Infections remain a major cause of morbidity and mortality in patients with Chronic Lymphocytic Leukemia (CLL). Although the advent of targeted therapies has reduced infection rates, many patients, often elderly, heavily pretreated, and burdened with comorbidities, still experience serious infectious complications.

This multicenter retrospective real-world study aimed to describe infectious events in CLL patients treated with second-generation Bruton's Tyrosine Kinase inhibitors (BTKis)—Acalabrutinib (Acala) and Zanubrutinib (Zanu)—and to identify key infection-related risk factors.

We analyzed 460 patients in the period 2019-2024 from 15 hematological centers: 324 received Acala and 136 Zanu. Patients treated with Zanu were older and had more frequent TP53 mutations, renal and pulmonary comorbidities, advanced Rai stage, and prior treatments.

During Acala therapy, 164 non-COVID infections occurred in 110 patients (34%), with an event rate of 0.51; 54.3% involved the respiratory tract. In the Zanu group, 71 infections occurred in 49 patients (36%), with a similar rate (0.52); 46.5% were respiratory.

Among Acala-treated patients, 48 infections were grade 3–4, occurring in 42 patients (13.0%; rate 0.14), including 32 respiratory infections and 9 cases of sepsis. Pathogens were identified in 21 cases: 12 bacterial (4 E. coli), 5 viral, and 4 fungal (3 Aspergillus, 1 Candida glabrata). In the Zanu group, 15 grade 3–4 infections occurred in 13 patients (9.6%; rate 0.11), including 8 respiratory infections and 3 cases of sepsis. Pathogens were isolated in 6 cases (5 bacterial, 1 viral).

Infections occurred earlier with Zanu (median 4.5 months vs 8.2 months with Acala; p=0.068), and grade 3–4 infections appeared significantly sooner (3.1 vs 7.8 months; p=0.025).

In the Acala group, risk factors for infections of any grade included age, diabetes, chronic obstructive pulmonary disease (COPD), CrCl <70 mL/min, comorbidity index (CIRS), prior lines of therapy, and history of infections or pneumonia in the previous 12 months. For Zanu, significant risk factors were diabetes, Rai stage, and prior infections or pneumonia.

For grade 3–4 infections, the only significant predictors were COPD and prior pneumonia for Acala (p<0.001), and prior pneumonia for Zanu (p<0.001). Stratifying patients by COPD and previous infection yielded three distinct risk groups (p<0.001); the cumulative 1-year incidence of infection reached 89.4% in those with both risk factors.

The 5-year overall survival (OS) was 71.2% with Acala (35 deaths, 16 infection-related) and 80.0% with Zanu (9 deaths, 4 infection-related). BTKi discontinuation due to infections occurred in 38 Acala patients (34.5%), with 7 permanent discontinuations (6 pneumonia, 1 sepsis); 6 of these patients died. In the Zanu group, 12 patients (24.5%) discontinued due to infections, with 1 permanent case related to pneumonia.

COVID-19 status was available for 455 patients. We documented 84 cases (26.2%) in the Acala group and 18 (13.4%) in the Zanu group. Nearly half of these patients also developed other infections (46.4% with Acala, 50% with Zanu). Hospitalization was required in 10 Acala-treated patients (11.9%) and 5 Zanu-treated patients (27.8%; p=0.08). COVID-19 was the cause of death in 3 cases, all in Acala group.

This large real-world study demonstrates a moderate rate of infections, mostly grade 1–2, during BTKi therapy. COPD and prior pneumonia emerged as key risk factors for severe infections, consistent with previous SEIFEM data on venetoclax plus anti-CD20 regimens (Autore et al., AJH 2024). Our findings support the need for closer monitoring and potentially tailored treatment strategies in patients with these specific risk factors.

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2025
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