Digestive complications in AML induction: Spotlight on neutropenic enterocolitis

Abstract

Abstract Intensive chemotherapy (ICT) remains the standard of care for eligible patients with acute myeloid leukemia (AML). ICT-related complications commonly involve the digestive tract, including neutropenic enterocolitis (NE), infectious colitis (IC), and not otherwise specified colitis (NOSC), often presenting with non-specific symptoms such as diarrhea and abdominal pain [Babakhanlou et al. J Hematol. 2023]. While NE is a serious complication with a high mortality rate in chemotherapy-induced neutropenia [Nematolahi et al. BMC Gastroenterol. 2025], its diagnosis and that of other digestive manifestations in AML patients remain challenging, with poorly defined incidence and outcomes. To describe digestive complications in AML treated with ICT, we conducted a prospective, multicenter in 3 French centers, open-label study between January 2019 and March 2024 (NCT03450512). All patients >18 years with newly diagnosed AML and receiving ICT were included. Patient data were collected at baseline. Blood and stool analysis, as well as computed tomography (CT) scans were performed if they experienced digestive symptoms during induction or consolidation courses. NE diagnosis was established according to Nesher's criteria [Nesher et al. Clin Infect Dis. 2013] (i.e. 3 major criteria (neutropenia <0.5 G/L, fever >38.3°C, bowel wall thickening on CT-scan >4 mm in cross-section and >30 mm longitudinally) and ≥1 minor criteria (abdominal pain, distension, cramping, diarrhea, lower gastrointestinal bleeding)), after ruling out differential diagnosis. IC was defined as diarrhea in patients with positive stool samples for bacteria (including C. difficile), viruses or parasites. Patients presenting digestive symptoms for whom neither stool analysis nor CT scan were performed were diagnosed as NOSC. Among 180 eligible patients, data for 177 patients were analyzed (2 not included due to consent withdrawal and inability for ICT; 1 excluded from analysis after acute promyelocytic leukemia diagnosis). Median age was 60 years (18–79) and 63% were male. Cardiac disease was the most prominent comorbidity (8.5%, 8 patients with ischemic heart disease, 6 cases of arrythmia, 1 of heart failure). Only 8 patients had a history of digestive issues (1 cancer, 1 diverticulosis, 1 celiac disease, 3 digestive surgeries, 2 peptic ulcers). AML diagnosis occurred de novo in 86.6% of cases and was classified as adverse risk in the European LeukemiaNet 2022 classification in 40%. Median leucocyte count was 6 G/L (1–335), median neutrophile count 1 G/L (0–76) and median circulating blasts 17% (0–97). Two patients presented with extramedullary AML digestive localization, 4 reported abdominal pain and 15 presented with fever. During induction therapy, most patients (74.6%) reported digestive symptoms, consisting mainly of diarrhea (68.4%) and abdominal pain (34.1%). Fever occurred in 53.7% of cases and antibiotics were used for almost all patients (97.7%). Digestive diagnosis were: NE in 63 cases (47.7%), IC in 10 (7.5%) and 59 NOSC (44.7%). At least one sign of severity was found on CT scan for 40% patients, mainly intra-abdominal effusion (32.3%), pneumoperitoneum (4.6%) and occlusion (4.6%). Thirty-nine patients (22%) were transferred to the Intensive Care Unit, with a 41% mortality rate during the stay. After induction, 67% of patients achieved complete response (CR) and 24 patients (13.6%) received intensive salvage therapy, with NE diagnosed in 4 cases, IC in 1 and NOSC in 6 patients. Among the 123 patients achieving CR, 116 received a first consolidation treatment, 73 patients received a second course, and 36 a third. Digestive symptoms were reported in 12%, 19% and 8% of cases respectively, with diarrhea and abdominal pain being most common. CT scan was not routinely performed. NE was only diagnosed in 6 patients across the three consolidation courses, while 27 patients presented NOSC. Overall survival (OS) was 84% for the cohort and 83% for patients presenting digestive symptoms during induction. There was no significant difference in OS according to the type of digestive complication during induction (p=0.5). Neutropenic enterocolitis (NE) was by far the most frequent digestive complication during intensive treatment of newly diagnosed AML patients, with a striking 47% incidence rate during induction, clearly underdiagnosed in current practice. Despite affecting nearly half of the patients, these digestive events, even severe, had no significant impact on OS.