BREYANZI is 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:

Limitations of Use: BREYANZI is not indicated for the treatment of patients with primary central nervous system (CNS) lymphoma [see Clinical Studies (14.1)].

BREYANZI is indicated for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have received at least 2 prior lines of therapy including, a Bruton tyrosine kinase (BTK) inhibitor and a B-cell lymphoma 2 (BCL-2) inhibitor.

This indication is approved under accelerated approval based on response rate and duration of response [see Clinical Studies (14.2)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

BREYANZI is indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) who have received 2 or more prior lines of systemic therapy.

This indication is approved under accelerated approval based on response rate and duration of response [see Clinical Studies (14.3)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

BREYANZI is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) who have received at least 2 prior lines of systemic therapy, including a Bruton tyrosine kinase (BTK) inhibitor.

See the respective Certificate of Release for Infusion (RFI Certificate) for each component, for the actual cell counts and volumes to be infused [see Dosage and Administration (2.2) and Dosage Forms and Strengths (3)].

A single dose of BREYANZI contains CAR-positive viable T cells (consisting of 1:1 CAR-positive viable T cells of the CD8 and CD4 components), with each component supplied separately in one to four single-dose vials. See Table 1 for dose range per indication.

Table 1: Dose Range

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col width="50%"/> <col width="50%"/> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First" style="border-left:1px solid;"> <span class="XmChange"><span class="Bold">Indication</span></span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First" style="border-left:1px solid;"> <span class="XmChange"><span class="Bold">BREYANZI dose range</span></span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First" style="border-left:1px solid;"> <span class="XmChange">LBCL after two or more lines of therapy (<a href="#ID_8f6d6b91-8946-4480-8bd5-be7bc47066cb">1.1</a>)</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First" style="border-left:1px solid;"> <span class="XmChange">50 to 110 × </span>10<span class="Sup">6</span><span class="XmChange"> CAR-positive viable T cells</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First" style="border-left:1px solid;"> <span class="XmChange">LBCL after one line of therapy (<a href="#ID_8f6d6b91-8946-4480-8bd5-be7bc47066cb">1.1</a>)</span> </p> </td><td class="Botrule Lrule Rrule Toprule" rowspan="4" valign="middle"> <p class="First" style="border-left:1px solid;"> <span class="XmChange">90 to 110 × </span>10<span class="Sup">6</span><span class="XmChange"> CAR-positive viable T cells</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First" style="border-left:1px solid;"> <span class="XmChange">CLL or SLL (<a href="#ID_5c5cf951-5bc1-4233-aa75-1f6fbf867c9b">1.2</a>) </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First" style="border-left:1px solid;"> <span class="XmChange">FL (<a href="#ID_d3a4fd62-e92c-4239-9310-0132ae026d3b">1.3</a>)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First" style="border-left:1px solid;"> <span class="XmChange">MCL (<a href="#ID_835e3e54-8c97-4bdf-8495-0bdb20945dfb">1.4</a>)</span> </p> </td> </tr> </tbody> </table></div>

BREYANZI is for autologous use only. The patient’s identity must match the patient identifiers on the BREYANZI cartons, vials, and syringe labels. Do not infuse BREYANZI if the information on the patient-specific labels does not match the intended patient.

Preparing the Patient for BREYANZI

Confirm the availability of BREYANZI before starting lymphodepleting chemotherapy.

Pretreatment

Administer the lymphodepleting chemotherapy regimen before infusion of BREYANZI: fludarabine 30 mg/m2/day intravenously (IV), and cyclophosphamide 300 mg/m2/day IV for 3 days. See the prescribing information for fludarabine and cyclophosphamide for information on dose adjustment in renal impairment.

Infuse BREYANZI 2 to 7 days after completion of lymphodepleting chemotherapy.

Delay the infusion of BREYANZI if the patient has unresolved serious adverse events from preceding chemotherapies, active uncontrolled infection, or active graft-versus-host disease (GVHD).

Premedication

To minimize the risk of infusion reactions, premedicate the patient with acetaminophen (650 mg orally) and diphenhydramine (25-50 mg, IV or orally), or another H1-antihistamine, 30 to 60 minutes prior to treatment with BREYANZI.

Avoid prophylactic use of systemic corticosteroids, as they may interfere with the activity of BREYANZI.

Receipt of BREYANZI

Preparing BREYANZI

Before thawing the vials

Thawing the vials

Dose preparation

Withdrawal of the required volume of cells from each vial into a separate syringe should be carried out using the following instructions:

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col width="50%"/> <col width="50%"/> <tbody class="Headless"> <tr> <td align="center" valign="top"> <p class="First">   a</p> </td><td valign="top"> <p class="First">                    b</p> </td> </tr> <tr> <td align="center" colspan="2" valign="top"><a name="id601"></a><img alt="Image" src="/dailymed/image.cfm?name=breyanzi-06.jpg&amp;setid=594bb413-af3b-4b97-afb3-bfe2b174f2ed"/></td> </tr> </tbody> </table></div>

BREYANZI Administration

BREYANZI contains human blood cells that are genetically modified with replication-incompetent, self-inactivating lentiviral vector. Follow universal precautions and local biosafety guidelines applicable for the handling and disposal, to avoid potential transmission of infectious diseases.

Monitoring

Cytokine Release Syndrome

Identify cytokine release syndrome (CRS) based on clinical presentation [see Warnings and Precautions (5.1)]. Evaluate for and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, manage according to the recommendations in Table 2. Patients who experience Grade 2 or higher CRS (e.g., hypotension not responsive to fluids, or hypoxia requiring supplemental oxygenation) should be monitored with continuous cardiac telemetry and pulse oximetry. For patients experiencing severe CRS, consider performing an echocardiogram to assess cardiac function. For severe or life-threatening CRS, consider intensive-care supportive therapy.

If concurrent neurologic toxicity is suspected during CRS, administer:

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 2: CRS Grading and Management Guidance</span> </caption> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tfoot> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">a</span> Lee criteria for grading CRS (Lee et al, 2014). </td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">b</span> If corticosteroids are initiated, continue corticosteroids for at least 3 doses or until complete resolution of symptoms, and consider corticosteroid taper.</td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">CRS Grade<span class="Sup">a</span></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Tocilizumab</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Corticosteroids<span class="Sup">b</span></span> </p> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Grade 1</span> </p> <p>Fever</p> </td><td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">If less than 72 hours after infusion, consider tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg).</p> <p>If 72 hours or more after infusion, treat symptomatically.</p> </td><td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">If less than 72 hours after infusion, consider dexamethasone 10 mg IV every 24 hours.</p> <p>If 72 hours or more after infusion, treat symptomatically.</p> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" rowspan="2" valign="top"> <p class="First"> <span class="Bold">Grade 2</span> </p> <p>Symptoms require and respond to moderate intervention.</p> <p>Oxygen requirement less than 40% FiO<span class="Sub">2</span>, or hypotension responsive to fluids or low dose of one vasopressor, or Grade 2 organ toxicity.</p> </td><td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Administer tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg).</p> <p>Repeat tocilizumab every 8 hours as needed if not responsive to intravenous fluids or increasing supplemental oxygen.<br/> <br/>Limit to a maximum of 3 doses in a 24-hour period; maximum total of 4 doses.</p> </td><td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">If less than 72 hours after infusion, administer dexamethasone 10 mg IV every 12‑24 hours.</p> <p>If 72 hours or more after infusion, consider dexamethasone 10 mg IV every 12‑24 hours. </p> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First">If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate dose and frequency of dexamethasone (10‑20 mg IV every 6 to 12 hours). </p> <p>If no improvement or continued rapid progression, maximize dexamethasone, switch to high-dose methylprednisolone 2 mg/kg if needed. After 2 doses of tocilizumab, consider alternative immunosuppressants. Do not exceed 3 doses tocilizumab in 24 hours, or 4 doses in total.</p> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" rowspan="2" valign="top"> <p class="First"> <span class="Bold">Grade 3</span> </p> <p>Symptoms require and respond to aggressive intervention.</p> <p>Oxygen requirement greater than or equal to 40% FiO<span class="Sub">2</span>, or hypotension requiring high-dose or multiple vasopressors, or Grade 3 organ toxicity, or Grade 4 transaminitis.</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Per Grade 2.</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Administer dexamethasone 10 mg IV every 12 hours.</p> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First">If no improvement within 24 hours or rapid progression of CRS, repeat tocilizumab and escalate dose and frequency of dexamethasone (10-20 mg IV every 6 to 12 hours). </p> <p>If no improvement or continued rapid progression, maximize dexamethasone, switch to high-dose methylprednisolone 2 mg/kg if needed. After 2 doses of tocilizumab, consider alternative immunosuppressants. Do not exceed 3 doses tocilizumab in 24 hours, or 4 doses in total.</p> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" rowspan="2" valign="top"> <p class="First"> <span class="Bold">Grade 4</span> </p> <p>Life-threatening symptoms</p> <p>Requirements for ventilator support or continuous veno‑venous hemodialysis (CVVHD) or Grade 4 organ toxicity (excluding transaminitis).</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Per Grade 2.</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Administer dexamethasone 20 mg IV every 6 hours.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First">If no improvement within 24 hours or rapid progression of CRS, escalate tocilizumab and corticosteroid use. If no improvement or continued rapid progression, maximize dexamethasone, switch to high-dose methylprednisolone 2 mg/kg if needed. After 2 doses of tocilizumab, consider alternative immunosuppressants. Do not exceed 3 doses tocilizumab in 24 hours, or 4 doses in total.</p> </td> </tr> </tbody> </table></div>

Neurologic Toxicity

Monitor patients for signs and symptoms of neurologic toxicities (Table 3). Rule out other causes of neurologic symptoms. Provide intensive care supportive therapy for severe or life-threatening neurologic toxicities. If neurologic toxicity is suspected, manage according to the recommendations in Table 3.

If concurrent CRS is suspected during neurologic toxicity, administer:

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 3: Neurologic Toxicity (NT) Grading and Management Guidance</span> </caption> <col width="20%"/> <col width="80%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="middle"><span class="Bold">NT Grade<span class="Sup">a</span></span></th><th align="left" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Corticosteroids and Antiseizure Medication</span></th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="2" valign="top"><span class="Sup">a</span> NCI CTCAE criteria for grading neurologic toxicities, version 4.03.</td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Grade 1</span> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis.<br/>If 72 hours or more after infusion, observe.<br/>If less than 72 hours after infusion, consider dexamethasone 10 mg IV every 12 to 24 hours for 2 to 3 days.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Grade 2</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis.<br/>Dexamethasone 10 mg IV every 12 hours for 2-3 days, or longer for persistent symptoms. Consider taper for a total steroid exposure of greater than 3 days.<br/>If no improvement after 24 hours or worsening of neurologic toxicity, increase the dose and/or frequency of dexamethasone up to a maximum of 20 mg IV every 6 hours.<br/>If no improvement after another 24 hours, rapidly progressing symptoms, or life-threatening complications arise, give methylprednisolone (2 mg/kg loading dose, followed by 2 mg/kg divided 4 times a day; taper within 7 days).</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Grade 3</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis.<br/>Dexamethasone 10 to 20 mg IV every 8 to 12 hours. Steroids are not recommended for isolated Grade 3 headaches.<br/>If no improvement after 24 hours or worsening of neurologic toxicity, escalate to methylprednisolone (dose and frequency as per Grade 2).<br/>If cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1-2 g, repeat every 24 hours if needed; taper as clinically indicated) and cyclophosphamide 1.5 g/m<span class="Sup">2</span>.</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Grade 4</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis.<br/>Dexamethasone 20 mg IV every 6 hours.<br/>If no improvement after 24 hours or worsening of neurologic toxicity, escalate to methylprednisolone (dose and frequency as per Grade 2).<br/>If cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1-2 g, repeat every 24 hours if needed; taper as clinically indicated), and cyclophosphamide 1.5 g/m<span class="Sup">2</span>.</p> </td> </tr> </tbody> </table></div>

BREYANZI is a cell suspension for infusion.

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A single dose of BREYANZI contains CAR-positive viable T cells that consist of CD8 and CD4 components, with each component supplied separately in single-dose vials [see Dosage and Administration (2.1)].

{ "type": "p", "children": [], "text": "A single dose of BREYANZI contains CAR-positive viable T cells that consist of CD8 and CD4 components, with each component supplied separately in single-dose vials [see Dosage and Administration (2.1)]." }

More than one vial of each of the CD8 component and/or CD4 component may be needed to achieve the dose of BREYANZI.

{ "type": "p", "children": [], "text": "More than one vial of each of the CD8 component and/or CD4 component may be needed to achieve the dose of BREYANZI." }

Each vial contains between 6.9 × 106 and 322 x 106 CAR-positive viable T cells in 4.6 mL cell suspension (between 1.5 × 106 and 70 x 106 CAR-positive viable T cells/mL).

{ "type": "p", "children": [], "text": "Each vial contains between 6.9 × 106 and 322 x 106 CAR-positive viable T cells in 4.6 mL cell suspension (between 1.5 × 106 and 70 x 106 CAR-positive viable T cells/mL)." }

The infusion volume is calculated based on the concentration of cryopreserved drug product CAR-positive viable T cells. The volume may differ for each component infused. See the RFI Certificate for details [see How Supplied/Storage and Handling (16)].

{ "type": "p", "children": [], "text": "The infusion volume is calculated based on the concentration of cryopreserved drug product CAR-positive viable T cells. The volume may differ for each component infused. See the RFI Certificate for details [see How Supplied/Storage and Handling (16)].\n" }

None.

{ "type": "p", "children": [], "text": "None." }

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 702 patients with non-Hodgkin lymphoma (NHL), CRS occurred in 54% of patients, including ≥ Grade 3 CRS (Lee grading system1) in 3.2% of patients. The median time to onset was 5 days (range: 1 to 63 days). CRS resolved in 98% 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%) included 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) [see Adverse Reactions (6.1)].

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

Monitor patients daily for at least 7 days following BREYANZI infusion at a REMS-certified healthcare facility for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after infusion. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated [see Dosage and Administration (2.3)].

Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time [see Patient Counseling Information (17)].

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 31% 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 days (range: 1 to 119 days). Of patients developing neurotoxicity, 82% also developed CRS.

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

Monitor patients daily for at least 7 days following BREYANZI infusion at a REMS-certified healthcare facility for signs and symptoms of neurologic toxicities and assess for other causes of neurological symptoms. Monitor patients for signs or symptoms of neurologic toxicities for at least 4 weeks after infusion and treat promptly. Manage neurologic toxicity with supportive care and/or corticosteroid as needed [see Dosage and Administration (2.3)].

Counsel patients to seek immediate medical attention should signs or symptoms of neurologic toxicity occur at any time [see Patient Counseling Information (17)].

Because of the risk of CRS and neurologic toxicities, BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS [see Boxed Warning and Warnings and Precautions (5.1, 5.2)]. The required components of the BREYANZI REMS are:

Further information is available at www.BreyanziREMS.com or contact Bristol-Myers Squibb at 1-866-340-7332.

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

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 34% of patients, with Grade 3 or higher infections occurred in 12% of all patients. Grade 3 or higher infections with an unspecified pathogen occurred in 7%, bacterial infections in 3.7%, viral infections in 2%, and fungal infections in 0.7% of patients. One patient with FL, who received four prior lines of therapy developed a fatal case of John Cunningham (JC) virus progressive multifocal leukoencephalopathy four months after treatment with BREYANZI. One patient with MCL, who received three 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.

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.

B-cell aplasia and hypogammaglobulinemia can occur in patients receiving BREYANZI.

In clinical trials of BREYANZI, hypogammaglobulinemia was reported as an adverse reaction in 10% 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.

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 [see Boxed Warning, Adverse Reactions (6.2), Patient Counseling Information (17)].  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.

Due to the potential for neurologic events, including altered mental status or seizures, patients receiving BREYANZI are at risk for developing altered or decreased consciousness or impaired coordination in the 8 weeks following BREYANZI administration. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, for at least 8 weeks.

Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome (IEC-HS), including fatal or life-threatening reactions, occurred following treatment with BREYANZI. Three of 89 (3%) safety evaluable patients with R/R CLL/SLL developed IEC-HS. Time to onset of IEC-HS ranged from 7 to 18 days. Two of the 3 patients developed IEC-HS in the setting of ongoing CRS and 1 in the setting of ongoing neurotoxicity. IEC-HS was fatal in 2 of 3 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.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety data described in the WARNINGS and PRECAUTIONS (N=702) and in this section reflect exposure to a single dose of BREYANZI in one randomized, open-label study with 89 patients (TRANSFORM) with relapsed or refractory LBCL, and five open-label, single-arm studies with 61 patients (PILOT) and 268 patients (TRANSCEND) with relapsed or refractory LBCL, 89 patients with relapsed or refractory CLL/SLL (TRANSCEND-CLL), 107 patients with relapsed or refractory FL (TRANSCEND-FL), and 88 patients with relapsed or refractory MCL (TRANSCEND-MCL Cohort).

Relapsed or Refractory LBCL After One Line of Therapy

TRANSFORM

The safety of BREYANZI was evaluated in the TRANSFORM, a randomized, open-label, multicenter study, in which patients with primary refractory LBCL or relapse within 1 year of first-line chemoimmunotherapy received BREYANZI (N=89) or standard therapy (N=91) [see Clinical Studies (14.1)]. Patients had not yet received treatment for relapsed or refractory lymphoma and were potential candidates for autologous HSCT. The trial excluded patients who were ineligible for transplant or who had age > 75 years, Eastern Cooperative Oncology Group (ECOG) performance status >1, history of central nervous system (CNS) disorders (such as seizures or cerebrovascular ischemia), uncontrolled infection, CrCl < 45 mL/min, alanine aminotransferase (ALT) > 5 times the upper limit of normal (ULN), left ventricular ejection fraction (LVEF) < 40%, or absolute neutrophil count (ANC) < 1.0 × 109 cells/L or platelets < 50 × 109 cells/L in the absence of bone marrow involvement.

The planned dose of BREYANZI was 100 × 106 CAR-positive viable T cells. The median age of the BREYANZI-treated population was 59 years (range: 20 to 74 years); 47% were male; 58% were White, 11% were Asian, and 5% were Black.

Serious adverse reactions occurred in 38% of patients. The most common nonlaboratory serious adverse reactions (> 2%) were CRS, sepsis, fever, febrile neutropenia, headache, aphasia, COVID-19 infection, and pulmonary embolism.

Table 4 presents selected nonlaboratory adverse reactions in patients treated with BREYANZI, and Table 5 describes selected new or worsening Grade 3 or 4 laboratory abnormalities.

The most common nonlaboratory adverse reactions (≥ 20%) were fever, CRS, musculoskeletal pain, headache, fatigue, nausea, constipation, and dizziness.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 4: Adverse Reactions in ≥ 10% of Patients Treated with BREYANZI in the TRANSFORM Study (N=89)</span> </caption> <col width="33%"/> <col width="34%"/> <col width="34%"/> <tfoot> <tr class="First"> <td align="left" colspan="3" valign="top"><span class="Sup">a</span> Tachycardia includes atrial flutter, sinus tachycardia, supraventricular tachycardia, tachycardia.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">b</span> Abdominal pain includes abdominal pain, abdominal pain lower, abdominal tenderness.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">c</span> Fatigue includes asthenia, fatigue, malaise.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">d</span> Edema includes edema peripheral, localized edema, pleural effusion swelling.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">e</span> Infections and infestations are grouped per high-level grouped term.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">f</span> Sepsis includes bacteremia, bacterial sepsis, enterococcal bacteremia, Escherichia bacteremia, Klebsiella bacteremia, Klebsiella sepsis, sepsis, septic shock, staphylococcal bacteremia.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">g</span> Musculoskeletal pain includes arthralgia, back pain, bone pain, flank pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, osteoarthritis, pain in extremity.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">h</span> Headache includes headache, migraine, migraine with aura.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">i</span> Dizziness includes dizziness, dizziness postural, syncope, vertigo.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">j</span> Motor dysfunction includes fine motor skill dysfunction, muscle spasms, muscular weakness.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">k</span> Tremor includes resting tremor, tremor, essential tremor.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">l</span> Insomnia includes insomnia, sleep disorder.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">m</span> Cough includes cough, productive cough.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">n</span> Rash includes catheter site rash, dermatitis acneiform, dermatitis exfoliative generalized, erythema multiforme, rash, rash maculo-papular, rash pruritic.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">o</span> Hypotension includes hypotension, orthostatic hypotension.</td> </tr> <tr class="Last"> <td align="left" colspan="3" valign="top"><span class="Sup">p</span> Hemorrhage includes conjunctival hemorrhage, cystitis hemorrhagic, epistaxis, gastrointestinal hemorrhage, hematoma, hematuria, retinal hemorrhage, vaginal hemorrhage.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Adverse Reaction </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Any Grade (%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Grade 3 or Higher (%)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Blood and lymphatic system disorders </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Febrile neutropenia </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Cardiac disorders </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Tachycardia<span class="Sup">a</span><span class="Italics"></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">15</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Gastrointestinal disorders </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Nausea </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">24</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Constipation </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">20</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Diarrhea </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">18</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Abdominal pain<span class="Sup">b</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">13</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Vomiting </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">General disorders and administration site conditions </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Fever </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">55</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Fatigue<span class="Sup">c</span><span class="Italics"></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">28</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Edema<span class="Sup">d</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">13</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Immune system disorders </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Cytokine release syndrome </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">49</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Infections and infestations<span class="Sup">e</span></span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Bacterial infectious disorders </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Infections with pathogen unspecified </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Sepsis<span class="Sup">f</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Metabolism and nutrition disorders </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Decreased appetite </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">15</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Musculoskeletal and connective tissue disorders </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Musculoskeletal pain<span class="Sup">g</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">36</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Nervous system disorders </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Headache<span class="Sup">h</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">34</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Dizziness<span class="Sup">i</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">20</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Motor dysfunction<span class="Sup">j</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Tremor<span class="Sup">k</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Psychiatric disorders </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Insomnia<span class="Sup">l</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">15</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Respiratory, thoracic, and mediastinal disorders </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Cough<span class="Sup">m</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Skin and subcutaneous tissue disorders </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Rash<span class="Sup">n</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Vascular disorders </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Hypotension<span class="Sup">o</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">15</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.2</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Hemorrhage<span class="Sup">p</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> </tbody> </table></div>

Other clinically important adverse reactions in < 10% of patients treated with BREYANZI included the following:

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 5: Grade 3 or 4 Laboratory Abnormalities Occurring in ≥ 10% of Patients Treated with BREYANZI in the TRANSFORM Study</span> </caption> <col width="49%"/> <col width="51%"/> <tfoot> <tr class="First"> <td align="left" colspan="2" valign="top"><span class="Sup">a</span> Baseline lab values were assessed prior to lymphodepleting chemotherapy.</td> </tr> <tr class="Last"> <td align="left" colspan="2" valign="top"><span class="Sup">b</span> Based on 88 evaluable patients, defined as those with both a baseline grade and at least one post-baseline grade for the particular lab.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Laboratory Abnormality<span class="Sup">a</span></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Grade 3 or 4 (%)<span class="Sup">b</span></span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Lymphocyte count decreased </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">98</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Neutrophil count decreased </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">89</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Platelet count decreased </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">48</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Hemoglobin decreased </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">32</p> </td> </tr> </tbody> </table></div>

Grade 4 laboratory abnormalities in ≥ 10% of patients were lymphocyte decrease (64%), neutrophil decrease (66%), and platelet decrease (34%).

PILOT

The safety of BREYANZI was evaluated in the PILOT study, a single-arm open-label study in transplant-ineligible patients with R/R LBCL after one line of chemoimmunotherapy [see Clinical Studies (14.1)]. The study enrolled patients who were ineligible for high-dose therapy and autologous HSCT due to organ function or age, but who had adequate organ function for CAR-T cell therapy. Patients with a history of relevant CNS disorders (such as seizures or cerebrovascular ischemia), ECOG performance status > 2, or uncontrolled infection were ineligible. The trial required LVEF ≥ 40%, adequate oxygen saturation on room air with ≤ Grade 1 dyspnea, AST, and ALT ≤ 5 x ULN, total bilirubin < 2.0 mg/dL, creatinine clearance > 30 mL/min, and adequate bone marrow function to receive lymphodepleting chemotherapy. The planned dose of BREYANZI was 100 × 106 CAR-positive viable T cells.

The median age was 74 years (range: 53 to 84 years), 90% were age ≥ 65 years, 61% were male. The ECOG performance status was 0 or 1 in 74% of patients and 2 in 26% of patients; 25% had CrCl < 60 ml/min; 20% had a baseline ANC < 1000/μL.

Serious adverse reactions occurred in 33% of patients. The most common nonlaboratory, serious adverse reactions (> 2%) were CRS, confusional state, gastrointestinal hemorrhage, muscular weakness, musculoskeletal pain, pulmonary embolism, and sepsis.

Table 6 presents selected nonlaboratory adverse reactions, and Table 7 describes selected new or worsening Grade 3 or 4 laboratory abnormalities.

The most common nonlaboratory adverse reactions (≥ 20%) were fatigue, CRS, fever, nausea, encephalopathy, hypotension, musculoskeletal pain, and edema.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 6: Adverse Reactions in ≥ 10% of Patients Treated with BREYANZI in the PILOT Study (N=61)</span> </caption> <col width="33%"/> <col width="33%"/> <col width="34%"/> <tfoot> <tr class="First"> <td align="left" colspan="3" valign="top"><span class="Sup">a</span> Tachycardia includes atrial fibrillation, sinus tachycardia, tachycardia.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">b</span> Fatigue includes asthenia, fatigue, malaise.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">c</span> Edema includes edema peripheral, pleural effusion, swelling.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">d</span> Grouped per high-level grouped term.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">e</span> Upper respiratory tract infection includes nasal congestion, paranasal sinus hypersecretion, rhinitis, rhinorrhea, upper respiratory tract infection.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">f</span> Musculoskeletal pain includes arthralgia, back pain, bone pain, flank pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, osteoarthritis, pain in extremity, spinal pain.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">g</span> Encephalopathy includes amnesia, apraxia, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, dyscalculia, encephalopathy, lethargy, memory impairment, mental status changes, somnolence.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">h</span> Dizziness includes dizziness, dizziness postural, syncope, vertigo.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">i</span> Tremor includes resting tremor, tremor.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">j</span> Cough includes cough, productive cough.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">k</span> Dyspnea includes acute respiratory distress syndrome, dyspnea, tachypnea, wheezing.</td> </tr> <tr class="Last"> <td align="left" colspan="3" valign="top"><span class="Sup">l</span> Hypotension includes hypotension, orthostatic hypotension.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Adverse Reaction </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Any Grade (%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Grade 3 or Higher (%)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Cardiac disorders </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Tachycardia<span class="Sup">a</span><span class="Italics"></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Gastrointestinal disorders </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Nausea </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">25</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Diarrhea </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">15</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Constipation </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">General disorders and administration site conditions </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Fatigue<span class="Sup">b</span><span class="Italics"></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">44</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Fever </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">38</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Edema<span class="Sup">c</span><span class="Italics"></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">20</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Immune system disorders </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Cytokine release syndrome </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">39</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Infections and infestations </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Infections with pathogen unspecified<span class="Sup">d</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">13</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4.9</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Upper respiratory tract infection<span class="Sup">e</span><span class="Italics"></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">13</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Bacterial infectious disorders </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Metabolism and nutrition disorders </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Decreased appetite </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">13</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Musculoskeletal and connective tissue disorders </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Musculoskeletal pain<span class="Sup">f</span><span class="Italics"></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">23</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4.9</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Nervous system disorders </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Encephalopathy<span class="Sup">g</span><span class="Italics"></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">23</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4.9</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Dizziness<span class="Sup">h</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Tremor<span class="Sup">i</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Headache </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Psychiatric disorders </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Insomnia </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Respiratory, thoracic, and mediastinal disorders </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Cough<span class="Sup">j</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">18</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Dyspnea<span class="Sup">k</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4.9</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Vascular disorders </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Hypotension<span class="Sup">l</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">23</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.6</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Hypertension </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4.9</p> </td> </tr> </tbody> </table></div>

Other clinically important adverse reactions in < 10% of patients included the following:

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 7: Grade 3 or 4 Laboratory Abnormalities Occurring in ≥ 10% of Patients Treated with BREYANZI in the PILOT Study (N=61)</span> </caption> <col width="49%"/> <col width="51%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="2" valign="top"><span class="Sup">a</span> Baseline lab values were assessed prior to lymphodepleting chemotherapy.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Laboratory Abnormality<span class="Sup">a</span></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Grade 3 or 4 (%)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Lymphocyte count decreased </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">97</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Neutrophil count decreased </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">80</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Hemoglobin decreased </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">30</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Platelet count decreased </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">26</p> </td> </tr> </tbody> </table></div>

Grade 4 laboratory abnormalities in ≥ 10% of patients were lymphocyte decrease (95%), neutrophil decrease (57%), and platelet decrease (20%).

Relapsed or Refractory LBCL After Two or More Lines of Therapy

TRANSCEND

The safety of BREYANZI was evaluated in the TRANSCEND study, in which 268 adult patients with R/R LBCL after 2 or more prior lines of therapy received a single dose of CAR-positive viable T cells [see Clinical Studies (14.1)]. Patients with a history of CNS disorders (such as seizures or cerebrovascular ischemia) or autoimmune disease requiring systemic immunosuppression were ineligible. The median age of the study population was 63 years (range: 18 to 86 years); 65% were male. The ECOG performance status at screening was 0 in 41% of patients, 1 in 58% of patients, and 2 in 1.5% of patients.

Serious adverse reactions occurred in 46% of patients. The most common nonlaboratory serious adverse reactions (> 2%) were CRS, encephalopathy, sepsis, febrile neutropenia, aphasia, pneumonia, fever, hypotension, dizziness, and delirium. Fatal adverse reactions occurred in 4% of patients.

Table 8 presents selected nonlaboratory adverse reactions reported in patients treated with BREYANZI, and Table 9 describes selected new or worsening Grade 3 or 4 laboratory abnormalities.

The most common nonlaboratory adverse reactions (≥ 20%) were fatigue, CRS, musculoskeletal pain, nausea, headache, encephalopathy, infections (pathogen unspecified), decreased appetite, diarrhea, hypotension, tachycardia, dizziness, cough, constipation, abdominal pain, vomiting, and edema.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 8: Adverse Reactions in ≥ 10% of Patients Treated with BREYANZI in the TRANSCEND Study (N=268)</span> </caption> <col width="38%"/> <col width="31%"/> <col width="31%"/> <tfoot> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">a</span> Tachycardia includes heart rate increased, sinus tachycardia, tachycardia.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">b</span> Abdominal pain includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">c</span> Fatigue includes asthenia, fatigue, malaise.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">d</span> Edema includes edema, edema peripheral, fluid overload, fluid retention, generalized edema, hypervolemia, peripheral swelling, pulmonary congestion, pulmonary edema, swelling.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">e</span> Infections and infestations are grouped by pathogen type and selected clinical syndromes.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">f</span> Infections with pathogen unspecified contains febrile neutropenia (9%).</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">g</span> Bacterial infection includes infections by pathogen type plus appendicitis, diverticulitis, peritonitis, skin infection, tooth infection.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">h</span> Upper respiratory tract infections include nasopharyngitis, pharyngitis, rhinitis, rhinovirus infection, sinusitis, upper respiratory tract congestion, upper respiratory tract infection.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">i</span> Musculoskeletal pain includes arthralgia, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, pain in extremity, spinal pain.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">j</span> Headache includes headache, head discomfort, migraine, sinus headache.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">k</span> Encephalopathy includes amnesia, bradyphrenia, cognitive disorder, confusional state, depersonalization/derealization disorder, depressed level of consciousness, disturbance in attention, encephalopathy, flat affect, hypersomnia, incoherent, lethargy, leukoencephalopathy, loss of consciousness, memory impairment, mental impairment, mental status changes, somnolence.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">l</span> Dizziness includes dizziness, presyncope, syncope, vertigo.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">m</span> Tremor includes essential tremor, resting tremor, tremor.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">n</span> Peripheral neuropathy includes hyperesthesia, hypoesthesia, meralgia paresthetica, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, sciatica, sensory loss.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">o</span> Aphasia includes aphasia, disorganized speech, dysarthria, dysphemia, dysphonia, slow speech, speech disorder.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">p</span> Motor dysfunction includes eyelid ptosis, motor dysfunction, muscle rigidity, muscle spasms, muscle spasticity, muscle tightness, muscle twitching, muscular weakness, myoclonus, myopathy.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">q</span> Insomnia includes insomnia, somnambulism.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">r</span> Anxiety includes anxiety, panic attack.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">s</span> Delirium includes agitation, delirium, delusion, disorientation, hallucination, ‘hallucination, visual’, irritability, restlessness.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">t</span> Renal failure includes acute kidney injury, blood creatinine increased, chronic kidney disease, renal failure, renal injury.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">u</span> Cough includes cough, productive cough, upper-airway cough syndrome.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">v</span> Dyspnea includes acute respiratory failure, dyspnea, dyspnea exertional, respiratory failure.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">w</span> Rash includes erythema, dermatitis acneiform, perineal rash, rash, rash erythematous, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic, rash pustular.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">x</span> Hypotension includes hypotension, orthostatic hypotension.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">y</span> Hemorrhage includes catheter site hemorrhage, conjunctival hemorrhage, epistaxis, hematoma, hematuria, hemorrhage, hemorrhage intracranial, pulmonary hemorrhage, retinal hemorrhage, vaginal hemorrhage.</td> </tr> </tfoot> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Adverse Reaction</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Any Grade (%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Grade 3 or Higher (%)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Cardiac disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Tachycardia<span class="Sup">a</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">25</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Gastrointestinal disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Nausea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">33</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Diarrhea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">26</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Constipation</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">23</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Abdominal pain<span class="Sup">b</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">21</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Vomiting</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">21</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">General disorders and administration site conditions</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Fatigue<span class="Sup">c</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">48</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Edema<span class="Sup">d</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">21</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Fever</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Chills</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Immune system disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Cytokine release syndrome</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">46</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4.1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Infections and infestations<span class="Sup">e</span></span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Infection with pathogen unspecified<span class="Sup">f</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">29</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Bacterial infection<span class="Sup">g</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">13</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Upper respiratory tract infection<span class="Sup">h</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">13</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Viral infection</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Metabolism and nutrition disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Decreased appetite</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">28</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Musculoskeletal and connective tissue disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Musculoskeletal pain<span class="Sup">i</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">37</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Nervous system disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Headache<span class="Sup">j</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">30</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Encephalopathy<span class="Sup">k</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">29</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">9</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Dizziness<span class="Sup">l</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">24</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Tremor<span class="Sup">m</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Peripheral neuropathy<span class="Sup">n</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Aphasia<span class="Sup">o</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Motor dysfunction<span class="Sup">p</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Psychiatric disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Insomnia<span class="Sup">q</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">14</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Anxiety<span class="Sup">r</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Delirium<span class="Sup">s</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Renal and urinary disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Renal failure<span class="Sup">t</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Respiratory, thoracic, and mediastinal disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Cough<span class="Sup">u</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">23</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Dyspnea<span class="Sup">v</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Skin and subcutaneous tissue disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Rash<span class="Sup">w</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">13</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Vascular disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Hypotension<span class="Sup">x</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">26</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">3.4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Hypertension</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">14</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">4.5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Hemorrhage<span class="Sup">y</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1.5</p> </td> </tr> </tbody> </table></div>

Other clinically important adverse reactions in < 10% of patients included the following:

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 9: Grade 3 or 4 Laboratory Abnormalities Occurring in ≥ 10% of Patients Treated with BREYANZI in the TRANSCEND Study</span> </caption> <col width="52%"/> <col width="48%"/> <tfoot> <tr> <td align="left" colspan="2" valign="top"><span class="Sup">a</span> Baseline lab values were assessed prior to lymphodepleting chemotherapy.</td> </tr> <tr> <td align="left" colspan="2" valign="top"><span class="Sup">b</span> The denominator varied from 239 to 268, based on the number of patients with a baseline value and at least one post-treatment value for the particular lab.</td> </tr> </tfoot> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Laboratory Abnormality<span class="Sup">a</span></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Grade 3 or 4 (%)<span class="Sup">b</span></span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Lymphocyte count decreased </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">95 </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Neutrophil count decreased </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">88 </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Platelet count decreased </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">41 </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Hemoglobin decreased </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">32 </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Phosphate decreased</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Fibrinogen decreased </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">14 </p> </td> </tr> </tbody> </table></div>

Relapsed or Refractory CLL/SLL

TRANSCEND-CLL

The safety of BREYANZI was evaluated in the TRANSCEND-CLL study, which included 89 adult patients with R/R CLL/SLL who had received at least 2 prior lines of therapy including a BTK inhibitor and a BCL-2 inhibitor before receiving a single dose of CAR‑positive viable T cells [see Clinical Studies (14.2)]. Patients with a history of CNS disorders (such as seizures or cerebrovascular ischemia) or autoimmune disease requiring systemic immunosuppression, Richter’s transformation, ECOG performance status >1 were ineligible. The trial required LVEF ≥ 40%, adequate oxygen saturation on room air with ≤ Grade 1 dyspnea, ALT ≤ 5 x ULN, total bilirubin < 2.0 mg/dL, creatinine clearance > 30 mL/min, and adequate bone marrow function to receive lymphodepleting chemotherapy.

The median age of the study population was 66 years (range: 49 to 82 years); 69% were male, 84% were White, 3% were Black, 1% were Asian. Two percent were Hispanic, and 89% were non-Hispanic. The ECOG performance status at screening was 0 in 40% of patients, and 1 in 60% of patients.

Serious adverse reactions occurred in 60% of patients. The most common nonlaboratory serious adverse reactions (> 2%) were CRS, encephalopathy, febrile neutropenia, pneumonia, hemorrhage, fever, renal failure, aphasia, abdominal pain, delirium, tumor lysis syndrome, upper respiratory tract infection, and hemophagocytic lymphohistiocytosis [IEC-HS]. Fatal adverse reactions occurred in 1.1% of patients.

Table 10 presents selected nonlaboratory adverse reactions reported in patients treated with BREYANZI, and Table 11 describes selected new or worsening Grade 3 or 4 laboratory abnormalities.

The most common nonlaboratory adverse reactions (≥ 20%) were CRS, encephalopathy, fatigue, musculoskeletal pain, nausea, edema, diarrhea, dyspnea, headache, fever, decreased appetite, constipation, tremor, dizziness, Infection with pathogen unspecified, rash, tachycardia, cough, and delirium.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 10: Adverse Reactions in ≥ 10% of Patients Treated with BREYANZI in the TRANSCEND-CLL Study (N=89)</span> </caption> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tfoot> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">a </span>Tachycardia includes atrial fibrillation, atrial flutter, sinus tachycardia, tachycardia, ventricular tachycardia.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">b </span>Diarrhea includes diarrhea</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">c </span>Abdominal pain includes abdominal pain, abdominal tenderness.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">d </span>Fatigue includes asthenia, fatigue, malaise.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">e </span>Edema includes ascites, face edema, hypervolemia, edema peripheral, pleural effusion, pulmonary edema, scrotal edema.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">f </span>Fever includes pyrexia.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">g </span>Grouped per high-level grouped term.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">h </span>Upper respiratory tract infection includes acute sinusitis, nasal congestion, nasopharyngitis, rhinitis, rhinovirus infection, sinusitis, upper respiratory tract infection.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">i </span>Musculoskeletal pain includes arthralgia, arthritis, back pain, bone pain, flank pain, musculoskeletal chest pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">j </span>Encephalopathy includes cognitive disorder, confusional state, disturbance in attention, encephalopathy, lethargy, memory impairment, mental status changes, somnolence.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">k </span>Headache includes headache, sinus headache.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">l </span>Dizziness includes dizziness, presyncope, syncope, vertigo.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">m </span>Motor dysfunction includes asterixis, muscle spasms, muscular weakness, myoclonus.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">n </span>Peripheral neuropathy includes hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">o </span>Taste disorder includes dysgeusia, taste disorder.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">p </span>Delirium includes agitation, delirium, hallucination, hallucination visual, intensive care unit delirium, irritability, restlessness.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">q </span>Renal failure includes acute kidney injury, chronic kidney disease, renal failure.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">r </span>Dyspnea includes dyspnea, respiratory failure, tachypnea, wheezing.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">s </span>Cough includes cough, productive cough, upper-airway cough syndrome.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">t </span>Rash includes dermatitis contact, erythema, petechiae, rash, rash macular, rash maculo-papular, scrotal erythema, seborrheic keratosis, urticaria.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">u </span>Hypotension includes hypotension, orthostatic hypotension.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">v </span>Hemorrhage includes epistaxis, hemorrhage intracranial, hematoma, hematuria, hemorrhoidal hemorrhage, intraventricular hemorrhage, lower gastrointestinal hemorrhage, traumatic hemothorax.</td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Adverse Reaction</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Any Grade (%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Grade 3 or Higher (%)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Blood and lymphatic system disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Febrile neutropenia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Cardiac disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Tachycardia<span class="Sup">a</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">21</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Gastrointestinal disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Nausea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">35</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Diarrhea<span class="Sup">b</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">30</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Constipation</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">24</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Abdominal pain<span class="Sup">c</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">18</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Vomiting </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">15</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">General disorders and administration site conditions</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Fatigue<span class="Sup">d</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">40</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4.5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Edema<span class="Sup">e</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">30</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4.5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Fever<span class="Sup">f</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">27</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Chills</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">17</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Immune system disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Cytokine release syndrome</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">83</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">9</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Infections and infestations</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Infection with pathogen unspecified<span class="Sup">g</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">23</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Upper respiratory tract infection<span class="Sup">h</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">19</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Viral infection<span class="Sup">g</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Metabolism and nutrition disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Decreased appetite</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">27</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4.5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Tumor lysis syndrome</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Musculoskeletal and connective tissue disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Musculoskeletal pain<span class="Sup">i</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">42</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Nervous system disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Encephalopathy<span class="Sup">j</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">44</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">18</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Headache<span class="Sup">k</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">28</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Tremor</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">24</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Dizziness<span class="Sup">l</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">21</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Motor dysfunction<span class="Sup">m</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">14</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Peripheral neuropathy<span class="Sup">n</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Taste disorder<span class="Sup">o</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Psychiatric disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Delirium<span class="Sup">p</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">20</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Insomnia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Anxiety</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Renal and urinary disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Renal failure<span class="Sup">q</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">15</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Respiratory, thoracic, and mediastinal disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Dyspnea<span class="Sup">r</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">27</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Cough<span class="Sup">s</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">20</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Skin and subcutaneous tissue disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Rash<span class="Sup">t</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">23</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Vascular disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Hypotension<span class="Sup">u</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">17</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Hemorrhage<span class="Sup">v</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Hypertension</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4.5</p> </td> </tr> </tbody> </table></div>

Other clinically important adverse reactions in < 10% of patients included the following:

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 11: Grade 3 or 4 Laboratory Abnormalities Occurring in ≥ 10% of Patients Treated with BREYANZI in the TRANSCEND-CLL Study</span> </caption> <col width="50%"/> <col width="50%"/> <tfoot> <tr class="First"> <td align="left" colspan="2" valign="top"><span class="Sup">a</span> Baseline lab values were assessed prior to lymphodepleting chemotherapy.</td> </tr> <tr class="Last"> <td align="left" colspan="2" valign="top"><span class="Sup">b</span> The denominator ranged from 85 to 89 for other measurements, based on the number of patients with a baseline value and at least one post-treatment value for the particular lab.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Laboratory Abnormality<span class="Sup">a</span></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Grade 3 or 4 (%)<span class="Sup">b</span></span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Neutrophil count decreased</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">94</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Lymphocyte count decreased</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">87</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">White blood cell decreased</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">85</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Platelet count decreased</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">53</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Hemoglobin decreased</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">49</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Hypophosphatemia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">24</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Hyponatremia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">18</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Hypocalcemia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11</p> </td> </tr> </tbody> </table></div>

Grade 4 laboratory abnormalities in ≥ 10% of patients were neutrophil count decreased (81%), lymphocyte count decreased (73%), white blood cell decreased (72%), and platelet count decreased (30%).

Relapsed or Refractory FL

TRANSCEND-FL

The safety of BREYANZI was evaluated in the TRANSCEND-FL study, in which 107 adult patients with relapsed or refractory FL after two or more prior lines of therapy received a single dose of BREYANZI [see Clinical Studies (14.3)]. Patients with a history of CNS disorders and active autoimmune disease requiring immunosuppressive therapy were ineligible. The median age was 62 years (range: 23 to 80 years), 38 % were female, and ECOG performance status was 0 in 61% and 1 in 39% of patients; 56% were White, 3% were Black, 9% were Asian; 5% were Hispanic and 69% were non-Hispanic.

Serious adverse reactions occurred in 26% of patients. The most common nonlaboratory serious adverse reactions (> 2%) were CRS, aphasia, febrile neutropenia, fever, and tremor.

Table 12 presents selected nonlaboratory adverse reactions reported in patients treated with BREYANZI, and Table 13 describes selected new or worsening Grade 3 or 4 laboratory abnormalities.

The most common nonlaboratory adverse reactions (≥ 20%) were CRS, headache, musculoskeletal pain, fatigue, constipation, and fever.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 12: Adverse Reactions* in ≥ 10% of Patients Treated with BREYANZI in the TRANSCEND-FL Study (N=107)</span> </caption> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tfoot> <tr> <td align="left" colspan="3" valign="top">*Includes adverse reactions up to 90 days following treatment with BREYANZI. </td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">a</span> Fatigue includes asthenia, fatigue, somnolence. </td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">b</span> Fever includes pyrexia. </td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">c</span> Grouped per high-level grouped term.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">d</span> Musculoskeletal pain includes arthralgia, back pain, bone pain, muscle spasms, flank pain, pain in extremity, myalgia, musculoskeletal pain, neck pain, muscle tightness, groin pain, tendonitis, and ligament sprain. </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Adverse Reaction</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Any Grade (%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Grade 3 or Higher (%)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Gastrointestinal disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Constipation</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">21</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Diarrhea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">15</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">General disorders and administration site conditions</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Fatigue<span class="Sup">a</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">23</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Fever<span class="Sup">b</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">20</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Immune system disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Cytokine release syndrome</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">59</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.9</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Infections and infestations</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Infection with pathogen unspecified<span class="Sup">c</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4.7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Musculoskeletal and connective tissue disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Musculoskeletal pain<span class="Sup">d</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">28</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Nervous system disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Headache</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">28</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">   Tremor</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">15</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> </tbody> </table></div>

Other clinically important adverse reactions in < 10% of patients included the following:

<div class="scrollingtable"><table width="100.14%"> <caption> <span>Table 13: Grade 3 or 4 Laboratory Abnormalities* Occurring in ≥ 10% of Patients Treated with BREYANZI in the TRANSCEND-FL Study (N=107)</span> </caption> <col width="50%"/> <col width="50%"/> <tfoot> <tr class="First"> <td align="left" colspan="2" valign="top">*Includes laboratory abnormalities up to 90 days following treatment with BREYANZI. </td> </tr> <tr> <td align="left" colspan="2" valign="top"><span class="Sup">a</span> Baseline lab values were assessed prior to lymphodepleting chemotherapy. </td> </tr> <tr class="Last"> <td align="left" colspan="2" valign="top"><span class="Sup">b</span> Based on the number of patients with a baseline value and at least one post treatment value for the particular lab.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Laboratory Abnormality<span class="Sup">a</span></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Grade 3 or 4 (%)<span class="Sup">b</span></span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Lymphocyte count decreased</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">94</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Neutrophil count decreased</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">79</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">White blood cell decreased</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">74</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Platelet count decreased</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">17</p> </td> </tr> </tbody> </table></div>

Grade 4 laboratory abnormalities in ≥ 10% of patients were lymphocyte count decreased  (78%), neutrophil count decreased (61%), white blood cell decreased (41%), and platelet count decreased (11%).

Relapsed or Refractory MCL

TRANSCEND-MCL Cohort

The safety of BREYANZI was evaluated in the TRANSCEND Study-MCL Cohort, in which 88 adult patients with relapsed or refractory MCL received a single dose of CAR-positive viable T cells [see Clinical Studies (14.4)]. Patients with a history of CNS disorders (such as seizures or cerebrovascular ischemia) or autoimmune disease requiring systemic immunosuppression were ineligible. The trial required left ventricular ejection fraction ≥ 40%, adequate oxygen saturation on room air with ≤ Grade 1 dyspnea, ALT ≤ 5 x ULN, total bilirubin < 2.0 mg/dL, creatinine clearance > 30 mL/min, and adequate bone marrow function to receive lymphodepleting chemotherapy. The median age of the study population was 69 years (range: 36 to 86 years); 76% were male, 88% were White, 6% were Asian and 2.3% were Black. Four percent were Hispanic, and 92% were non-Hispanic. The ECOG performance status at screening was 0 in 54% of patients, and 1 in 46% of patients.

Serious adverse reactions occurred in 53% of patients. The most common nonlaboratory serious adverse reactions (> 2%) were CRS, confusional state, fever, encephalopathy, mental status changes, pleural effusion, upper respiratory tract infection, and decreased appetite. Fatal adverse reactions occurred in 4.5% of patients.

Table 14 presents selected nonlaboratory adverse reactions reported in patients treated with BREYANZI, and Table 15 describes selected new or worsening Grade 3 or 4 laboratory abnormalities.

The most common nonlaboratory adverse reactions (≥ 20%) were CRS, fatigue, musculoskeletal pain, encephalopathy, edema, headache, and decreased appetite.

<div class="scrollingtable"><table width="100.14%"> <caption> <span>Table 14: Adverse Reactions* in ≥ 10% of Patients Treated with BREYANZI in the TRANSCEND-MCL Cohort (N=88)</span> </caption> <col width="35%"/> <col width="33%"/> <col width="33%"/> <tfoot> <tr class="First"> <td align="left" colspan="3" valign="top">*Includes adverse reactions up to 90 days following treatment with BREYANZI. </td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">a</span> Tachycardia includes atrial fibrillation, sinus tachycardia, tachycardia, ventricular tachycardia.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">b</span> Abdominal pain includes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain upper.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">c</span> Fatigue includes asthenia, fatigue, malaise.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">d</span> Edema includes hypervolemia, localized edema, edema, edema peripheral, peripheral swelling, pleural effusion, pulmonary edema.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">e</span> Fever includes pyrexia.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">f</span> Grouped per high-level grouped term.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">g</span> Upper respiratory tract infection includes nasal congestion, rhinitis, rhinorrhea, rhinovirus infection, upper respiratory tract infection.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">h</span> Musculoskeletal pain includes arthralgia, back pain, bone pain, musculoskeletal pain, myalgia, neck pain, pain in extremity.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">i</span> Encephalopathy includes confusional state, depressed level of consciousness, encephalopathy, lethargy, memory impairment, mental status changes, somnolence.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">j</span> Dizziness includes dizziness, dizziness postural, syncope, vertigo.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">k</span> Motor dysfunction includes fine motor skill dysfunction, muscle spasms, muscle tightness, muscular weakness. </td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">l</span> Insomnia includes insomnia, sleep disorder.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">m</span> Renal failure includes acute kidney injury, blood creatinine increased.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">n</span> Dyspnea includes dyspnea, tachypnea, wheezing.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">o</span> Rash includes dermatitis contact, rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">p</span> Hypotension includes hypotension, orthostatic hypotension.</td> </tr> <tr class="Last"> <td align="left" colspan="3" valign="top"><span class="Sup">q</span> Hemorrhage includes catheter site hemorrhage, epistaxis, hematoma, hematuria, hemorrhage, hemorrhoidal hemorrhage, rectal hemorrhage.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Adverse Reaction</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Any Grade (%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Grade 3 or Higher (%)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Cardiac disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Tachycardia<span class="Sup">a</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">17</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Gastrointestinal disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Nausea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">18</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Diarrhea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">17</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Abdominal pain<span class="Sup">b</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">15</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Constipation</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">14</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">General disorders and administration site conditions</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Fatigue<span class="Sup">c</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">39</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Edema<span class="Sup">d</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">25</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Fever<span class="Sup">e</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">17</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Chills</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Immune system disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Cytokine release syndrome</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">61</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Infections and infestations</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Infection with pathogen unspecified<span class="Sup">f</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Upper respiratory tract infection<span class="Sup">g</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">13</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Metabolism and nutrition disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Decreased appetite</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">21</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4.5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Musculoskeletal and connective tissue disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Musculoskeletal pain<span class="Sup">h</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">38</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Nervous system disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Encephalopathy<span class="Sup">i</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">30</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">9</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Headache</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">23</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Dizziness<span class="Sup">j</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Motor dysfunction<span class="Sup">k</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Tremor</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Psychiatric disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Insomnia<span class="Sup">l</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">14</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Anxiety</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">13</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Renal and urinary disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Renal failure<span class="Sup">m</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">15</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Respiratory, thoracic, and mediastinal disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Dyspnea<span class="Sup">n</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Cough</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Skin and subcutaneous tissue disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Rash<span class="Sup">o</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Vascular disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Hypotension<span class="Sup">p</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">15</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Hemorrhage<span class="Sup">q</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Hypertension</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.4</p> </td> </tr> </tbody> </table></div>

Other clinically important adverse reactions in < 10% of patients included the following:

<div class="scrollingtable"><table width="100.14%"> <caption> <span>Table 15: Grade 3 or 4 Laboratory Abnormalities<span class="Sup">*</span> Occurring in ≥ 10% of Patients Treated with BREYANZI in the TRANSCEND-MCL Cohort</span> </caption> <col width="50%"/> <col width="50%"/> <tfoot> <tr class="First"> <td align="left" colspan="2" valign="top"><span class="Sup">*</span>Includes lab abnormalities up to 90 days following treatment with BREYANZI. </td> </tr> <tr> <td align="left" colspan="2" valign="top"><span class="Sup">a</span> Baseline lab values were assessed prior to lymphodepleting chemotherapy.</td> </tr> <tr class="Last"> <td align="left" colspan="2" valign="top"><span class="Sup">b</span> The denominator ranged from 87 to 88 for laboratory measurements, based on the number of patients with a baseline value and at least one post-treatment value for the particular lab.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Laboratory Abnormality<span class="Sup">a</span></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Grade 3 or 4 (%)<span class="Sup">b</span></span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Lymphocyte count decreased</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">89</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Neutrophil count decreased</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">85</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">White blood cell decreased</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">83</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Platelet count decreased</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">39</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Hemoglobin decreased</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">33</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Uric acid increased</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Sodium decreased</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10</p> </td> </tr> </tbody> </table></div>

Grade 4 laboratory abnormalities in ≥ 10% of patients were lymphocyte count decreased (84%), neutrophil count decreased (52%), white blood cell decreased (52%), and platelet count decreased (22%).

Because adverse events to marketed products are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure.

The following adverse events have been identified during postmarketing use of BREYANZI.

Nervous System Disorder: Immune effector cell-associated neurotoxicity syndrome (ICANS).

Neoplasms: T cell malignancies

HIV and the lentivirus used to make BREYANZI have limited, short spans of identical genetic material (RNA). Therefore, some commercial HIV nucleic acid tests may yield false-positive results in patients who have received BREYANZI.

Risk Summary

There are no available data with BREYANZI use in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with BREYANZI to assess whether it can cause fetal harm when administered to a pregnant woman.

It is not known if BREYANZI has the potential to be transferred to the fetus. Based on the mechanism of action, if the transduced cells cross the placenta, they may cause fetal toxicity, including B-cell lymphocytopenia and hypogammaglobulinemia. Therefore, BREYANZI is not recommended for women who are pregnant, and pregnancy after BREYANZI infusion should be discussed with the treating physician.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Risk Summary

There is no information regarding the presence of BREYANZI in human milk, the effect on the breastfed infant, and the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BREYANZI and any potential adverse effects on the breastfed infant from BREYANZI or from the underlying maternal condition.

Pregnancy Testing

Pregnancy status of females with reproductive potential should be verified. Sexually active females of reproductive potential should have a pregnancy test prior to starting treatment with BREYANZI.

Contraception

See the prescribing information for fludarabine and cyclophosphamide for information on the need for effective contraception in patients who receive lymphodepleting chemotherapy.

There are insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with BREYANZI.

Infertility

There are no data on the effects of BREYANZI on fertility.

The safety and efficacy of BREYANZI have not been established in pediatric patients.

In clinical trials of BREYANZI, 111 (41%) of 268 patients with two or more prior lines of therapy for LBCL, and 89 (59%) of 150 patients with one prior line of therapy for LBCL, were 65 years of age or older; 27 (10%) and 28 (19%) were 75 years of age or older, respectively. In patients with CLL/SLL, 51 (57%) of 89 were 65 years of age or older, and 9 (10%) were 75 years of age or older. In patients with FL, 42 (39%) of 107 were 65 years of age or older, and 10 (9%) were 75 years of age or older. In patients with MCL, 64 (73%) of 88 patients were 65 years of age or older, and 18 (21%) were 75 years of age or older. No clinically important differences in safety or effectiveness of BREYANZI were observed between patients aged ≥ 65 and younger patients.

BREYANZI (lisocabtagene maraleucel) is a CD19-directed genetically modified autologous T cell immunotherapy administered as a defined composition of CAR-positive viable T cells (consisting of CD8 and CD4 components). The CAR is comprised of the FMC63 monoclonal antibody-derived single-chain variable fragment (scFv), IgG4 hinge region, CD28 transmembrane domain, 4-1BB (CD137) costimulatory domain, and CD3 zeta activation domain. In addition, BREYANZI includes a nonfunctional truncated epidermal growth factor receptor (EGFRt) that is co-expressed on the cell surface with the CD19-specific CAR.

{ "type": "p", "children": [], "text": "BREYANZI (lisocabtagene maraleucel) is a CD19-directed genetically modified autologous T cell immunotherapy administered as a defined composition of CAR-positive viable T cells (consisting of CD8 and CD4 components). The CAR is comprised of the FMC63 monoclonal antibody-derived single-chain variable fragment (scFv), IgG4 hinge region, CD28 transmembrane domain, 4-1BB (CD137) costimulatory domain, and CD3 zeta activation domain. In addition, BREYANZI includes a nonfunctional truncated epidermal growth factor receptor (EGFRt) that is co-expressed on the cell surface with the CD19-specific CAR." }

BREYANZI is a T cell product. BREYANZI is prepared from the patient’s T cells, which are obtained via a standard leukapheresis procedure. The purified CD8-positive and CD4-positive T cells are separately activated and transduced with the replication-incompetent lentiviral vector containing the anti-CD19 CAR transgene. The transduced T cells are expanded in cell culture, washed, formulated into a suspension, and cryopreserved as separate CD8 and CD4 component vials that together constitute a single dose of BREYANZI. The product must pass a sterility test before release for shipping as a frozen suspension in patient-specific vials. The product is thawed prior to administration [see Dosage and Administration (2.2) and How Supplied/Storage and Handling (16)].

{ "type": "p", "children": [], "text": "BREYANZI is a T cell product. BREYANZI is prepared from the patient’s T cells, which are obtained via a standard leukapheresis procedure. The purified CD8-positive and CD4-positive T cells are separately activated and transduced with the replication-incompetent lentiviral vector containing the anti-CD19 CAR transgene. The transduced T cells are expanded in cell culture, washed, formulated into a suspension, and cryopreserved as separate CD8 and CD4 component vials that together constitute a single dose of BREYANZI. The product must pass a sterility test before release for shipping as a frozen suspension in patient-specific vials. The product is thawed prior to administration [see Dosage and Administration (2.2) and How Supplied/Storage and Handling (16)]." }

The BREYANZI formulation contains 75% (v/v) Cryostor® CS10 [containing 7.5% dimethylsulfoxide (v/v)], 24% (v/v) Multiple Electrolytes for Injection, Type 1, 1% (v/v) of 25% albumin (human).

{ "type": "p", "children": [], "text": "The BREYANZI formulation contains 75% (v/v) Cryostor® CS10 [containing 7.5% dimethylsulfoxide (v/v)], 24% (v/v) Multiple Electrolytes for Injection, Type 1, 1% (v/v) of 25% albumin (human)." }

BREYANZI is a CD19-directed genetically modified autologous cell immunotherapy administered as a defined composition to reduce variability in CD8-positive and CD4-positive T cell dose. The CAR is comprised of an FMC63 monoclonal antibody-derived single chain variable fragment (scFv), IgG4 hinge region, CD28 transmembrane domain, 4-1BB (CD137) costimulatory domain, and CD3 zeta activation domain. CD3 zeta signaling is critical for initiating activation and antitumor activity, while 4-1BB (CD137) signaling enhances the expansion and persistence of BREYANZI.

CAR binding to CD19 expressed on the cell surface of tumor and normal B cells induces activation and proliferation of CAR T cells, release of pro-inflammatory cytokines, and cytotoxic killing of target cells.

Following BREYANZI infusion, pharmacodynamic responses were evaluated over a 4-week period by measuring transient elevation of soluble biomarkers such as cytokines, chemokines, and other molecules. Peak elevation of soluble biomarkers was observed within the first 14 days after BREYANZI infusion and returned to baseline levels within 28 days.

B-cell aplasia, defined as CD19+ B cells comprising less than 3% of peripheral blood lymphocytes, is an on-target effect of BREYANZI. B-cell aplasia was observed in the majority of patients for up to 1 year following BREYANZI infusion.

Following infusion, BREYANZI exhibited an initial expansion followed by a bi-exponential decline.

Relapsed or Refractory LBCL

The median time of maximal expansion in peripheral blood occurred 10-12 days after infusion. BREYANZI was present in peripheral blood for an estimated median of 12.1 months (range: 0.1+ to 24.2+ months).

Among patients who received two or more prior lines of therapy for LBCL (TRANSCEND), responders (N=135) had a 2.3-fold higher median Cmax than nonresponders (N=37) (35,335 vs. 15,527 copies/µg). Responders had a 1.8-fold higher median AUC0-28d than nonresponders (273,552 vs. 155,240 day*copies/µg).

Patients < 65 years old (N=142) had a 3.1-fold and 2.3-fold higher median Cmax and AUC0-28d, respectively, compared to patients ≥ 65 years old (N=96). Sex, race, ethnicity, and body weight did not show clear relationships to Cmax and AUC0-28d.

Relapsed or Refractory CLL/SLL

The median time of maximal expansion in peripheral blood occurred 14 days after infusion. BREYANZI was present in peripheral blood for an estimated median of 12.0 months (range: 0.1+ to 30.1+ months).

Among patients who received prior therapy for CLL/SLL (TRANSCEND-CLL), responders (N=27) had a 2.0-fold higher median Cmax than nonresponders (N=25) (99,559 vs. 48,948 copies/µg). Responders had a 1.9-fold higher median AUC0-28d than nonresponders (793,893 vs. 408,307 day*copies/µg).

Relapsed or Refractory FL

The median time of maximal expansion in peripheral blood occurred 10 days after infusion. Median Cmax and AUC0-28d are 30,530 copies/µg and 253,400 day*copies/µg, respectively. BREYANZI was present in peripheral blood for an estimated median of 12.0 months (range: 0.3+ to 24.0+ months).

Relapsed or Refractory MCL

The median time of maximal expansion in peripheral blood occurred 10 days after infusion. Median Cmax and AUC0-28d were 30,968 copies/µg and 375,006 day*copies/µg, respectively. BREYANZI was present in peripheral blood for an estimated median of 17.9 months (range: 0.1+ to 24.2+ months).

Patients receiving medications for CRS and/or neurologic toxicities

In general, patients with higher CAR-T cell expansion tended to have higher rates of CRS and neurologic toxicities. Some patients required tocilizumab and/or corticosteroids for the management of CRS or neurologic toxicities [see Dosage and Administration (2.3)]. BREYANZI continued to expand and persist in patients who received tocilizumab and/or corticosteroids treatment. In TRANSCEND, patients treated with tocilizumab (N=49) had a 3.6-fold and 3.7-fold higher median Cmax and AUC0-28d of BREYANZI, respectively, compared to patients who did not receive tocilizumab (N=189). Similarly, patients who received corticosteroids (N=50) had a 3.8-fold and 3.7-fold higher median Cmax and AUC0‑28d of BREYANZI, respectively, compared to patients who did not receive corticosteroids (N=188).

BREYANZI has the potential to induce anti-product antibodies. The immunogenicity of BREYANZI has been evaluated using an electrochemiluminescence (ECL) immunoassay for the detection of binding antibodies against the extracellular CD19-binding domain of BREYANZI. Pre-existing anti-product antibodies were detected in 11% (28/261) in TRANSCEND, 1% (1/89) in TRANSFORM, 0% (0/51) in PILOT, 2% (2/86) in TRANSCEND-CLL, 2% (2/102) in TRANSCEND-FL, and 13% (11/87) in TRANSCEND-MCL Cohort of patients. Treatment-induced or treatment-boosted anti-product antibodies were detected in 11% (27/257) in TRANSCEND, 1% (1/89) in TRANSFORM, 2% (1/49) in PILOT, 7% (6/84) in TRANSCEND-CLL, 18% (18/100) in TRANSCEND-FL, and 18% (15/85) in TRANSCEND-MCL Cohort of patients. Due to the small number of patients who had anti-product antibodies, the relationship between anti-product antibody status and efficacy, safety, or pharmacokinetics was not conclusive.

No carcinogenicity or genotoxicity studies have been conducted with BREYANZI. No studies have been conducted to evaluate the effects of BREYANZI on fertility. In vitro studies with BREYANZI manufactured from healthy donors and patients showed no evidence for transformation and/or immortalization and no preferential integration near genes associated with oncogenic transformation.

Relapsed or Refractory LBCL After One Line of Therapy

TRANSFORM

A randomized, open-label, multicenter trial evaluated the efficacy of BREYANZI in adult patients with relapsed or refractory LBCL after first-line chemoimmunotherapy (TRANSFORM; NCT03575351). Patients had not yet received treatment for relapsed or refractory lymphoma, were potential candidates for autologous HSCT, and were required to have primary refractory disease or relapse within 12 months from complete response (CR) to initial chemoimmunotherapy. Eligibility criteria required adequate organ function and blood counts for HSCT.

In total, 184 patients were randomized in a 1:1 ratio to receive a single infusion of BREYANZI (planned dose, 100 × 106 CAR-positive viable T cells) or to receive standard therapy consisting of 3 cycles of chemoimmunotherapy followed by high-dose therapy and autologous HSCT in patients who attained CR or PR. All patients underwent leukapheresis prior to randomization.

Patients randomized to BREYANZI were to receive lymphodepleting chemotherapy consisting of fludarabine 30 mg/m2/day and cyclophosphamide 300 mg/m2/day concurrently for 3 days followed by BREYANZI infusion 2 to 7 days after completion of lymphodepleting chemotherapy. Bridging chemotherapy was permitted between leukapheresis and the start of lymphodepleting chemotherapy. BREYANZI was administered in the inpatient (79%) and outpatient (21%) setting.

In the overall study population, the median age was 59 years (range: 20 to 75 years), 57% were male, 59% were White, 10% were Asian, and 4% were Black. Diagnoses included de novo DLBCL NOS (55%), high-grade B-cell lymphoma (23%), primary mediastinal large B-cell lymphoma (10%), and DLBCL arising from indolent lymphoma (8%). Of these patients, 73% had primary refractory disease to last therapy and 27% had relapsed disease within 12 months of achieving CR to first-line therapy.

Of 92 patients randomized to receive BREYANZI, 89 (97%) received BREYANZI. The median time from leukapheresis to product availability was 26 days (range: 19 to 84 days), and the median time from leukapheresis to product infusion was 36 days (range: 25 to 91 days). Fifty-eight (63%) patients received bridging therapy. One patient received a nonconforming product (manufacturing failure; 1.1%).

Of the 92 patients randomized to receive standard therapy, 91 started treatment and 43 (47%) received high-dose therapy and HSCT. The most common reason for not receiving HSCT was lack of efficacy of the salvage chemotherapy.

The primary efficacy measure was event-free survival (EFS) as determined by an independent review committee (IRC). Other efficacy measures included progression-free survival. Efficacy is summarized in Table 16 and Figure 1. The estimated 1-year EFS was 45% [95% CI: 29, 59] in the BREYANZI arm and 24% [95% CI: 14, 35] in the standard therapy arm.

Of the 92 patients in the BREYANZI arm, the estimated median duration of response (DOR) was not reached (95% CI: 7.9 months, NR) in patients who achieved CR (N=61) and 2.3 months (95% CI: 2.1, NR) in patients who achieved a best response of PR (N=18).

An interim analysis of overall survival was conducted at the time of the primary EFS analysis. The interim analysis of overall survival did not meet the criteria for statistical significance. Forty-six patients randomized to the standard therapy arm (50%) subsequently received BREYANZI on protocol.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 16: Efficacy Results in Patients with Relapsed or Refractory LBCL (TRANSFORM Study)</span> </caption> <col width="43%"/> <col width="28%"/> <col width="29%"/> <tfoot> <tr class="First"> <td align="left" colspan="3" valign="top">NR=not reached; CI=confidence interval.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">a</span> Per the Lugano criteria, as assessed by an IRC.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">b</span> EFS is defined as time from randomization to the earliest date of disease progression or relapse, death from any cause, failure to achieve CR or PR by 9 weeks post-randomization, or start of new lymphoma therapy due to efficacy concerns.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">c</span> Kaplan-Meier estimate.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">d</span> Based on a stratified Cox proportional hazards model. For all stratified analyses, stratification was based on response to first-line therapy (primary refractory vs relapsed) and second-line age-adjusted International Prognostic Index.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">e</span> Cochran-Mantel-Haenszel test.</td> </tr> <tr class="Last"> <td align="left" colspan="3" valign="top"><span class="Sup">f</span> p-value is compared with 0.012 of the allocated alpha for this pre-specified interim analysis.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Outcome</span><span class="Sup">a</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">BREYANZI Arm</span> </p> <p> <span class="Bold">(N=92)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Standard Therapy Arm</span> </p> <p> <span class="Bold">(N=92)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Event-Free Survival<span class="Sup">b</span></span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Number of events, n (%) </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">35 (38)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">63 (69)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Median, months [95% CI]<span class="Sup">c</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10.1 [6.1, NR]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.3 [2.2, 4.3]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Hazard ratio [95% CI]<span class="Sup">d</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First">0.34 [0.22, 0.52]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     One-sided p-value </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First">&lt;0.0001<span class="Sup">f</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Complete Response Rate, % [95% CI] </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">66 [56, 76]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">39 [29, 50]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Difference in CR rate, % [95% CI] </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First">27 [12, 41]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     One-sided p-value<span class="Sup">e</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First">&lt;0.0001<span class="Sup">f</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Progression-Free Survival </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Number of events, n (%) </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">28 (30)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">43 (47)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Median, months [95% CI]<span class="Sup">c</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">14.8 [6.6, NR]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5.7 [3.9, 9.4]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Hazard ratio [95% CI]<span class="Sup">d</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First">0.41 [0.25, 0.66]</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     One-sided p-value </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First">0.0001<span class="Sup">f</span> </p> </td> </tr> </tbody> </table></div>

Figure 1: Kaplan-Meier Plot of IRC-Assessed Event-Free Survival (Intention-to- Treat Analysis)

PILOT

The efficacy of BREYANZI was evaluated in a single-arm, open-label, multicenter trial (PILOT; NCT03483103) in transplant-ineligible patients with relapsed or refractory LBCL after one line of chemoimmunotherapy. The study enrolled patients who were not eligible for high-dose therapy and autologous HSCT due to organ function or age, while also having adequate organ function for CAR-T cell therapy. The study required at least one of the following criteria: age ≥ 70 years, adjusted diffusing capacity of the lung for carbon monoxide (DLCO) ≤ 60%; LVEF < 50%; creatinine clearance < 60mL/min; AST or ALT greater than 2 × ULN, or ECOG performance status of 2. The planned dose of BREYANZI was 100 × 106 CAR-positive viable T cells. Bridging therapy for disease control was permitted between leukapheresis and the start of lymphodepleting chemotherapy. Of the 61 patients treated with BREYANZI, 32 (53%) received bridging therapy.

BREYANZI was administered 2 to 7 days following completion of lymphodepleting chemotherapy. The lymphodepleting chemotherapy regimen consisted of fludarabine 30 mg/m2/day and cyclophosphamide 300 mg/m2/day concurrently for 3 days. BREYANZI was administered in the inpatient (67%) and outpatient (33%) setting.

Of 74 patients who underwent leukapheresis, 61 (82%) received BREYANZI and comprise the main efficacy population; 1 (1.4%) received CAR-positive T cells that did not meet the product specifications for BREYANZI (manufacturing failure); and 12 (16%) did not receive CAR-positive T cells for other reasons.

Of the 61 patients who received BREYANZI, the median age was 74 years (range: 53 to 84 years), 61% were male, 89% were White, 3% were Asian, and 2% were Black. Diagnoses included de novo DLBCL NOS (51%), high-grade B-cell lymphoma (33%), and DLBCL arising from follicular lymphoma (15%). Of these patients, 53% had primary refractory disease, 23% had relapse within 12 months of completing first-line therapy, and 25% had relapse >12 months after first-line therapy.

Efficacy was based on CR rate and DOR, as determined by an independent review committee (IRC) using 2014 Lugano criteria (Tables 17 and 18). The median time to CR was 1 month (range 0.8 to 6.9 months).

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 17: Response Rate in Relapsed or Refractory LBCL (PILOT Study)</span> </caption> <col width="33%"/> <col width="34%"/> <col width="34%"/> <tfoot> <tr class="First"> <td align="left" colspan="3" valign="top">CI=confidence interval; NR=Not reached.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">a</span> Per the Lugano criteria, as assessed by an IRC.</td> </tr> <tr class="Last"> <td align="left" colspan="3" valign="top"><span class="Sup">b</span> 2-sided 95% exact Clopper-Pearson confidence intervals.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Outcome<span class="Sup">a</span></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">BREYANZI-Treated</span> </p> <p> <span class="Bold">(N=61)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">All Leukapheresed Patients</span> </p> <p> <span class="Bold">(N=74)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Overall Response, n (%) </span> </p> <p>[95% CI]<span class="Sup">b</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">49 (80%)</p> <p>[68%, 89%]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">50 (68%)</p> <p>[56%, 78%]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Complete Response </span> </p> <p>[95% CI] </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">33 (54%)</p> <p>[41%, 67%]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">34 (46%)</p> <p>[34%, 58%]</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Partial Response </span> </p> <p>[95% CI] </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16 (26%)</p> <p>[16%, 39%]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16 (22%)</p> <p>[13%, 33%]</p> </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 18: Duration of Response in the PILOT Study</span> </caption> <col width="44%"/> <col width="56%"/> <tfoot> <tr class="First"> <td align="left" colspan="2" valign="top">DOR=duration of response; CI=confidence interval; CR=complete response; PR=partial response; NR=not reached.</td> </tr> <tr> <td align="left" colspan="2" valign="top"><span class="Sup">a</span> Per the Lugano criteria, as assessed by an IRC.</td> </tr> <tr> <td align="left" colspan="2" valign="top"><span class="Sup">b</span> Kaplan-Meier method is used to obtain 2-sided 95% confidence intervals.</td> </tr> <tr> <td align="left" colspan="2" valign="top"><span class="Sup">c</span> Kaplan-Meier estimate.</td> </tr> <tr class="Last"> <td align="left" colspan="2" valign="top"><span class="Sup">+ </span>Indicates a censored value.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Outcome<span class="Sup">a</span></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">BREYANZI-Treated</span> </p> <p> <span class="Bold">(N=61)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Number of Responders </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">49</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">DOR</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Median [95% CI], months <span class="Sup">b</span> </p> <p>Range, months</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11.2 [5.1, NR]</p> <p>0.0<span class="Sup">+</span> to 22.8<span class="Sup">+</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">DOR if Best Response is CR</span> </p> <p>Median [95% CI], months </p> <p>Range, months </p> <p>Rate at 6 months [95% CI] <span class="Sup">c</span> </p> <p>Rate at 12 months [95% CI] <span class="Sup">c</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> </p> <p>NR [11.2, NR]</p> <p>2.0<span class="Sup">+</span> to 22.8<span class="Sup">+</span> </p> <p>83% [64, 93]</p> <p>68% [45, 83]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">DOR if Best Response is PR </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Median [95% CI], months </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.1 [1.4, 2.3]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Range, months </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.0<span class="Sup">+</span> to 7.9</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Rate at 6 months [95% CI] <span class="Sup">c</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8.2% [0.5, 30.5]</p> </td> </tr> </tbody> </table></div>

Relapsed or Refractory LBCL After Two or More Lines of Therapy

TRANSCEND

The efficacy of BREYANZI was evaluated in an open-label, multicenter, single-arm trial (TRANSCEND; NCT02631044) in adult patients with relapsed or refractory large B-cell non-Hodgkin lymphoma after at least 2 lines of therapy. The study included patients with ECOG performance status ≤ 2, prior autologous and/or allogeneic HSCT, and secondary CNS lymphoma involvement. The study excluded patients with a creatinine clearance of less than 30 mL/min, ALT > 5 times the ULN, or LVEF < 40%. There was no prespecified threshold for blood counts; patients were eligible to enroll if they were assessed by the investigator to have adequate bone marrow function to receive lymphodepleting chemotherapy. Bridging therapy for disease control was permitted between apheresis and the start of lymphodepleting chemotherapy, including intrathecal chemotherapy or radiation therapy for treatment of CNS involvement with lymphoma.

BREYANZI was administered 2 to 7 days following completion of lymphodepleting chemotherapy. The lymphodepleting chemotherapy regimen consisted of fludarabine 30 mg/m2/day and cyclophosphamide 300 mg/m2/day concurrently for 3 days. BREYANZI was administered in the inpatient and outpatient setting.

Of 299 patients who underwent leukapheresis for whom BREYANZI was manufactured in the dose range of 50 to 110 × 106 CAR-positive viable T cells:

Of the 192 patients in the main efficacy population, the median age was 63 years (range: 18 to 86 years), 69% were male, 84% were White, 6% were Black, and 4.7% were Asian. The median number of prior therapies was 3 (range: 1 to 8). Diagnoses were de novo DLBCL (53%), DLBCL transformed from indolent lymphoma (25%), high-grade B-cell lymphoma (14%), primary mediastinal large B-cell lymphoma (7%), follicular lymphoma, grade 3B (1.0%). Of these patients, 64% had disease refractory to last therapy, 53% had primary refractory disease, 37% had prior HSCT and 2.6% had CNS involvement.

Efficacy was based on CR rate and DOR, as determined by an IRC using 2014 Lugano criteria (Tables 19 and 20). The median time to first response (CR or partial response [PR]) was 1.0 month (range: 0.7 to 8.9 months). The median time to first CR was 1.0 month (range 0.8 to 12.5 months). Of the 104 patients who achieved CR, 23 initially had stable disease (6 patients) or PR (17 patients), with a median time to improvement of 2.2 months (range: 0.7 to 11.6 months).

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 19: Response Rate in Main Efficacy Population (TRANSCEND Study)</span> </caption> <col width="40%"/> <col width="60%"/> <tfoot> <tr> <td align="left" colspan="2" valign="top">CI=confidence interval.</td> </tr> <tr> <td align="left" colspan="2" valign="top"><span class="Sup">a</span> Per the Lugano criteria, as assessed by an IRC.</td> </tr> </tfoot> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">BREYANZI-Treated</span> <br/> <span class="Bold">N=192</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Overall Response Rate<span class="Sup">a</span>, n</span> <br/>[95% CI]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">141 (73%)<br/>[67%, 80%]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Complete Response, n</span> <br/>[95% CI]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">104 (54%)<br/>[47%, 61%]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Partial Response, n</span> <br/>[95% CI]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">37 (19%)<br/>[14%, 26%]</p> </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 20: Duration of Response in the TRANSCEND Study</span> </caption> <col width="49%"/> <col width="51%"/> <tfoot> <tr> <td align="left" colspan="2" valign="top">DOR=duration of response; CI=confidence interval; CR=complete response; PR=partial response; NR=not reached.</td> </tr> <tr> <td align="left" colspan="2" valign="top"><span class="Sup">a</span> Evaluable for efficacy.</td> </tr> <tr> <td align="left" colspan="2" valign="top"><span class="Sup">b</span> KM method was used to obtain 2-sided 95% confidence intervals.</td> </tr> <tr> <td align="left" colspan="2" valign="top"><span class="Sup">+</span> Indicates a censored value.</td> </tr> </tfoot> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">BREYANZI-Treated<span class="Sup">a</span></span> <br/> <span class="Bold">N=192</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Number of Responders</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">141</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">DOR (Months)</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Median [95% CI]<span class="Sup">b</span> </p> <p>Range</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16.7 [5.3, NR]</p> <p>0.0<span class="Sup">+</span> to 23.5<span class="Sup">+</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">DOR if Best Response is CR (Months)</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Median [95% CI] </p> <p>Range</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">NR [16.7, NR]</p> <p>0.7<span class="Sup">+</span> to 23.5<span class="Sup">+</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">DOR if Best Response is PR (Months)</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Median [95% CI] </p> <p>Range</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.4 [1.1, 2.2]</p> <p>0.0<span class="Sup">+</span> to 22.8<span class="Sup">+</span> </p> </td> </tr> </tbody> </table></div>

Response durations were longer in patients who achieved a CR, as compared to patients with a best response of PR (Table 20). Of the 104 patients who achieved CR, 68 (65%) had remission lasting at least 6 months and 64 (62%) had remission lasting at least 9 months.

Of the 287 patients who underwent leukapheresis and had radiographically evaluable disease, 27 additional patients achieved a response, apart from the responses noted in Table 19. The IRC-assessed overall response rate in the leukapheresed population (n=287) was 59% (95% CI: 53, 64), with a CR rate of 43% (95% CI: 37, 49) and PR rate of 15% (95% CI: 11, 20). These efficacy results include responses that may have been contributed solely by bridging therapy, responses after receipt of product outside of the intended dose range, and responses to product that did not meet release specifications.

TRANSCEND-CLL

The efficacy of BREYANZI was evaluated in a phase 1/2, open-label, multicenter, single-arm trial (TRANSCEND-CLL; NCT03331198) in adult patients with R/R CLL or SLL who had received at least 2 prior lines of therapy including a BTK inhibitor and a BCL-2 inhibitor. Patients with del(17p), complex karyotype, and unmutated immunoglobulin heavy chain variable region (IGHV) were included in the study. The study enrolled patients with ECOG performance status of ≤ 1. The study excluded patients with a creatinine clearance of less than 30 mL/min, ALT > 5 times the ULN (except for subjects with leukemic infiltration of the liver), or LVEF < 40%. There was no prespecified threshold for blood counts; patients were eligible to enroll if they were assessed by the investigator to have adequate bone marrow function to receive lymphodepleting chemotherapy. The planned dose of BREYANZI was 100 × 106 CAR-positive viable T cells. Bridging therapy for disease control was permitted between apheresis and the start of lymphodepleting chemotherapy.

Of the 89 patients, BREYANZI was administered 2 to 11 days following completion of lymphodepleting chemotherapy. The lymphodepleting chemotherapy regimen consisted of fludarabine 30 mg/m2/day and cyclophosphamide 300 mg/m2/day concurrently for 3 days. BREYANZI was administered in the inpatient (88%) and outpatient (12%) settings.

Of 113 patients who underwent leukapheresis, 94 received BREYANZI. Of the 94, 84 received BREYANZI at 90 to 111 × 106 CAR-positive T cells and 10 received a cell-dose outside of this dose range; 3 received CAR-positive T cells that did not meet the product specifications for BREYANZI (manufacturing failure); and 16 other patients did not receive BREYANZI for other reasons.

The median time from leukapheresis to product availability was 24 days (range: 19 to 84 days), and the median time from leukapheresis to product infusion was 36 days (range: 28 to 384 days). Of the 89 patients treated with BREYANZI, 69 (78%) received bridging therapy.

Patients had measurable disease present before BREYANZI administration based on IRC assessment. Nineteen of 84 patients were not evaluable for efficacy (13 patients did not have baseline disease assessments performed after completion of bridging therapy, 1 patient lacked measurable disease, and 5 had Richter’s transformation). Of the 65 efficacy-evaluable patients, the median age was 66 years (range: 49 to 82 years), 68% were male, 80% were White, 3% were Black, 1% were Asian. Two‑percent were Hispanic and 89% were non-Hispanic. Eighty-three percent of patients had at least one high risk genetic attribute including 43% del(17p), 45% TP53 mutation, 45% unmutated IGHV, and 62% with complex karyotype. Fifty-one percent of the patients had bulky disease. The median number of prior therapies was 5 (range: 2 to 12). All 65 patients were exposed to a BTK inhibitor, of which 88% were refractory, 1.5% were relapsed, and 11% were intolerant. Of 65 patients who received a BCL-2 inhibitor, 92% were refractory, none relapsed, and 6% were intolerant. A total of 83% had disease refractory to last therapy.

Efficacy was based on ORR (including CR and PR) and DOR as determined by an IRC using 2018 International Workshop CLL (iwCLL) criteria (Tables 21 and 22). The median time to first response (CR or PR) was 1.1 months (range: 0.8 to 17.4 months). The median time to first CR was 3.0 months (range 1.1 to 17.9 months).

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 21: Response Rate in Relapsed or Refractory CLL/SLL (TRANSCEND-CLL Study)</span> </caption> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tfoot> <tr class="First"> <td align="left" colspan="3" valign="top">CI=confidence interval; iwCLL=international workshop on chronic lymphocytic leukemia; IRC=independent review committee.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">a</span> Per the 2018 iwCLL criteria, as assessed by IRC.</td> </tr> <tr class="Last"> <td align="left" colspan="3" valign="top"><span class="Sup">b</span> 2-sided 95% exact Clopper-Pearson CIs.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Outcome</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">BREYANZI Treated</span> </p> <p> <span class="Bold">(N=65) </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">All Leukapheresed Patients</span> </p> <p> <span class="Bold">(N=113)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">Overall Response Rate<span class="Sup">a</span>, n (%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">29 (45)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">42 (37)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">[95% CI]<span class="Sup">b</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">[32.3, 57.5]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">[28.3, 46.8]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">Complete Response<span class="Sup">a</span>, n (%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">13 (20)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16 (14)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">[95% CI]<span class="Sup">b</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">[11.1, 31.8]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">[8.3, 22.0]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">Partial Response<span class="Sup">a</span>, n (%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16 (25)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">26 (23)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">[95% CI]<span class="Sup">b</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">[14.8, 36.9]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">[15.6, 31.9]</p> </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 22: Duration of Response in the TRANSCEND-CLL Study</span> </caption> <col width="50%"/> <col width="50%"/> <tfoot> <tr class="First"> <td align="left" colspan="2" valign="top">CI=confidence interval; NR=not reached.</td> </tr> <tr> <td align="left" colspan="2" valign="top"><span class="Sup">a</span> Per the 2018 iwCLL criteria, as assessed by IRC.</td> </tr> <tr> <td align="left" colspan="2" valign="top"><span class="Sup">b</span> Kaplan-Meier method was used to obtain 2-sided 95% CIs.</td> </tr> <tr class="Last"> <td align="left" colspan="2" valign="top"><span class="Sup">+</span> Indicates a censored value.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">BREYANZI-Treated</span> </p> <p> <span class="Bold">N=65</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Number of Responders</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">29</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">DOR<span class="Sup">a </span>(months)</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Median [95% CI]<span class="Sup">b</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">35.3 [12.4, NR]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Range</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.0<span class="Sup">+</span>, 35.3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">DOR if Best Response is CR<span class="Sup">a</span></span><span class="Bold">(months)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">N=13</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Median [95% CI]<span class="Sup">b</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">NR [15.0, NR]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Range</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.0<span class="Sup">+</span>, 30.0<span class="Sup">+</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Rate at 12 months (%) [95% CI]<span class="Sup">b</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">100 [NR, NR]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Rate at 18 months (%) [95% CI]<span class="Sup">b</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">87.5 [38.7, 98.1]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">DOR if Best response is PR<span class="Sup">a</span></span><span class="Bold">(months)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">N=16</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Median [95% CI]<span class="Sup">b</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12.4 [8.9, NR]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Range</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4.1, 35.3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Rate at 12 months (%) [95% CI]<span class="Sup">b</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">60.3 [32.0, 79.8]</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Rate at 18 months (%) [95% CI]<span class="Sup">b</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">46.9 [21.4, 68.9]</p> </td> </tr> </tbody> </table></div>

Minimal residual disease (MRD) negative status was defined as less than one CLL cell per 104 leukocytes using ClonoSEQ, a next generation sequencing assay (NGS) at any time post infusion (MRD‑negativity rate). There was no statistical testing of MRD-negativity rate. In patients who achieved CR, the MRD-negativity rate was 100% (13/13, 95% CI: 75.3, 100) in peripheral blood and 92.3% (12/13, 95% CI: 64, 99.8) in the bone marrow.

TRANSCEND-FL

The efficacy of BREYANZI was evaluated in a Phase 2, open-label, multicenter, single-arm trial (TRANSCEND‑FL; NCT04245839) in adult patients with relapsed or refractory FL after two or more lines of systemic therapy (including an anti-CD20 antibody and an alkylating agent). The study enrolled patients with ECOG performance status of ≤ 1. The study excluded patients with a creatinine clearance of ≤ 30 mL/min, ALT > 5 times the ULN, or LVEF < 40%. There was no prespecified threshold for blood counts; patients were eligible to enroll if they were assessed by the investigator to have adequate bone marrow function to receive lymphodepleting chemotherapy. The planned dose of BREYANZI was 100 × 106 CAR-positive viable T cells. Bridging therapy for disease control was permitted between apheresis and the start of lymphodepleting chemotherapy.

A single dose of BREYANZI was administered 2 to 7 days following completion of lymphodepleting chemotherapy. The lymphodepleting chemotherapy regimen consisted of fludarabine 30 mg/m2/day and cyclophosphamide 300 mg/m2/day concurrently for 3 days. Six percent of patients were treated with BREYANZI in outpatient setting.

Of 114 patients who underwent leukapheresis, 107 received BREYANZI and the median dose administered was 100.02 x 106 CAR-positive viable T-cells (range: 93.4 to 109.2 x 106 CAR-positive viable T cells).The primary efficacy analysis included 94 patients who had PET-positive disease at study baseline or confirmation of PET-positive disease after bridging therapy, received conforming product in intended dose range and had at least 9 months of follow up from the date of first response.

The median time from leukapheresis to product availability was 29 days (range: 20 to 55 days), and the median time from leukapheresis to product infusion was 50 days (range: 31 to 313 days). Of the 107 patients treated with BREYANZI, 40 (40%) received bridging therapy.

The median age was 63 years (range: 23 to 80 years), 62% were male, ECOG performance status was 0 in 63% and 1 in 37% of patients; 55% were White, 3% were Black, 9% were Asian; 5% were Hispanic and 69% were non-Hispanic. The median number of prior systemic therapies was 3 (range: 2 to 10), with 46% receiving 2 prior lines, 22% receiving 3 prior lines and 32% receiving ≥ 4 prior lines. Twenty percent had received rituximab with lenalidomide, 25% had received a PI3K inhibitor, and 29% of patients had prior autologous HSCT. Eighty-nine percentage patients had Stage III-IV disease at study entry, 29% had bulky disease, 64% had progression within 6 months of the most recent regimen, and 50% had progression within 24 months of initial diagnosis (POD24).

Efficacy was based on ORR, defined as the percentage of patients with a best overall response (BOR) of CR or PR after BREYANZI infusion and duration of response as determined by an IRC (Tables 23 and 24). The median time to first response (CR or PR) was 1.0 month (range: 0.6 to 3.3 months). The median time to first CR was 3.0 months (range 0.6 to 18.0 months).

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 23: Response Rate in Patients with Relapsed or Refractory FL</span> </caption> <col width="36%"/> <col width="30%"/> <col width="34%"/> <tfoot> <tr class="First"> <td align="left" colspan="3" valign="top">CI=confidence interval.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">a</span> Evaluable for efficacy.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">b</span> Per the Lugano criteria, as assessed by an IRC.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">c</span> Two-sided 95% confidence interval based on exact Clopper-Pearson method.</td> </tr> <tr class="Last"> <td align="left" colspan="3" valign="top"><span class="Sup">d</span> CR required a negative bone marrow biopsy after treatment in patients who did not have a negative bone marrow biopsy between their most recent disease progression and prior to initiation of lymphodepleting chemotherapy.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">BREYANZI‑Treated<span class="Sup">a</span></span> </p> <p> <span class="Bold">(N=94)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">All Leukapheresed Patients</span> </p> <p> <span class="Bold">(N=114)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Overall Response Rate<span class="Sup">b</span>, n (%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">90 (95.7)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">105 (92.1)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">[95% CI]<span class="Sup">c</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">[89.5, 98.8)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">[85.5, 96.3]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Complete Response<span class="Sup">d</span>, n (%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">69 (73.4)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">78 (68.4)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">[95% CI]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">[63.3, 82.0]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">[59.1, 76.8)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Partial Response, n (%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">21 (22.3)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">27 (23.7)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">[95% CI]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">[14.4, 32.1]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">[16.2, 32.6]</p> </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 24: Duration of Response<span class="Sup">a</span> in Patients with Relapsed or Refractory FL</span> </caption> <col width="47%"/> <col width="53%"/> <tfoot> <tr class="First"> <td align="left" colspan="2" valign="top">DOR= duration of response; CI=confidence interval; CR=complete response; PR=partial response; NR=not reached. </td> </tr> <tr> <td align="left" colspan="2" valign="top"><span class="Sup">a</span> Median follow-up for DOR is 16.8 months (95% CI: 16.3 to 17.0).</td> </tr> <tr> <td align="left" colspan="2" valign="top"><span class="Sup">b</span> Evaluable for efficacy. </td> </tr> <tr> <td align="left" colspan="2" valign="top"><span class="Sup">c</span> Median [95% CI] are estimated from KM estimates. </td> </tr> <tr> <td align="left" colspan="2" valign="top"><span class="Sup">+</span> Indicates a censored value.</td> </tr> <tr class="Last"> <td align="left" colspan="2" valign="top"><span class="Sup">d</span> KM estimate of probability of continued response at the specified month.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">BREYANZI Treated<span class="Sup">b</span></span> </p> <p> <span class="Bold">N = 94</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Number of Responders </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">90</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">DOR (months) </span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Median [95% CI]<span class="Sup">c</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">NR (18.0, NR)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Range </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.9, 23.1<span class="Sup">+</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Rate at 12 months, (%) [95% CI]<span class="Sup">d</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">80.9 (71.0, 87.7)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Rate at 18 months, (%) [95% CI]<span class="Sup">d</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">77.1 (65.9, 85.0)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">DOR if best response is CR (months) </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">N=69</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Median [95% CI]<span class="Sup">c</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">NR [NR, NR]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Range </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.8, 23.1<span class="Sup">+</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Rate at 12 months, (%)  [95% CI]<span class="Sup">d</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">88.2 (77.7, 93.9)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Rate at 18 months, (%)  [95% CI]<span class="Sup">d</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">83.1 (70.0, 90.9)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">DOR if best response is PR (months) </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">N=21</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Median [95% CI]<span class="Sup">c</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">18.04 [4.17, NR]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Range </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.9, 22.4<span class="Sup">+</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Rate at 12 months, (%) [95% CI]<span class="Sup">d</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">56.7 (33.3, 74.7)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Rate at 18 months, (%) [95% CI]<span class="Sup">d</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">56.7 (33.3, 74.7)</p> </td> </tr> </tbody> </table></div>

TRANSCEND-MCL Cohort

The efficacy of BREYANZI was evaluated in an open-label, multicenter, single-arm trial (TRANSCEND-MCL Cohort; NCT02631044) in adult patients with relapsed or refractory MCL who had received at least two prior lines of therapy including a BTK inhibitor, an alkylating agent, and an anti-CD20 agent. The study included patients with ECOG performance status of ≤ 1, prior autologous and/or allogeneic HSCT, and secondary CNS lymphoma involvement. The study excluded patients with a creatinine clearance ≤ 30 mL/min, alanine aminotransferase > 5 times the upper limit of normal or left ventricular ejection fraction (LVEF) < 40%. There was no prespecified threshold for blood counts; patients were eligible to enroll if they were assessed by the investigator to have adequate bone marrow function to receive lymphodepleting chemotherapy. The planned dose of BREYANZI was 100 × 106 CAR-positive viable T cells. Bridging therapy for disease control was permitted between apheresis and the start of lymphodepleting chemotherapy.

BREYANZI was administered 2 to 7 days following completion of lymphodepleting chemotherapy. The lymphodepleting chemotherapy regimen consisted of fludarabine 30 mg/m2/day and cyclophosphamide 300 mg/m2/day concurrently for 3 days. BREYANZI was administered in the inpatient (85%) and outpatient (15%) setting.

Of 89 patients who underwent leukapheresis, 71 received BREYANZI and the median dose administered was 99.8 x 106 CAR-positive viable T cells (range: 90 to 103 x 106 CAR-positive viable T cells). The primary efficacy analysis included a total of 68 patients with MCL who received at least 2 prior lines of therapy including a BTK inhibitor, had PET-positive disease at study baseline or after bridging therapy, received conforming product in the intended dose range, and had at least 6 months of follow up from the date of first response.

The median time from leukapheresis to product availability was 24 days (range: 17 to 80 days), and the median time from leukapheresis to product infusion was 36 days (range: 28 to 489 days). Of the 68 patients in the main efficacy population, 44 (65%) received bridging therapy.

The median age was 69 years (range: 36 to 86 years); 75% were male, ECOG performance status was 0 in 57% and 1 in 43% of patients; 87% were White, 1.5% were Black, 6% were Asian; 6% were Hispanic and 91% were non-Hispanic. The median number of prior therapies was 3 (range: 2 to 11) and 32% had received prior HSCT. Twenty-nine percent of patients had blastoid morphology and 10% had CNS lymphoma involvement at baseline. Sixty-nine percent of patients had disease refractory to their last therapy for MCL, defined as best response of partial response (PR), stable disease (SD), or progressive disease (PD) to last systemic or HSCT treatment with curative intent. All 68 patients were exposed to BTK inhibitor, of which 56% were refractory, defined as any response to prior BTK inhibitor that was less than PR.

Efficacy was based on ORR, defined as the percentage of patients with BOR of either CR or PR after BREYANZI infusion, as determined by an IRC using 2014 Lugano classification. Other efficacy measures included complete response rate and DOR, as determined by IRC (Tables 25 and Table 26).

Both the median time to first response (CR or PR) and the median time to first CR were 1 month (range: 0.7 to 3 months).

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 25: Response Rate in Relapsed or Refractory MCL (TRANSCEND-MCL Cohort)</span> </caption> <col width="41%"/> <col width="27%"/> <col width="30%"/> <tfoot> <tr class="First"> <td align="left" colspan="3" valign="top">CI=confidence interval. </td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">a</span> Evaluable for efficacy.</td> </tr> <tr> <td align="left" colspan="3" valign="top"><span class="Sup">b</span> Per the 2014 Lugano classification (including bone marrow biopsy assessments), as assessed by IRC.</td> </tr> <tr class="Last"> <td align="left" colspan="3" valign="top"><span class="Sup">c</span> 2-sided 95% exact Clopper-Pearson CIs.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Outcome</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">BREYANZI-Treated<span class="Sup">a</span></span> </p> <p> <span class="Bold">(N=68)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">All Leukapheresed Patients</span> </p> <p> <span class="Bold">(N=89)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Overall Response Rate<span class="Sup">b</span>, n (%)</span> </p> <p>[95% CI]<span class="Sup">c</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">58 (85.3)</p> <p>(74.6, 92.7)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">65 (73.0)</p> <p>(62.6, 81.9)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">     Complete Response, n (%)</span> </p> <p>     [95% CI]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">46 (67.6)</p> <p>(55.2, 78.5)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">51 (57.3)</p> <p>(46.4, 67.7)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">     Partial Response, n (%)</span> </p> <p>     [95% CI]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">12 (17.6)</p> <p>(9.5, 28.8)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">14 (15.7)</p> <p>(8.9, 25.0)</p> </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 26: Duration of Response<span class="Sup">a</span> in the TRANSCEND-MCL Cohort</span> </caption> <col width="49%"/> <col width="49%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="2" valign="top">CI=confidence interval; NE=not evaluable; NR=not reached.<br/> <span class="Sup">a </span> Median follow-up for DOR is 22.2 months (95% CI: 16.7 to 22.8).<br/> <span class="Sup">b</span> Per the 2014 Lugano classification (including bone marrow biopsy assessments), as assessed by IRC.<br/> <span class="Sup">c</span> Kaplan-Meier method was used to obtain 2-sided 95% CIs.<br/> <span class="Sup">d</span> KM estimate of probability of continued response at the specified month.<br/> <span class="Sup">+</span> Indicates a censored value.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">BREYANZI-Treated</span> </p> <p> <span class="Bold">(N=68)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Number of Responders</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">58</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">DOR<span class="Sup">b</span> (months)</span> </p> <p>Median [95% CI]<span class="Sup">c</span> </p> <p>Range</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">13.3 [6.0, 23.3]</p> <p>0.0<span class="Sup">+</span>, 23.3<span class="Sup">+</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> Rate at 12 months (%) [95% CI]<span class="Sup">d</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">51.4 [37.5, 63.7]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> Rate at 18 months (%) [95% CI]<span class="Sup">d</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">38.8 [25.0, 52.4]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">DOR if Best Response is CRb (months)</span> </p> <p>Median [95% CI]<span class="Sup">c</span> </p> <p>Range</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">N=46</span> </p> <p>17.5 [7.5, NR]</p> <p>0.6, 23.3<span class="Sup">+</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Rate at 12 months (%) [95% CI]<span class="Sup">d</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">57.8 [41.9, 70.7]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Rate at 18 months (%) [95% CI]<span class="Sup">d </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">48.0 [31.6, 62.6]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">DOR if Best Response is PRb (months)</span> </p> <p>Median [95% CI]<span class="Sup">c</span> </p> <p>Range</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">N=12</span> </p> <p>2.2 [1.8, 13.3]</p> <p>0.0<span class="Sup">+</span>, 14.5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Rate at 12 months (%) [95% CI]<span class="Sup">d</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">27.3 [6.5, 53.9]</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Rate at 18 months (%) [95% CI]<span class="Sup">d</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.0 [NE, NE]</p> </td> </tr> </tbody> </table></div>

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BREYANZI consists of genetically modified autologous T cells, supplied in vials as separate frozen suspensions of each CD8 component (NDC 73153-901-08) and CD4 component (NDC 73153-902-04). Each CD8 or CD4 component is packed in a carton containing up to 4 vials, depending upon the concentration of the cryopreserved drug product CAR-positive viable T cells. The cartons for each CD8 component and CD4 component are in an outer carton (NDC 73153-900-01). BREYANZI is shipped directly to the cell lab or clinical pharmacy associated with the infusion center in the vapor phase of a liquid nitrogen shipper. A Release for Infusion (RFI) Certificate for each component and patient-specific syringe labels are affixed inside the shipper.

{ "type": "p", "children": [], "text": "BREYANZI consists of genetically modified autologous T cells, supplied in vials as separate frozen suspensions of each CD8 component (NDC 73153-901-08) and CD4 component (NDC 73153-902-04). Each CD8 or CD4 component is packed in a carton containing up to 4 vials, depending upon the concentration of the cryopreserved drug product CAR-positive viable T cells. The cartons for each CD8 component and CD4 component are in an outer carton (NDC 73153-900-01). BREYANZI is shipped directly to the cell lab or clinical pharmacy associated with the infusion center in the vapor phase of a liquid nitrogen shipper. A Release for Infusion (RFI) Certificate for each component and patient-specific syringe labels are affixed inside the shipper." }

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Advise the patient to read the FDA-approved patient labeling (Medication Guide).

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Ensure that patients understand the risk (11%) of manufacturing failure. In case of a manufacturing failure, a second manufacturing of BREYANZI may be attempted. While the patient awaits the product, additional bridging therapy (not the lymphodepletion) may be necessary. This bridging therapy may be associated with adverse events during the pre-infusion period, which could delay or prevent the administration of BREYANZI.

{ "type": "p", "children": [], "text": "Ensure that patients understand the risk (11%) of manufacturing failure. In case of a manufacturing failure, a second manufacturing of BREYANZI may be attempted. While the patient awaits the product, additional bridging therapy (not the lymphodepletion) may be necessary. This bridging therapy may be associated with adverse events during the pre-infusion period, which could delay or prevent the administration of BREYANZI." }

Advise patients that they will be monitored daily for at least 7 days following the BREYANZI infusion at a REMS-certified healthcare facility and instruct patients to remain within 2 hours of a REMS-certified healthcare facility for at least 4 weeks following the infusion.

{ "type": "p", "children": [], "text": "Advise patients that they will be monitored daily for at least 7 days following the BREYANZI infusion at a REMS-certified healthcare facility and instruct patients to remain within 2 hours of a REMS-certified healthcare facility for at least 4 weeks following the infusion." }

Prior to infusion, advise patients of the following risks:

{ "type": "p", "children": [], "text": "Prior to infusion, advise patients of the following risks:" }

{ "type": "", "children": [], "text": "" }

Advise patients of the need to:

{ "type": "p", "children": [], "text": "Advise patients of the need to:" }

{ "type": "", "children": [], "text": "" }

Manufactured by:

{ "type": "p", "children": [], "text": "Manufactured by:" }

Juno Therapeutics Inc., a Bristol-Myers Squibb Company, Bothell, WA 98021. US License No.: 2156.

{ "type": "p", "children": [], "text": "Juno Therapeutics Inc., a Bristol-Myers Squibb Company, Bothell, WA 98021. US License No.: 2156." }

Celgene Corporation, a Bristol-Myers Squibb Company, Summit, NJ 07901. US License No.: 2252.

{ "type": "p", "children": [], "text": "Celgene Corporation, a Bristol-Myers Squibb Company, Summit, NJ 07901. US License No.: 2252." }

Bristol-Myers Squibb Company, Devens, MA 01434. US License No.: 1713.

{ "type": "p", "children": [], "text": "Bristol-Myers Squibb Company, Devens, MA 01434. US License No.: 1713." }

BREYANZI® is a trademark of Juno Therapeutics, Inc., a Bristol-Myers Squibb Company.

{ "type": "p", "children": [], "text": "BREYANZI® is a trademark of Juno Therapeutics, Inc., a Bristol-Myers Squibb Company." }

Pat. https://www.bms.com/patient-and-caregivers/our-medicines.html

{ "type": "p", "children": [], "text": "Pat. https://www.bms.com/patient-and-caregivers/our-medicines.html" }

BREPI.008/MG.007

{ "type": "p", "children": [], "text": "BREPI.008/MG.007" }

<div class="scrollingtable"><table width="100%"> <col width="100%"/> <thead> <tr class="First Last"> <th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">MEDICATION GUIDE</span> <br/> <span class="Bold">BREYANZI<span class="Sup">®</span> (pronounced braye an' zee)</span> <br/> <span class="Bold">(lisocabtagene maraleucel)</span></th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="1" valign="top">This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: May 2024</td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Read this Medication Guide before you start your BREYANZI treatment. The more you know about your treatment, the more active you can be in your care. Talk with your healthcare provider if you have questions about your health condition or treatment. Reading this Medication Guide does not take the place of talking with your healthcare provider about your treatment.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Underline">What is the most important information I should know about BREYANZI?</span></span> <br/>BREYANZI may cause side effects that are life-threatening and can lead to death. Call your healthcare provider or get emergency help right away if you get any of the following:</p> <dl> <dt>•</dt> <dd>difficulty breathing</dd> <dt>•</dt> <dd>fever (100.4°F/38°C or higher)</dd> <dt>•</dt> <dd>chills/shaking chills</dd> <dt>•</dt> <dd>confusion</dd> <dt>•</dt> <dd>severe nausea, vomiting, diarrhea</dd> <dt>•</dt> <dd>fast or irregular heartbeat</dd> <dt>•</dt> <dd>dizziness/lightheadedness</dd> <dt>•</dt> <dd>severe fatigue or weakness</dd> </dl> <p>It is important that you tell your healthcare providers that you have received BREYANZI and to show them your BREYANZI Patient Wallet Card. Your healthcare provider may give you other medicines to treat your side effects.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Underline">What is BREYANZI?</span></span> <br/>BREYANZI is a prescription medicine used to treat four types of non-Hodgkin lymphoma: </p> <dl> <dt>•</dt> <dd>Large B cell lymphoma, when:<dl> <dt>o</dt> <dd>your first treatment has not worked or your cancer returned within a year of your first treatment OR</dd> <dt>o</dt> <dd>your first treatment has not worked or your cancer returned after the first treatment, and you are not eligible for hematopoietic stem cell transplantation because of medical conditions or age OR</dd> <dt>o</dt> <dd>two or more kinds of treatment have not worked or stopped working.</dd> </dl> </dd> <dt>•</dt> <dd>Chronic lymphocytic leukemia or small lymphocytic lymphoma when two or more kinds of treatment have not worked or stopped working.</dd> <dt>•</dt> <dd>Follicular lymphoma, when two or more kinds of treatment have not worked or stopped working.</dd> <dt>•</dt> <dd>Mantle cell lymphoma when two or more kinds of treatment have not worked or stopped working, including a prior Bruton tyrosine kinase (BTK) inhibitor medicine.</dd> </dl> <p>BREYANZI is different than other cancer medicines because it is made from your own white blood cells, which have been genetically modified to recognize and attack your lymphoma cells. </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Underline">Before getting BREYANZI, tell your healthcare provider about all your medical problems, including if you have or have had:</span></span> </p> <dl> <dt>•</dt> <dd>Neurologic problems (such as seizures, stroke, or memory loss)</dd> <dt>•</dt> <dd>Lung or breathing problems</dd> <dt>•</dt> <dd>Heart problems</dd> <dt>•</dt> <dd>Liver problems</dd> <dt>•</dt> <dd>Kidney problems</dd> <dt>•</dt> <dd>A recent or active infection</dd> </dl> <p> <span class="Bold">Tell your healthcare provider about all the medications you take,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Underline">How will I receive BREYANZI?</span></span> </p> <dl> <dt>•</dt> <dd>BREYANZI is made from your own white blood cells, so your blood will be collected by a process called “leukapheresis” (LOO-kuh-feh-REE-sis).</dd> <dt>•</dt> <dd>It takes about 3-4 weeks from the time your cells are received at the manufacturing site and are available to be shipped back to your healthcare provider, but the time may vary.</dd> <dt>•</dt> <dd>Before you get BREYANZI, you will get 3 days of chemotherapy to prepare your body.</dd> <dt>•</dt> <dd>When your BREYANZI is ready, your healthcare provider will give it to you through a catheter (tube) placed into your vein (intravenous infusion). BREYANZI is given as infusions of 2 different cell types.<dl> <dt>o</dt> <dd>You will receive infusions of one cell type, immediately followed by the other cell type. </dd> <dt>o</dt> <dd>The time for infusion will vary but will usually be less than 15 minutes for each of the 2 cell types. </dd> </dl> </dd> <dt>•</dt> <dd>During the first week, you will be monitored daily by the facility where you received your treatment. </dd> <dt>•</dt> <dd>You should plan to stay within 2 hours of the location where you received your treatment for at least 4 weeks after getting BREYANZI. Your healthcare provider will check to see that your treatment is working and help you with any side effects that may occur. </dd> <dt>•</dt> <dd>You may be hospitalized for side effects and your healthcare provider will discharge you if your side effects are under control, and it is safe for you to leave the hospital. </dd> <dt>•</dt> <dd>Your healthcare provider will want to do blood tests to follow your progress. It is important that you do have your blood tested. If you miss an appointment, call your healthcare provider as soon as possible to reschedule.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Underline">What should I avoid after receiving BREYANZI?</span></span> </p> <dl> <dt>•</dt> <dd>Do not drive, operate heavy machinery, or do other activities that could be dangerous if you are not mentally alert, for at least 8 weeks after you get BREYANZI. This is because the treatment can cause temporary memory and coordination problems, including sleepiness, confusion, dizziness, and seizures.</dd> <dt>•</dt> <dd>Do not donate blood, organs, tissues, or cells for transplantation.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Underline">What are the possible or reasonably likely side effects of BREYANZI?</span></span> </p> <p>The most common side effects of BREYANZI are:</p> <dl> <dt>•</dt> <dd>fatigue</dd> <dt>•</dt> <dd>difficulty breathing</dd> <dt>•</dt> <dd>fever (100.4°F/38°C or higher)</dd> <dt>•</dt> <dd>chills/shaking chills</dd> <dt>•</dt> <dd>confusion</dd> <dt>•</dt> <dd>difficulty speaking or slurred speech</dd> <dt>•</dt> <dd>severe nausea, vomiting, diarrhea</dd> <dt>•</dt> <dd>headache</dd> <dt>•</dt> <dd>dizziness/lightheadedness</dd> <dt>•</dt> <dd>fast or irregular heartbeat</dd> <dt>•</dt> <dd>swelling</dd> <dt>•</dt> <dd>low blood pressure</dd> <dt>•</dt> <dd>muscle pain</dd> </dl> <p>BREYANZI can increase the risk of life-threatening infections that may lead to death. Tell your healthcare provider right away if you develop fever, chills, or any signs or symptoms of an infection.<br/>BREYANZI can lower one or more types of your blood cells (red blood cells, white blood cells, or platelets). After treatment, your healthcare provider will test your blood to check for this. Tell your healthcare provider right away if you get a fever, are feeling tired, or have bruising or bleeding.</p> <p>BREYANZI may increase your risk of getting cancers including certain types of blood cancers. Your healthcare provider should monitor you for this.<br/>Having BREYANZI in your blood may cause a false-positive HIV test result by some commercial tests.<br/>These are not all the possible side effects of BREYANZI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Underline">General information about the safe and effective use of BREYANZI</span></span> <br/>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. If you would like more information about BREYANZI, talk with your healthcare provider. You can ask your healthcare provider for information about BREYANZI that is written for health professionals.<br/>For more information, go to BREYANZI.com or call 1-888-805-4555.<br/>Manufactured by:</p> <p>Juno Therapeutics Inc., a Bristol-Myers Squibb Company, Bothell, WA 98021. US License No.: 2156.</p> <p>Celgene Corporation, a Bristol-Myers Squibb Company, Summit, NJ 07901. US License No.: 2252.</p> <p>Bristol-Myers Squibb Company, Devens, MA 01434. US License No.: 1713.<br/>BREYANZI<span class="Sup">®</span> is a trademark of Juno Therapeutics, Inc., a Bristol-Myers Squibb Company.<br/>Pat. https://www.bms.com/patient-and-caregivers/our-medicines.html <br/>BREMG.007 5/2024 </p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"100%\"/>\n<thead>\n<tr class=\"First Last\">\n<th align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Bold\">MEDICATION GUIDE</span>\n<br/>\n<span class=\"Bold\">BREYANZI<span class=\"Sup\">®</span> (pronounced braye an' zee)</span>\n<br/>\n<span class=\"Bold\">(lisocabtagene maraleucel)</span></th>\n</tr>\n</thead>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\" colspan=\"1\" valign=\"top\">This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: May 2024</td>\n</tr>\n</tfoot>\n<tbody>\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Read this Medication Guide before you start your BREYANZI treatment. The more you know about your treatment, the more active you can be in your care. Talk with your healthcare provider if you have questions about your health condition or treatment. Reading this Medication Guide does not take the place of talking with your healthcare provider about your treatment.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"><span class=\"Underline\">What is the most important information I should know about BREYANZI?</span></span>\n<br/>BREYANZI may cause side effects that are life-threatening and can lead to death. Call your healthcare provider or get emergency help right away if you get any of the following:</p>\n<dl>\n<dt>•</dt>\n<dd>difficulty breathing</dd>\n<dt>•</dt>\n<dd>fever (100.4°F/38°C or higher)</dd>\n<dt>•</dt>\n<dd>chills/shaking chills</dd>\n<dt>•</dt>\n<dd>confusion</dd>\n<dt>•</dt>\n<dd>severe nausea, vomiting, diarrhea</dd>\n<dt>•</dt>\n<dd>fast or irregular heartbeat</dd>\n<dt>•</dt>\n<dd>dizziness/lightheadedness</dd>\n<dt>•</dt>\n<dd>severe fatigue or weakness</dd>\n</dl>\n<p>It is important that you tell your healthcare providers that you have received BREYANZI and to show them your BREYANZI Patient Wallet Card. Your healthcare provider may give you other medicines to treat your side effects.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"><span class=\"Underline\">What is BREYANZI?</span></span>\n<br/>BREYANZI is a prescription medicine used to treat four types of non-Hodgkin lymphoma: </p>\n<dl>\n<dt>•</dt>\n<dd>Large B cell lymphoma, when:<dl>\n<dt>o</dt>\n<dd>your first treatment has not worked or your cancer returned within a year of your first treatment OR</dd>\n<dt>o</dt>\n<dd>your first treatment has not worked or your cancer returned after the first treatment, and you are not eligible for hematopoietic stem cell transplantation because of medical conditions or age OR</dd>\n<dt>o</dt>\n<dd>two or more kinds of treatment have not worked or stopped working.</dd>\n</dl>\n</dd>\n<dt>•</dt>\n<dd>Chronic lymphocytic leukemia or small lymphocytic lymphoma when two or more kinds of treatment have not worked or stopped working.</dd>\n<dt>•</dt>\n<dd>Follicular lymphoma, when two or more kinds of treatment have not worked or stopped working.</dd>\n<dt>•</dt>\n<dd>Mantle cell lymphoma when two or more kinds of treatment have not worked or stopped working, including a prior Bruton tyrosine kinase (BTK) inhibitor medicine.</dd>\n</dl>\n<p>BREYANZI is different than other cancer medicines because it is made from your own white blood cells, which have been genetically modified to recognize and attack your lymphoma cells. </p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"><span class=\"Underline\">Before getting BREYANZI, tell your healthcare provider about all your medical problems, including if you have or have had:</span></span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Neurologic problems (such as seizures, stroke, or memory loss)</dd>\n<dt>•</dt>\n<dd>Lung or breathing problems</dd>\n<dt>•</dt>\n<dd>Heart problems</dd>\n<dt>•</dt>\n<dd>Liver problems</dd>\n<dt>•</dt>\n<dd>Kidney problems</dd>\n<dt>•</dt>\n<dd>A recent or active infection</dd>\n</dl>\n<p>\n<span class=\"Bold\">Tell your healthcare provider about all the medications you take,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"><span class=\"Underline\">How will I receive BREYANZI?</span></span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>BREYANZI is made from your own white blood cells, so your blood will be collected by a process called “leukapheresis” (LOO-kuh-feh-REE-sis).</dd>\n<dt>•</dt>\n<dd>It takes about 3-4 weeks from the time your cells are received at the manufacturing site and are available to be shipped back to your healthcare provider, but the time may vary.</dd>\n<dt>•</dt>\n<dd>Before you get BREYANZI, you will get 3 days of chemotherapy to prepare your body.</dd>\n<dt>•</dt>\n<dd>When your BREYANZI is ready, your healthcare provider will give it to you through a catheter (tube) placed into your vein (intravenous infusion). BREYANZI is given as infusions of 2 different cell types.<dl>\n<dt>o</dt>\n<dd>You will receive infusions of one cell type, immediately followed by the other cell type. </dd>\n<dt>o</dt>\n<dd>The time for infusion will vary but will usually be less than 15 minutes for each of the 2 cell types. </dd>\n</dl>\n</dd>\n<dt>•</dt>\n<dd>During the first week, you will be monitored daily by the facility where you received your treatment. </dd>\n<dt>•</dt>\n<dd>You should plan to stay within 2 hours of the location where you received your treatment for at least 4 weeks after getting BREYANZI. Your healthcare provider will check to see that your treatment is working and help you with any side effects that may occur. </dd>\n<dt>•</dt>\n<dd>You may be hospitalized for side effects and your healthcare provider will discharge you if your side effects are under control, and it is safe for you to leave the hospital. </dd>\n<dt>•</dt>\n<dd>Your healthcare provider will want to do blood tests to follow your progress. It is important that you do have your blood tested. If you miss an appointment, call your healthcare provider as soon as possible to reschedule.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"><span class=\"Underline\">What should I avoid after receiving BREYANZI?</span></span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Do not drive, operate heavy machinery, or do other activities that could be dangerous if you are not mentally alert, for at least 8 weeks after you get BREYANZI. This is because the treatment can cause temporary memory and coordination problems, including sleepiness, confusion, dizziness, and seizures.</dd>\n<dt>•</dt>\n<dd>Do not donate blood, organs, tissues, or cells for transplantation.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"><span class=\"Underline\">What are the possible or reasonably likely side effects of BREYANZI?</span></span>\n</p>\n<p>The most common side effects of BREYANZI are:</p>\n<dl>\n<dt>•</dt>\n<dd>fatigue</dd>\n<dt>•</dt>\n<dd>difficulty breathing</dd>\n<dt>•</dt>\n<dd>fever (100.4°F/38°C or higher)</dd>\n<dt>•</dt>\n<dd>chills/shaking chills</dd>\n<dt>•</dt>\n<dd>confusion</dd>\n<dt>•</dt>\n<dd>difficulty speaking or slurred speech</dd>\n<dt>•</dt>\n<dd>severe nausea, vomiting, diarrhea</dd>\n<dt>•</dt>\n<dd>headache</dd>\n<dt>•</dt>\n<dd>dizziness/lightheadedness</dd>\n<dt>•</dt>\n<dd>fast or irregular heartbeat</dd>\n<dt>•</dt>\n<dd>swelling</dd>\n<dt>•</dt>\n<dd>low blood pressure</dd>\n<dt>•</dt>\n<dd>muscle pain</dd>\n</dl>\n<p>BREYANZI can increase the risk of life-threatening infections that may lead to death. Tell your healthcare provider right away if you develop fever, chills, or any signs or symptoms of an infection.<br/>BREYANZI can lower one or more types of your blood cells (red blood cells, white blood cells, or platelets). After treatment, your healthcare provider will test your blood to check for this. Tell your healthcare provider right away if you get a fever, are feeling tired, or have bruising or bleeding.</p>\n<p>BREYANZI may increase your risk of getting cancers including certain types of blood cancers. Your healthcare provider should monitor you for this.<br/>Having BREYANZI in your blood may cause a false-positive HIV test result by some commercial tests.<br/>These are not all the possible side effects of BREYANZI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"><span class=\"Underline\">General information about the safe and effective use of BREYANZI</span></span>\n<br/>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. If you would like more information about BREYANZI, talk with your healthcare provider. You can ask your healthcare provider for information about BREYANZI that is written for health professionals.<br/>For more information, go to BREYANZI.com or call 1-888-805-4555.<br/>Manufactured by:</p>\n<p>Juno Therapeutics Inc., a Bristol-Myers Squibb Company, Bothell, WA 98021. US License No.: 2156.</p>\n<p>Celgene Corporation, a Bristol-Myers Squibb Company, Summit, NJ 07901. US License No.: 2252.</p>\n<p>Bristol-Myers Squibb Company, Devens, MA 01434. US License No.: 1713.<br/>BREYANZI<span class=\"Sup\">®</span> is a trademark of Juno Therapeutics, Inc., a Bristol-Myers Squibb Company.<br/>Pat. https://www.bms.com/patient-and-caregivers/our-medicines.html <br/>BREMG.007 5/2024 </p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

lisocabtagene maraleucelBreyanzi™

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lisocabtagene maraleucelBreyanzi®

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NDC 73153-900-01Rx only

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FOR AUTOLOGOUS & INTRAVENOUS USE ONLY

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Dispense with Medication Guide

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Dosage: See Release for Infusion Certificate (inside shipper).

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Contains DMSO 7.5% v/v.

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1 to 4 single-dose vials/component. Each vialcontains up to 70 x 106 CAR-positive viable T cells/mL.4.6 mL per vial.

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Store at ≤ -130°C; vapor phase of liquid nitrogen.Do not filter or irradiate.Not evaluated for infectious substances.Discard unused portion.

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Manufactured by:Juno Therapeutics, Inc., a Bristol-Myers Squibb CompanyBothell, WA 98021Phone: 1-888-805-4555 US License #: 2156

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304029

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NDC 73153-900-01

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VERIFYPATIENTID

{ "type": "p", "children": [], "text": "VERIFYPATIENTID" }

First: FIRST NAMELast: LAST NAMEDate of birth: DD-MMM-YYYYJOIN: XXXX-XXXXXAph ID/DIN: XXX XXX XXX XXX

{ "type": "p", "children": [], "text": "First: FIRST NAMELast: LAST NAMEDate of birth: DD-MMM-YYYYJOIN: XXXX-XXXXXAph ID/DIN: XXX XXX XXX XXX" }

CD8component

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CD4component

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Lot XXXX-XXXXXYXXXX-XXXXXY

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Expiration DD-MMM-YYYYDD-MMM-YYYY

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STOPConfirm patient IDprior to infusion

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