Liver Steatosis and Metabolic Toxicities in Acute Lymphoblastic Leukemia Adults Undergoing Asparaginase-Based Therapy: Findings from a Non-Invasive Assessment Study

Background After the incorporation of pediatric-inspired regimens (PIR) to treat adolescents and young adults with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL), overall survival has improved considerably, but at the cost of a higher rate of metabolic complications in adult leukemia survivors during and after treatment. Both asparaginase and corticosteroids, the backbone of PIR, have been associated with the development of diabetes mellitus (DM) and hypertriglyceridemia. Liver steatosis may play a role, as it is both linked with metabolic syndrome and asparaginase toxicities. Aim We aimed to associate liver steatosis assessed non-invasively by transient elastography and CT scan imaging of the liver with the development of DM and hypertriglyceridemia in adult patients receiving a PIR (modified CALGB 10403). Methods Adult patients aged 18 years or more from a tertiary care center in Mexico with a new diagnosis of ALL, LL, or mixed-phenotype acute leukemia (MPAL) who received asparaginase-based therapy (modified CALGB 10403) between February 2017 and May 2024 were included. Patients' demographics and comorbidities at diagnosis, and rate of new onset DM and hypertriglyceridemia were collected. Liver steatosis was assessed before initiating treatment and was defined according to published criteria: a controlled attenuation parameter (CAP) score ≥ 275 dB/m in liver elastography, or a liver attenuation at least 10 HU lower than that of the spleen and/or an absolute liver attenuation lower than 40 HU in non-contrast CT, or a liver attenuation at least 20 HU lower than that of the spleen in contrast-enhanced CT. Results Ninety-two patients were included with the following diagnoses: 85 (92.4%) B-ALL, 4 (4.3%) T-ALL, 2 (2.2%) LL, and 1 (1.1%) MPAL. At diagnosis, median age was 27.5 years (range, 17-53), 52 (56.5%) were male, median BMI was 26.15 kg/m2 (range, 13.8-39.8), with 52 (56.5%) classified as having either overweight or obesity, and 10 (10.9%) had a previous DM diagnosis. Prior initiating treatment, liver elastography and CT scan were performed in 44 (47.8%) and 74 patients (80.4%), respectively, and both assessments were done in 37 patients (40.2%). Liver steatosis was found in 14 (31.8%) and 13 (18.3%) patients assessed by elastography and CT scan, respectively. With a median follow-up of 20 months (range, 1-85), and excluding patients with a previous DM diagnosis, 14 patients (17.1%) developed DM during or after finishing intensive chemotherapy, and 10 (71.4%) had insulin use. Comparing patients who developed DM to those who did not, a BMI ≥ 25 kg/m2 (92.9% vs 44.1%, OR 16.45, 95% CI [2.03-133.06], p<0.001) and liver steatosis either by elastography (55.6% vs 14.3%, OR 7.5, 95% CI [1.38-40.56], p=0.023), or CT scan (41.7% vs 14%, OR 4.38, 95% CI [1.08-17.76], p=0.044) were associated with new onset DM. Neither age, sex, nor steroid choice (prednisone or dexamethasone) were associated with this complication. Hypertriglyceridemia > 300 mg/dl during induction developed in 41 patients (47.7%). When comparing patients who developed it to those who did not, a BMI ≥ 30 kg/m2 (36.6% vs 17.8%, OR 2.66, 95% CI [0.98-7.2], p=0.049), age ≥ 30 years (56.1% vs 31.1%, OR 2.82, 95% CI [1.17-6.83], p=0.019), use of dexamethasone (85.4% vs 62.2%, OR 3.54, 95% CI [1.23-10.17], p=0.015), and liver steatosis either by elastography (45.8% vs 15.8%, OR 4.51, 95% CI [1.03-19.65], p=0.037), or CT scan (30.3% vs 9.4%, OR 4.2, 95% CI [1.03-17.06], p=0.035) were associated with hypertriglyceridemia > 300 mg/dl during induction therapy. Conclusions Metabolic toxicities are frequent in Hispanic young adult ALL patients receiving asparaginase-based chemotherapy, as nearly 1 out of 5 patients developed new onset DM, and almost half developed hypertriglyceridemia during induction. Liver steatosis, defined by either elastography or CT scan, is associated with developing these complications. Non-invasive liver steatosis assessment may identify a subgroup of patients who could benefit from early interventions to prevent metabolic complications after asparaginase-based therapy, and this finding warrants further prospective exploration.