On June 30, 2021, asparaginase erwinia chrysanthemi (recombinant)-rywn was approved as a component of a multiagent chemotherapeutic regimen for treatment of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma in adult and pediatric patients 1 month or older who have developed hypersensitivity to Escherichi coli–derived asparaginase.1
Supporting Efficacy Data
Approval was based on findings in the multicohort, multicenter JZP458-201 trial (ClinicalTrials.gov identifier NCT04145531).1,2 A total of 102 patients with ALL or lymphoblastic lymphoma with hypersensitivity to E coli–derived asparaginase (pegaspargase) as a component of a multiagent chemotherapeutic regimen were treated with recombinant asparaginase erwinia chrysanthemi at various dosages given intramuscularly (IM) every Monday, Wednesday, and Friday for a total of six doses to replace each dose of pegaspargase.
Among all patients, median age was 10 years (range = 1–24 years), 57% were male, and 73% were White, 12% were Black/African American, and 5% were Asian. Overall, 94% had experienced a hypersensitivity reaction to pegaspargase and 7% had silent inactivation (ie, the development of neutralizing antibodies and associated asparaginase inactivity in the absence of clinical symptoms).
The main efficacy outcome measure was demonstration of achievement and maintenance of nadir serum asparaginase activity ≥ 0.1 U/mL. The results of modeling and simulations showed that for a dosage of 25 mg/m2 every 48 hours, the proportion of patients maintaining nadir serum asparaginase activity ≥ 0.1 U/mL at 48 hours after a dose was 93.6% (95% confidence interval [CI] = 92.6%–94.6%).
How It Works
Asparaginase erwinia chrysanthemi is an enzyme that catalyzes the conversion of the amino acid L-asparagine into aspartic acid and ammonia. The pharmacologic effect consists in the killing of leukemic cells due to depletion of plasma asparagine. Leukemic cells with a low expression of asparagine synthetase have a reduced ability to synthesize asparagine and therefore depend on an exogenous source of asparagine for survival.
How It Is Used
When replacing a long-acting asparaginase product, the recommended dosage of recombinant asparaginase erwinia chrysanthemi is 25 mg/m2 IM every 48 hours for the required duration of asparaginase activity. Prescribing information for the long-acting asparaginase product should be consulted to determine the duration of administration of the recombinant agent as replacement therapy.
Bilirubin, transaminases, and glucose should be monitored and clinical examinations performed prior to treatment, every 2 to 3 weeks during treatment, and as indicated clinically. If results are abnormal, patients should be monitored until recovery from the cycle of therapy.
Product labeling provides instructions on treatment modification and management for adverse reactions including hypersensitivity reactions, pancreatitis, thrombosis, hemorrhage, and hepatotoxicity. Treatment should be permanently discontinued for grade 3 to 4 hypersensitivity reactions, confirmed clinical necrotizing or hemorrhagic pancreatitis, severe or life-threatening thrombosis, and total bilirubin > 10 times the upper limit of normal.
The safety data presented below are from 33 patients from the JZP458-201 trial who received recombinant asparaginase erwinia chrysanthemi at 25 mg/m2 IM on Monday, Wednesday, and Friday for six doses as a replacement for pegaspargase as a component of multiagent chemotherapy.
All patients developed neutropenia, anemia, or thrombocytopenia. The most common nonhematologic adverse events of any grade (incidence > 20%) were abnormal liver test (70%), nausea (46%), musculoskeletal pain (39%), fatigue (36%), infection (30%), headache (30%), pyrexia (27%), drug hypersensitivity (24%), febrile neutropenia (24%), decreased appetite (21%), stomatitis (21%), bleeding (21%), and hyperglycemia (21%). The most common grade 3 to 4 adverse events included febrile neutropenia (24%), abnormal liver test (12%), infection (12%), and nausea, stomatitis, and dehydration (9% each).
Serious adverse events occurred in 55% of patients, the most common (incidence ≥ 5%) being febrile neutropenia, dehydration, pyrexia, stomatitis, diarrhea, drug hypersensitivity, infection, nausea, and viral infection. Adverse events led to permanent discontinuation of treatment in 9% of patients, with causes consisting of hypersensitivity reaction (6%) and infection (3%). Adverse events led to death in one patient due to infection.
Recombinant asparaginase erwinia chrysanthemi has warnings/precautions for hypersensitivity, pancreatitis, thrombosis, hemorrhage, and hepatotoxicity. The agent is contraindicated in patients with a history of serious hypersensitivity reactions to it, including anaphylaxis, serious pancreatitis during previous L-asparaginase therapy, serious thrombosis during previous L-asparaginase therapy, or serious hemorrhagic events during previous L-asparaginase therapy. Patients should be advised not to breastfeed while receiving recombinant asparaginase erwinia chrysanthemi.
1. U.S. Food and Drug Administration: FDA approves asparaginase erwinia chrysanthemi (recombinant) for leukemia and lymphoma. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-asparaginase-erwinia-chrysanthemi-recombinant-leukemia-and-lymphoma. Accessed July 13, 2021.
2. Rylaze (asparaginase erwinia chrysanthemi (recombinant)-rywn) injection, for intramuscular use, prescribing information, Jazz Pharmaceuticals, June 2021. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761179s000lbl.pdf. Accessed July 13, 2021.