A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403
Author(s): Wendy Stock, Selina M. Luger, Anjali S. Advani, Jun Yin, Richard C. Harvey, Charles G. Mullighan, Cheryl L.
Willman, Noreen Fulton,
Kristina M. Laumann, Greg Malnassy, Elisabeth Paietta, Edy Parker, Susan Geyer, Krzysztof Mro´ zek, Clara D. Bloomfield,
Ben Sanford,
Guido Marcucci, Michaela Liedtke, David F. Claxton, Matthew C. Foster, Jeffrey A. Bogart, John C. Grecula,
Frederick R. Appelbaum, Harry Erba, Mark R. Litzow, Martin S. Tallman, Richard M. Stone, and Richard A. Larso
Published: April 2019
Copyright: ©2019 by The American Society of Hematology
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Disclaimer
This journal article reprint is being provided as a professional courtesy by Jazz Pharmaceuticals, Inc. This scientific publication contains information that may or may not be contained within the accompanying package insert. The study discussed in this scientific publication did not include any Jazz Pharmaceuticals product. Providing this reprint should not be construed as a recommendation for use of any Jazz Pharmaceuticals product for nonapproved uses. Prior to prescribing any Jazz Pharmaceuticals product, please refer to the accompanying Prescribing Information, which includes the approved indication and a discussion of the benefits and risks associated with our product.
The opinions expressed in this reprint do not necessarily reflect those of Jazz Pharmaceuticals. Readers are encouraged to contact the primary authors with questions regarding the content of the reprint. Jazz Pharmaceuticals does not assume responsibility for any injury and/or damage to persons or property out of or related to any use of the information contained in this reprint.
Financial Disclosure Statement
At the time of publication, W.S. served on advisory boards for Pfizer, Amgen, and Jazz Pharmaceuticals; S.M.L. received clinical trial support from Onconova, Celgene, Cyclacel, Hoffman-La Roche, Incyte, Biosight, and Kura and served on an advisory board for Pfizer; A.S.A. received honoraria from Pfizer, Sigma Tau, and Jazz Pharmaceuticals; C.G.M. received honoraria from Amgen and Pfizer; E. Parker owns stock in Teva Pharmaceuticals and Johnson & Johnson; M.S.T. received research funding from AbbVie, AROG, Cellerant, Orsenix, ADC Therapeutics, and Biosight and served on advisory boards for Daiicho-Sankyo, Orsenix, KAHR, Rigel, Abbvie, and Nohla. The remaining authors declare no competing financial interests.
Detailed information on funding amounts received by the authors of this publication is available at http://www.cms.gov/openpayments.
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.