Double-class-exposed* patients are a difficult-to-treat population with limited treatment options1-3

CLL cell icon

CLL and SLL may start off indolent, but as the disease progresses, it can become more aggressive and difficult to treat4-6

Doctor wearing stethoscope icon

There is no standard of care, and treatment options are limited for patients who have received a BTKi and a BCL-2i.7,8

Cumulative toxicities cycle icon

Cumulative toxicities can also arise from disease progression and long-term therapies9-14

Patients with R/R CLL or SLL need more treatment options that deliver deep and durable responses1,2

Current treatment options are associated with poor outcomes for double-class-exposed* patients after the immediate next line of therapy15†

Figures are based on real-world data of 548 patients with CLL or SLL exposed to both a BTKi and BCL-2i12†

Extremely rare CR15

34% ORR12†

13-month mDOR12†
(95% CI: 10.6, 19.5)

Achieving uMRD is uncommon16

Patients with R/R CLL or SLL need more treatment options that deliver deep and durable responses1,2

*Double-class-exposed patients have received both a BTKi and BCL-2i.2

†Data from a retrospective observational study of 548 patients with CLL and exposure to both a BTKi and BCL-2i. The data utilized were from the Flatiron Health electronic health record-derived database, and originated from ~280 cancer clinics in the U.S. Patients had at least 2 clinic visits in the database showing evidence of receiving systemic therapy on or after January 1, 2011. Comparisons between real-world and clinical-trial data of patients with CLL should be made with caution.12

BCL-2i, B-cell lymphoma-2 inhibitor; BTKi, Bruton tyrosine kinase inhibitor; CI, confidence interval; CLL, chronic lymphocytic leukemia; CR, complete response; mDOR, median duration of response; ORR, overall response rate; R/R, relapsed or refractory; SLL, small lymphocytic lymphoma; uMRD, undetectable minimal residual disease.

IDENTIFY PATIENTS
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. Patel K, Pagel JM. Current and future treatment strategies in chronic lymphocytic leukemia. J Hematol Oncol. 2021;14(1):69. doi:10.1186/s13045-021-01054-w
  2. Siddiqi T, Maloney DG, Kenderian SS, et al. Lisocabtagene maraleucel in chronic lymphocytic leukaemia 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. O’Brien SM, Furman RR, Byrd JC, Smith A. Clinical roundtable monograph: unmet needs in the treatment of chronic lymphocytic leukemia: integrating a targeted approach. Clin Adv Hematol Oncol. 2014;12(1 suppl 3):1-13.
  4. Strati P, Keating MJ, O’Brien SM, et al. Outcomes of first-line treatment for chronic lymphocytic leukemia with 17p deletion. Haematologica. 2014;99(8):1350-1355. doi:10.3324/haematol.2014.104661
  5. Gaidano G, Rossi D. The mutational landscape of chronic lymphocytic leukemia and its impact on prognosis and treatment. Hematology Am Soc Hematol Educ Program. 2017;2017(1):329-337. doi:10.1182/asheducation-2017.1.329
  6. Skånland SS, Mato AR. Overcoming resistance to targeted therapies in chronic lymphocytic leukemia. Blood Adv. 2021;5(1):334-343. doi:10.1182/bloodadvances.2020003423
  7. Roeker LE, Mato AR. Approaches for relapsed CLL after chemotherapy-free frontline regimens. Hematology Am Soc Hematol Educ Program. 2020;2020(1):10-17. doi:10.1182/hematology.2020000168
  8. Lew TE, Lin VS, Cliff ER, et al. Outcomes of patients with CLL sequentially resistant to both BCL2 and BTK inhibition. Blood Adv. 2021;5(20):4054-4058. doi:10.1182/bloodadvances.2021005083
  9. Burger JA, O’Brien S. Evolution of CLL treatment — from chemoimmunotherapy to targeted and individualized therapy. Nat Rev Clin Oncol. 2018;15(8):510-527. doi:10.1038/s41571-018-0037-8
  10. Simon F, Bohn JP. Next-generation sequencing-optimal sequencing of therapies in relapsed/refractory chronic Lymphocytic leukemia (CLL). Curr Oncol Rep. 2023;25(10):1181-1189. doi:10.1007/s11912-023-01454-w
  11. Bennett R, Anderson MA, Seymour JF. Unresolved questions in selection of therapies for treatment-naïve chronic lymphocytic leukemia. J Hematol Oncol. 2023;16(1):72. doi:10.1186/s13045-023-01469-7
  12. Eyre TA, Hess LM, Sugihara T, et al. Clinical outcomes among patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) who received treatment with a covalent BTK and BCL2 inhibitor in the United States: a real-world database study. Leuk Lymphoma. 2023;64(5):1005-1016. doi:10.1080/10428194.2023.2190436
  13. Hertler A, Flood WA, Page R, Brooks B, D’Amato SL, Kolodziej M. The challenge of developing pathways in a rapidly evolving clinical space: Chronic Lymphocytic leukemia as a case study. J Clin Pathways. 2020;6(2). doi:10.25270/jcp.2020.3.00002
  14. Lew TE, Anderson MA, Seymour JF. Promises and pitfalls of targeted agents in chronic lymphocytic leukemia. Canc Drug Resist. 2020;3(3):415-444. doi:10.20517/cdr.2019.108
  15. 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.CRR-19-3815
  16. Ahn IE, Farooqui MZH, Tian X, et al. Depth and durability of response to ibrutinib in CLL: 5-year follow-up of a phase 2 study. Blood. 2018;131(21):2357-2366. doi:10.1182/blood-2017-12-820910

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References
  1. Patel K, Pagel JM. Current and future treatment strategies in chronic lymphocytic leukemia. J Hematol Oncol. 2021;14(1):69. doi:10.1186/s13045-021-01054-w
  2. Siddiqi T, Maloney DG, Kenderian SS, et al. Lisocabtagene maraleucel in chronic lymphocytic leukaemia 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. O’Brien SM, Furman RR, Byrd JC, Smith A. Clinical roundtable monograph: unmet needs in the treatment of chronic lymphocytic leukemia: integrating a targeted approach. Clin Adv Hematol Oncol. 2014;12(1 suppl 3):1-13.
  4. Strati P, Keating MJ, O’Brien SM, et al. Outcomes of first-line treatment for chronic lymphocytic leukemia with 17p deletion. Haematologica. 2014;99(8):1350-1355. doi:10.3324/haematol.2014.104661
  5. Gaidano G, Rossi D. The mutational landscape of chronic lymphocytic leukemia and its impact on prognosis and treatment. Hematology Am Soc Hematol Educ Program. 2017;2017(1):329-337. doi:10.1182/asheducation-2017.1.329
  6. Skånland SS, Mato AR. Overcoming resistance to targeted therapies in chronic lymphocytic leukemia. Blood Adv. 2021;5(1):334-343. doi:10.1182/bloodadvances.2020003423
  7. Roeker LE, Mato AR. Approaches for relapsed CLL after chemotherapy-free frontline regimens. Hematology Am Soc Hematol Educ Program. 2020;2020(1):10-17. doi:10.1182/hematology.2020000168
  8. Lew TE, Lin VS, Cliff ER, et al. Outcomes of patients with CLL sequentially resistant to both BCL2 and BTK inhibition. Blood Adv. 2021;5(20):4054-4058. doi:10.1182/bloodadvances.2021005083
  9. Burger JA, O’Brien S. Evolution of CLL treatment — from chemoimmunotherapy to targeted and individualized therapy. Nat Rev Clin Oncol. 2018;15(8):510-527. doi:10.1038/s41571-018-0037-8
  10. Simon F, Bohn JP. Next-generation sequencing-optimal sequencing of therapies in relapsed/refractory chronic Lymphocytic leukemia (CLL). Curr Oncol Rep. 2023;25(10):1181-1189. doi:10.1007/s11912-023-01454-w
  11. Bennett R, Anderson MA, Seymour JF. Unresolved questions in selection of therapies for treatment-naïve chronic lymphocytic leukemia. J Hematol Oncol. 2023;16(1):72. doi:10.1186/s13045-023-01469-7
  12. Eyre TA, Hess LM, Sugihara T, et al. Clinical outcomes among patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) who received treatment with a covalent BTK and BCL2 inhibitor in the United States: a real-world database study. Leuk Lymphoma. 2023;64(5):1005-1016. doi:10.1080/10428194.2023.2190436
  13. Hertler A, Flood WA, Page R, Brooks B, D’Amato SL, Kolodziej M. The challenge of developing pathways in a rapidly evolving clinical space: Chronic Lymphocytic leukemia as a case study. J Clin Pathways. 2020;6(2). doi:10.25270/jcp.2020.3.00002
  14. Lew TE, Anderson MA, Seymour JF. Promises and pitfalls of targeted agents in chronic lymphocytic leukemia. Canc Drug Resist. 2020;3(3):415-444. doi:10.20517/cdr.2019.108
  15. 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.CRR-19-3815
  16. Ahn IE, Farooqui MZH, Tian X, et al. Depth and durability of response to ibrutinib in CLL: 5-year follow-up of a phase 2 study. Blood. 2018;131(21):2357-2366. doi:10.1182/blood-2017-12-820910