Summary Safety Review - Rylaze (crisantaspase) - Assessing the Potential Risk of Hepatic Sinusoidal Obstruction Syndrome

Rylaze (crisantaspase)

Hepatic sinusoidal obstruction syndrome (SOS) (a potentially fatal condition where small veins in the liver become blocked), previously known as veno-occlusive disease (VOD)

• Health Canada’s review found a possible link between the use of Rylaze and the risk of hepatic SOS.

• Health Canada will work with the manufacturer to update the product safety information in the Canadian product monograph (CPM) to include the risk of hepatic SOS.

Rylaze belongs to a class of prescription drugs called asparaginases. In Canada, there are 2 long-acting asparaginase therapies (Asparlas [calaspargase pegol] and Oncaspar [pegaspargase]), for which the CPMs include the risk of hepatic SOS, and 1 short-acting asparaginase therapy (Rylaze), for which the CPM does not include the risk of hepatic SOS.

Health Canada reviewed the potential risk of hepatic SOS with the use of Rylaze. This safety review was triggered by a labelling update in the United States (U.S.) for all asparaginase therapies. Recognizing that Rylaze has only recently entered the Canadian market, this review also considered evidence related to other short-acting asparaginase therapies authorized internationally.

• Rylaze is a prescription drug authorized for sale in Canada for the treatment of specific types of cancer of the blood and bone marrow (acute lymphoblastic leukemia or lymphoblastic lymphoma) in adults and pediatric patients 1 year of age and older. It is most commonly used when patients have had a severe hypersensitivity reaction to similar medicines and had to stop using them.

• Rylaze has been marketed in Canada since 2023. It is available as a solution for intramuscular (into a muscle) injection at 10mg/0.5mL.

• Health Canada reviewed the available information provided by the manufacturer and the U.S. Food and Drug Administration, as well as from searches of the Canada Vigilance Database^a and the scientific literature.

• At the time of the review, Health Canada had received 1 Canadian report of hepatic SOS in a patient taking Rylaze. However, this case did not meet the criteria for further assessment to determine if there was a link.

• Health Canada reviewed 8 international cases of hepatic SOS in patients taking short-acting asparaginase, including 2 cases associated with Rylaze and 3 cases from the published literature.^1-3 All 8 cases were found to be possibly linked to the use of short-acting asparaginase.

  • Five of the 8 cases reviewed involved pediatric patients.

  • Five of the 8 cases were considered life-threatening, including 3 deaths (1 in an adult patient and 2 in pediatric patients).

  • Though confounders (other factors that may have contributed to the occurrence of hepatic SOS, such as the use of other medications as part of the cancer treatment and underlying medical conditions that are known to cause hepatic dysfunction) were present in all 8 cases, a contributory role for short-acting asparaginase could not be ruled out.

• Health Canada also reviewed 10 articles published in the scientific literature, which supported a possible link between the use of short-acting asparaginase and the risk of hepatic SOS.^1-10

• Health Canada’s review found a possible link between the use of Rylaze and the risk of hepatic SOS.

• Health Canada will work with the manufacturer to update the CPM to include the risk of hepatic SOS.

• Health Canada encourages consumers and healthcare professionals to report any side effects related to the use of Rylaze, and other health products, to the Canada Vigilance Program.

• Health Canada will continue to monitor safety information involving Rylaze, as it does for all health products on the Canadian market, to identify and assess potential harms. Health Canada will take appropriate and timely action should new health risks be identified.

The analysis that contributed to this safety review included scientific and medical literature, Canadian and international information, and what is known about the use of Rylaze both in Canada and internationally.

For additional information, contact the Marketed Health Products Directorate.

1. Papadopoulos A, Ntaios G, Kaiafa G, et al. Veno-occlusive disease of the liver during induction therapy for acute lymphoblastic leukemia. International Journal of Hematology. 2008;88(4):441-442. doi:https://doi.org/10.1007/s12185-008-0172-6

2. Yamamoto, S., Akiyama, K., Oyama, N. et al. Fatal hepatic sinusoidal obstruction syndrome in a child with primary CNS lymphoma during induction therapy. International Journal of Hematology. 2012;96(2):284-286. doi:https://doi.org/10.1007/s12185-012-1128-4

3. Sahoo RK, Sharma A. Sinusoidal obstruction syndrome during induction therapy for acute lymphoblastic leukemia managed with N-acetyl Cysteine. Pediatric Blood & Cancer. 2011;57(4):700. doi:https://doi.org/10.1002/pbc.23142

4. Mondelaers V, Suciu S, De Moerloose B, et al. Prolonged versus standard native E. coli asparaginase therapy in childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma: final results of the EORTC-CLG randomized phase III trial 58951. Haematologica. 2017;102(10):1727-1738. doi: https://doi.org/10.3324/haematol.2017.165845. Epub 2017 Jul 27.

5. Cheng C, Dores GM, Nayernama, A, et al. Hepatic veno-occlusive disease with asparaginase products: a review of cases reported to the FDA adverse event reporting system and published in the literature. Pediatric Hematology and Oncology. 2024;41(7):519–529. doi:https://doi.org/10.1080/08880018.2024.2395365

6. Toksvang LN, De Pietri S, Nielsen SN, et al. Hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites. Pediatric Blood & Cancer. 2017;64(9): e26519. doi:https://doi.org/10.1002/pbc.26519

7. Hauben M, Vegni F, Reich L, et al. Postmarketing hepatic adverse event experience with PEGylated/non-PEGylated drugs: a disproportionality analysis. European Journal of Gastroenterology & Hepatology. 2007;19(11):934-41. doi:https://doi.org/10.1097/meg.0b013e3282efa502

8. Mertens R, Brost H, Granzen B, Nowak-Göttl U. Antithrombin treatment of severe hepatic veno-occlusive disease in children with cancer. European Journal of Pediatrics. 1999;158(3):S154-S158. doi:https://doi.org/10.1007/PL00014344

9. Mauro M, Saggiorato G, Sartori MT, et al. Venoocclusive disease due to chemotherapy for pediatric acute lymphoblastic leukemia is associated with increased levels of plasminogen-activator inhibitor-1. Pediatric Blood & Cancer. 2018;65(6). doi:https://doi.org/10.1002/pbc.26963

10. Collins PW. Pathogenesis of Thrombotic Complications of Haematological Malignancies. Hematology. 1999;1(1):19-26. doi:https://doi.org/10.1080/10245332.1996.11746281

1. Canadian reports can be accessed through the Canada Vigilance Online Database.