It is important to consider the toxicities of individual agents, along with the patient’s age, comorbidities, performance status, and other factors, before starting therapy. Treatment-related toxicities are relatively easy to manage in younger patients but can cause life-threatening complications in older patients. Combination chemotherapy is associated with well-documented toxicities that detract from quality of life. I am often hesitant to use multi-agent chemotherapy in my patients with MCL, particularly if there is no long-term curative intent. I hope that our current treatments are eventually replaced by more targeted therapies that cause less collateral damage to our patients.

That being said, the optimal approach is to prevent toxicities and then to manage them as best we can when they do occur. Bone marrow biopsy can help to identify patients with dysplasia and a low myeloid reserve, which would argue for a low tolerance to multi-agent chemotherapy. Factors that could affect drug clearance, such as renal and hepatic status, are important to assess, as is cardiac function, particularly in patients who may be candidates for CHOP or hyper-CVAD regimens. With anti-CD20 and chemotherapy, we may encourage some degree of hypogammaglobulinemia, so impairment of immune function is also a possibility. Some of the common concerns from patients include “chemo brain” and hair loss.

The targeted therapies are generally better tolerated than the older agents, and I think that the Bruton tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib are real bright spots. The ibrutinib trials have identified some toxicities that may need to be managed, including diarrhea, fatigue, arthralgias, and myalgias. Serious adverse reactions are rare with acalabrutinib; however, atrial fibrillation has been observed in some individuals, and patients should be made aware of common adverse events such as headaches, which usually resolve within 1 month without medical treatment. Ibrutinib and acalabrutinib may cause impairment of platelet aggregation, and bleeding complications have been observed in some patients. Therefore, recommendations for withholding aspirin prior to major surgical procedures would also apply to patients receiving these therapies. I would advise caution regarding the use of warfarin or other anticoagulants in patients treated with ibrutinib or acalabrutinib due to the increased risk of major bleeding complications with these drugs. Head-to-head comparisons in large trials are needed to know whether off-target toxicities are less common with acalabrutinib than with ibrutinib, and I would welcome such trials. I would also welcome having the choice of 2 BTK inhibitors in the treatment of other non-MCL B-cell malignancies, should the evidence support such uses.. Sometimes patients simply tolerate certain drugs better than others, and there may be idiosyncratic reasons for that. The results of ongoing trials of combination therapies, including some with BTK inhibitors and venetoclax or lenalidomide, may provide insights into the potential role of nonchemotherapy combinations as first-line agents in patients with MCL.