Hypersensitivity reactions (HSRs) are common in patients receiving asparaginase1
Adapted from Shinnick et al, 2013.2
Native E. coli asparaginase, a bacterial protein, may trigger an immune response, resulting in proliferation and release of antibodies from plasma B cells2
Antibodies may directly bind to the surface of the mast cell, thereby activating it. Antibodies are also present in the plasma2
Upon reexposure, the antigen may bind to:
- Antibodies that are present on the surface of the mast cell (characterized by an IgE response or Type 1 reaction)2
- Free antibodies (mainly IgG or IgM) may neutralize or clear the antigen2
Antigens bound to antibodies on mast cells trigger the release of histamine and other mediators that can cause clinical symptoms, including HSRs2,3
HSR symptoms can compromise the safety of patients and their treatment3
HSR symptoms may be localized or systemic, and common symptoms include4,5:
Wheezing, dyspnea, bronchospasm, respiratory distress
Nausea/vomiting, abdominal pain, diarrhea
Urticaria, pruritis, erythema, angioedema
Headache, lethargy, malaise
Urticaria, pruritis, erythema, angioedema
Headache, lethargy, malaise
Once an HSR occurs, a patient is at increased risk for another reaction when treated with asparaginase derived from the same source6
RYLAZE is indicated as a component of a multi-agent chemotherapeutic regimen given by intramuscular injection for the treatment of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in adult and pediatric patients 1 month or older who have developed hypersensitivity to E. coli-derived asparaginase.
IMPORTANT SAFETY INFORMATION
RYLAZE is contraindicated in patients with a history of:
- Serious hypersensitivity reactions to Erwinia asparaginase, including anaphylaxis
- Serious pancreatitis during previous asparaginase therapy
- Serious thrombosis during previous asparaginase therapy
- Serious hemorrhagic events during previous asparaginase therapy
Warnings and Precautions
Hypersensitivity reactions after the use of RYLAZE occurred in 25% of patients in clinical trials, and it was severe in 2% of patients. The median time from the first dose of RYLAZE to the onset of the first hypersensitivity event was 27 days (range 1-171 days). The most commonly observed reaction was rash (17%), and no patient experienced a severe rash. The median time from the first dose to the first onset of rash was 33.5 days (range 1-127 days).
Hypersensitivity reactions observed with L-asparaginase class products include angioedema, urticaria, lip swelling, eye swelling, rash or erythema, blood pressure decreased, bronchospasm, dyspnea, and pruritus.
Because of the risk of serious allergic reactions (e.g., life-threatening anaphylaxis), administer RYLAZE in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (e.g., epinephrine, oxygen, intravenous steroids, antihistamines). Discontinue RYLAZE in patients with serious hypersensitivity reactions.
Pancreatitis was reported in 14% of patients in clinical trials of RYLAZE and was severe in 6%. Clinical pancreatitis occurred in 5% of patients, and it was severe in 4% of patients. Elevated amylase or lipase without clinical diagnosis of pancreatitis was observed in 9% of patients, and it was severe in 2% of patients treated with RYLAZE. Hemorrhagic or necrotizing pancreatitis have been reported with L-asparaginase class products.
Inform patients of the signs and symptoms of pancreatitis, which, if left untreated, could be fatal. Evaluate patients with symptoms compatible with pancreatitis to establish a diagnosis. Assess serum amylase and lipase levels in patients with any signs or symptoms of pancreatitis. Discontinue RYLAZE in patients with severe or hemorrhagic pancreatitis. In the case of mild pancreatitis, withhold RYLAZE until the signs and symptoms subside and amylase and/or lipase levels return to 1.5 times the ULN. After resolution of mild pancreatitis, treatment with RYLAZE may be resumed.
Serious thrombotic events, including sagittal sinus thrombosis and pulmonary embolism, have been reported following treatment with L-asparaginase class products. Discontinue RYLAZE for a thrombotic event, and administer appropriate antithrombotic therapy. Consider resumption of treatment with RYLAZE only if the patient had an uncomplicated thrombosis.
Bleeding was reported in 17% of patients treated with RYLAZE, and it was severe in 1%. Most commonly observed reactions were bruising (8%) (contusion, increased tendency to bruise and injection site bruising) and nose bleeding (6%), which was severe in 1% of patients. Other observed bleeding reactions included hematuria (2%), disseminated intravascular coagulopathy (1%), rectal bleeding (1%) and gingival bleeding (1%).
In patients treated with asparaginase class products, hemorrhage may be associated with increased prothrombin time (PT), increased partial thromboplastin time (PTT), and hypofibrinogenemia. Consider appropriate replacement therapy in patients with severe or symptomatic coagulopathy.
Elevated bilirubin and/or transaminases occurred in 62% of patients treated with RYLAZE in clinical trials, and 12% had Grade ≥3 elevations.
Inform patients of the signs and symptoms of hepatotoxicity. Evaluate bilirubin and transaminases prior to treatment every 2-3 weeks and as indicated clinically during treatment with RYLAZE. In the event of serious liver toxicity, discontinue treatment with RYLAZE and provide supportive care.
Serious adverse reactions occurred in 55% of patients who received RYLAZE. The most frequent serious adverse reactions (in ≥5% of patients) were febrile neutropenia, dehydration, pyrexia, stomatitis, diarrhea, drug hypersensitivity, infection, nausea, and viral infection.
The most common adverse reactions (incidence >20%) with RYLAZE are 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%).
Use in Specific Populations
Pregnancy and Lactation
RYLAZE can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective non-hormonal contraceptive methods during treatment with RYLAZE and for 3 months after the last dose. Advise women not to breastfeed during treatment with RYLAZE and for 1 week after the last dose.
Please see full Prescribing Information.
E. coli=Escherichia coli; IgE=immunoglobulin E; IgG=immunoglobulin G; IgM=immunoglobulin M.
References: 1. Burke MJ. How to manage asparaginase hypersensitivity in acute lymphoblastic leukemia. Future Oncol. 2014;10(16):2615-2627. 2. Shinnick SE, Browning ML, Koontz SE. Managing hypersensitivity to asparaginase in pediatrics, adolescents, and young adults. J Pediatr Oncol Nurs. 2013;30(2):63-77. 3. Asselin B. Immunology of infusion reactions in the treatment of patients with acute lymphoblastic leukemia. Future Oncol. 2016;12(13):1609-1621. 4. Woo MH, Hak LJ, Storm MC, et al. Anti-asparaginase antibodies following E. coli asparaginase therapy in pediatric acute lymphoblastic leukemia. Leukemia. 1998;12(10):1527-1533. 5. Woods D, Winchester K, Towerman A, et al. From the Children’s Oncology Group: evidence-based recommendations for PEG-asparaginase nurse monitoring, hypersensitivity reaction management, and patient/family education. J Pediatr Oncol Nurs. 2017;34(6):387-396. 6. Woo MH, Hak LJ, Storm MC, et al. Hypersensitivity or development of antibodies to asparaginase does not impact treatment outcome of childhood acute lymphoblastic leukemia. J Clin Oncol. 2000;18(7):1525-1532.