Abstract
Introduction Asparaginase-induced hepatotoxicity (AIH) is well recognized and occurs to some degree in the majority of patients with acute lymphoblastic leukemia treated with asparaginase-containing regimens with acute lymphoblastic leukemia (ALL). AIH is generally reversible. However, it can lead to acute complications and delays in other chemotherapy administration. Here we outline incidence of hepatotoxicity with the goal to better understand its clinical implications.
Methods In this IRB approved study, we retrospectively evaluated medical records of 86 patients aged 18 to 40 years, diagnosed with ALL and treated with asparaginase-containing regimens between 2013 and 2024 at the University of Kansas Medical Center. Data collection included baseline demographics, disease immunophenotype (B-ALL, T-ALL, or mixed phenotype), detailed cytogenetics (FISH for BCR-ABL1, MLL rearrangement, complex karyotype), and available next-generation sequencing data (including IKZF1 deletion, Ph-like status). Severe liver toxicity was defined in accordance with CTCAE v5.0: grade 3 ALT or AST (either >5.0–20.0× upper limit of normal (ULN) or >5× baseline if elevated at baseline) and total bilirubin >3.0–10.0× ULN or baseline, whichever was applicable. Either transaminase or bilirubin elevations met criteria for case inclusion.
Results The cohort had a median age of 29, with 64.4% being male, and 35.6% being female. Within the cohort, 23.1% of patients had a BMI ≥30, while 76.7% had a BMI <30. B-ALL accounted for 79.8% of cases, followed by T-ALL at 19.2%, and mixed phenotype disease accounted for 0.9%. Molecular alterations included BCR-ABL1 in 9.6%, MLL/KMT2A rearrangements in 5.7%, and IKZF1 deletion in 11.5%, and Ph-like (identified by FISH) in 8.6%. Complex karyotypes occurred in 11.5% of patients. Of those with baseline imaging, 12% had preexisting radiographically evident liver abnormalities. Grade 3/4 asparaginase-related severe hepatotoxicity developed in 26% of the cohort, primarily during the early induction phase and mostly characterized by ALT or AST elevation. Hyperbilirubinemia without transaminitis was isolated in 12% of the cohort. Of the patients with BMI <30, 16.7% developed grade 3 or higher hepatotoxicity. Chemo delays in this group attributed to hepatotoxicity accounted for 9.1%. Of the cohort with a BMI ≥30, 45% had chemo delays related to hepatotoxicity.
Conclusion Our analysis demonstrates that clinically meaningful asparaginase-induced liver toxicity is encountered in roughly a quarter of young adult ALL patients. Consistent with prior reports, liver toxicity was more common in those with high BMI. Chemotherapy delays occurred more commonly in patients with AIH. An ongoing cooperative group randomized study is assessing prophylactic L-carnitine as a means to decrease AIH and ultimately improve clinical outcomes. Given the absence of formal management guidelines and known risk factors such as obesity and age, risk assessments may improve individualized monitoring and treatment strategies.
