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Pediatric-inspired asparaginase-containing regimens are recommended treatment options for frontline treatment of AYA patients with ALL1

ALL outcomes have improved over the past 40 years in pediatric patients, while AYA patients* have inferior outcomes compared to the pediatric population2,3

Acute lymphoblastic leukemia relative survival rates by time since diagnosis in pediatric and AYA patients4

Acute lymphoblastic leukemia relative survival rates

*AYA patients are defined as patients aged 15 to 39 years at diagnosis.1

  • ​​KM curve of ALL relative survival rates by time since diagnosis, including all stages by age, both sexes, and all races. Data from the SEER registries, 2000-20204

AYA survival rates decline with increasing age4

  • 92.3% (95% CI: 91.6-93.0) 5-year relative survival rate in patients aged <15 years
  • 66.9% (95% CI: 65.1-68.6) 5-year relative survival rate in patients aged 15 to 39 years

Treating AYA patients can be challenging due to several factors5-7

  • Differences in disease biology5,6
  • Lack of uniform treatment strategy5
  • Underrepresentation in clinical trials5
  • Treatment compliance/adherence7
 

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for ALL recommend as preferred regimens certain pediatric-inspired asparaginase-containing regimens in the treatment of AYA patients with:

  • Ph- B-ALL (frontline therapy)1
  • T-ALL (frontline therapy)1
  • Pediatric-inspired regimens are not recommended for Ph+
 

NCCN® makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.1

The majority of frontline therapy protocols recommended by the NCCN Guidelines® for AYA patients with Ph-negative ALL include asparaginase as part of the treatment regimen.1

Preferred multiagent frontline therapy regimens for AYA patients (ages 15-39) are based on protocols and data from multi-institutional studies1,a

[GRAPH WRAPPER DO NOT DELETE]

aThis age range (15-39) is not a firm reference point because some of the recommended regimens have not been comprehensively tested across all ages.

bPediatric-inspired regimen.

Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Lymphoblastic Leukemia V.2.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed July 22, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.1

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Protocol

Ph- B-ALL

Preferred
Other Recommended

T-ALL

Preferred
Other Recommended

CALGB 10403b

w
w

COG AALL 0434b

w

DFCI ALLbbased on DFCI Protocol 00-01

w
w

GRAALL-2005b

w
w

PETHEMA ALL-96b(if aged <30 years)

w
w

Dose-adjusted Hyper-CVAD

wo
wo

USC/MSKCC ALLbregimen based on CCG-1882 regimen (if aged ≥18 years)

w
w

Linker 4-drug regimen(if aged <60 years)

w
w

ECOG 1910

w
= With asparaginase
= Without asparaginase

Ph- B-ALL

= With asparaginase
= Without asparaginase
Protocol
Preferred
Other Recommended

CALGB 10403b

w

COG AALL 0434b

DFCI ALLbbased on DFCI Protocol 00-01

w

GRAALL-2005b

w

PETHEMA ALL-96b(if aged <30 years)

w

Dose-adjusted Hyper-CVAD

wo

USC/MSKCC ALLbregimen based on CCG-1882 regimen (if aged ≥18 years)

w

Linker 4-drug regimen(if aged <60 years)

w

ECOG 1910

w

T-ALL

= With asparaginase
= Without asparaginase
Protocol
Preferred
Other Recommended

CALGB 10403b

w

COG AALL 0434b

w

DFCI ALLbbased on DFCI Protocol 00-01

w

GRAALL-2005b

w

PETHEMA ALL-96b(if aged <30 years)

w

Dose-adjusted Hyper-CVAD

wo

USC/MSKCC ALLbregimen based on CCG-1882 regimen (if aged ≥18 years)

w

Linker 4-drug regimen(if aged <60 years)

w

ECOG 1910

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; AYA=adolescent and young adult; B-ALL=B-cell acute lymphoblastic leukemia; CALGB=Cancer and Leukemia Group B; CCG=Children's Cancer Group; CI=confidence interval; COG=Children’s Oncology Group; CVAD=cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone; DFCI=Dana-Farber Cancer Institute; ECOG=Eastern Cooperative Oncology Group; GRAALL=Group for Research on Adult Acute Lymphoblastic Leukemia; KM=Kaplan-Meier; MSKCC=Memorial Sloan Kettering Cancer Center; PETHEMA=Programa de Estudio y Tratamiento de las Hemopatías Malignas; Ph-=Philadelphia chromosome negative; Ph+=Philadelphia chromosome positive; SEER=surveillance, epidemiology, and end results; T-ALL=T-cell acute lymphoblastic leukemia; USC=University of Southern California.

References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Lymphoblastic Leukemia. V.2.2024. All rights reserved. Accessed July 22, 2024. To view the most recent and complete version of the guidelines, go online to NCCN.org 2. 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. 3. Wolfson JA, Richman JS, Sun C-L, et al. Causes of inferior outcome in adolescents and young adults with acute lymphoblastic leukemia: across oncology services and regardless of clinical trial enrollment. Cancer Epidemiol Biomarkers Prev. 2018;27(10):1133-1141. 4. SEER*Explorer: An interactive website for SEER cancer statistics [Internet]. Surveillance Research Program, National Cancer Institute; 2024 Apr 17. [updated: 2024 Jun 27; cited 2024 Sep 26]. Available from: https://seer.cancer.gov/statistics-network/explorer/. Data source(s): SEER Incidence Data, November 2023 Submission (1975-2021), SEER 22 registries (excluding Illinois and Massachusetts). Expected Survival Life Tables by Socio-Economic Standards. 5. Rajendra A, Jain H, Bonda VN, et al. Outcomes and prognostic factors in adolescents and young adults with ALL treated with a modified BFM-90 protocol. Blood Adv. 2021;5(5):1178-1193. 6. Lee JW. Optimal therapy for adolescents and young adults with acute lymphoblastic leukemia-current perspectives. Blood Res. 2020;55(S1):S27-S31. 7. Robertson EG, Wakefield CE, Marshall KH, et al. Strategies to improve adherence to treatment in adolescents and young adults with cancer: a systematic review. Clin Oncol Adolesc Young Adults. 2015;5:35-49. 8. Ram R, Wolach O, Vidal L, et al. Adolescents and young adults with acute lymphoblastic leukemia have a better outcome when treated with pediatric-inspired regimens: systematic review and meta-analysis. Am J Hematol. 2012;87(5):472-478.

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