Btkis and DRC show a reduction of infections and need of hospitalization towards BR and other chemo-immunotherapies in waldenstrom macroglobulinemia.

Abstract Infections are a major source of morbidity and mortality in patients with Waldenström Macroglobulinemia (WM). During the last years, treatments with Bruton's Tyrosine Kinase inhibitors (BTKis) have increased in WM, with a perceived reduction on infection rates but data on infection incidence are generally extrapolated from clinical trials, and real-world evidence remains limited.The aim of our study is to describe in a real-world setting the infectious complications in patients with WM treated with chemo-immunotherapy (CIT) or BTKis to evaluate their incidence in first and second line of treatment and to identify additional factors of infectious risk.This retrospective multicentre study included 489 patients diagnosed with WM and treated since 2008 across 14 Italian hematological centres.In the first-line setting, treatments were distributed as follows: bendamustine-rituximab (BR, n=165), dexamethasone-rituximab-cyclophosphamide (DRC, n=152), other CIT regimens (n=62), rituximab or steroids alone (n=52), chemotherapy alone (n=41), and BTKis (n=17). A total of 111 infections were recorded, with the following rates per regimen: BR 32.1% (53/165), DRC 14.5% (22/152), other CIT 24.2% (15/62), rituximab/steroids 9.6% (5/52), chemotherapy 29.3% (12/41), and BTKis 23.5% (4/17).When evaluating hospitalization and exposure-adjusted infection rates for the main schemes, BR had a hospitalization rate of 34% (18/53), with an infection rate of 5.65 per 100 person-months and 1.92 per 100 person-months for infections requiring hospitalization; other CIT 26.7% (4/15), 4.25 and 1.13. In contrast, DRC showed lower rates: 22.7% hospitalization, 2.49, and 0.56 per 100 person-months respectively. BTKis showed the lowest rates: 25% hospitalization, 0.72, and 0.18 per 100 person-months.In the second-line setting, 203 patients received subsequent therapies: BTKis (n=102), BR (n=26), DRC (n=16), bortezomib-based regimens (n=19), chemotherapy (n=22), and rituximab alone (n=18). A total of 63 infections occurred, distributed as follows: BTKis 35.3% (36/102), BR 30.8% (8/26), DRC 12.5% (2/16), bortezomib 42.1% (8/19), chemotherapy 31.8% (7/22), and rituximab 11.1% (2/18).BTKis in second line had a hospitalization rate of 27.8% (10/36), with an infection rate of 1.0 per 100 person-months and 0.28 for those requiring hospitalization. BR showed higher rates: 37.5% (3/8) hospitalization, 5.52, and 2.07 per 100 person-months, respectively. DRC 0% (0/2), 2.53 and no hospitalization, bortezomib-based regimens 62.5% (5/8), with 1.11 and 0.69 infections per 100 person-months.Overall, infection rates were similar between first and second-line therapies within the same treatment group. BTKis showed lower infection rates respect to those of BR and other CIT regimens, (in first line BTKis vs BR: <0.001; vs DRC: 0.012; vs other CIT: <0.001; in second line BTKis vs BR: <0.001)) and severity, measured by hospital admissions (BTKis vs BR 0.002). These rates became significantly lower when adjusted for drug exposure time. Notably, DRC demonstrated the lowest infection rate among CIT schemes, especially in first-line therapy.This large retrospective real-world study highlights the favourable infectious safety profile of BTKis in the treatment of WM, particularly when compared to traditional chemo-immunotherapy regimens both in the small group of WM patients treated in first line and the greater population of WM relapsed patients. The lower incidence of infections and related hospitalizations with BTKis was observed in both first- and second-line settings, suggesting their potential as a safer long-term option in WM management. Among CIT regimens, DRC also emerged as a well-tolerated alternative with a lower risk of infectious complications, especially in the elderly population. These findings underscore the importance of incorporating infection risk into treatment decisions and support the broader use of BTKis in appropriate clinical contexts.