The Toxicity Profile of Repeated Dosing of Peg-Asparaginase in 152 Adults with Acute Lymphoblastic Leukemia
Authors: Aldoss Ibrahim , Pullarkat Vinod , Chaudhary Preeti , Douer Dan 
Published: October 2019

PEG-Asparaginase (PEG-Asp) is an active drug in acute lymphoblastic leukemia (ALL) and due to its recognized therapeutic importance, it is universally used in all pediatric ALL regimens. In contrast, PEG-Asp is included less frequently in adult ALL regimens and there is a reluctance of using the drug by adults oncologists. The reasons are concerns that its unique toxicities are more common and of greater severity with increasing age as wells as the widespread use of other non-Asp based adult-only ALL regimens, mostly in the US. Consequently, adult oncologists are less experienced in managing PEG-Asp toxicities. More recent studies have shown improved outcomes in adult ALL using multiple PEG-asp doses. We therefore analyzed PEG-asp toxicities in a large cohort of adults with ALL treated uniformly at the University of Southern California (USC).
Patients were treated with a pediatric like regimen which included 6 scheduled doses of PEG-Asp during induction and consolidation cycles (Douer D et al. J Clin Oncol. 2014;32:905-11). Patients' eligible for this retrospective analysis had ALL, aged 18 to 60 years, and were treated with PEG-Asp between the years 2003 and 2013.
We identified 152 patients with a median age of 32 (18-60) years, who met the eligibility criteria of whom the majority were Hispanics (74%). The total number of recorded administered doses of PEG-Asp was 522; median number of doses per patient was 3. Among all patients, 44 (29%) completed all scheduled 6 doses of PEG-Asp. Ten patients were still undergoing treatment at time of this analysis. Among the remaining 98 patients who did not receive all scheduled PEG-Asp doses, only 29% (n=28) had to discontinue the drug because of toxicity. Other reasons for discontinuing PEG-Asp therapy were proceeding to allogeneic hematopoietic stem cell transplantation (21%), relapsed/refractory disease (17%), and death during treatment [in CR secondary to other causes not related to PEG-Asp] (9%). Grade III/IV PEG-Asp toxicities are detailed in Table 1. As expected, hepatotoxicity was the most common toxicity, with very frequent grade III/IV elevation of AST/ALT. Among patients who developed grade III/IV hyperbilirubenemia and received additional scheduled doses of PEG-Asp, only 37.5% developed recurrent grade III/IV hyperbilirubenmia. The median time for developing grade III hyperbilirubenmia was 15 days, and the median time for resolution of grade III/IV hyperbilirubinrmia (to Grade I) was 9 days. Thrombosis occurred in 11% of patients despite not using antithrombin III replacement in this cohort. Patients were not given cryoprecipitate unless fibrinogen levels were 60mg/ml or less. The only recoded PEG-Asp related death was from cavernous sinus thrombosis. All cases of thrombosis were venous in origin and 35% of them occurred after cryoprecipitate replacement for hypofibrinogenemia. Thrombosis was most common during the first 2 doses of PEG-Asp (94%). There was no recurrent thrombosis in the 10 patients who developed PEG-Asp induced thrombosis and received more PEG-Asp while they were on anticoagulation. Although hypofibrinogenemia was very common, bleeding was extremely rare. Grade III/IV hypertriglyceridemia was common and always reversible. We found no association between Grade III/IV hypertriglyceridemia and clinical pancreatitis. None of the cases of pancreatitis were fatal. PEG-Asp induced allergic reaction was an uncommon event.
Table 1. Grade III/IV toxicity rate Toxicity Per total number of doses (n=522) Anytime per individual patient (n =152) Allergy 1.2% 4% Pancreatitis 3.6% 12.6% Bilirubin 9.4% 23.8% AST/ALT 28.8% 55% Thrombosis (Gr II-V) 3% 11% Bleeding 0.2% 0.7% Hypertriglyridemia 38.6% 51.4% Fibrinogen < 100 17% 47.2%
In summary (1) In adults (up to age 60 years) PEG-asp has a similar toxicity spectrum as pediatric patients. (2) Repeated doses can be safely administered despite hepatotoxicity. (3) PEG-Asp toxicity was not the main reason of discontinuing the drug in this study (less than third of cases). (4) The majority of patients can be safely managed without antithrombin III or cryoprecipitate therapy. Together with using recently published guidelines (Stock et al. Leuk Lymphoma. 2011;52:2237-53) our study shows that PEG-Asp toxicities are mostly tolerable and manageable, and the risk of therapy related mortality is extremely low.

Disclosures
Douer: Sigma Tau: Membership on an entity's Board of Directors or advisory committees.