L-Asparaginase (L-ASP) Related Toxicities with Asparaginase Erwinia Chrysanthemi in a Large Compassionate Use Protocol.

Abstract

2568 Background: L-asparaginase (L-ASP) is an important component of multi-agent chemotherapy for treatment of Acute Lymphoblastic Leukemia (ALL) in children and young adults. The pegylated E. coli derived form, Oncaspar® (PEG-ASP), is most commonly used because of its longer half-life and lower immunogenicity compared to the native enzyme; however, clinical hypersensitivity reactions still occurs in 10–30% of patients (pts) requiring its discontinuation. Asparaginase Erwinia Chrysanthemi (Erwinaze™) is an L-ASP derived from a different bacterium and is immunologically distinct from the E. coli L-ASP. We conducted a compassionate use trial of Erwinaze in pts with ALL and hypersensitivity to native E. coli or PEG-ASP to collect safety information. Patients and Methods: Pts of any age with ALL or lymphoblastic lymphoma (LBL) who developed a Grade ≥2 clinical hypersensitivity reaction to PEG-ASP or native E. coli ASP (Elspar®) were eligible. Pts with a history of pancreatitis, previous allergic reaction to Erwinaze, or pregnant, were excluded. The study was IRB approved at each institution and pts/family provided informed consent/assent. Safety information on Erwinaze-related adverse events (AEs) were captured on Case Report Forms (CRFs) submitted to the Sponsor when the pt completed his/her entire Erwinaze treatment plan. AEs may have also been reported directly by the investigational sites. Results: Between February 2006 and November 2011, 1,368 pts were treated with Erwinaze. CRFs were received in 893 pts and 47 additional AEs were received from patients for which a CRF was not obtained. The average age was 9.6 years (range 1–66). The majority of patients (63.5%) were male. Of the pts for which CRFs were received (893); 77.6% were able to conclude their Erwinaze treatment. Discontinuation was due to allergic reaction in 8.8%; other AEs 4.7%; at the physician or patient discretion 7.5%; and missing information in 1.3%. Anaphylaxis was reported in 8 pts (0.9%) and Grade ≥2 clinical hypersensitivity reactions in 130 (13.8%). The incidence of pancreatitis was 3.9%, hemorrhagic or thrombosis abnormalities 2.4%, hyperglycemia 3.6% and elevation in liver enzymes 3.5%. There were 18 deaths on study; 11 disease progression, 3 intracranial hemorrhage, 4 other individual reports. Conclusion: This is the largest study of pts treated with Erwinaze to determine the toxicity profile. Erwinaze was well tolerated with no unexpected toxicities identified beyond those associated with L-Asp treatment. This compassionate use trial permitted the continuation and completion of asparaginase treatment in 77.6% of pts with hypersensitivity reactions to E. coli formulations. Final results will be available for presentation. Disclosures: Plourde: Jazz Pharmaceuticals: Employment, Equity Ownership. Mercedes:Jazz Pharmaceuticals: Employment. Corn:EUSA Pharma: Employment.

Activity and Toxicity of Intravenous Erwinia Asparaginase Following Allergy to E. coli‐Derived Asparaginase in Children and Adolescents With Acute Lymphoblastic Leukemia

“…Overall, toxicities associated with intravenously administered Erwinia asparaginase appeared consistent with previous reports in children treated with intramuscular Erwinia asparaginase after E. coli ‐asparaginase allergy, although the overall frequency of hypersensitivity reactions with intravenous administration reported here may be higher than previously reported with intramuscular administration . It is notable, however, that in our study, there were no reported episodes of anaphylaxis.…”

“…Of all patients, 87% completed Cycle 1, and approximately half (53%) completed their full course of planned asparaginase with the switch from pegaspargase to intravenous Erwinia asparaginase. In a compassionate‐use trial evaluating the safety of Erwinia asparaginase in 940 patients who had developed hypersensitivity reaction to E. coli ‐derived asparaginase, 13.6% of patients developed hypersensitivity reaction with Erwinia asparaginase; the majority of patients (91%) in that study had received Erwinia asparaginase intramuscularly . In a subgroup analysis of the 29 patients who had received Erwinia asparaginase intravenously, 17.2% of patients developed hypersensitivity reaction with Erwinia asparaginase and 58.6% of patients receiving intravenous Erwinia asparaginase completed their planned asparaginase treatment.…”

“…However, patients who do not receive their full asparaginase treatment‐course due to asparaginase‐related toxicity may have inferior outcomes compared with those who receive all intended asparaginase doses . In patients with allergy to E. coli ‐derived asparaginase, Erwinia asparaginase, an antigenically distinct preparation derived from Erwinia chrysanthemi with a shorter biological half‐life, can be substituted …”

Evaluation of Biomodified L-Asparaginase Was79 Side Effects in Chronic Experiment on Rabbits

“…При анализе массива данных о побочных эффектах L-аспарагиназ в клинической практике установлено, что изменения общего количества лейкоцитов возникают у 3,8 % больных. У части пациентов количество лейкоцитов уменьшается за счет лимфоидных элементов, у 2,3 % лейкоцитопения проявляется в виде нейтропении [17,22].…”

“…Гепатотоксичность -один из распространенных видов токсичности L-аспарагиназ. В доклинических исследованиях EcA и ErA ее проявления в виде вакуолизации гепатоцитов, повышения уровня трансаминаз, жировой дистрофии печени были отмечены у кроликов и обезьян, причем у животных, получавших ErA, они были менее выраженными [15] [28], однако у некоторых пациентов, получавших высокие и низкие дозы ErA, было отмечено удлинение интервала QT [22]. Реализация повреждающего действия Was79 на органы и ткани в значительной мере зависела от индивидуальной чувствительности организма животных.…”