Incidence of asparaginase-related hepatotoxicity, pancreatitis, and thrombotic events in adults with acute lymphoblastic leukemia treated with a pediatric-inspired regimen

Abstract

Asparaginase is a critical component of acute lymphoblastic leukemia (ALL) treatment in children; however, its use in adults is often avoided as a result of toxicities including hepatotoxicity, thrombosis, and pancreatitis which have been reported more commonly in adults than in children. In this retrospective analysis, short-acting L-asparaginase (L-ASP) and long-acting polyethylene glycol (PEG)-asparaginase (PEG-ASP) were compared for grade 3-4 toxicities and characterized by patient and drug-related factors to identify strategies for toxicity avoidance in adults with ALL. Asparaginase was administered during sequential courses of chemotherapy using a pediatric-inspired treatment regimen. Forty-eight patients who received PEG-ASP and nine patients who received L-ASP were identified. The rates of toxicity were as follows for the PEG-ASP and L-ASP groups, respectively: hepatotoxicity (60% vs. 33%, P = 0.275), pancreatitis (17% vs. 22%, P = 0.650), thrombosis (19.0% vs. 0%, P = 0.328), or any grade 3-4 toxicity (71% vs. 44%, P = 0.143). Toxicity did not correlate with dose, either by individual dose based on flat or BSA-based measures. Logistic regression identified obesity as a risk factor for heptatotoxicity (OR = 8.44, 95% CI: 1.395-51.117). Hypofibrinogenemia was identified as a pharmacodynamic marker for predicting hepatotoxicity. In conclusion, grade 3-4 toxicity was not statistically different between adult ALL patients receiving PEG-ASP and L-ASP, but toxicity was strongly associated with obesity and hypofibrinogenemia, not dose.

L-carnitine does not ameliorate asparaginase-associated hepatotoxicity in a C57BL6 mouse model

“…Mice were sacrificed and tissues collected after overnight fasting at the end of the 2 week regimens. Consistent with murine data [13] and ultrasound observations in patients [1], hepatic steatosis was induced by pegaspargase treatment alone ( p = 5.9×10 −4 ) (Figure 2(A–B)). One of the most common clinical signs of hepatotoxicity, hyperbilirubinemia, was also induced by pegaspargase treatment, indicated by both total bilirubin and direct bilirubin levels (p = 0.0076 for total bilirubin, and p = 0.0088 for direct bilirubin) (Figure 2(C–D)).…”

“…Asparaginase-associated hepatotoxicity (AAH) is common in patients treated for acute lymphoblastic leukemia (ALL), usually manifested as hyperbilirubinemia, transaminitis, and steatosis, and prolonged prothrombin time [1]. It represents a significant cause of treatment delay and interruption, and limits the use of asparaginase in adults despite its benefit on treatment outcome [2, 3].…”

National Italian Delphi panel consensus: which measures are indicated to minimize pegylated-asparaginase associated toxicity during treatment of adult acute lymphoblastic leukemia?

“…There was consensus that hepatic toxicity is the most common complication in adult patients receiving Peg-ASP [36]. Clinicians agreed that in the presence of BMI > 30 and pre-existing hepatic steatosis a reduction of Peg-ASP dosage is required.…”

“…Clinicians agreed that in the presence of BMI > 30 and pre-existing hepatic steatosis a reduction of Peg-ASP dosage is required. Higher age, obesity (body mass index [BMI] > 30) are indeed established risk factors for the development of severe hepatic toxicity) [ 36 , 37 ]. Acute onset of hepatic steatosis (with anatomo-pathological features of micro-vesicular steatosis) is a common consequence of ASP treatment [ 38 , 39 ], so pre-existing hepatic steatosis should be considered a warning for the development of ASP-related hepatic toxicity.…”

Managing toxicities with asparaginase-based therapies in adult ALL: summary of an ESMO Open–Cancer Horizons roundtable discussion

“…41 42 Most TE cases occur during asparaginase and corticosteroid therapy. [43][44][45][46][47] Asparaginase has been associated with increased levels of procoagulant factors, [48][49][50][51][52] while corticosteroids may inhibit fibrinolysis by increasing levels of factor VIII, von Willebrandt factor (vWF) and plasminogen activator inhibitor-1. 48 53 The reported incidence of symptomatic TE in childhood ALL is about 5%, but increases with age 41 42 45 49 54 55 already at the age of 10 years.…”