Should we consider CAR (Chimeric Antigen Receptor) T-cell therapy for a 45-year-old patient with relapsed or refractory Diffuse Large B-Cell Lymphoma (DLBCL) who has undergone salvage chemotherapy with R-DHAP (Rituximab, Dexamethasone, High-dose Ara-C, and Platinum) or R-ICE (Rituximab, Ifosfamide, Carboplatin, and Etoposide)?

Should CAR T-Cell Therapy Be Considered for This Patient?

Yes, CAR T-cell therapy should be strongly considered as the preferred treatment option for this 45-year-old patient with relapsed/refractory DLBCL after salvage chemotherapy, as it demonstrates superior outcomes compared to autologous stem cell transplantation in early relapsed disease. 1

Primary Treatment Recommendation

CAR T-cell therapy (tisagenlecleucel or axicabtagene ciloleucel) is now the standard of care for patients with relapsed/refractory DLBCL who have received at least two prior lines of therapy, including rituximab and anthracycline-based chemotherapy. 2 The FDA approval is based on demonstrated efficacy in this exact clinical scenario, with an overall response rate of 52% and complete response rate of 40% in adult r/r DLBCL patients. 2

Key Evidence Supporting CAR T Over ASCT

• Recent randomized trials in patients without HIV demonstrate that CAR T-cell therapy in early relapsed DLBCL is associated with better outcomes than autologous stem cell transplantation (ASCT). 1
• This represents a paradigm shift from the traditional salvage chemotherapy → ASCT pathway that was previously standard. 1
• The European Society for Medical Oncology now recognizes CAR T as an option following two lines of treatment, which this patient has received. 1

Patient Eligibility Assessment

Prerequisites for CAR T-Cell Therapy

Before proceeding, verify the following eligibility criteria based on FDA labeling 2:

• CD20 positivity must be confirmed (required for tisagenlecleucel, which targets CD19 on B-cells). 2
• Performance status: Patient should have ECOG performance status < 2. 2
• Organ function requirements: 2
  • Creatinine clearance ≥ 60 mL/min
  • ALT ≤ 5 times upper limit of normal
  • Cardiac ejection fraction ≥ 45%
  • Absolute lymphocyte count ≥ 300/µL
• No active CNS malignancy. 2
• No prior allogeneic hematopoietic stem cell transplant. 2

Response to Salvage Chemotherapy

The patient's response to R-DHAP or R-ICE salvage chemotherapy should be assessed by PET-CT imaging to determine chemosensitivity. 3 However, unlike the traditional ASCT pathway where chemosensitivity was mandatory, CAR T-cell therapy can be considered even in patients with stable or progressive disease after salvage therapy. 1, 2

• Chemosensitive disease (complete or partial response) indicates better prognosis but is not an absolute requirement for CAR T. 3
• Patients with refractory disease to salvage therapy should still be considered for CAR T rather than proceeding to ASCT. 1, 4

Treatment Pathway Algorithm

Step 1: Immediate Referral to CAR T Center

Early referral to a CAR T-capable center is critical, as the median time from leukapheresis to CAR T infusion is 113 days (range 47-196 days). 2 This delay necessitates bridging therapy in most patients.

Step 2: Bridging Chemotherapy Management

Ninety percent of patients in the pivotal JULIET trial required bridging chemotherapy between leukapheresis and lymphodepleting chemotherapy to control disease burden. 2

• Acceptable bridging regimens include physician's choice of chemotherapy, with most patients receiving 1-2 regimens. 2
• The goal is disease control, not necessarily achieving complete response, as CAR T can work even with residual disease. 2

Step 3: Lymphodepleting Chemotherapy

Standard lymphodepletion consists of fludarabine (25 mg/m² IV daily × 3 days) plus cyclophosphamide (250 mg/m² IV daily × 3 days), or alternatively bendamustine (90 mg/m² IV daily × 2 days). 2

• Lymphodepletion can be omitted if white blood cell count is < 1000 cells/µL. 2
• CAR T infusion occurs 2-11 days after completion of lymphodepleting chemotherapy. 2

Comparison with Traditional ASCT Pathway

Why CAR T Is Preferred Over ASCT in This Patient

For patients who relapsed after rituximab-containing first-line therapy, the traditional ASCT pathway yields poor outcomes, with 3-year progression-free survival of only 23% in patients relapsing within 12 months. 1, 5

• The CORAL study demonstrated that patients with early relapse (< 12 months) or prior rituximab exposure have significantly worse outcomes with salvage chemotherapy followed by ASCT. 5
• At age 45, this patient is well within the age range where CAR T demonstrates excellent efficacy (median age 56 years in JULIET trial). 2

When ASCT Remains an Option

ASCT should still be considered for patients who: 1, 4

• Relapse > 12 months after initial diagnosis
• Did not receive rituximab in first-line therapy
• Have excellent response to salvage chemotherapy with low IPI scores

However, even in these favorable scenarios, CAR T is now considered equivalent or superior based on recent evidence. 1

Critical Pitfalls to Avoid

Common Errors in Management

• Do not delay CAR T referral while pursuing multiple lines of salvage chemotherapy. The FDA approval covers patients after ≥ 2 prior lines, which this patient has already received. 2
• Do not assume chemoresistance to salvage therapy precludes CAR T. Unlike ASCT, CAR T can work in chemorefractory disease. 2
• Do not proceed directly to ASCT without considering CAR T first. The evidence now favors CAR T in early relapsed disease. 1
• Do not use excessive bridging chemotherapy regimens. Most patients require only 1-2 bridging regimens; excessive therapy may compromise T-cell collection. 2

Monitoring for CAR T-Specific Toxicities

Patients receiving CAR T require monitoring for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). 2 These toxicities are manageable with tocilizumab and corticosteroids but require specialized center expertise.

Alternative Considerations

If CAR T Is Not Feasible

If the patient is not eligible for CAR T due to contraindications or lack of access, then proceed with the traditional pathway: 4

• Salvage chemotherapy (R-ICE or R-DHAP) followed by high-dose chemotherapy with ASCT for chemosensitive disease. 4, 5
• For chemoresistant disease, consider allogeneic stem cell transplantation or enrollment in clinical trials with novel agents. 4

Role of Radiation Therapy

Radiation therapy can provide excellent local control (84% at 1 year) for limited-stage relapsed disease post-CAR T failure, particularly when comprehensive RT is used. 6 However, this is a salvage option after CAR T, not an alternative to it.

Expected Outcomes with CAR T

In the JULIET trial of adult r/r DLBCL patients, tisagenlecleucel achieved: 2

• Overall response rate: 52%
• Complete response rate: 40%
• Median duration of response: Not reached in responders
• Responses maintained beyond 18 months in peripheral blood

These outcomes are superior to historical ASCT data in similar patient populations, particularly those with early relapse or prior rituximab exposure. 1, 5