Breyanzi^® Clinical Perspectives: Treating a young and fit, transplant-ineligible patient with 2L LBCL

Voiceover:

BREYANZI is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:

• adult patients with large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:
  • refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy; or
  • refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplantation (HSCT) due to comorbidities or age; or
  • relapsed or refractory disease after two or more lines of systemic therapy.

Limitations of Use: BREYANZI is not indicated for the treatment of patients with primary central nervous system lymphoma.

Dr. Nazish Ahmad:

I have this patient, Mae. She is 60 years old. Nonprofit volunteer. She was diagnosed with diffuse large B-cell lymphoma. She received 3 cycles of R-CHOP, and we repeated some imaging. And unfortunately, she had refractory disease. Her ECOG performance status is 2, ejection fraction of 55%, and creatinine clearance of 60. What would you offer this patient?

Dr. Patrick Connor Johnson:

So this is a patient I would absolutely be thinking about CAR T-cell therapy with liso-cel. We actually have a trial, the PILOT trial, which focused on transplant-ineligible adults with relapsed refractory large B-cell lymphoma. And patients in this trial would receive standard dosing of liso-cel. But the definition of transplant eligible was based on in some patients their age, and in other patients their comorbid conditions. Close to a quarter of patients in that trial actually had an ECOG performance status of 2. And so patients that were transplant ineligible could certainly receive liso-cel, regardless of time from relapse for their initial therapy. In that trial, patients had a response rate of 80% and a complete response rate of 54%, which I think is encouraging efficacy data in a patient population ineligible for transplant.

Dr. Nazish Ahmad:

Breyanzi was studied in the broadest range of patients with second-line large B-cell lymphoma, including older patients with moderate comorbidities. The PILOT trial included transplant-ineligible patients. The primary endpoint was overall response rate. Select secondary endpoints included complete response, duration of response, progression-free survival, event-free survival, and overall survival. Median patient age was 74 years, ranging from 53 to 84 years old. Patients included in the study had ECOG performance status ranging from 0 to 2.

Dr. Patrick Connor Johnson:

In the PILOT trial, more than half of patients achieved deep and durable complete responses with liso-cel. The overall response rate was 80%, with a 54% complete response rate. There are analysis limitations for PFS and overall survival. The median PFS was 9 months, and median overall survival was not reached.

Dr. Nazish Ahmad:

How do you talk to your patients about Breyanzi and its side effects?

Dr. Patrick Connor Johnson:

I typically highlight cytokine release syndrome, or CRS, and neurotoxicity. For CRS, this occurred in 45% of patients in the clinical trial of liso-cel in the second-line large B-cell lymphoma setting. It was Grade 3 or higher in 1% of patients. Neurotoxicity occurred in 27% of patients, was Grade 3 in 7% of patients, and there were no Grade 4 or Grade 5 events. One of the other things you may have heard about is that there's been a change in some of the monitoring requirements with CAR T cells. Previously, patients had to stay within 2 hours of the treating center for 4 weeks and couldn't drive for 8 weeks after infusion. And those have been reduced to 2 weeks, both for monitoring and for driving. I'm curious if you think that's going to impact some of your conversations with patients.

Dr. Nazish Ahmad:

Oh, absolutely. You know, our patients, especially from where I am, it's very important for them to get to be able to drive to their doctors and other things that they want to do in their lives. So, absolutely, that is a huge impact.

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Important Safety Information

WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, AND SECONDARY HEMATOLOGICAL MALIGNANCIES

• Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving BREYANZI. Do not administer BREYANZI to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab with or without corticosteroids.
• Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving BREYANZI, including concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with BREYANZI. Provide supportive care and/or corticosteroids as needed.
• T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including BREYANZI.

Cytokine Release Syndrome

Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred following treatment with BREYANZI. In clinical trials of BREYANZI, which enrolled a total of 769 patients with non-Hodgkin lymphoma (NHL), CRS occurred in 56% of patients, including ≥ Grade 3 CRS in 3.4% of patients. The median time to onset was 5 days (range: 1 to 63 days). CRS resolved in 99% of patients with a median duration of 5 days (range: 1 to 37 days). One patient had fatal CRS and 5 patients had ongoing CRS at the time of death. The most common manifestations of CRS (≥10%) were fever, hypotension, chills, tachycardia, hypoxia, and headache.

Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, diffuse alveolar damage, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).

Ensure that 2 doses of tocilizumab are available prior to infusion of BREYANZI.

Neurologic Toxicities

Neurologic toxicities that were fatal or life-threatening, including immune effector cell-associated neurotoxicity syndrome (ICANS), occurred following treatment with BREYANZI. Serious events including cerebral edema and seizures occurred with BREYANZI. Fatal and serious cases of leukoencephalopathy, some attributable to fludarabine, also occurred.

In clinical trials of BREYANZI, CAR T cell-associated neurologic toxicities occurred in 32% of patients, including ≥ Grade 3 cases in 10% of patients. The median time to onset of neurotoxicity was 8 days (range: 1 to 63 days). Neurologic toxicities resolved in 88% of patients with a median duration of 7.5 days (range: 1 to 119 days). Of patients developing neurotoxicity, 83% also developed CRS.

The most common neurologic toxicities (≥5%) included encephalopathy, tremor, aphasia, delirium, and headache.

CRS and Neurologic Toxicities Monitoring

Monitor patients daily for at least 7 days following BREYANZI infusion for signs and symptoms of CRS and neurologic toxicities and assess for other causes of neurological symptoms. Continue to monitor patients for signs and symptoms of CRS and neurologic toxicities for at least 2 weeks after infusion and treat promptly. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated. Manage neurologic toxicity with supportive care and/or corticosteroid as needed. Advise patients to avoid driving for at least 2 weeks following infusion. Counsel patients to seek immediate medical attention should signs or symptoms of CRS or neurologic toxicity occur at any time.

Hypersensitivity Reactions

Allergic reactions may occur with the infusion of BREYANZI. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO).

Serious Infections

Severe infections, including life-threatening or fatal infections, have occurred in patients after BREYANZI infusion. In clinical trials of BREYANZI, infections of any grade occurred in 33% of patients, with Grade 3 or higher infections occurring in 12% of all patients. Grade 3 or higher infections with an unspecified pathogen occurred in 7%, bacterial infections in 3.5%, viral infections in 2%, and fungal infections in 0.7% of patients. One patient who received 4 prior lines of therapy developed a fatal case of John Cunningham (JC) virus progressive multifocal leukoencephalopathy 4 months after treatment with BREYANZI. One patient who received 3 prior lines of therapy developed a fatal case of cryptococcal meningoencephalitis 35 days after treatment with BREYANZI.

Febrile neutropenia developed after BREYANZI infusion in 8% of patients. Febrile neutropenia may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated.

Monitor patients for signs and symptoms of infection before and after BREYANZI administration and treat appropriately. Administer prophylactic antimicrobials according to standard institutional guidelines. Avoid administration of BREYANZI in patients with clinically significant, active systemic infections.

Viral reactivation: Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. In clinical trials of BREYANZI, 35 of 38 patients with a prior history of HBV were treated with concurrent antiviral suppressive therapy. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing. In patients with prior history of HBV, consider concurrent antiviral suppressive therapy to prevent HBV reactivation per standard guidelines.

Prolonged Cytopenias

Patients may exhibit cytopenias not resolved for several weeks following lymphodepleting chemotherapy and BREYANZI infusion. In clinical trials of BREYANZI, Grade 3 or higher cytopenias persisted at Day 29 following BREYANZI infusion in 35% of patients, and included thrombocytopenia in 25%, neutropenia in 22%, and anemia in 6% of patients. Monitor complete blood counts prior to and after BREYANZI administration.

Hypogammaglobulinemia

B-cell aplasia and hypogammaglobulinemia can occur in patients receiving BREYANZI. In clinical trials of BREYANZI, hypogammaglobulinemia was reported as an adverse reaction in 9% of patients. Hypogammaglobulinemia, either as an adverse reaction or laboratory IgG level below 500 mg/dL after infusion, was reported in 30% of patients. Monitor immunoglobulin levels after treatment with BREYANZI and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement as clinically indicated.

Live vaccines: The safety of immunization with live viral vaccines during or following BREYANZI treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during BREYANZI treatment, and until immune recovery following treatment with BREYANZI.

Secondary Malignancies

Patients treated with BREYANZI may develop secondary malignancies. T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including BREYANZI. Mature T cell malignancies, including CAR-positive tumors, may present as soon as weeks following infusion, and may include fatal outcomes. Monitor lifelong for secondary malignancies. In the event that a secondary malignancy occurs, contact Bristol-Myers Squibb at 1-888-805-4555 for reporting and to obtain instructions on collection of patient samples for testing.

Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome (IEC-HS)

Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome (IEC-HS), including fatal or life-threatening reactions, occurred following treatment with BREYANZI. Seven out of 769 (0.9%) patients with R/R NHL exposed to BREYANZI developed IEC-HS. Time to onset of IEC-HS ranged from 7 to 32 days. Of the 7 patients, 3 patients developed IEC-HS with overlapping occurrence of CRS and neurotoxicity, 2 patients developed IEC-HS with overlapping occurrence of neurotoxicity, and 1 patient developed IEC-HS with overlapping occurrence of CRS. IEC-HS was fatal in 2 of 7 patients. One patient had fatal IEC-HS and one had ongoing IEC-HS at time of death. IEC-HS is a life-threatening condition with a high mortality rate if not recognized and treated early. Treatment of IEC-HS should be administered per current practice guidelines.

Adverse Reactions

The most common adverse reaction(s) (incidence ≥30%) in:

• LBCL are fever, CRS, fatigue, musculoskeletal pain, and nausea. The most common Grade 3-4 laboratory abnormalities include lymphocyte count decrease, neutrophil count decrease, platelet count decrease, and hemoglobin decrease.

Please see full Prescribing Information, including Boxed WARNINGS and Medication Guide.