Department of Medicine
Harvard Medical School
Director, Center for Lymphoma
Massachusetts General Hospital
Jeremy S. Abramson, MD, MMSc, has disclosed that he has received consulting fees from Abbvie, Amgen, Celgene, Gilead, Humanigen, Juno, Karyopharm, Merck, Novartis, Seattle Genetics, and Verastem.
Bruton’s tyrosine kinase (BTK) inhibitors are transformative therapies for patients with mantle cell lymphoma (MCL), marginal zone lymphoma, chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma, and Waldenström macroglobulinemia (WM). Two oral BTK inhibitors, acalabrutinib and ibrutinib, have been approved by the FDA in various settings. However, this class of agents has unique toxicities that require monitoring and prompt management. Understanding the range, intensity, and optimal management of adverse events (AEs) associated with BTK inhibitor therapy is essential to achieving the best possible outcomes for patients treated with these agents. In addition, clinicians must explain these risks to patients, including what signs to look for, management strategies, and when to call the doctor.
Diarrhea usually occurs early on with BTK inhibitor therapy, is seen in nearly one half of patients, and is generally not associated with infection or inflammatory colitis. Typically, diarrhea associated with BTK inhibition is not severe and resolves on its own within the first 1-2 months of being on therapy. I let patients know to expect it and encourage them to obtain over-the-counter antidiarrheal medications as needed. I also reassure them that the toxicity usually passes quickly.
Notably, patients receiving a BTK inhibitor may be already immunocompromised from their disease or a previous treatment. Immunocompromised patients who experience fever or abdominal pain concomitant with their diarrhea should be evaluated for infectious diarrhea unrelated to BTK inhibition.
Bleeding and Bruising
Bleeding and bruising are very common AEs from BTK inhibitor therapy, although serious bleeding is rare. Certainly, the risk of bleeding and bruising is increased for patients who are receiving antiplatelet agents or anticoagulants, including serious life-threatening bleeds (eg, gastrointestinal bleeding or intracranial hemorrhages). I make sure patients understand the increased bleeding risk before beginning therapy with a BTK inhibitor. In addition, we ask patients to stop taking their BTK inhibitor for 3 days before and after any minor invasive procedure and for a full week before and after a major surgical procedure to minimize the risk of bleeding or other periprocedural complications.
Patients receiving anticoagulants. One challenge is determining whether a patient receiving an anticoagulant or an antiplatelet agent should continue that treatment if they are considering BTK inhibitor–based therapy as well; I approach this on a patient-by-patient basis. For patients who are just receiving aspirin for cardiac protection, I prefer to keep them on it, with dose reduction to 81 mg if they are taking a full-dose aspirin. But if a patient were having frequent episodes of minor bleeding or bruising, then I would consider whether the aspirin was truly necessary and whether it could be held safely.
Patients who are already therapeutically anticoagulated are at the highest risk from BTK inhibitor–associated bleeding and bruising. Patients receiving warfarin have been excluded from all trials with BTK inhibitors because of the excess bleeding risk. In my practice, I avoid giving a BTK inhibitor concurrent with warfarin.
Consider alternative treatments. If a patient does require therapeutic anticoagulation, does he/she actually need to receive a BTK inhibitor? Some patients may have a disease for which there is a similarly effective therapy without a concomitant bleeding risk. For example, for a patient with relapsed CLL who is therapeutically anticoagulated, instead of a BTK inhibitor, I would consider the BCL-2 inhibitor venetoclax plus rituximab to minimize concern about bleeding.
If, however, a BTK inhibitor is clearly the best or only good choice for the patient, then I counsel the patient that there is an increased risk of bleeding when used with anticoagulation. In this setting, we typically use anticoagulation with a newer anticoagulant like apixaban and encourage the patient to call if he/she sees any evidence of bleeding, signs or symptoms of intracranial bleeding, or other symptoms of hemorrhage.
Similarly, for patients who have to initiate an anticoagulant during BTK inhibitor treatment, I will consider whether they could stop the BTK inhibitor. If long-term BTK inhibition is still the best option for them, then we typically provide anticoagulation with apixaban, again with discussion about the increased risk.
Any patient treated for a hematologic malignancy is likely to be at risk of cytopenias (neutropenia, thrombocytopenia, anemia), with higher risk in patients with previous chemotherapy. Severe cytopenias are uncommon; cytopenias related to BTK inhibitor therapy typically do not warrant dose reduction.
Based on the prescribing information, for patients who experience grade ≥ 3 neutropenia with infection or fever while receiving ibrutinib, the BTK inhibitor should be held until resolution to baseline or grade 1 before restarting at a reduced dose. For patients receiving acalabrutinib who experience grade 3 thrombocytopenia with bleeding, grade 4 thrombocytopenia, or grade 4 neutropenia lasting longer than 7 days, the BTK inhibitor should be held until resolution to baseline or grade 1 before restarting at a reduced dose. On the fourth occurrence of these AEs, the BTK inhibitors (either ibrutinib or acalabrutinib) should be discontinued.
Rashes occur in approximately 20% of patients receiving either ibrutinib or acalabrutinib. Although this type of AE is not life threatening, in can be quite bothersome to patients. For patients who do experience rashes, we typically recommend holding the BTK inhibitor and begin supportive care. Once the rash resolves, the BTK inhibitor can generally be resumed, and if the rash recurs, then we can try a dose reduction.
Another toxicity that appears unique to ibrutinib is myalgias, or muscle cramping. This can be seen at any time, but the risk increases the longer a patient receives ibrutinib. Although this is not a dangerous toxicity, it can be quite troublesome and has not infrequently been a reason to consider dose reducing or even discontinuing treatment. For some patients, it may make sense to determine if they have a severe electrolyte abnormality. For most patients, acetaminophen or ibuprofen as needed is sufficient to mitigate symptoms but not as effective long-term therapy. Typically, we reduce the dose of ibrutinib or possibly hold ibrutinib and resume once myalgia resolve. Another option would be to switch patients from ibrutinib to acalabrutinib, which does not appear to cause myalgias.
Headaches are quite common with acalabrutinib (approximately 40% of patients), tending to occur early and become less significant over time. These headaches are exquisitely sensitive to caffeine—a sip of coffee or other caffeinated beverage typically helps the headache abate rapidly. This a very manageable toxicity. Headaches do not seem to appear in patients receiving ibrutinib.
Atrial fibrillation overlaps somewhat with the issues around bruising and bleeding; however, this AE appears to be more common with ibrutinib (approximately 10%) vs acalabrutinib (< 5% of patients). Atrial fibrillation has not been observed as often with acalabrutinib, with the caveat that fewer patients have been treated with acalabrutinib and most have been treated for a shorter duration of therapy. Consequently, we do not know for sure whether it is an ongoing risk. Standard initial management of atrial fibrillation typically includes antiarrhythmic therapy. Sometimes these patients are candidates for cardioversion under the care of a cardiologist.
Anticoagulation risk. The real challenge of managing patients with atrial fibrillation is choosing optimal anticoagulation therapy. It is a personalized decision based on the BTK inhibitor’s indication as well as the suggested anticoagulation therapy and the patient’s overall risk profile. For patients with new atrial fibrillation, if there exists a sufficient risk of stroke (per available risk models), anticoagulation would be recommended. We usually suggest apixaban, with discussion of the risks and benefits of such an approach. We also consider whether they need to continue ibrutinib. For example, if a patient’s CLL has been in remission for several years, a holiday from ibrutinib is feasible with monitoring. If the disease progresses, the patient may be a candidate for venetoclax or another agent.
A rare serious reaction to ibrutinib (and other drugs) is pneumonitis; this has not been seen to date with acalabrutinib, but again, far fewer patients have received this agent. Pneumonitis is typically treated with steroids and stopping the ibrutinib, given that this toxicity can be severe and life threatening. An alternate BTK inhibitor, such as acalabrutinib, could be considered.
For patients who receive anticoagulation due to atrial fibrillation, multidisciplinary care is important to assess the role of the BTK inhibitor in their disease, as well as the anticoagulation and optimal cardiac management. I always contact patients’ cardiologists, their primary care physicians, or their cardio-oncology team to determine optimal care.
Quality of Life
Unlike chemotherapy, where a certain amount of short-term toxicity is accepted to control the disease, BTK inhibitors are taken over the long term and can impair quality of life. I emphasize to patients that it has to be well tolerated and that they should not ignore AEs or suffer them in silence. These drugs are usually very well tolerated, but some patients will develop AEs that may warrant dose reduction or discontinuation. This is important to discuss with patients including the need for supportive care. If discontinuation is needed, we often have other effective options that can offer ongoing disease control without degrading quality of life.
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