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Asparaginase has been a core component of multiagent treatment regimens in ALL/LBL for more than 45 years1

Asparaginase deprives leukemia cells of asparagine1

  • Asparaginase converts serum asparagine into aspartic acid and ammonia, depriving leukemia cells of asparagine1
  • The depletion of asparagine prohibits RNA and protein synthesis, leading to leukemia cells being unable to proliferate and survive1,2

Since the introduction of asparaginase in ALL treatment protocols, survival estimates have seen steady improvement1,3

Asparaginase Survival Outcomes ChartAsparaginase Survival Outcomes Chart

Adapted from Pui et al, 2013.3

Kaplan-Meier analysis of survival for 2852 children with newly diagnosed ALL who were enrolled in 15 consecutive studies at St. Jude Children’s Research Hospital from 1962 to 2007. Ten-year survival estimates are shown.3

 

Maintaining periods of asparaginase activity over the course of therapy is essential to the treatment success of patients treated for ALL/LBL5

 
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Sustained asparaginase activity is critical to patient outcomes5

Review data from COG about the impact of asparaginase on disease-free survival for high-risk patients5,6

IMPACT OF ASPARAGINASE >

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:

  • History of serious hypersensitivity reactions to Erwinia asparaginase, including anaphylaxis
  • History of serious pancreatitis during previous asparaginase therapy
  • History of serious thrombosis during previous asparaginase therapy
  • History of serious hemorrhagic events during previous asparaginase therapy
  • Severe hepatic impairment

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, including Hepatic Veno-Occlusive Disease

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.

Hepatotoxicity, including severe, life-threatening, and potential fatal cases of hepatic veno-occlusive disease (VOD), have been observed in patients treated with asparaginase class products in combination with standard chemotherapy, including during the induction phase of multiphase chemotherapy. Do not administer RYLAZE to patients with severe hepatic impairment.

Inform patients of the signs and symptoms of hepatotoxicity. Evaluate bilirubin and transaminases prior to each cycle of RYLAZE and at least weekly during cycles of treatment that include RYLAZE, through four weeks after the last dose of RYLAZE. Monitor frequently for signs and symptoms of hepatic VOD, which may include rapid weight gain, fluid retention with ascites, hepatomegaly (which may be painful), and rapid increase of bilirubin. For patients who develop abnormal liver tests after RYLAZE, more frequent monitoring for liver test abnormalities and clinical signs and symptoms of VOD is recommended. In the event of serious liver toxicity, including VOD, 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; COG=Children's Oncology Group; LBL=lymphoblastic lymphoma; RNA=ribonucleic acid.

References: 1. Egler RA, Ahuja SP, Matloub Y. L–asparaginase in the treatment of patients with acute lymphoblastic leukemia. J Pharmacol Pharmacother. 2016;7(2):62-71. 2. Pavlova NN, Hui S, Ghergurovich JM, et al. As extracellular glutamine levels decline, asparagine becomes an essential amino acid. Cell Metab. 2018;27(2):428-438. 3. Pui C-H, Evans WE. A 50-year journey to cure childhood acute lymphoblastic leukemia. Semin Hematol. 2013;50(3):185-196. 4. Salzer WL, Asselin BL, Plourde PV, et al. Development of asparaginase Erwinia chrysanthemi for the treatment of acute lymphoblastic leukemia. Ann N Y Acad Sci. 2014;1329:81-92. 5. Salzer W, Bostrom B, Messinger Y, et al. Asparaginase activity levels and monitoring in patients with acute lymphoblastic leukemia. Leuk Lymphoma. 2018;59(8):1797-1806. 6. 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.

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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:

  • History of serious hypersensitivity reactions to Erwinia asparaginase, including anaphylaxis
  • History of serious pancreatitis during previous asparaginase therapy
  • History of serious thrombosis during previous asparaginase therapy
  • History of serious hemorrhagic events during previous asparaginase therapy
  • Severe hepatic impairment