Epidemiology Of Invasive Aspergillosis (IA) During Induction Therapy In Adults With Acute Lymphoblastic Leukemia (ALL): A Graall-2005 Study
Authors: Mariette Clara , Thiebaut Anne , Cahn Jean-Yves , Hocquet Didier , Huynh Agnes , Isnard Françoise , Legrand Faezeh , Lhéritier Véronique , Tavernier Emmanuelle , Raffoux Emmanuel , Ifrah Norbert , Schmidt Aline , Dombret Herve 
Published: October 2019

Abstract

Background
IA is a major cause of morbidity and mortality for patients with hematological malignancies and has been mainly reported in patients with acute myeloblastic leukemia (AML) and stem cell transplantation. Much less is known about the role of IA during the treatment of lymphoproliferative diseases like ALL. Here, we retrospectively evaluated the characteristics of patients and the incidence of IA occurring during the induction course in adult ALL patients enrolled in the GRAALL-2005 trial.

Methods
We collected the data of 36 patients with IA during induction chemotherapy. All were included between May 2006 and October 2012 in the multicentric GRAALL-2005 phase III trial. According to ALL characteristics, these patients were treated in 3 different substudies: GRAALL, GRAALL-Rituximab (GRAALL-R) for CD20+ ALL, GRAAPH for Philadelphia (Ph) chromosome-positive ALL. IA was defined retrospectively using the EORTC modified criteria (De Pauw, CID 2008).

Results
Among the 969 patients enrolled, 36 (3.7%) developed IA during induction therapy. The median age was 30 years for all patients receiving induction and 47 years (range, 18 to 59) for patients with IA. We observed 18 IA (3%) by the GRAALL protocol (593 patients enrolled), 16 (8.3%) by the GRAALL-R protocol (191 patients enrolled), and 2 (0.7%) by the GRAAPH protocol (270 patients enrolled). In the GRAALL-R protocol, IA was diagnosed in 6 patients randomly assigned to receive rituximab and in 10 patients treated in the control group. The median time between first day of induction therapy and IA diagnosis was 20 days (range, -2 to 71). The median time between the first day of neutropenia and IA diagnosis was 18 days (range, 0 to 76). At the time of IA diagnosis, 13 patients were hospitalized in laminar airflow rooms, 10 patients in rooms with overpressure, 1 patient in a room with high-efficiency particulate filter, 5 patients in conventional rooms, 1 patient received home care and the type of hospitalization was unknown for the 6 remaining patients. Four patients with IA (11%) had received antifungal drug for invasive fungal infection (IFI) prophylaxis: one patient received fluconazole, one received caspofungin, and two received liposomal amphotericin B. All patients with IA presented pulmonary symptoms associated with a sinusal or cutaneous localization in 1 and 2 patients respectively. The diagnosis of IA was classified as possible in 7 episodes (19 %), probable in 22 episodes (61%), proven in 4 episodes (11%), and indeterminate in the remaining 3 episodes. Detection of Aspergillus antigen in serum by latex agglutination was positive in 24 cases (67%). Chest CT scans were taken for 33 patients (92%): nodules were found in 19 patients, halo sign in 20 patients, and “air crescent sign” in 1 patient. Bronchoalveolar lavage was performed in 11 patients (31%): culture was positive in 7 of them and Aspergillus antigen was positive in 2 of them. Biopsies where positive in 4 cases: in pulmonary biopsy in 3 patients and in cutaneous biopsy in 1 patient. Of all the Aspergillus isolates identified to the species level, Aspergillus fumigatus was isolated from 4 patients and Aspergillus flavus from 1 patient. Overall and IA-attributable 12-week mortality was 8 (0.8%) and 6 (16.7%) patients respectively.

Conclusion
IA is less frequently observed during induction therapy in adult ALL as compared to adult AML patients. However, the attributable mortality appears to be high in these patients. They are as at risk patients for IA and should be included in prophylactic and empirical antifungal clinical trials.

Disclosures:
No relevant conflicts of interest to declare.