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Hypersensitivity to E. coli-derived asparaginase

Understand the impact of hypersensitivity to E. coli-derived asparaginase on treatment continuity.

Asparaginase therapy has been a core component of multiagent treatment regimens for patients with acute lymphoblastic leukemia and lymphoblastic lymphoma for more than 45 years.

Asparaginase is an enzyme that targets and mediates hydrolysis of asparagine, an amino acid that leukemia cells—as well as healthy cells—require for growth.

Asparaginase converts serum asparagine into aspartic acid and ammonia, depriving leukemia cells of asparagine.

The depletion of asparagine prohibits protein synthesis, leading to leukemia cells being unable to proliferate and survive.

Asparaginase-containing treatment regimens for ALL and LBL most commonly utilize long-acting E. coli-derived asparaginase.

Exposure to asparaginase treatment can trigger an immune response in the body that results in the proliferation of antibodies from plasma B cells, which can lead to hypersensitivity.

Immunoglobulin E, or IgE, antibodies can activate immune cells called mast cells, which are central to the physiology that underlies clinical hypersensitivity.

IgE antibodies attach their fragment crystallizable, or Fc region, to the mast cell, exposing their fragment antigen binding region, known as Fab, to encounter an antigen.

If a patient is re-exposed to the antigen, the Fab region of the IgE antibody crosslinks to the antigen.

When IgE antibodies are bound to mast cells in the presence of asparaginase, mast-cell degranulation is triggered, leading to the release of immune mediators of chemical substances, such as histamines, prostaglandins, leukotrienes, and cytokines, which trigger activation of other immune cells.

In this manner, these IgE antibodies can cause hypersensitivity.

Hypersensitivity can affect a range of organ systems.

Severe hypersensitivity reactions can include anaphylaxis and even lead to death.

Immunoglobulin G, or IgG, is another type of antibody.

IgG antibodies can bind and create immune complexes with asparaginase in the blood, leading to phagocytosis, which neutralizes asparaginase in the blood. This leads to the rapid clearance of asparaginase, and significant reduction in asparaginase activity.

IgG antibodies can compromise asparaginase efficacy by shortening asparaginase half-life, causing subtherapeutic asparaginase levels, and reduced depletion of asparagine.

To help maintain asparaginase activity and optimal asparagine depletion, patients experiencing hypersensitivity to E. coli-derived asparaginase should switch to an immunologically distinct asparaginase.

The switch should occur as soon as clinically possible, ideally within 48 to 72 hours, to ensure that asparaginase activity is maintained and patients do not miss a scheduled dose.

Patients who develop hypersensitivity to asparaginase therapy are at increased risk of experiencing another reaction if treated again with asparaginase derived from the same source.

Switching to recombinant Erwinia chrysanthemi-derived asparaginase—which has minimal immunologic cross-reactivity to E. coli-derived asparaginase—can help prevent missed doses and provide sustained asparaginase activity.

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.

E. coli=Escherichia coli.

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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