Ibrutinib Linked to Serious Infections in Patients with Lymphoid Cancer

The tyrosine kinase inhibitor ibrutinib may be associated with serious infections in patients with lymphoid cancer, a recent study published online in Clinical Infectious Diseases suggests.

“We found an 11.4% incidence of serious infections among patients with lymphoid cancer who received ibrutinib therapy,” write Tilly Varughese, MD, from Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, and colleagues.

“Serious bacterial infections were observed in 6.1% of ibrutinib recipients, and IFI developed in 4.2%.”

Ibrutinib is a small molecule inhibitor of Bruton's tyrosine kinase (BTK) that has been effectively used to treat various lymphoid cancers; it binds to and irreversibly inhibits BTK and blocks downstream B-cell receptor activation.

Although ibrutinib initially received US Food and Drug Administration (FDA) approval for the treatment of mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), and Waldenström macroglobulinemia, the FDA has more recently approved expanding its use to include patients with marginal zone lymphoma and chronic graft-versus-host disease. The drug is also under evaluation in patients with solid tumors.

Although ibrutinib is typically well tolerated, opportunistic infections such as Pneumocystis jirovecii pneumonia (PJP), cryptococcosis, and invasive mold infection have been reported in some patients receiving ibrutinib. However, the extent of such infections in this patient population remains unclear.

With this in mind, Dr. Varughese and colleagues set out to investigate the range of serious infections that may arise in patients receiving ibrutinib.

They reviewed the electronic medical records of patients aged 18 years and older with lymphoid cancer at MSKCC who received ibrutinib from January 2012 to December 2016, and conducted a retrospective analysis of the safety outcomes.

They excluded patients who did not have at least 30 days of clinical follow-up after treatment initiation.

To identify infections, the researchers reviewed patients’ clinical charts and analyzed a combination of data from clinical laboratory tests, imaging studies, microbial culture results, and histopathologic or cytologic evaluations.

The study included 378 patients aged 18 years or older with lymphoid malignancies, who had received 5-year ibrutinib therapy as either monotherapy or in combination with other agents.

According to the authors, CLL (44%) and MCL (16%) were the most common underlying malignancies, and most patients (84%) received ibrutinib as monotherapy.

Dr. Varughese and colleagues found that 43 patients (11.4%) developed serious infections, with most arising during the first year of ibrutinib therapy: 23 (53.5%) of these patients developed invasive bacterial infections, 16 (37.2%) developed invasive fungal infections (IFIs), and 4 (9.3%) developed viral infections.

Among patients with serious bacterial infections, Staphylococcus aureus was most commonly identified. Furthermore, among those with serious fungal infections, pulmonary and disseminated invasive aspergillosis, pulmonary cryptococcosis, PJP, and Candida albicans infection were identified. Viral infections included 3 cases of pneumonia due to respiratory viruses and 1 case of hepatitis B reactivation.

“Infection resulted in death in 6 of the 43 patients (14%),” the authors note.

Dr. Varughese and colleagues also found that previous receipt of 3 or more anti-tumor therapies and the presence of neutropenia at any time during ibrutinib treatment were risk factors for developing serious infections.

Although the authors conclude that patients with lymphoid cancer receiving ibrutinib are at risk for a variety of serious infections, they acknowledge some of the limitations of their study. For example, the patient sample was derived from only MSKCC, they say, which may have underestimated the incidence of serious infections.

“As the indications for ibrutinib use continue to expand, it is likely that more patient groups may be at risk for serious infections associated with its use, highlighting the need for further study to define those most likely to benefit from close clinical monitoring for infectious complications and from targeted prophylaxis strategies,” the authors emphasize.

Dr. Parry graduated from the University of Liverpool, England in 1997 and is a board-certified veterinary pathologist. After 13 years working in academia, she founded Midwest Veterinary Pathology, LLC where she now works as a private consultant. She is passionate about veterinary education and serves on the Indiana Veterinary Medical Association’s Continuing Education Committee. She regularly writes continuing education articles for veterinary organizations and journals and has also served on the American College of Veterinary Pathologists’ Examination Committee and Education Committee.