A phase 3 randomized trial comparing inolimomab vs usual care in steroid-resistant acute GVHD.

Treatment of steroid-resistant acute graft-versus-host disease (GVHD) remains an unmet clinical need. Inolimomab, a monoclonal antibody to CD25, has shown encouraging results in phase 2 trials. This phase 3 randomized, open-label, multicenter trial compared inolimomab vs usual care in adult patients with steroid-refractory acute GVHD. Patients were randomly selected to receive treatment with inolimomab or usual care (the control group was treated with antithymocyte globulin [ATG]). The primary objective was to evaluate overall survival at 1 year without changing baseline allocated therapy. A total of 100 patients were randomly placed: 49 patients in the inolimomab arm and 51 patients in the ATG arm. The primary criteria were reached by 14 patients (28.5%) in the inolimomab and 11 patients (21.5%) in the ATG arms, with a hazard ratio of 0.874 (P = .28). With a minimum follow-up of 1 year, 26 (53%) and 31 (60%) patients died in the inolimomab and ATG arms, respectively. Adverse events were similar in the 2 arms, with fewer viral infections in the inolimomab arm compared with the ATG arm. The primary end point of this randomized phase 3 trial was not achieved. The lack of a statistically significant effect confirms the need for development of more effective treatments for acute GVHD. This trial is registered to https://www.clinicaltrialsregister.eu/ctr-search/search as EUDRACT 2007-005009-24.

Development of asparaginase Erwinia chrysanthemi for the treatment of acute lymphoblastic leukemia.

Since it was identified in 1963 as the antileukemic agent in guinea pig serum, L-asparaginase (ASNase) has become an integral component of chemotherapy protocols to treat patients with acute lymphoblastic leukemia (ALL). Escherichia coli and Erwinia chrysanthemi provide the sources of ASNase used clinically today. From the time ASNase was first introduced into treatment protocols, the 5-year survival rate has increased significantly, particularly in children and adolescents. E. coli-derived ASNase was approved in 1978 to be used as part of a multiagent chemotherapy to treat ALL. However, the development of hypersensitivity in 10-30% of patients often leads to treatment discontinuation. E. chrysanthemi-derived ASNase (referred to herein as ASNase Erwinia chrysanthemi) is immunologically distinct from E. coli ASNase and therefore does not cross-react with the E. coli enzyme. In 2011, ASNase Erwinia chrysanthemi was approved in the United States for patients who develop hypersensitivity to E. coli-derived ASNase. When indicated, a switch from ASNase E. coli to ASNase E. chrysanthemi allows patients to continue to receive treatment and maintain therapeutic levels of ASNase activity. Therapeutic drug monitoring may help ensure that therapeutic enzyme levels are maintained. Pegylated recombinant ASNase Erwinia chrysanthemi is currently being developed to improve pharmacokinetic properties and reduce immunogenicity.

Measurement of subvisible particulates in lyophilised Erwinia chrysanthemi L-asparaginase and relationship with clinical experience.

In order to generate further characterisation data for the lyophilised product Erwinia chrysanthemi L-asparaginase, reconstituted drug product (DP; marketed as Erwinase or Erwinaze) was analysed for subvisible (2-10 µm) particulate content using both the light obscuration (LO) method and the newer flow-imaging microscopy (FIM) technique. No correlation of subvisible particulate counts exists between FIM and LO nor do the counts correlate with activity at both release and on stability. The subvisible particulate content of lyophilised Erwinia L-asparaginase appears to be consistent and stable over time and in line with other parenteral biopharmaceutical products. The majority (ca. 75%) of subvisible particulates in L-asparaginase DP were at the low end of the measurement range by FIM (2-4 µm). In this size range, FIM was unable to definitively classify the particulates as either protein or non-protein. More sensitive measurement techniques would be needed to classify the particulates in lyophilised L-asparaginase into type (protein and non-protein), so the LO technique has been chosen for on-going DP analyses. E. chrysanthemi L-asparaginase has a lower rate of hypersensitivity compared with native Escherichia coli preparations, but a subset of patients develop hypersensitivity to the Erwinia enzyme. A DP lot that had subvisible particulate counts on the upper end of the measurement range by both LO and FIM had the same incidence of allergic hypersensitivity in clinical experience as lots at all levels of observed subvisible particulate content, suggesting that the presence of L-asparaginase subvisible particulates is not important with respect to allergic response.

Safety profile of asparaginase Erwinia chrysanthemi in a large compassionate-use trial.

BACKGROUND: L-Asparaginase is an integral component of standard chemotherapy regimens for the treatment of acute lymphoblastic leukemia (ALL). Clinical hypersensitivity, a common reason for treatment discontinuation, has been reported in 10-30% of patients receiving Escherichia coli-derived asparaginase. After hypersensitivity, E. coli-derived asparaginase should be discontinued and an alternative asparaginase preparation, such as asparaginase Erwinia chrysanthemi, may be initiated. We conducted a compassionate-use study to collect additional safety information on asparaginase Erwinia chrysanthemi and to support FDA approval of the product. PROCEDURE: Patients with ALL or lymphoblastic lymphoma (LBL; N = 1368) who developed a hypersensitivity reaction (grade ≥2) to an E. coli-derived asparaginase participated in this trial. The recommended asparaginase Erwinia chrysanthemi dose was 25,000 IU/m(2) three days per week (Monday/Wednesday/Friday) for two consecutive weeks for each missed pegylated E. coli-derived asparaginase dose and 25,000 IU/m(2) for each missed nonpegylated asparaginase dose for the completion of their planned asparaginase treatment. RESULTS: Adverse event reports and/or case report forms were completed for 940 patients. The most common adverse event (AE) was hypersensitivity (13.6%). Eighteen patients (1.9%) died during the study. Most patients (77.6%) completed their planned asparaginase treatment with asparaginase Erwinia chrysanthemi. There was no apparent difference in the incidence of the most commonly reported AEs with asparaginase treatment by age, administration, or disease state. CONCLUSIONS: This study further established the safety profile of asparaginase Erwinia chrysanthemi in patients with ALL or LBL who had a hypersensitivity reaction to an E. coli-derived asparaginase.