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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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Kinase Selectivity of BTK Inhibitors

Each of these 3 BTK inhibitors exhibits different kinase selectivity. In addition to its direct effects on BTK, these BTK inhibitors can affect other kinases, such as TEC (tyrosine kinase expressed in hepatocellular carcinoma)and ITK (interleukin-2–inducible kinase).12 Inhibition of other kinases may lead to some of the AEs observed with BTK inhibitors, such as thrombocytopenia.

As a more selective BTK inhibitor, acalabrutinib requires much higher doses than does ibrutinib to affect other kinases (eg, ITK, EGFR epidermal growth factor receptor, JAK3 Janus kinase 3, TEC). Given the physiologic doses that are administered with therapy, acalabrutinib generally has less effect on other kinases and thus fewer AEs. Zanubrutinib is also a more selective BTK inhibitor and similarly requires higher doses than ibrutinib to inhibit these other kinases.

As mentioned, inhibition of these kinases may lead to toxic effects. We have found that EGFR inhibition can potentially lead to rash, cardiac toxicity, and diarrhea.13 Both ERBB4 and BMX inhibition also can lead to cardiac toxicity. ITK inhibition can lead to antibody-dependent cellular cytotoxicity or thrombocytopenia, whereas TEC inhibition can have platelet effects. Finally, JAK3 inhibition can lead to immune effects.

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AEs With BTK Inhibitors: Introduction

Various AEs are associated with BTK inhibitor therapy. However, it can be challenging to compare agents’ AE rates because some AEs, such as atrial fibrillation, were not fully characterized when the FDA approved the first BTK inhibitor, ibrutinib, in 2013.9 It is only with longer follow-up that we have better characterized the safety profile of ibrutinib.

We do not yet have comparable prolonged follow-up for acalabrutinib or zanubrutinib, which were approved by the FDA in 2017 and 2019, respectively.10,11 This makes it difficult to know whether the incidence of rarer AEs is actually lower with these newer, more selective BTK inhibitors or if the lower incidence reflects a shorter time for data collection and relative inexperience with these newer agents. That being said, we do have emerging comparative data from head-to-head clinical trials such as ELEVATE-RR, ALPINE, and ASPEN, which we will discuss later.

AEs of Available BTK Inhibitors: Cytopenias, Infection, Bruising and Hemorrhage, Lymphocytosis

Some of the common AEs that occur with BTK inhibitors include cytopenias, infection, bruising and hemorrhage, and lymphocytosis.

The cytopenias associated with BTK inhibitors include neutropenia, thrombocytopenia, and anemia.9-11 Neutropenia is an on-target toxicity of BTK inhibitors and also may arise from hematopoiesis suppression due to tumor burden.14,15 Grade 3/4 neutropenia has been observed in up to 29% of patients receiving ibrutinib, up to 23% receiving acalabrutinib, and 26% receiving zanubrutinib.9-11 The rates of grade 3/4 thrombocytopenia are generally lower, occurring in up 17% of patients receiving ibrutinib, up to 8% receiving acalabrutinib, and 11% receiving zanubrutinib. Finally, grade 3/4 anemia has been observed in up to 13% of patients receiving ibrutinib, up to 11% receiving acalabrutinib, and 8% receiving zanubrutinib.

Grade 3-5 infections are fairly common among patients receiving BTK inhibitors. These can occur in up to 29% of patients receiving ibrutinib, up to 18% receiving acalabrutinib, and 27% receiving zanubrutinib.9-11 The increased risk of infection observed with BTK inhibitors likely arises from multiple mechanisms, including off-target inhibition of ITK leading to immune impairment, inhibition of natural killer cell antibody-dependent cellular cytotoxicity, and decreased macrophage phagocytosis.16 Inhibition of macrophage response likely plays a role in the increased risk of Aspergillus fumigatus infections observed in patients receiving ibrutinib.

Patients receiving BTK inhibitors also can experience bruising and hemorrhage. The bleeding observed with BTK inhibitors is likely due to on-target BTK inhibition and off-target inhibition of TEC family kinases, which are involved in platelet aggregation through glycoprotein VI signaling.16 Ibrutinib has been associated with hemostatic failure, bruising and subcutaneous bleeding occurring after relatively minor trauma in up to 50% of patients.9 Grade ≥3 hemorrhage is less common and occurs in about 6% of patients. For acalabrutinib, bleeding events typically have included petechiae or easy bruising, and those occur in approximately 30% of patients at any grade. Grade ≥3 hemorrhage occurs in ≤3% of patients receiving acalabrutinib.10 For zanubrutinib, any-grade hemorrhage has been reported in 35% of patients, whereas grade ≥3 events occur in 3.4% of patients.11

Lymphocytosis is another class effect of BTK inhibitors. BTK inhibition interferes with BCR-mediated retention of malignant B-cells in lymphoid tissue, leading to a transient efflux of malignant B-cells from these tissue compartments.17,18 Lymphocytosis is observed in up to 77% of patients receiving ibrutinib, 26% receiving acalabrutinib, and 41% receiving zanubrutinib.9-11

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AEs of Available BTK Inhibitors: Gastrointestinal, Musculoskeletal, and Other Common AEs

Gastrointestinal toxicity represents another off-target effect of BTK inhibitors.19 Grade ≥3 gastrointestinal events are quite uncommon with BTK inhibitors, whereas any-grade diarrhea occurs in up to 63% of patients receiving ibrutinib, up to 35% receiving acalabrutinib, and 22% to 23% receiving zanubrutinib.9-11 Any-grade nausea occurs in up to 31% receiving ibrutinib, 22% receiving acalabrutinib, and 13% to 18% receiving zanubrutinib.

Other complications can include musculoskeletal toxicities such as arthralgias, pain, and myalgias. The etiology of arthralgia in patients receiving BTK inhibitors remains to be determined.16 Given that arthralgia occurs less frequently with more specific BTK inhibitors, this AE may be due to effects on kinases targeted more by ibrutinib.

These musculoskeletal events occur in up to 37% of patients receiving ibrutinib, up to 23% receiving acalabrutinib, and 14% to 45% receiving zanubrutinib.9-11 Musculoskeletal toxicities are typically grade 1/2, but grade ≥3 events can occur in up to 6% of patients receiving ibrutinib, 1.1% receiving acalabrutinib, and 1.1% to 9% receiving zanubrutinib.

Other common AEs that have been associated with BTK inhibitors include rash, headache, and fatigue.9-11 Rash is generally believed to be due to off-target inhibition of EGFR, although it also has been suggested that rash occurring early in therapy may be associated with transient lymphocytosis.14 Rash occurs in 20% to 36% of patients receiving BTK inhibitors.9-11

Any-grade headache occurs in up to 19% of patients receiving ibrutinib, up to 39% receiving acalabrutinib, and up to 18% receiving zanubrutinib. Grade ≥3 headaches rarely occur with any of the available BTK inhibitors.

Fatigue also is common across the BTK inhibitors, occurring in up to 41% of patients receiving ibrutinib, up to 23% receiving acalabrutinib, and up to 31% receiving zanubrutinib. Fatigue is typically low grade.

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AEs of Available BTK Inhibitors: Hypertension, Atrial Fibrillation, and Cardiac Arrhythmias

Cardiotoxicity can occur with the available BTK inhibitors, in particular hypertension, atrial fibrillation, and cardiac arrhythmias.9-11 Hypertension occurs in up to 19% of patients receiving ibrutinib, up to 5% receiving acalabrutinib, and 12% to 14% receiving zanubrutinib.

Atrial fibrillation may be caused by off-target inhibition of cardiac phosphoinositide 3-kinase (PI3K), with preclinical and clinical observations suggesting greater susceptibility in those with decreased cardiac PI3K activity.16 The reported incidence varies between BTK inhibitors and by malignancy, with 2% to 11% with ibrutinib, 0% to 5% with acalabrutinib, and 2.8% with zanubrutinib.9-11

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