Infectious Complications Among Patients Treated with Azacitidine and Venetoclax for Acute Myeloid Leukemia: A Multicentric Real-Life Analysis of the French Auraml Group

Azacitidine and venetoclax (AZA/VEN) is currently a standard of care for patients with acute myeloid leukemia (AML) unfit for intensive chemotherapy. However, AZA/VEN is associated with an increased hematological toxicity compared to azacytidine alone. While infectious complications may impact patient outcome, risk factors for infections and more specifically febrile neutropenia (FN) in AZA/VEN patients are unknown. Moreover, the impact of azole prophylaxis on invasive fungal infection occurrence remains elusive in this context. In this multicentric study, we aimed to study the infectious complications among patients treated with AZA/VEN for AML in a real-life setting.

VENAURA registry (N=585) retrospectively collated AZA/VEN data from 12 different French centers (Saint-Etienne, Clermont-Ferrand, Lyon (Hopital Lyon Sud, Centre Léon Bérard), Vichy, Annecy, Chambery, Valence, Bourgoin-Jallieu, Grenoble, Roanne) in Auvergne Rhône Alpes (AURA) region, between January 2019 and February 2024. We retrospectively analyzed 310 patients treated with AZA/VEN for newly diagnosed (ND) or relapse/refractory (R/R) AML from the VENAURA registry.

Overall, 196/310 patients (63%) were male, the median age was 70 (19.1-86) and 24% had an ECOG > 1. Patients were treated frontline (56%) or RR (44%) for a median of 3 cycles [IQR 2-5] (min-max 1-43) and were classified as adverse in 63% of cases according to the ELN-2022 classification. First AZA/VEN cycle was performed on an outpatient basis in 49% of cases, 32% had PMN < 0.5 G/L initially and 39% received posaconazole prophylaxis; the median dose of venetoclax was 400 mg/d [IQR 400-400] (min-max 50-400) without posaconazole and 100 mg/d [IQR 100-100] (min-max 70-400) with posaconazole, for a median duration of 21 days [IQR 21-28] (min-max 1-43).

During the first 6 cycles of treatment, 65% of patients experienced at least one episode of infection or FN (n=203), and 55% during the first cycle of treatment. FN was experiences by 59% of patients by cycle 6 and by 48% during cycle 1. A total of 366 episodes of infection or FN were described among the 206 patients who had at least one infection, including 107/366 (29%) episodes of fever of unknown origin, 125/366 (34%) clinically documented infections (i.e. with clinical or radiological signs of infection), 126/366 (34%) microbiologically documented infections and 8/366 (2%) invasive fungal infections (IFI).

A total of 8 IFI were described concerning 2.6% of patients overall: 6 invasive pulmonary aspergillosis, 1 pulmonary mucormycosis and 1 fungemia due to C. parapsilosis. Five IFI occurred during cycle 1, 2 during cycle 2 et 1 during cycle 3. Among these 8 patients, 5 were receiving prophylaxis with posaconazole at the time of the IFI diagnosis.

Median time to cycle 2 was 36 days [IQR 30.5-42] among patients with infection during cycle 1 and 30 days [IQR 28-36] among patients without infection (p<0.0001). Seventy two percent and 81% of patients reached cycle 2, depending on whether they were infected or not in cycle 1, respectively (p=0.06). We created a multivariable model that included all the factors associated with an infection during the first cycle of AZA/VEN. In this model, ECOG >1 (OR 2.26 [1.04-5.16], p=0.044), posaconazole prophylaxis (OR 2.30 [1.19-4.44], p=0.013) and ND AML (OR 3.11 [1.56-6.33], p=0.0014) were independently associated with a risk of infection during cycle 1, whereas age, outpatient management, baseling PMN < 0.5 G/L, receiving more than 14 days of VEN or having a complexe/monosomal karyotype were not. Overall mortality at last follow-up was not different among patients who had an infection compared to the others (49% vs 43% respectively, p=0.34).

In this real life multicentric cohort of AML patients treated with AZA/VEN, the incidence of infection was similar to that in the VIALE-A trial. Interestingly, IFI were uncommon and seemed to affect patients whether they had posaconazole prophylaxis or not. Moreover, patients who received posaconazole where more likely to have an infection overall, after adjustment on potential confounders. We can hypothesize that patients receiving posaconazole might have greater exposure to venetoclax despite dose adjustment, due to the interaction between the two drugs. Nevertheless, our results raise questions about the usefulness and safety of posaconazole prophylaxis in this patient population. An update on the 585 patients will be presented at the meeting.