Important Safety Information on Yescarta (axicabtagene ciloleucel) and the Risk of Cerebral Edema in Primary Mediastinal B Cell Lymphoma (PMBCL)

Patients being treated with Yescarta for primary mediastinal B-cell lymphoma (PMBCL) may be at increased risk for developing cerebral edema, including fatal events, compared to other large B-cell lymphomas. Cerebral edema is a known risk of CAR T-cell therapy and is described in the Yescarta Canadian product monograph (CPM).

 

Audience

Healthcare providers who may prescribe, administer or monitor patients receiving chimeric antigen receptor (CAR) T-cell therapies at treatment centres accredited to administer Yescarta (axicabtagene ciloleucel).

 

Key messages

• Patients being treated with Yescarta (axicabtagene ciloleucel) for primary mediastinal B-cell lymphoma (PMBCL) may be at increased risk for developing cerebral edema, including fatal events, compared to other large B-cell lymphomas.
• While cerebral edema is a known manifestation of more severe immune effector cell-associated neurotoxicity syndrome (ICANS) with chimeric antigen receptor (CAR) T-cell therapy, patients with PMBCL may be at a higher risk of this complication.
• Healthcare professionals are advised to:
  • Closely monitor for symptoms of ICANS in PMBCL patients during the first 7-14 days of Yescarta therapy, as cerebral edema with acutely increasing intracranial pressure (ICP) can develop rapidly following mild neurological symptoms.
  • Promptly initiate treatment for ICANS as per applicable guidelines. Initiate prompt evaluation (e.g., neuroimaging) and consultation (e.g., neurosurgery) if cerebral edema is suspected.
  • Note that published case reports have suggested that intrathecal therapy may be useful for the management of ICANS.
• Health Canada is continuing to review this issue for both Yescarta and the CAR T-cell therapy class, and will take additional risk minimization actions, if required, when the review is complete.

 

Background

Yescarta is a CD19-directed genetically modified autologous T-cell immunotherapy indicated for the treatment of adult patients with:

• diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBL) that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy.
• relapsed or refractory large B-cell lymphoma (LBCL) after two or more lines of systemic therapy, including DLBCL not otherwise specified, PMBCL, HGBL, and DLBCL arising from follicular lymphoma.

Yescarta is also authorized under a Notice of Compliance with conditions (NOC/c) for the treatment of adult patients with relapsed or refractory grade 1, 2 or 3a follicular lymphoma (FL) after two or more lines of systemic therapy, pending the results of trials to verify its clinical benefit.

Cerebral edema is a known risk of CAR T-cell therapy and is included in the Yescarta CPM.  Recently, the manufacturer investigated the cumulative incidence of cerebral edema reported in the post-market setting by disease subtype and year (since 2017). The identified risk of cerebral edema overall in lymphoma was not found to be higher than the rate known at the time of labelling. However, an increased reporting rate for cerebral edema, including fatal events, was observed in patients with PMBCL compared to other large B-cell lymphomas.

The cerebral edema reporting rate for patients with PMBCL was found to be 1.4% (0.9% fatal) compared with 0.2% (0.1% fatal) for patients with DLBCL. The cerebral edema reporting rate in US and EU patient registry studies was consistent at 1.7% (0.8% fatal) in PMBCL and 0.7% (0.2% fatal) in DLBCL.

Cerebral edema may evolve as a manifestation of ICANS but does not follow a predictable clinical course and, in some cases, has occurred after only mild neurologic symptoms.

The etiology of cerebral edema in PMBCL patients is not fully understood. Risk factors include, but are not limited to: Superior vena cava (SVC) syndrome, sepsis or other systemic infections, kidney disease, hyponatremia, large mediastinal mass, brain radiation and other prior therapies.

Health Canada is continuing to review this issue for both Yescarta and the CAR-T cell therapy class, and will take additional risk mitigation actions, if required, when the review is complete.

 

Information for consumers

Yescarta is a treatment for large B-cell lymphoma and follicular lymphoma – two forms of white blood cell cancer.

• For large B-cell lymphomas, Yescarta is used when the standard treatment has not worked or if the cancer returns within 12 months after that standard treatment. It is also used when patients have already had two or more other treatments and the cancer did not respond or got worse after initially getting better.
• For follicular lymphoma, Yescarta is used after two or more treatments have not worked or the cancer has returned after treatment. Yescarta has been authorized with conditions for this use, meaning it has passed Health Canada’s review, but the manufacturer has agreed to complete more studies to ensure the drug works the way it should.

Serious brain swelling (called cerebral edema) is a known risk with Yescarta. However, recent information has revealed that patients receiving Yescarta for primary mediastinal B-cell lymphoma (PMBCL) may have a higher chance of developing cerebral edema compared to other types of lymphoma. This condition can happen quickly, sometimes after only mild symptoms have initially occurred. Healthcare professionals are being advised to monitor patients with PMBCL more frequently during the first one to two weeks of Yescarta treatment. Patients should discuss any questions or concerns about this information with their healthcare professional.

 

Information for healthcare professionals

An increased reporting rate for cerebral edema, including fatal events, was observed in patients with PMBCL compared to other large B-cell lymphomas.

Healthcare professionals are advised to:

• Closely monitor for symptoms of ICANS in PMBCL patients during the first 7-14 days of Yescarta therapy, as cerebral edema with acutely increasing ICP can develop rapidly following mild neurological symptoms.
• Promptly initiate treatment for ICANS per applicable guidelines. Initiate prompt evaluation (e.g., neuroimaging) and consultation (e.g., neurosurgery) if cerebral edema is suspected.
• Note that published case reports have suggested that intrathecal therapy may be useful for the management of ICANS. Clinical status and contraindications for lumbar puncture should be appropriately considered.

 

Action taken by Health Canada

Health Canada has worked with Gilead Sciences Canada, Inc. to prepare this alert for Yescarta. Health Canada is communicating this important safety information to healthcare professionals and Canadians via the Recalls and Safety Alerts Database on the Healthy Canadians Web Site. This communication will be further distributed through the MedEffect^TM e-Notice email notification system. Health Canada is reviewing the issue and may take additional actions when the review is complete.

 

Report health or safety concerns

Managing marketed health product-related side effects depends on healthcare professionals and consumers reporting them. Any case of cerebral edema or other serious or unexpected side effects in patients receiving Yescarta should be reported to Gilead Sciences Canada, Inc. or Health Canada.

Gilead Sciences Canada, Inc.

Medical Information Department

6925 Century Avenue, Mississauga Ontario, L5N 7K2

Toll free: 1-866-207-4267

Email: CA.MedInfo@gilead.com

To correct your mailing address or fax number, contact Gilead Sciences Canada, Inc.

You can report any suspected adverse reactions associated with the use of health products to Health Canada by:

• Calling toll-free at 1-866-234-2345; or
• Visiting MedEffect Canada's Web page on Adverse Reaction Reporting (http://www.hc-sc.gc.ca/dhp-mps/medeff/report-declaration/index-eng.php) for information on how to report online, by mail or by fax.

For other health product inquiries related to this communication, contact Health Canada at:

Marketed Health Products Directorate, Bureau of Biologics, Radiopharmaceuticals and Self-Care Products

E-mail: mhpd-dpsc@hc-sc.gc.ca

Telephone: 613-954-6522

Fax: 1-800-465-7735

 

Original signed by

Lieven Billen

Director, Medical Affairs

 

References

Contact the company for a copy of any references.