Introduction. The so called “less intensive” therapies, such as hypomethylating agents (HMA)±venetoclax (VEN), for acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (HR-MDS) have allowed the treatment of elderly patients (pts). However, a significant percentage of infections have already been reported so far, particularly pneumonia, mainly during the first two courses of treatment, even if the results are not always comparable due to the heterogeneity of the reported data and the different objectives of the studies. To better evaluate the clinical impact of infections in elderly AML and HR-MDS pts treated with HMA±VEN, we evaluated all the consecutive pts treated at the Hematology Division of our Institution between November 1st, 2018, and June 30th, 2024. Patients and Methods. During the observation period, all the infectious complications of the newly diagnosed AML or HR-MDS pts treated at our Institution with HMA±VEN, either azacytidine or decitabine, were recorded and correlated with age, gender, blast count, de novo vs secondary AML/HR-MDS, phase of hematological disease (first 2 vs subsequent courses), antibiotic (AB) or antifungal (AF) prophylaxis, and outcome. All pts were treated in an outpatient setting. Moreover, data concerning HMA+VEN treated pts were compared with those of a historical control of AML pts aged 65y or older and treated with intensive chemotherapy between 2016 and 2023. Results. Overall, 103 HMA±VEN pts were collected, 62 treated with HMA alone, and 41 with HMA+VEN. Median age was 78y (62-88), and M/F ratio 68/35. Only 13 (12.6%) pts were affected by HR-MDS and 62 (60.2%) had a de novo AML/HR-MDS. Eighteen (17.5%) pts received decitabine±VEN. Overall, 841 courses of HMA (490) or HMA±VEN (351) were delivered. AB prophylaxis was provided in 90 (89.3%) and AF prophylaxis in 80 (77.7%). Fifty-one (49.5%) HMA±VEN pts developed infections (27/62, 43.5%, HMA and 24/41, 58.5%, HMA+VEN, p=0.1615). Concerning the type of infection, only bloodstream infections (BSI) were significantly more frequent in HMA+VEN (14/41, 36.6%) than HMA alone pts (7/62, 11.3%, p=0.0031). Considering infections according to the number of courses delivered, pneumonia and BSI were significantly higher during the first 2 courses, with active phase of disease, both in HMA alone pts (11/112, 9.8% vs 11/378, 2.9%, p=0.0069, and 4/112, 3.6% vs 3/378, 0.8%, p=0.0512, respectively) and HMA+VEN pts (8/78, 10.2% vs 6/273, 2.2%, p=0.004, and 11/78, 15.5% vs 4/273, 1.5%, respectively), whereas no difference of incidence of invasive fungal infections (IFI) was observed according to phase of treatment (1/112, 0.9% vs 3/378, 0.8%, p=1, and 2/78, 2.6% vs 2/273, 0.7%, p=0.211, respectively). At multivariable analysis, a de novo AML/HR-MDS (HR 2.24, 95% CI 1.29-3.9), active phase of hematologic disease (5.34, 3.16-9.03) and decitabine (3.65, 2.1-6.33) were associated with an increased risk of infections. After a median follow-up of 10 mo, 87/103 pts have died (84.5%). Median overall survival was significantly higher in HMA+VEN (11.6 mo) than in HMA pts (9.1 mo) (p=0.01). Mortality attributable to infections was only 6/103 (5.9%). When compared to a historical control group of 98 AML pts aged 65y or more (median age 69y) and treated with intensive chemotherapy, we observed a lower incidence of BSI in HMA+VEN pts (15/41, 36.6%) vs 60/98 (61.2%) (p=0.0093), particularly during consolidation (4/24, 16%, vs 37/69, 53.6%, p=0.0003), whereas no statistically significant differences were observed for pneumonia (14/41, 34.1%, vs 46/98, 46.7%, p=0.95) and IFI (4/41, 9.8% vs 13/98, 13.3%, p=0.778). Conclusion. Our study confirms a higher incidence of infections during the first two courses of HMA±VEN; active phase of disease, a de novo diagnosis of AML/HR-MDS and the choice of decitabine were independently associated with an increased risk of infections. Compared to elderly AML pts treated with intensive chemotherapy, even with the limits of a retrospective study, the incidence of infections, particularly BSI, was lower in HMA+VEN cohort, where median age was even higher. Together with the data of a low mortality attributable to infections, HMA±VEN regimens are confirmed safe also for an outpatient setting.

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2025
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