Feasibility of High Doses Peg-Asparaginase Administration in a Cohort of Adult Acute Lymphoblastic Leukemia Patients
Authors: Minetto Paola , Bisso Nadia , Guolo Fabio , Clavio Marino , Marcolin Riccardo , Ballerini Filippo , Miglino Maurizio , Gobbi Marco , Lemoli Roberto Massimo 
Published: October 2019

Abstract
Background: The application of pediatric-inspired regimens for the treatment of adult acute lymphoblastic leukemia (ALL) patients has led to a significant improvement in clinical outcome. The increased use of non-myelosuppressive agents such as peg-asparaginase (PEG-ASP) in modern adult protocols greatly contributed to improve treatment outcome. However, concerns about the safety of PEG-ASP administration in adults have emerged. Patient-related factors as high body mass index (BMI) or pre-exhistinghepatic steatosis have already been identified as risk factors contributing to PEG-ASP related toxicity. However, few data are available on the role of specific concomitant medications potentially contributing to PEG-ASP toxicity.
Aims: To identify patients and therapy-related factors contributing to the development of PEG-ASP associated toxicity in a cohort of adult ALL patients who received intensive induction treatment according to a full pediatric or an alternative intensive regimen.
Methods: Since 2013, 26 adult ALL patients received PEG-ASP in our Center. Median age was 47 years (range 19-76). Nineteen patients were treated in front-line setting: 11 according to the full pediatric protocol AIEOP-BFM 2009 (median age 36, range 19-56), 4 patients according to a national pediatric-like protocol for adult patients (median age: 47,5, range 39-59) and 1 patient aged 76 received PEG-ASP plus reduced-intensity chemo. Ten patients received PEG-ASP as part of salvage therapy for relapsed/refractory disease.
Methods: PEG-ASP- related toxicities were recorded and classified according to the guidelines published by Stock et al (Leukemia and Lymphoma, 2011). The incidence of PEG-ASP-related toxicity was analyzed considering as a separate episode each course of therapy including PEG-ASP administration (with a median duration per episode of 1 month, range 0,5-2 months). Patient features, timing and doses of chemotherapic agents and concomitant medications were recorded. A total of 49 episodes were analyzed
Results: No grade III-IV pancreatic, thrombotic or hemorrhagic adverse event were observed. Isolated hyperbilirubinemia was the most frequent adverse event observed (n. 24 grade II, N. 5 grade III, N. 2 grade IV). Grade III hepatotoxicity was observed in 5 patients; 3 patients had grade IV hepatotoxicity. In all of them, ultrasonography showed the onset of acute liver steatosis. All 3 patients had received concomitant therapy with Idarubicin (IDA), vincristine (VCR) and vancomycin. In all the 3 cases patients died due to superimposed infections.
In univariate analysis age > 45 yrs, administration of PEG-ASP therapy with active leukemia or BMI >25 were not related with an increased incidence of grade III-IV hepatotoxicity which was instead significantly higher when a cumulative dose of IDA of at least 20 mg/sqm over a single episode (p 0.047, HR 1.48) was administered. Cumulative dose of VCR of at least 2 mg/sqm determined a borderline increase in toxicity risk (p 0.055, HR 4.75). Administration of estroprogestinic hormones were significantly associated with the risk of developing hepatic-toxicity (p 0.024, HR 1.33). No increase was observed with any dose of prednisone/dexametasone, daunorubicin, cyclophosphamide, cytarabine, methotrexate, and 6-mercaptopurine. Among antimicrobial therapies, vancomycin, synthetic penicillines + B-lactamases inhibitors and Carbapenems administration increased the risk of grade III-IV hepatotoxicity (p 0.009, HR 1.85, p 0.010 HR 3.02, p 0.047 HR 2.02). No significant increase in the risk of toxicity was observed with azoles. Notably, none of the patients undergoing full pediatric induction, which contains higher cumulative doses of PEG-ASP, experienced grade IV hepatotoxicity.
A multivariate logistic regression analysis disclosed that administration of IDA, sexual hormones and synthetic penicillines + B-lactamases inhibitors were independent predictors of grade III/IV hepatotoxicity (p 0.014, 0.024, 0.041; Tab. I).
Conclusion: In our experience the toxicity profile of PEG-ASP in adult patients is overall manageable even when high doses were administered according to a full pediatric schedule. Our data suggest that the development of severe hepatic toxicity is significantly influenced by chemotherapy schedule and specific concomitant medications.

Disclosures
Gobbi: Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Pfister: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Ariad: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy.