CLL Monthly MinutesLeukemia

Retrospective Analysis Suggests Higher Risk of Secondary Cancers with BTK Inhibitors in CLL

Recent data suggest that patients with CLL who received treatment with a BTK inhibitor had a rate of developing a second cancer over twice as high as that expected in the general population.
Web Exclusives – February 23, 2021

Patients with chronic lymphocytic leukemia (CLL) tend to be older (half aged >71 years when first diagnosed) and, because of abnormalities in their immune system, are at increased risk of complications due to infections.1 They are also at increased risk of developing a second, unrelated cancer.1

Medically, these second cancers are called secondary primary malignancies (SPMs). Previous studies have shown that patients with CLL are at higher risk for SPMs, although the exact reason, whether from specific treatments or environmental or genetic factors, remains to be determined.1

In recent years, targeted therapies like ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, have revolutionized CLL therapy.1 Treatment with BTK inhibitors results in CLL disease control, but also has effects on the patient’s immune response.1 Researchers believe that abnormal immune function may play a role in developing SPMs; and a recent retrospective study evaluated the risk of developing secondary cancers in patients with CLL who had received treatment with ibrutinib or acalabrutinib, a second-generation BTK inhibitor approved for CLL treatment in November 2019 in the United States.1

Investigators looked at electronic medical records of patients in a single institution who received a BTK inhibitor between December 1, 2009, and December 1, 2017.1 Overall, 691 patients were identified.1 Approximately 1 in 5 (20%) were previously untreated, whereas 60% had been previously treated with alkylating chemotherapy (such as chlorambucil), and 55% had been previously treated with purine nucleoside analog therapy (such as fludarabine or cladribine) before receiving a BTK inhibitor.1 Most patients in the study (79%) had received ibrutinib, whereas the other 21% had received acalabrutinib.1

The majority of patients in this study had approximately 4 years of medical follow-up that could be searched for the development of SPMs.1 Approximately 20% of patients were diagnosed with a skin cancer that was not melanoma after starting a BTK inhibitor.1 Another 9% of patients were diagnosed with secondary tumors, a rate that is just over twice as high as that expected in the general population.1 Rates of lung cancer, melanoma, bladder cancer, Merkel-cell carcinoma, and salivary gland cancer were all significantly increased in the study patients, although other secondary tumors were also identified.1

Investigators then sought to identify any risk factors that could explain the higher rate of SPMs seen in patients with CLL in this study. Closer analysis found that patients who had ever smoked were 2 to 3 times more likely to develop a secondary cancer, whereas patients who had stronger immune systems before starting BTK inhibitors (as measured by having high CD8 T-cell counts) were slightly less likely to develop SPMs.1 Notably, patients who had received prior chemotherapy treatments did not show a higher rate of SPMs, and no differences were seen between patients who took ibrutinib or acalabrutinib.1

Given the relatively high rates of SPMs seen in this study, the investigators suggest that patients with CLL who are treated with BTK inhibitors should be routinely screened for secondary cancers to achieve early detection and optimal treatment outcomes.1

It is important to note that although this study found higher rates of secondary cancers in patients with CLL taking BTK inhibitors, there are important limitations. Most notably, the retrospective design of the study does not control for other risk factors that may be causing secondary cancers and does not permit researchers to conclusively determine that there is an association between BTK inhibitors and secondary cancers in CLL. However, more rigorous prospective studies may be warranted to further explore this potential association.


  1. Bond DA, Huang Y, Fisher JL, et al. Second cancer incidence in CLL patients receiving BTK inhibitors. Leukemia. 2020;34:3197-3205.

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Last modified: February 24, 2021

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