CLL Treatment: More Infections Among Real-World Patients2023-03-09
A new real-world analysis finds that severe infection rates were higher than in clinical trials in 67 patients with chronic lymphocytic leukemia (CLL) or B-cell lymphoma who took ibrutinib (Imbruvica), idelalisib (Zydelig), or venetoclax (Venclexta).
For example, “the rate of severe infection for ibrutinib in clinical trials ranged from 12.8% to 45% with median follow-up ranging from 27 to 65 months. In our study, the rate of severe infection was 45.3% within a shorter median follow-up period of 23.3 months,” said study lead author Amanda Tey, MPharm, a hematology pharmacist with Monash Health in Clayton, Australia, in an interview.
The results suggest that “real-world severe infection risk is higher than previously appreciated,” said Ms. Tey, whose findings were published in the European Journal of Hematology. “Poor performance status and a high comorbidity burden further increase this risk.”
According to the study, there are limited data about real-world infection rates for patients with CLL or B-cell lymphoma who take the three drugs.
Both the underlying blood cancer and the drugs themselves may disrupt the immune system in these patients, Ms. Tey noted. “Ibrutinib inhibits interleukin-2-inducible T-cell kinase, which has a role in T-cell maturation. Idelalisib reduces regulatory T-cell activity and natural killer cell and neutrophil inflammatory responses. Venetoclax is associated with a high rate of neutropenia.”
For the new retrospective, single-center study, researchers tracked adult patients who’d received the drugs from 2014 to 2021 in a hospital network serving 1.5 million people in the Australian state of Victoria. The primary outcome was severe infection of grade 3 or higher. Patients were excluded for such factors as having been primarily treated at other facilities, receiving less than 30 days of treatment, or having been treated for other indications such as primary central nervous system lymphoma.
Of the 67 patients in the study, the numbers taking the drugs were 53 (ibrutinib), 8 (idelalisib), and 6 (venetoclax). Eleven patients took more than one drug. Median age was 73 years, and 73% of patients were male.
Patients spent a median 23.3, 4.8, and 3.5 months taking ibrutinib, idelalisib, and venetoclax, respectively, before treatment stopped or data were collected. Patients were commonly prescribed antimicrobials to prevent pneumocystis jirovecii pneumonia and herpes simplex virus (HSV)/varicella zoster virus (VZV) infection.
Researchers found that 48% of the patients had at least one serious infection: 45% of those on ibrutinib, 63% of those on idelalisib, and 50% of those on venetoclax. Seven patients died of infections.
In comparison, the researchers reported, a systematic review of idelalisib in blood cancer clinical trials reported an overall infection rate of 28%, while clinical trials reported an infection rate of 17.5%-22% in patients taking venetoclax for CLL.
Poor performance status and higher levels of comorbidity were linked to higher risk of infection, and infections occurred at a median of 5.4 months.
Lead author Ms. Tey highlighted the fact that most of the patients in the new study had relapsed/refractory disease. The infection risk in the real-world first-line setting is unknown, she said. “Furthermore, due to the size of our study and high uptake of antimicrobial prophylaxis, the optimal prophylaxis strategy for these patients remains unclear.”
In an interview, infectious disease physician Gemma Reynolds, MChD, MPH, of Austin Health and Peter MacCallum Cancer Center in Melbourne, said the study findings reflect “a lot of what we know from other observational studies and clinical practice. There is a risk of infection, and serious infection, associated with these agents. Sometimes the pathogen is classically opportunistic, but often it is bacterial, and respiratory sites are common. Infections often occur early into a course of therapy.”
Dr. Reynolds, who didn’t take part in the study, urged colleagues to cast a wide net if a patient appears to have an infection but doesn’t respond to conventional therapies such as antibiotics. “Unusual infections are possible,” she said, and aggressive early workups may be advisable via blood cultures, viral swabs, sputum culture, early imaging, bronchoscopy, and preemptive monitoring in patients with a prior infection history with a disease such as CMV.
Alessandra Ferrajoli, MD, a hematologist/oncologist at MD Anderson Cancer Center who also didn’t take part in the study, agreed in an interview that the findings reflect those found in other reports. “It should be highlighted that the population studied is at particular high risk for infections given the high proportion of patients with recurrent disease (85%), many patients with concurrent hypogammaglobulinemia (64%), and the patient median age of 73 years and a high comorbidities burden,” she said. “In my view, this explains the higher rate of infections reported in this study, when compared to other case series.”
Dr. Ferrajoli added that there’s no standard antimicrobial prophylaxis for patients with B-cell malignancies receiving targeted therapies. “Anti-HSV/VZV prophylaxis is commonly implemented. Additional antiviral, antimicrobial, and antifungal prophylaxis should be used based on patients’ absolute neutrophil and T-cell count and individual risk factors, including prior history of infections such as CMV, prior splenectomy, and history of invasive fungal infections.”
The study was funded by Monash Health, the National Health and Medical Research Council (Australia), and the Society of Hospital Pharmacists of Australia. Ms. Tey reported no disclosures. Some of the study authors reported multiple disclosures. Dr. Reynolds discloses a PhD scholarship from the National Health and Medical Research Council. Dr. Ferrajoli reported no disclosures.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.
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