Lack of efficacy of levocarnitine for the treatment of pegylated asparaginase-related hepatotoxicity during induction or salvage chemotherapy in adults with acute lymphoblastic leukemia: A comparative, retrospective, University of California hematologic malignancies consortium (UCHMC) study

Abstract

Abstract Background: Pegylated E. coli L-asparaginase (PEGAsp) is a common component of therapy for acute lymphoblastic leukemia (ALL). Hepatotoxicity related to PEGAsp occurs in approximately half of adults and can lead to prolonged hospitalization, delay in subsequent chemotherapy, liver failure, and, rarely, death. A preclinical rodent study proposed the utility of levocarnitine (L-carnitine) for the treatment of PEGAsp hepatotoxicity (Roesmann et al. 2014) but clinical data has been limited to non-comparative, selective case reports and case series. Methods: We performed a comparative, multi-institutional, retrospective study to determine the efficacy of L-carnitine for treatment of PEGAsp-associated hepatotoxicity in adults with ALL. Eligible patients were adults 18 years of age or older with ALL who received at least one dose of PEGAsp before 01/01/2024 at the University of California (UC) Irvine, UC San Francisco, UC Los Angeles, UC San Diego, or the University of Washington and had PEGAsp-associated hyperbilirubinemia and/or ALT elevation. Three cohorts were compared: (1) no L-carnitine (none), (2) L-carnitine given after PEGAsp administration (treatment, tx), (3) L-carnitine given prior to and after PEGAsp administration (prophylaxis + treatment, ppx+tx). Comparisons were performed for 4 toxicity groups: total bilirubin (TBili) >ULN, TBili >3 g/dL, ALT elevation (ALT >ULN), and ALT >3X ULN. Bivariate analyses were performed for comparison, Chi-squared tests were used for categorical variables, and Kruskal-Wallis tests were used for comparisons of medians. Results: In total, 180 patients with PEGAsp-associated hepatotoxicity were identified (N=123 none, 36 tx, and 21 ppx+tx). The median age was 34 years (range 18-72) and 62% were male. Hispanic ethnicity was identified by 48% of patients. ALL subtypes were 68% B-ALL, 16% T-ALL, and 16% ALL not otherwise specified. By cohort, the median BMI was 26.5 kg/m2none, 30.8 kg/m2tx, and 23.5 kg/m2ppx+tx. When compared to the no L-carnitine cohort, patients who received L-carnitine tx after PEGAsp had a higher BMI (tx vs none, p<0.0001), had pre-existing steatosis on liver imaging prior to PEGAsp (64% tx vs 30% none, p=0.001), and were Hispanic (67% tx vs 45% none, p=0.02). The median dose of PEGAsp was 3,750 units, and when used, a median dose of 4 grams of L-carnitine per day. For the TBili >ULN cohort (N=99 none, 36 tx, and 15 ppx+tx), median peak TBilis were 2.9, 8.1, and 2.8 mg/dL (p<0.0001), respectively. Days to peak TBili was longer for the L-carnitine tx group (16 none, 19 tx, 15 ppx+tx, p=0.03). No significant differences were observed among the TBili >ULN groups for days to improvement in hyperbilirubinemia or days to resolution of hyperbilirubinemia. For the TBili >3X ULN cohort (N=48 none, 31 tx, and 7 ppx+tx), median peak TBilis were 7.2, 9.3, and 10.4 mg/dL (p=0.3), respectively. No significant differences were observed among the TBili >3X ULN groups for days to peak TBili, days to improvement in hyperbilirubinemia, or days to resolution of hyperbilirubinemia. For the ALT >ULN cohort (N=104 none, 34 tx, and 16 ppx+tx), median peak ALTs were 219, 229, and 189 U/L (p=0.24), respectively. No significant differences were observed among the ALT >ULN groups for days to peak ALT, days to improvement in hyperbilirubinemia, or days to resolution of hyperbilirubinemia. For the ALT >3X ULN cohort (N=58 none, 21 tx, and 8 ppx+tx), median peak ALTs were 321, 369, and 375 U/L (p=0.91), respectively. No significant differences were observed among the ALT >3X ULN groups for days to peak ALT, days to improvement in hyperbilirubinemia, or days to resolution of hyperbilirubinemia. Conclusion: In this comparative, multi-institutional, retrospective study, L-carnitine did not demonstrate a benefit for the treatment of PEGAsp-associated hyperbilirubinemia or transaminitis in adults with ALL.