Lisocabtagene

Introduction to Lisocabtagene Maraleucel

Lisocabtagene maraleucel (Breyanzi) is an innovative chimeric antigen receptor (CAR) T-cell therapy approved by the FDA in 2021. It represents a significant advancement in the treatment of certain types of relapsed or refractory large B-cell lymphomas in adult patients. As one of the newer CAR T-cell therapies, lisocabtagene maraleucel offers a unique approach with its distinct manufacturing process and product composition.

Mechanism of Action

Lisocabtagene maraleucel is a form of adoptive cell transfer therapy that utilizes genetically modified autologous T cells. The process involves:

  1. Collection of the patient's own T cells through leukapheresis
  2. Genetic modification of T cells to express a chimeric antigen receptor (CAR) specific to CD19
  3. Expansion and purification of the modified T cells in vitro
  4. Infusion of the CAR T cells back into the patient

The engineered CAR T cells recognize and bind to CD19, an antigen expressed on the surface of B cells and B cell malignancies. This binding activates the T cells, leading to proliferation and cytokine release, ultimately resulting in the destruction of CD19-positive cells, including malignant B cells.

The CAR construct in lisocabtagene maraleucel consists of:

  • An extracellular single-chain variable fragment (scFv) specific for CD19
  • A CD28 hinge and transmembrane domain
  • A 4-1BB (CD137) costimulatory domain
  • A CD3-zeta T-cell activation domain

Unique features of lisocabtagene maraleucel include:

  • Distinct manufacturing process that results in a defined composition of CD4+ and CD8+ CAR T cells
  • Administered as separate CD4+ and CD8+ CAR T-cell components in a 1:1 ratio
  • This defined composition aims to reduce product variability and potentially optimize efficacy and safety profiles

Indications

Lisocabtagene maraleucel is FDA-approved for the following indications in adult patients:

  1. Relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, 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
    • Follicular lymphoma grade 3B
  2. Large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or relapses within 12 months of first-line chemoimmunotherapy
  3. Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after one line of therapy in patients who are not eligible for hematopoietic stem cell transplantation (HSCT)

It's important to note that while lisocabtagene maraleucel is currently approved for use in adult patients, ongoing clinical trials are exploring its potential use in pediatric populations with relapsed or refractory B-cell malignancies.

Administration

The administration of lisocabtagene maraleucel involves several steps:

  1. Pre-treatment evaluation: Assess the patient's eligibility and overall health status
  2. Leukapheresis: Collect the patient's T cells
  3. Bridging therapy: Administer as needed to control the disease while CAR T cells are being manufactured
  4. Lymphodepleting chemotherapy: Fludarabine (30 mg/m²/day) and cyclophosphamide (300 mg/m²/day) for 3 days
  5. Lisocabtagene maraleucel infusion: Administered as a single intravenous infusion of CD4+ and CD8+ components
  6. Post-infusion monitoring: Closely observe the patient for at least 4 weeks following infusion

The recommended dose is:

  • For adult patients weighing ≤ 100 kg: 90-110 × 10^6 CAR-positive viable T cells
  • For adult patients weighing > 100 kg: 90-110 × 10^6 CAR-positive viable T cells per m² body surface area, not exceeding 110 × 10^6 CAR-positive viable T cells

Key administration notes:

  • Lisocabtagene maraleucel is provided as separate CD4+ and CD8+ components
  • The CD4+ and CD8+ components should be administered sequentially, with the CD8+ component administered first
  • There should be no more than 3 hours between the start of infusion of the first component and the completion of infusion of the second component

It's crucial to note that lisocabtagene maraleucel should only be administered in certified healthcare facilities by trained personnel experienced in the management of potential complications.

Efficacy

Lisocabtagene maraleucel has shown impressive efficacy in clinical trials:

  • TRANSCEND NHL 001 trial (relapsed/refractory large B-cell lymphoma):
    • Overall response rate: 73%
    • Complete response rate: 53%
    • Median duration of response: 16.7 months
  • TRANSFORM trial (second-line therapy for large B-cell lymphoma):
    • Event-free survival at median follow-up of 6.2 months: 14.8 months (vs 5.7 months with standard of care)
    • Overall response rate: 86% (vs 48% with standard of care)
    • Complete response rate: 66% (vs 39% with standard of care)
  • PILOT trial (first relapse/refractory large B-cell lymphoma in transplant-ineligible patients):
    • Overall response rate: 80%
    • Complete response rate: 54%
    • Median duration of response: Not reached at median follow-up of 12.3 months

Long-term follow-up studies are ongoing to assess the durability of responses. The ability to achieve high response rates in heavily pretreated patients and in earlier lines of therapy represents a significant advancement in the treatment of these aggressive lymphomas.

Adverse Effects

While lisocabtagene maraleucel can be highly effective, it is associated with significant potential adverse effects:

  1. Cytokine Release Syndrome (CRS):
    • Occurs in 46% of patients, with 4% experiencing grade 3 or higher
    • Symptoms include fever, hypotension, hypoxia, and organ dysfunction
    • Median time to onset: 5 days (range: 1 to 15 days)
    • Managed with supportive care and tocilizumab (anti-IL-6 receptor antibody)
  2. Neurological Toxicities:
    • Occurs in 35% of patients, with 12% experiencing grade 3 or higher
    • Can include encephalopathy, aphasia, delirium, and headache
    • Median time to onset: 9 days (range: 1 to 66 days)
    • Usually reversible, managed with supportive care and corticosteroids if severe
  3. Prolonged Cytopenias:
    • Common, including neutropenia, thrombocytopenia, and anemia
    • Can persist beyond 28 days post-infusion
  4. Hypogammaglobulinemia:
    • Due to B-cell aplasia
    • May require immunoglobulin replacement therapy
  5. Infections:
    • Increased risk due to lymphodepletion and B-cell aplasia
    • Prophylactic antimicrobials are often used
  6. Tumor Lysis Syndrome:
    • Can occur due to rapid tumor cell death
    • Managed with standard tumor lysis syndrome protocols

It's worth noting that the rates of severe CRS and neurological toxicities with lisocabtagene maraleucel appear to be lower compared to some other CAR T-cell therapies, potentially due to its unique manufacturing process and defined composition.

Monitoring and Follow-up

Close monitoring is crucial for patients receiving lisocabtagene maraleucel:

  • Inpatient monitoring for at least 7 days post-infusion
  • Daily assessment of vital signs, neurological status, and organ function
  • Regular blood tests to monitor for CRS, tumor lysis syndrome, and cytopenias
  • Neurological assessment using immune effector cell-associated encephalopathy (ICE) scoring
  • Monitor for signs and symptoms of infection
  • Long-term follow-up for B-cell recovery and potential late effects
  • Avoid live vaccines for at least 6 weeks prior to and following treatment
  • Instruct patients to stay within proximity of the certified healthcare facility for at least 4 weeks following infusion
  • Advise patients to refrain from driving or engaging in hazardous activities for at least 8 weeks following infusion
  • Lifelong monitoring for secondary malignancies

Specific monitoring considerations:

  • CRS monitoring: Assess for fever, hypotension, hypoxia, and organ dysfunction
  • Neurological toxicity monitoring: Perform regular neurological exams and ICE scoring
  • Cytopenia monitoring: Regular complete blood counts with differential
  • Hypogammaglobulinemia monitoring: Periodic immunoglobulin level assessment

Healthcare providers should be prepared to rapidly implement the management protocols for CRS and neurological toxicities, including the use of tocilizumab and corticosteroids when indicated. The unique administration of lisocabtagene maraleucel as separate CD4+ and CD8+ components requires careful attention to infusion protocols and timing.



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