Hypersensitivity reactions (HSRs) can have a devastating and stressful impact on patients and their families
When a patient experiences an HSR due to E. coli asparaginase treatment, it can have serious consequences beyond the impact on clinical outcomes
Hesitation to continue therapy
HSRs can be frightening to patients, family members, and staff, and can lead to concerns about continuing with the same PEG-asparaginase treatment
Clinical hypersensitivity is the most common reason for patients to stop asparaginase treatment1
Risk of death
Subsequent reactions can be severe and possibly life-threatening2,3
HSRs may compromise efficacy of asparaginase therapy4
In addition to causing symptoms of an HSR, anti-asparaginase antibodies can also impact the effectiveness of treatment:
- Shortened asparaginase half-life5
- Subtherapeutic asparaginase levels6
- Reduced depletion of asparagine7
- Missed asparaginase doses8
Hypersensitivity is associated with an inability to deplete asparagine7
Adapted from Tong et al, 2014.7
HSRs may lead to asparaginase treatment interruptions and decreased efficacy4,9
- Most HSRs occur during consolidation10
- Replacement therapy should begin as soon as clinically possible, ideally within 48 to 72 hours following an HSR11
Protocol AALL1732: Scheduled doses of PEG-asparaginase12
Interruptions may impact AALL1732 protocols for patients with high-risk favorable B-ALL (pictured).12
An HSR that interferes with subsequent asparaginase doses could result in a prolonged time period between complete consecutive doses of asparaginase, decreasing the efficacy of ALL/LBL therapy1
Switching to an asparaginase with no immunologic crossreactivity can help preserve patient outcomes9
- Compared to those who experienced an HSR and subsequently missed doses, higher-risk (high-risk + slow early responders for SR) patients who switched to an Erwinia-derived asparaginase therapy due to an HSR were at lower risk of relapse and had higher rates of DFS8
- Rechallenging patients can compromise their outcomes and expose them to further HSRs3,13
To protect patient outcomes, consider switching
to an immunologically distinct asparaginase
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.
ALL=acute lymphoblastic leukemia; B-ALL=B-cell acute lymphoblastic leukemia; DFS=disease-free survival; E. coli=Escherichia coli; HD=high dose; HSR=hypersensitivity reaction; IM=interim maintenance; IT=intrathecal; LBL=lymphoblastic lymphoma; PEG-asparaginase=polyethylene glycol-conjugated asparaginase; SR=standard risk.
References: 1. Asselin BL, Fisher V. Impact of clinical and subclinical hypersensitivity to asparaginase in acute lymphoblastic leukemia. Clin J Oncol Nurs. 2014;18(6):E107-E112. 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. Liu Y, Smith CA, Panetta JC, et al. Antibodies predict pegaspargase allergic reactions and failure of rechallenge. J Clin Oncol. 2019;37(23):2051-2061. 4. Asselin B. Immunology of infusion reactions in the treatment of patients with acute lymphoblastic leukemia. Future Oncol. 2016;12(13):1609-1621. 5. Asselin BL, Whitin JC, Coppola DJ, et al. Comparative pharmacokinetic studies of three asparaginase preparations. J Clin Oncol. 1993;11(9):1780-1786. 6. Zalewska-Szewczyk B, Andrzejewski W, Młynarski W, et al. The anti-asparagines antibodies correlate with L-asparagines activity and may affect clinical outcome of childhood acute lymphoblastic leukemia. Leuk Lymphoma. 2007;48(5):931-936. 7. Tong WH, Pieters R, Kaspers GJL, et al. A prospective study on drug monitoring of PEGasparaginase and Erwinia asparaginase and asparaginase antibodies in pediatric acute lymphoblastic leukemia. Blood. 2014;123(13):2026-2033. 8. Gupta S, Wang C, Raetz EA, et al. Impact of asparaginase discontinuation on outcome in childhood acute lymphoblastic leukemia: a report from the Children’s Oncology Group. J Clin Oncol. 2020;38(17):1897-1905. 9. van der Sluis IM, Vrooman LM, Pieters R, et al. Consensus expert recommendations for identification and management of asparaginase hypersensitivity and silent inactivation. Haematologica. 2016;101(3):279-285. 10. Hijiya N, van der Sluis IM. Asparaginase-associated toxicity in children with acute lymphoblastic leukemia. Leuk Lymphoma. 2016;57(4):748-757. 11. Burke MJ. How to manage asparaginase hypersensitivity in acute lymphoblastic leukemia. Future Oncol. 2014;10(16):2615-2627. 12. Slayton W. Inotuzumab ozogamicin and post-induction chemotherapy in treating patients with high-risk B-ALL, mixed phenotype acute leukemia, and B-LLy. University of Florida Health Cancer Center. Accessed March 28, 2022. https://cancer.ufl.edu/patient-care/treatment-options/clinical-trials/find-a-clinical-trial/protocol-summary/?protocol_id=29883&protocol_no=OCR29882. 13. Swanson HD, Panetta JC, Barker PJ, et al. Predicting success of desensitization after pegaspargase allergy. Letter. Blood. 2020;135(1):71-75.