A Phase 1/2, open-label, multicenter, single-arm trial1

TRANSCEND CLL 004 evaluated Breyanzi® in adult patients with R/R CLL or SLL who have received at least 2 prior lines of therapy including a BTKi and a BCL-2i1

Primary endpoint: ORR (including CR and PR) and DOR1
Select secondary endpoints: safety, uMRD, PFS, OS2
Patients were allowed to receive bridging therapy1
The study population consisted mainly of patients with difficult-to-treat disease, with 83% (56/65) having high-risk features* and 51% (33/65) having bulky disease1†

Breyanzi demonstrated deep and durable complete responses (CR), with 87.5% of CR maintained at 18 months1,3

DOR by best overall response1,3

Overview All data
Duration of response by best overall response for patients in Transcend CLL 004 trial. Duration of response by best overall response for patients in Transcend CLL 004 trial. Duration of response by best overall response for patients in Transcend CLL 004 trial. Duration of response by best overall response for patients in Transcend CLL 004 trial.

Months CR PR All Responders
0 9 12 21
6 8 11 19
12 7 7 14
18 3 5 8
24 1 3 4
30 0 0 1
36 0 0 0
    Primary endpoint:
  • 45% ORR (29/65)
    (95% CI: 32.3, 57.5)
  • 20% CR‡ (13/65)
    (95% CI: 11.1, 31.8)
  • 25% PR (16/65)
    (95% CI: 14.8, 36.9)
  • 35.3-month mDOR for all responders (95% CI: 12.4, NR)1
  • mDOR was not reached for those achieving a CR1
  • View an exploratory analysis of mPFS by minimal residual disease status

*Defined as patients having at least 1 of the following features: del(17p), mutated TP53, unmutated IGHV, or at least 3 chromosomal aberrations (complex karyotype).1

†Defined as having at least 1 lymph node lesion with the longest diameter of ≥5 cm.3

‡Per the 2018 iwCLL criteria, as assessed by IRC.

BCL-2i, B-cell lymphoma-2 inhibitor; BTKi, Bruton tyrosine kinase inhibitor; CI, confidence interval; CLL, chronic lymphocytic leukemia; CR, complete response; DOR, duration of response; IGHV, immunoglobulin heavy chain gene; mDoCR, median duration of complete response; mDOR, median duration of response; NR, not reached; ORR, overall response rate; PFS, progression-free survival; R/R, relapsed or refractory; SLL, small lymphocytic lymphoma, uMRD, undetectable minimal residual disease.

Median PFS of 12 months was observed in TRANSCEND CLL 0041,3‡

Overview All data
mPFS for patients of Breyanzi in TRANSCEND CLL 004 clinical trial. mPFS for patients of Breyanzi in TRANSCEND CLL 004 clinical trial. mPFS for patients of Breyanzi in TRANSCEND CLL 004 clinical trial. mPFS for patients of Breyanzi in TRANSCEND CLL 004 clinical trial.

Months CR PR Non-responder Total
0 9 12 28 49
6 8 12 6 26
12 8 9 2 19
18 5 6 2 13
24 2 5 0 7
30 1 1 0 2
36 0 1 0 1
42 0 0 0 0

Analysis limitations:

  • PFS was a secondary endpoint of TRANSCEND CLL 004 and was not statistically tested in the setting of a single-arm trial
  • PFS data are not in the USPI and should be interpreted with caution in a single-arm trial
  • The statistical significance of PFS is not known

mPFS was not reached in patients who achieved a CR1

Median OS of 33.6 months was observed in TRANSCEND CLL 0041,3||

OS1

Overview All data
30-month overall survival for patients in TRANSCEND CLL 004 clinical trial. 30-month overall survival for patients in TRANSCEND CLL 004 clinical trial. 30-month overall survival for patients in TRANSCEND CLL 004 clinical trial. 30-month overall survival for patients in TRANSCEND CLL 004 clinical trial.

Months CR PR Non-responder Total
0 9 12 28 49
6 8 12 18 38
12 8 11 7 26
18 6 9 4 19
24 2 7 4 13
30 1 2 2 5
36 0 1 1 2
42 0 0 1 1
48 0 0 0 0
  • 33-month mOS (95% CI:19.9, NR)1

mOS was not reached in patients who achieved a CR1

Analysis limitations:

  • OS was a secondary endpoint in TRANSCEND CLL 004 and was not statistically tested in the setting of a single-arm trial
  • OS data are not in the USPI and should be interpreted with caution in a single-arm trial
  • The statistical significance of OS is not known

*Defined as patients having at least 1 of the following features: del(17p), mutated TP53, unmutated IGHV, or at least 3 chromosomal aberrations (complex karyotype).1

†Defined as having at least 1 lymph node lesion with the longest diameter of ≥5 cm.2

‡Median follow-up 20.8 months (95% CI: 17.6-24.4).3

||Defined as the time from Breyanzi infusion to the date of death due to any cause.2

BCL-2i, B-cell lymphoma-2 inhibitor; BTKi, Bruton tyrosine kinase inhibitor; CI, confidence interval; CLL, chronic lymphocytic leukemia; CR, complete response; DOR, duration of response; IGHV, immunoglobulin heavy chain gene; mOS, median overall survival; mPFS, median progression-free survival; NR, not reached; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; R/R, relapsed or refractory; SLL, small lymphocytic lymphoma, uMRD, undetectable minimal residual disease.

TRANSCEND CLL 004 studied Breyanzi in a broad range of patients, including those with difficult-to-treat disease1

Three hypothetical Breyanzi patients Three hypothetical Breyanzi patient

Patient and disease characteristics (N=65)1*§

Median age of patients in TRANSCEND CLL 004 clinical trial.

66
Median age

(range: 49-82)

5 Median number prior therapies

(range: 2-12)

ECOG PS 0-1

High-risk features†

del(17p)

TP53 mutated

Complex karyotype||

Unmutated IGHV

Bulky disease§

100%

83%

43%

45%

62%

45%

51%

Patients studied had a median of 5 prior lines of therapy, plus high rates of high-risk cytogenetics and bulky disease1

*Defined as patients having at least 1 of the following features: del(17p), mutated TP53, unmutated IGHV, or at least 3 chromosomal aberrations (complex karyotype).1

†Defined as having at least 1 lymph node lesion with the longest diameter of ≥5 cm.2

‡Measurable disease reconfirmed prior to lymphodepletion.2

§The planned dose of BREYANZI was 100 × 106 CAR-positive viable T cells.1

||Defined as having at least 3 chromosomal aberrations.4

ALT, alanine transaminase; BCL-2i, B-cell lymphoma-2 inhibitor; BTKi, Bruton tyrosine kinase inhibitor; CAR, chimeric antigen receptor; CLL, chronic lymphocytic leukemia; CNS, central nervous system; CR, complete response; CrCl, creatinine clearance; CY, cyclophosphamide; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; FLU, fludarabine; IGHV, immunoglobulin heavy chain gene; LVEF, left ventricular ejection fraction; ORR, overall response rate; PFS, progression-free survival; R/R, relapsed or refractory; SLL, ULN, upper limit of normal; uMRD, undetectable minimal residual disease.

Important Safety Information
LESS
Indication
BREYANZI is a CD19-directed genetically modified autologous T cell immunotherapy 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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
Important Safety Information

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

  • Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving BREYANZI. Do not administer BREYANZI to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab with or without corticosteroids.
  • Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving BREYANZI, including concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with BREYANZI. Provide supportive care and/or corticosteroids as needed.
  • T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including BREYANZI.
  • BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS.
Cytokine Release Syndrome
Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred following treatment with BREYANZI. In clinical trials of BREYANZI, which enrolled a total of 702 patients with non-Hodgkin lymphoma (NHL), CRS occurred in 54% of patients, including ≥ Grade 3 CRS 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%) were fever, hypotension, tachycardia, chills, hypoxia, and headache.
Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, diffuse alveolar damage, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).
Ensure that 2 doses of tocilizumab are available prior to infusion of BREYANZI.
Neurologic Toxicities
Neurologic toxicities that were fatal or life-threatening, including immune effector cell-associated neurotoxicity syndrome (ICANS), occurred following treatment with BREYANZI. Serious events including cerebral edema and seizures occurred with BREYANZI. Fatal and serious cases of leukoencephalopathy, some attributable to fludarabine, also occurred.
In clinical trials of BREYANZI, CAR T cell-associated neurologic toxicities occurred in 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, headache, dizziness, and delirium
CRS and Neurologic Toxicities Monitoring
Monitor patients daily for at least 7 days following BREYANZI infusion at a REMS-certified healthcare facility for signs and symptoms of CRS and neurologic toxicities and assess for other causes of neurological symptoms. Monitor patients for signs and symptoms of CRS and neurologic toxicities for at least 4 weeks after infusion and treat promptly. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated. Manage neurologic toxicity with supportive care and/or corticosteroid as needed. Counsel patients to seek immediate medical attention should signs or symptoms of CRS or neurologic toxicity occur at any time.
BREYANZI REMS
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. The required components of the BREYANZI REMS are:
  • Healthcare facilities that dispense and administer BREYANZI must be enrolled and comply with the REMS requirements.
  • Certified healthcare facilities must have on-site, immediate access to tocilizumab.
  • Ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after BREYANZI infusion, if needed for treatment of CRS.
Further information is available at www.BreyanziREMS.com, or contact Bristol-Myers Squibb at 1-866-340-7332.
Hypersensitivity Reactions
Allergic reactions may occur with the infusion of BREYANZI. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO).
Serious Infections
Severe infections, including life-threatening or fatal infections, have occurred in patients after BREYANZI infusion. In clinical trials of BREYANZI, infections of any grade occurred in 34% of patients, with Grade 3 or higher infections occurring in 12% of all patients. Grade 3 or higher infections with an unspecified pathogen occurred in 7%, bacterial infections in 3.7%, viral infections in 2%, and fungal infections in 0.7% of patients. One patient who received 4 prior lines of therapy developed a fatal case of John Cunningham (JC) virus progressive multifocal leukoencephalopathy 4 months after treatment with BREYANZI. One patient who received 3 prior lines of therapy developed a fatal case of cryptococcal meningoencephalitis 35 days after treatment with BREYANZI.
Febrile neutropenia developed after BREYANZI infusion in 8% of patients. Febrile neutropenia may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated.
Monitor patients for signs and symptoms of infection before and after BREYANZI administration and treat appropriately. Administer prophylactic antimicrobials according to standard institutional guidelines. Avoid administration of BREYANZI in patients with clinically significant, active systemic infections.
Viral reactivation: Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. In clinical trials of BREYANZI, 35 of 38 patients with a prior history of HBV were treated with concurrent antiviral suppressive therapy. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing. In patients with prior history of HBV, consider concurrent antiviral suppressive therapy to prevent HBV reactivation per standard guidelines.
Prolonged Cytopenias
Patients may exhibit cytopenias not resolved for several weeks following lymphodepleting chemotherapy and BREYANZI infusion. In clinical trials of BREYANZI, Grade 3 or higher cytopenias persisted at Day 29 following BREYANZI infusion in 35% of patients, and included thrombocytopenia in 25%, neutropenia in 22%, and anemia in 6% of patients. Monitor complete blood counts prior to and after BREYANZI administration.
Hypogammaglobulinemia
B-cell aplasia and hypogammaglobulinemia can occur in patients receiving BREYANZI. In clinical trials of BREYANZI, hypogammaglobulinemia was reported as an adverse reaction in 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.
Secondary Malignancies
Patients treated with BREYANZI may develop secondary malignancies. T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including BREYANZI. Mature T cell malignancies, including CAR-positive tumors, may present as soon as weeks following infusion, and may include fatal outcomes. Monitor lifelong for secondary malignancies. In the event that a secondary malignancy occurs, contact Bristol-Myers Squibb at 1- 888-805-4555 for reporting and to obtain instructions on collection of patient samples for testing.
Effects on Ability to Drive and Use Machines
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)
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.
Adverse Reactions
The most common adverse reactions (incidence ≥30%) in CLL/SLL are cytokine release syndrome, encephalopathy, fatigue, musculoskeletal pain, nausea, edema, and diarrhea. The most common Grade 3-4 laboratory abnormalities include neutrophil count decrease, white blood cell decrease, hemoglobin decrease, platelet count decrease, and lymphocyte count decrease.
Please see full Prescribing Information, including Boxed WARNINGS and Medication Guide.
References
  1. Breyanzi [package insert]. Summit, NJ: Bristol-Myers Squibb Company; 2024.
  2. Siddiqi T, Maloney DG, Kenderian SS, et al. Lisocabtagene maraleucel in chronic lymphocytic leukemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study. Lancet. 2023;402(10402):641-654. doi:10.1016/S0140-6736(23)01052-8
  3. Data on file. BMS-REF-DOF-LIS-0046. Princeton, NJ: Bristol-Myers Squibb Company, 2024.
  4. Mato AR, Roeker LE, Jacobs R, et al. Assessment of the efficacy of therapies following venetoclax discontinuation in CLL reveals BTK inhibition as an effective strategy. Clin Cancer Res. 2020;26(14):3589-3596. doi:10.1158/1078-0432.CCR-19-3815

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References
  1. Breyanzi [package insert]. Summit, NJ: Bristol-Myers Squibb Company; 2024.
  2. Siddiqi T, Maloney DG, Kenderian SS, et al. Lisocabtagene maraleucel in chronic lymphocytic leukemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study. Lancet. 2023;402(10402):641-654. doi:10.1016/S0140-6736(23)01052-8
  3. Data on file. BMS-REF-DOF-LIS-0046. Princeton, NJ: Bristol-Myers Squibb Company, 2024.
  4. Mato AR, Roeker LE, Jacobs R, et al. Assessment of the efficacy of therapies following venetoclax discontinuation in CLL reveals BTK inhibition as an effective strategy. Clin Cancer Res. 2020;26(14):3589-3596. doi:10.1158/1078-0432.CCR-19-3815