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Hypersensitivity can have a devastating and stressful impact on patients and their families

 

When a patient experiences hypersensitivity due to E. coli asparaginase treatment, it can have serious consequences beyond the impact on clinical outcomes

 

Hesitation to continue therapy

Hypersensitivity can be frightening to patients, family members, and staff, and can lead to concerns about continuing with the same PEG-asparaginase treatment

Halting therapy

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

Hypersensitivity may compromise efficacy of asparaginase therapy4

In addition to causing symptoms of a hypersensitivity reaction, 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

Asparaginase Depletion ChartAsparaginase Depletion Chart

Adapted from Tong et al, 2014.7

Newly diagnosed patients (N=89) from the DCOG ALL-10 protocol were treated with PEG-asparaginase and serum asparagine levels were measured at weeks 0, 2, 4, 14, and 24 during PEG-asparaginase therapy. This included children between 1 and 18 years of age with newly diagnosed ALL and stratified as medium-risk patients. At the start of the intensification phase, the asparagine levels were normal in almost all patients (normal range 40-80 μM).7

Hypersensitivity may lead to asparaginase treatment interruptions and decreased efficacy4,9

  • Most hypersensitivity reactions occur during consolidation10
  • Replacement therapy should begin as soon as clinically possible, ideally within 48 to 72 hours following a hypersensitivity reaction11

Example of standard protocol: Scheduled doses of PEG-asparaginase12

Standard Protocol ChartStandard Protocol Chart

Interruptions may impact protocols for patients with high-risk B-ALL (pictured).12

Hypersensitivity 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 minimal immunologic crossreactivity can help preserve patient outcomes9,13

  • Compared to those who experienced hypersensitivity and subsequently missed doses, higher risk (high-risk + slow early responders for SR) patients who switched to an Erwinia-derived asparaginase therapy due to hypersensitivity were at lower risk of relapse and had higher rates of DFS8
  • Rechallenging patients can compromise their outcomes and further expose them to hypersensitivity3,14
 
 

When hypersensitivity threatens patient outcomes, consider switching       
to an immunologically distinct asparaginase.

 
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Help protect patient outcomes

RYLAZE is the only FDA-approved Erwinia asparaginase for the treatment of ALL/LBL for patients who develop hypersensitivity to E. coli asparaginase15

WHY RYLAZE? >

Indication

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

Contraindications

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

Hypersensitivity reactions after the use of RYLAZE occurred in 29% of patients in clinical trials, and it was severe in 6% of patients. Anaphylaxis was observed in 2% of patients after intramuscular administration. Discontinuation of RYLAZE due to hypersensitivity reactions occurred in 5% of patients. Hypersensitivity reactions were higher in patients who received intravenous asparaginase erwinia chrysanthemi (recombinant)-rywn. The intravenous route of administration is not approved.

In patients administered RYLAZE intramuscularly in clinical trials, the median number of doses of RYLAZE that patients received prior to the onset of the first hypersensitivity reaction was 12 doses (range: 1-64 doses). The most commonly observed reaction was rash (19%), and 1 patient (1%) experienced a severe rash.

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.

Premedicate patients prior to administration of RYLAZE as recommended. 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

Pancreatitis, including elevated amylase or lipase, was reported in 20% of patients in clinical trials of RYLAZE and was severe in 8%. Symptomatic pancreatitis occurred in 7% of patients, and it was severe in 6% of patients. Elevated amylase or lipase without symptomatic pancreatitis was observed in 13% 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.

Thrombosis

Serious thrombotic events, including sagittal sinus thrombosis and pulmonary embolism, have been reported in 1% of patients following treatment with RYLAZE. 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.

Hemorrhage

Bleeding was reported in 25% of patients treated with RYLAZE, and it was severe in 2%. Most commonly observed reactions were bruising (12%) and nose bleed (9%).

In patients treated with L-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.

Hepatotoxicity

Elevated bilirubin and/or transaminases occurred in 75% of patients treated with RYLAZE in clinical trials, and 26% had Grade ≥3 elevations. Elevated bilirubin occurred in 28% of patients treated with RYLAZE in clinical trials, and 2% had Grade ≥3 elevations. Elevated transaminases occurred in 73% of patients treated with RYLAZE in clinical trials, and 25% 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.

Adverse Reactions

The most common adverse reactions (incidence >20%) with RYLAZE are abnormal liver test, nausea, musculoskeletal pain, infection, fatigue, headache, febrile neutropenia, pyrexia, hemorrhage, stomatitis, abdominal pain, decreased appetite, drug hypersensitivity, hyperglycemia, diarrhea, pancreatitis, and hypokalemia.

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; ASP=PEG-asparaginase; B-ALL=B-cell acute lymphoblastic leukemia; DCOG=Dutch Childhood Oncology Group; DFS=disease-free survival; E. coli=Escherichia coli; HD=high dose; 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 October 9, 2023. https://ufhealth.org/clinical-trials/inotuzumab-ozogamicin-and-post-induction-chemotherapy-in-treating-patients-with-high-risk-b-all-mix#details 13. Maese L, Loh ML, Choi MR, et al. Recombinant Erwinia asparaginase (JZP458) in acute lymphoblastic leukemia: results from the phase 2/3 AALL1931 study. Blood. 2023;141(7):704-712. 14. Swanson HD, Panetta JC, Barker PJ, et al. Predicting success of desensitization after pegaspargase allergy. Letter. Blood. 2020;135(1):71-75. 15. RYLAZE [package insert]. Palo Alto, CA: Jazz Pharmaceuticals, Inc.

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Indication

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

IMPORTANT SAFETY 
INFORMATION AND INDICATION

Contraindications

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
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RYLAZE is a registered trademark of Jazz Pharmaceuticals Ireland Limited.

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