug–drug interactions between BTK inhibitors and CYP3A inhibitors, CYP3A inducers, and gastric acid–reducing agents.

Strong CYP3A inhibitors decrease AUC by >5-fold and clearance by >80%, which is why avoiding concomitant use and dose modification is recommended for both ibrutinib and acalabrutinib. For zanubrutinib, the recommendations are to decrease the starting dose to 80 mg once daily with interruption as needed for adverse reactions.9-11

Moderate CYP3A inhibitors decrease AUC by 2- to 5-fold and clearance by 50% to 80%. Dose modification is recommended for both ibrutinib and acalabrutinib, but only as needed due to adverse reactions for zanubrutinib.

Strong CYP3A inducers increase the AUC by >5-fold and clearance by >80%. The recommendations are to avoid concomitant use for all 3 BTK inhibitors, although if their use cannot be avoided, the dose can be increased for acalabrutinib.

Gastric acid–reducing agents can interact with acalabrutinib. The recommendations are to avoid concomitant use of proton pump inhibitors, take acalabrutinib 2 hours before an H2 receptor antagonist, and separate acalabrutinib dosing by ≥2 hours before and after antacids.

Pharmacists and medication nurses usually are the first to identify potential drug–drug interactions and suggest alternatives for patients receiving BTK inhibitor therapy. In my practice, there is a strong partnership between pharmacists and nurses on patient counseling and identifying interactions. The pharmacists typically provide the initial education and counseling when a patient is starting new therapy, and the nurses are responsible for ongoing education and counseling.

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