Venetoclax infectious risk score to identify patients with chronic lymphocytic leukemia at high infectious risk during venetoclax treatment: A multicenter <scp>SEIFEM</scp> study
Authors: Francesco Autore, Andrea Visentin, Marina Deodato, Candida Vitale, Eugenio Galli, Alberto Fresa, Rita Fazzi, Alessandro Sanna, Jacopo Olivieri, Ilaria Scortechini, Maria Ilaria Del Principe, Paolo Sportoletti, Luana Schiattone, Nilla Maschio, Davide Facchinelli, Francesco Marchesi, Marta Coscia, Alessandra Tedeschi, Livio Trentin, Idanna Innocenti, Anna Candoni, Alessandro Busca, Livio Pagano, Luca Laurenti
Journal: American Journal of Hematology (2024)

Four groups according to VIRS stratification. Infections are a major source of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL). The development of targeted agents decreased the infection rate but patients, often elderly, with comorbidities and heavily treated, could experience serious infectious complications. Treatment with the new molecules has increased in routine clinical practice, but data on infection incidence are generally extrapolated from clinical trials, and real-world data are rare. The aim of our study is to describe in a real-world setting the infectious complications in patients with CLL treated with venetoclax in routine clinical practice, to evaluate the incidence of clinically or microbiologically documented bacterial, fungal, and viral complications and to identify additional factors of infectious risk in these patients. This retrospective multicenter (n = 14) study included 287 CLL patients treated since 2017 with venetoclax single agent (151 patients, of whom 9 naïve patients) until progression or toxicity or venetoclax plus anti-CD20 antibody (136 patients, of whom 110 rituximab as part of VR protocol for 24 months in relapsed/refractory patients and 26 obinutuzumab as part of VO protocol for 12 months in naïve patients). Basal characteristics of the two groups are summarized in Table S1. Comparing the two groups, patients receiving venetoclax monotherapy were older, more frequently had del17p/TP53mut, renal impairment, and lower basal levels of immunoglobulins; they also showed more previous infections in the 12 months before the beginning of the treatment with venetoclax. Infectious events were classified according to clinical and microbiological criteria following the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5. In a median follow-up of 24 months (range 1–89 months), we registered 285 infections of any grade, in 158 patients (55%). The median time to first infection was 219 days for any grade infection and 224 days for grade 3–5 infections; 35% of patients showed any grade infection during the first year, 20.7% a grade 3–5 infection. When comparing time of first infection of any grade between the patients treated with venetoclax and those treated with venetoclax plus anti-CD20, we registered a trend toward a higher rate of infection in the latter group after the first year (p = .066; Figure S1a), not confirmed on infections of grade 3–5 (p = .521; Figure S1b). In Table S2, we described sites and pathogens, when isolated, of the infections distinguished between grade 1–2 and grade 3–5. One-hundred eighty-one infections of grade 1–2 developed in 114 patients (39.7%) during the study. The majority of infections involved the respiratory tract (58.6%, 106 events), followed by genitourinary tract (12.7%, 23 events) and gastrointestinal tract (8.8%, 16 events). Pathogens implicated in the infections were isolated only in 57 (31.5%) cases: 36 viral, 18 bacterial, and 3 fungal. We recorded 103 episodes of grade 3–5 infections, which occurred in 73 patients (25.4%). The most common site of infection involved the respiratory tract (68.9%, 71 events), followed by sepsis (12.6%, 13 events) and gastrointestinal tract infections (6.8%, 7 events). Of the 103 severe infections, 64 (62.1%) were microbiologically proven, 40 of which were viral, 21 bacterial, and 3 fungal. Treatment was withdrawn for infections in 80 patients (27.9%): in 58 (20.2%) treatment was temporarily discontinued, while in 22 (7.7%) the discontinuation was permanent. The temporary withdrawals had median lengths of 20 days (range 3–200), in 35 cases hospitalization was necessary. The infectious causes of definitive withdrawals were mainly pneumonia (12 cases) and sepsis (8 cases) and in 18 cases patients died. Over a median overall survival (OS) of 55 months, we registered a total amount of 82 deaths (28.5%), 21 due to infections during venetoclax (7.3%), 36 due to CLL progression/Richter syndrome, 10 due to second neoplasia, 10 due to infections during subsequent therapies, 1 for toxicity, and 4 for other causes. When comparing patients with and without infection, chronic obstructive pulmonary disease (COPD) (hazard ratio [HR] 2.45, confidence interval [CI] 1.66–3.62, p < .001), previous infection within 12 months before the start of treatment (HR 2.12, CI 1.54–2.93, p < .001), renal impairment CrCl <70 mL/min (HR 1.41, CI 1.02–1.94, p = .034), at least one previous treatment (HR 2.63, CI 1.16–5.96, p = .02), and Rai stage III-IV (HR 1.48, CI 1.07–2.04, p = .017) were more frequently associated with infection in univariate analysis. In multivariable analysis COPD (HR 2.04; CI 1.37–3.03, p = .0004), previous infections (HR 1.99; CI 1.43–2.76, p < .0001), and at least one previous treatment (HR 2.59; CI 1.14–5.89, p = .022) were significant (Table S3). We then developed the venetoclax infectious risk score (VIRS) including these three variables (COPD, previous infections within 12 months before the start of treatment, and at least one previous treatment), assigning 1 point to each of them and obtaining four groups: very low-, low-, intermediate- and high-risk patients, depending on the presence of no, 1, 2, or 3 risk factors, respectively. The cumulative incidence of infection within the first year and 2 years from the beginning of the treatment were 19.5% and 19.5% for the very low-risk group (0 points), 24.2% and 40.9% for the low-risk group (1 point), 51.4% and 68.5% for the intermediate-risk group (2 points), and 74.1% and 80.5% for the high-risk group (3 points), respectively (p < .001; Figure 1). When considering only grade 3–5 infections, risk factors significant in the univariate analysis were COPD (HR 2.52, 95% CI 1.43–4.43, p < .001), smoke (HR 1.75, 95% CI 1.01–3.05, p = .045), and previous infections (HR 1.63, 95% CI 1.01–2.66, p = .048). COPD was the only significant risk factor in the multivariable analysis (HR 2.21, 95% CI 1.24–3.93, p = .007; Table S4). COPD had no impact on OS in Cox regression (HR 0.89, 95% CI 0.45–1.73, p = .738). OS was significantly affected by previous infections (HR 1.60, 95% CI 1.01–2.51, p = .041) and concomitant severe infections (HR 1.95, 95% CI 1.23–3.08, p = .004). This is one of the largest series to describe the incidence of infections in a cohort of patients with CLL treated with venetoclax in a real-life setting. Our incidence is aligned with other real-world experiences, slightly higher than in trials, probably due to differences in cohorts' characteristics, mainly age and previous lines of treatment. Our study population was generally older and less fit, including patients who are typically excluded from clinical trials and under-represented in other real-world studies. In comparison to the reported rate of severe infections of 16% of the phase 1b study,1 20% of the phase 22 and 17.5% of the phase 3,3 real-world study on compassionate access venetoclax reported a higher rate of severe infections (25.4%)4 that was superimposable to our results. To note, in the first three studies median age of the patients was 68, 67, and 64.5 years, respectively, lower than ours (70 years). In the FILO study,4 the younger median age (67 years) was probably compensated by a higher number of previous lines (4 lines vs. 2 of ours and of the other 2 studies). If we consider only relapsed/refractory CLL patients treated with venetoclax in combination to rituximab nearly 80% of patients experienced an infection, but only 16% had a severe infection.1 In our experience, 57% of the patients experienced an infection of any grade, 25.8% had severe infections. This combination is likely more immunosuppressive, resulting in a higher rate of infections also due to the use of the monoclonal antibody. The rate of 7.3% of the patients dying from infection-related causes is slightly lower than 10.6% found in a real-life study, which, however, analyzed a cohort of patients treated with all the new molecules.5 The most common site of infection was the respiratory tract, then we registered sepsis, gastrointestinal and genitourinary tract infections. Focusing on etiology, virus were predominant, followed by bacteria; fungal infections were very few. The low rate of bacterial and fungal infections, along with routine clinical practice, are insufficient to recommend the routine use of anti-bacterial and anti-fungal prophylaxis in the absence of other risk factors. Our multivariate analysis identified COPD, previous infections, and previous treatments as risk factors able to stratify patients treated with venetoclax in terms of risk for infections, reaching a cumulative incidence of infection of 74.1% within the first year and 80.5% within the first 2 years. These variables were also previously described as risk factors for infections in patients treated with ibrutinib,6 suggesting increased frailty in this subgroup of patients. Based on the development of VIRS, we could consider selecting patients on venetoclax therapy with specific risk factors for infection, to be closely monitored and possibly given specific antimicrobial prophylaxis if at high risk. Nevertheless, the duration of venetoclax treatment should also be considered; in fact, when it is used monotherapy in continuous administration, it may be difficult to add prophylaxis for a very long period without evidence in the literature. From our study, we could suggest to focus on patients exposed to at least one previous CLL treatment who have COPD and to investigate whether they experienced at least an infection in the 12 months prior to starting venetoclax. According to our analysis, this cohort is a selected population with a very high risk of infection and should be better and more closely studied. FA, LP, and LL performed research. AV, MD, CV, AF, RF, AS, JO, IS, MIDP, PS, LS, NM, DF, FM, MC, AT, LT, and II collected data. EG and AF performed data analysis. FA, EG, AF, and LL wrote the manuscript. AC, AB, and LP supervised the study. All authors reviewed the manuscript. The authors acknowledge Paolo Nicoli (AOU San Luigi Gonzaga—Orbassano, Torino), Ilaria Angeletti (A.O. Santa Maria, Terni), and Paolo Falcucci (IRCCS Regina Elena National Cancer Institute, Roma). The authors also acknowledge Prof. Diana Giannarelli (Facility of Epidemiology and Biostatistics, GSTeP, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome) for revising the statistical analysis. MoH—Ricerca Corrente 2024. The authors declare that they have no competing interests. Data available on request from the authors. Table S1. Patients' characteristics and comparison between patients treated with venetoclax and patients treated with venetoclax plus anti-CD20. Table S2. Sites and pathogens of the infections distinguished between grade 1–2 and grade 3–5. Table S3. Cox univariate and multivariable analysis for any grade infections. Table S4. Cox univariate and multivariable analysis for grade 3–5 infections. Figure S1a. Time of first infection of any grade between the patients treated with venetoclax (0) and those treated with venetoclax plus anti-CD20 antibody (1). Figure S1b. Time of first infection of grade 3–5 between the patients treated with venetoclax (0) and those treated with venetoclax plus anti-CD20 antibody (1). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.