Adult Hispanic Patients Receiving Pediatric-Inspired Asparaginase-Containing ALL Regimens Have High Rates of Hepatotoxicity, Pancreatitis, and Treatment Change
Authors: Nassar Ahmad , Borboa Ivan Arnaud , Krule Alexander , Zalapa Jessica , Naffakh Noor , Sun Ryan , Demichelis Roberta , Quigley John G 
Published: December 2024

Background: Adult acute lymphoblastic leukemia (ALL) remains a significant cause of morbidity and mortality despite recent advances including the use of pediatric-inspired regimens (PIR). While generally safe, PIR can cause toxicities, particularly hepatotoxicity and pancreatitis related to the use of asparaginase and increased steroids when compared to adult ALL regimens. The prevalence of hepatic steatosis is increased in Hispanic individuals (especially in the Mexican population) and previously we noted Hispanic ALL patients receiving PIR (H-PIR) developed high rates of hepatotoxicity and pancreatitis (Khan et al., Blood, 2021;138:4396). Here we examined whether rates of hepatotoxicity, pancreatitis, and treatment changes related to these complications are increased in adult H-PIR compared to Hispanic patients receiving adult regimens (H-AR) or non-Hispanic patients receiving PIR (NH-PIR).

Methods: We conducted a multicenter, retrospective study of 100 adult H-PIR patients treated from 2010-2023 at academic centers in Chicago (n=31) and Mexico City (n=69). Baseline characteristics including therapy and the incidence of hepatotoxicity, pancreatitis, and hepatotoxicity- or pancreatitis-related treatment change were analyzed. Rates were compared to those of 54 H-AR patients treated during the same timeframe (n=11, Chicago and n=43, Mexico City). Evidence of persistent liver enzyme or imaging abnormalities and the percentage of patients alive and in CR on most recent assessment were also studied. Rates of hepatotoxicity and pancreatitis in the H-PIR cohort were compared to those reported for pts on the CALGB 10403 trial (Stock et al., Blood, 2019;133:1548), which included 15% Hispanic pts. Statistical testing was performed using Fisher exact test and Chi-square test.

Results: The median age of the H-PIR cohort was 26 yrs (IQR 21-36), 62% were male, and 85% had B-cell ALL. Pre-treatment, 26% of H-PIR pts were obese, 23% had diabetes or hyperglycemia (i.e., glucose &gt;200 mg/dL), 46% hyperlipidemia. H-AR pts had similar baseline characteristics. At diagnosis, 58% in both cohorts had elevated liver enzymes, without evidence of viral hepatitis. Compared to the H-AR cohort, fewer H-PIR patients had hepatomegaly (39% vs. 57%, p=0.13), but more had steatosis on imaging (19% vs 8.6%, p=0.29).

In the H-PIR cohort, 51% developed grade 3/4 transaminitis or hyperbilirubinemia and 9% developed pancreatitis during treatment, compared to 28% (p=0.009) and 2% (p=0.17) among H-AR patients, respectively.

Notably, 26% of pts in the H-PIR cohort had treatment changes due to hepatotoxicity or pancreatitis compared to 7.4% of H-AR pts (p=0.01).

More H-PIR than H-ARP pts developed steatosis on imaging or biopsy (63% vs 48%, p=0.13), or cirrhosis (4% vs 2%, p=0.66) during treatment. On most recent liver assessment (median follow-up from diagnosis 14 months), 72% of H-PIR and 74% of H-AR pts had persistent liver enzyme elevation or abnormal imaging. 61% of H-PIR and 22% of H-AR pts were alive and in CR on most recent assessment (median follow-up from diagnosis 20 months).

In a separate analysis, we compared rates of hepatotoxicity and pancreatitis in our H-PIR cohort with patients treated on the CALGB 10403 PIR trial (median age 24 yrs, 85% non-Hispanic). Our H-PIR cohort had higher rates of grade 3/4 transaminitis or hyperbilirubinemia, 51%, compared to grade 3/4 transaminitis in 28% and elevated bilirubin in 18% in patients on CALGB 10403. Our H-PIR cohort also had higher rates of pancreatitis (9% vs 5%).

Conclusion: This study found significantly higher rates of hepatotoxicity, resulting in treatment changes in H-PIR, compared to H-AR patients. There were no significant differences between H-PIR toxicities and those reported in the majority NH-PIR, CALGB 10403.

Our findings suggest that Hispanic patients receiving PIR may benefit from close monitoring and tailored strategies to mitigate hepatic complications and optimize outcomes. Planned genomic analyses may also allow identification of specific contributors to increased hepatotoxicity in Hispanic patients receiving PIR.

The study will be expanded to include other academic centers to enable further analysis of patients receiving H-PIR or NH-PIR to validate our results and assess the influence of toxicities and treatment changes on disease outcomes.