Real-Life Study on Gilteritinib Related Infections (GilteRInf): An Italian Seifem Study
Authors: Buzzatti Elisa , Marchesi Francesco , Lessi Federica , Pezone Sara , Papayannidis Cristina , Zappasodi Patrizia , Forghieri Fabio , Fianchi Luana , Quattrone Martina , Abbenante Mariachiara , Piccioni Anna Lina , Facchinelli Davide , Dargenio Michelina , Cefalo Maria Giovanna , Armiento Daniele , Terrenato Irene , Venditti Adriano , Busca Alessandro , Pagano Livio , Del Principe Maria Ilaria 
Published: December 2024

Background. Refractory/relapsed (R/R) acute myeloid leukemia (AML) patients (pts) have a poor prognosis with standard chemotherapy, even worsened by the occurrence of infections due to persistent neutropenia. In patients with R/R FLT3-mutated AML, ADMIRAL trial demonstrated Gilteritinib's superiority over chemotherapy in terms of overall survival (OS), with a good safety profile. Given the recent approval, real-life experiences in the management and outcome of infectious complications are lacking, especially regarding invasive fungal diseases (IFD), since azoles are known for their interactions with Gilteritinib. In light of this, we conducted an ambispective real-life study on 13 Italian centers to assess the infectious risk in patients receiving Gilteritinib compared to R/R patients treated with chemotherapy.

Methods. Infectious events (IE) diagnosed between April 2020 and June 2024 were recorded from the SEIFEM (Sorveglianza Epidemiologica Infezioni nelle Emopatie) group. Descriptive statistics were computed. Univariate logistic regression models were applied to test the risk of infection, log-rank test was applied to compare subgroups for OS analysis.

Results. So far, we enrolled 107 pts with FLT3 mutated AML, 93 treated with Gilteritinib, 14 with intensive chemotherapy according to medical decision. Median age was 60.1 (range 25-93), 50 pts (47%) were male, 57 (53%) were female. Fifty-six patients (52%) had 0/1 comorbidity, while 39 (36%) had more than one. Thirty-two percent was submitted to a previous allogeneic transplantation. In Gilteritinib group, the number of pts with no IE was significantly higher than in the control arm (p=0.031), but no statistical difference was found regarding the grades of IE according to common toxicity criteria of adverse event (CTCAE) version 5, the number of pts with IFD and fever of undetermined origin (FUO). A trend of significance was observed regarding the number of pts with bacterial IE (p=0.057).

Considering only the Gilteritinib set, no association was found between the onset of infection and any variable tested, such as age, sex, comorbidities, ELN onset risk, secondary leukemia, response to induction, previous allogeneic transplantation, number of previous lines, bone marrow blasts before Gilteritinib). At least one FUO occurred in 48 (52%) pts and in 52 (56%) at least one IE. Among 78 total infectious events, 36 (46%) were bacterial, 4 (5%) viral, 8 (10%) SARS-CoV-2 related, 10 (13%) IFD, 3 (4%) caused by Pneumocystis jirovecii, 17 (22%) not specified. Overall, we counted 31 (40%) pneumonitis, 7 (9%) urinary tract infections, 31 (40%) sepsis, 9 (11%) other IE. In 52 (66%) cases pts needed hospitalization or their hospitalization was prolonged because of the IE. Grading according to CTCAE version 5 was distributed as follows: grade (G)1-2 29 (37%) cases, G3-4 40 (51%), G5 9 (12%). Notably, the G5 events were 3 (33%) bacterial sepsis and 6 (66%) pneumonitis. Among those, 4 resulted of fungal nature (1 proven, 2 probable and 1 possible) and occurred in pts resistant to Gilteritinib. Only one of them was given antifungal prophylaxis. Fifty-two (66.6%) IE resolved within 30 days, while 100% of the stable IE within 30 days, were resolved in 60 days. Azoles were used in 35 (38%) pts for prophylaxis/therapy (22 used posaconazole, 11 isavuconazole, 1 voriconazole, 1 fluconazole) and toxicities were reported in 4 (11%) cases (1 prolonged QTc and 1 liver toxicity). In 7 (7.5%) pts toxicities/infections led to the interruption of the drug.

Median follow-up was 59.9 months with an OS of 24 months (95%CI: 19-30). The presence of at least one IE and one FUO was significantly associated with a shorter OS(p=0.025 and 0.012 respectively).

Conclusions. In summary, there is a difference in the incidence of infection between the two arms, but the comparison needs further confirmation by expanding the control group. However, Gilteritinib therapy is not free from infectious complications, but most of the patients recovered within 30 days. The mortality rate attributable to infection was not negligible and having at least one IE emerges as a risk factor for reduced survival. Moreover, almost all the fatal pneumonitis were fungal, but they occurred in a frail subgroup of pts resistant to Gilteritinib. Therefore, the role of prophylaxis needs to be carefully evaluated in this setting of pts, especially given that azoles appear to be quite safe in association with Gilteritinib.