By Alexandra Lovell, PharmD, BCOP
What is brexucabtagene autoleucel?
Brexucabtagene autoleucel is a modified autologous chimeric antigen receptor (CAR) T-cell immunotherapy. A patient's own T cells are harvested and genetically modified ex vivo to express a CAR targeting CD19. The anti-CD19 CAR includes a murine anti-CD19 single-chain variable fragment linked to CD28 and CD3-zeta costimulatory domains.
How does brexucabtagene autoleucel work?
Brexucabtagene autoleucel binds to cancer cells expressing CD19 and normal B cells. Once the CAR-T cells are engaged, the CD28 and CD3-zeta costimulatory domains activate downstream signaling cascade to cause T-cell activation, proliferation, acquisition of effector functions, and secretion of inflammatory cytokines and chemokines. This leads to the killing of cells that express CD19.
What is this approved for?
Brexucabtagene autoleucel is FDA-approved for treatment of adults with relapsed or refractory mantle cell lymphoma (MCL) or B-cell acute lymphoblastic leukemia (ALL).
What is the basis for this approval?
The ZUMA-2 and ZUMA-3 trials evaluated brexucabtagene autoleucel in relapsed/refractory MCL and ALL, respectively. In ZUMA-2, 60 efficacy-evaluable patients with MCL had a median of three prior lines of therapy (N Engl J Med 2020; doi: 10.1056/NEJMoa1914347). The overall response rate was 85 percent with a complete remission rate of 62 percent and a median time to response was 28 days. The median duration of response was not reached after a median of 12 months of follow-up. In ZUMA-3, 52 percent of the 54 evaluable patients with ALL achieved complete response (Lancet 2021; doi: 10.1016/S0140-6736(21)01222-8). With a median of 7 months of follow-up, the median duration of complete response was not reached. Median time to complete response was 56 days. Notably, patients with CNS disease were excluded from ZUMA-3.
How do you administer this drug?
Brexucabtagene autoleucel is given by intravenous infusion. It is for autologous use only and the patient identity should be verified against the identifiers on the cassette and infusion bag. The product must be thawed and administered over 30 minutes once thawed.
Are there any pre-medications needed?
The patient should receive lymphodepleting chemotherapy (fludarabine and cyclophosphamide) in the days prior to the infusion. Pre-medications include acetaminophen and diphenhydramine or another H1-antihistamine 30-60 minutes prior to infusing the cells.
What are the common side effects associated with brexucabtagene autoleucel (> or =20%)?
The most common adverse events are fever, cytokine release syndrome (CRS), neurologic toxicities, prolonged cytopenias, hypotension, encephalopathy, fatigue, tachycardia, arrhythmia, infection, febrile neutropenia, chills, hypoxia, cough, tremor, musculoskeletal pain, headache, nausea, edema, motor dysfunction, constipation, diarrhea, decreased appetite, dyspnea, rash, insomnia, pleural effusion, and aphasia.
What are the uncommon side effects associated with brexucabtagene autoleucel (less than 20%)?
Coagulopathy, hypersensitivity reactions, abdominal pain, mouth pain, dysphagia, cerebral edema, hypogammaglobulinemia, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, aphasia, dizziness, delirium, anxiety, renal insufficiency, thrombosis, and secondary malignancies have been reported.
Are there any important drug interactions I should be aware of?
There are no drug interactions; however, systemic corticosteroids should be avoided unless used for management of toxicity as they may interfere with the activity of brexucabtagene autoleucel.
How do I adjust the dose in the setting of renal or hepatic insufficiency?
No dose adjustments are needed in patients with renal dysfunction or hepatic impairment, although these patients were not studied. The recommended target dose is 2 x 106 and 1 x 106 CAR-positive T cells per kilogram body weight for MCL and ALL, respectively.
What should my patients know about brexucabtagene autoleucel?
- Brexucabtagene autoleucel is made from cells from each individual patient. The patient's blood will be collected a few weeks prior to the infusion in a process called leukapheresis. Prior to receiving brexucabtagene autoleucel, patients will receive 3 days of chemotherapy.
- Patients should be monitored at a certified health care facility daily for at least 7 days after the infusion for MCL and 14 days for ALL. Side effects can occur weeks after the infusion. Patients must be in close proximity of the health care facility for at least 4 weeks and avoid driving or operating heavy machinery for 8 weeks after the infusion. Patients should always carry the brexucabtagene autoleucel wallet card on them.
- Patients should contact their doctor immediately if they experience fever, infection, chills, difficulty breathing, dizziness or lightheadedness, confusion, or difficulty speaking.
What else should I know about brexucabtagene autoleucel?
Brexucabtagene autoleucel requires each institution that administers it to be enrolled in a Risk Evaluation and Mitigation Strategy (REMS) program. Important aspects of this include having tocilizumab on site and immediately accessible for the treatment of CRS. Additionally, all health care providers involved in the prescribing, dispensing, and administration of brexucabtagene autoleucel are trained in the management of CRS and neurologic toxicities. The full requirement for the REMS program can be found at https://bit.ly/3vfwZWI.
What useful links are available for this drug?
- Drug Information: https://bit.ly/3BgQvG5
- Safety Information: https://bit.ly/3Bpi1RT
- FDA Approval: https://bit.ly/3S5Wgw4
Any ongoing clinical trials related to brexucabtagene autoleucel?
Brexucabtagene autoleucel is also being studied in pediatric and adolescent patients with relapsed or refractory ALL or B-cell non-Hodgkin lymphoma. More information is available at clinicaltrials.gov.
Alexandra Lovell, PHARMD, BCOP, is Clinical Pharmacy Specialist in Leukemia at the University of Texas MD Anderson Cancer Center in Houston.