What is LAR (Lymphocyte Activation Regimen) with DLI (Donor Lymphocyte Infusion)?

LAR with DLI: Lymphocyte Activation Regimen with Donor Lymphocyte Infusion

Donor Lymphocyte Infusion (DLI) combined with a Lymphocyte Activation Regimen (LAR) is a therapeutic approach used primarily for patients with relapsed hematologic malignancies after allogeneic hematopoietic stem cell transplantation (HSCT), designed to enhance the graft-versus-leukemia effect while minimizing graft-versus-host disease.

What is DLI?

Donor Lymphocyte Infusion (DLI) is a form of adoptive immunotherapy where lymphocytes from the original stem cell donor are collected and infused into the patient who has relapsed after allogeneic HSCT. The key aspects of DLI include:

• Mechanism of action: DLI works by inducing a graft-versus-leukemia (GVL) effect where donor T cells recognize and eliminate residual malignant cells 1

• Administration approaches:

  • Bulk dose regimen (BDR): Single, relatively large dose of lymphocytes
  • Escalating dose regimen (EDR): Starting with smaller doses that increase over time (preferred approach)

• Efficacy by disease type:

  • Most effective in Chronic Myeloid Leukemia (CML): 60-90% disease-free survival at 3 years 2, 3
  • Less effective in acute leukemias: <50% response rates with 20-50% 3-year disease-free survival 4
  • Limited benefit in Acute Lymphoblastic Leukemia (ALL): Overall survival approximately 13% at 3 years 5

What is LAR?

Lymphocyte Activation Regimen (LAR) refers to strategies used to enhance the activity of donor lymphocytes before or during DLI. These approaches aim to improve the efficacy of DLI by:

1. Optimizing the lymphocyte environment before infusion
2. Enhancing T-cell activation and expansion to improve anti-tumor effects
3. Reducing the risk of graft-versus-host disease (GVHD) while preserving GVL effects

Clinical Applications of LAR with DLI

1. Relapsed Disease After Allogeneic HSCT

For patients who relapse after allogeneic HSCT, the NCCN guidelines recommend:

• Initial approach: Monitored withdrawal of immune suppression 2
• For molecular/cytogenetic relapse: DLI is most effective when administered early after relapse detection 2
• For hematologic relapse: Consider disease reduction with TKIs (for Ph+ leukemias) or other targeted therapies before DLI 2

2. Disease-Specific Approaches

For Ph-positive ALL:

• DLI has shown limited benefit when used alone 2
• Recommended approach: Combine TKIs (imatinib, dasatinib, nilotinib) with DLI to manage relapse after allogeneic HSCT 2
• For patients with T315I mutation, ponatinib plus DLI may be considered 2

For Acute Myeloid Leukemia (AML):

• Second allogeneic HSCT or DLI may induce long-term survival in patients with relapse after first allogeneic HSCT 2
• Survival probabilities at 3 years: 4% (relapse <6 months), 12% (6-24 months), 26% (2-3 years), and 38% (>3 years) 2

For CML:

• DLI is highly effective, especially in chronic phase 2
• Recommended approach: Consider TKI therapy before DLI to reduce disease burden 2

Technical Aspects and Timing

Washout Periods

Before DLI administration, appropriate washout periods are recommended:

• After previous DLI: At least 4 weeks (6-8 weeks may be safer to rule out GVHD) 2
• After allogeneic HSCT: Patients should be off immunosuppression and GVHD-free (minimum 1 month) 2

Administration Strategies

• Escalating dose regimen is preferred over bulk dose regimen to reduce GVHD risk (10% vs 44%, p=0.011) 3
• Timing: DLI is most effective when administered for molecular or cytogenetic relapse rather than hematologic relapse 4

Combination Approaches

DLI with Novel Agents

• Blinatumomab + DLI: Promising combination for B-cell malignancies, where blinatumomab reduces initial leukemic burden and DLI provides longer-lasting remission 6
• TKI + DLI: For Ph+ leukemias, combining TKIs with DLI may improve outcomes 2

Complications and Management

GVHD

• Occurs in approximately one-third of patients receiving DLI 4
• Risk factors: bulk dosing, unrelated donors, short interval from HSCT
• Prevention strategy: Use escalating dose regimen rather than bulk dose 3

Treatment-Related Mortality

• Ranges from 5-20% after DLI 4
• Higher risk in patients with active GVHD or infections

Important Considerations

• Patient selection is crucial: Best outcomes in patients with low disease burden and longer time from transplant to relapse
• Disease monitoring: Regular molecular monitoring (PCR for BCR-ABL in Ph+ leukemias) is essential to detect early relapse when DLI is most effective
• Donor availability: Original donor must be available and willing to donate lymphocytes
• Timing of intervention: Earlier intervention at molecular relapse rather than hematologic relapse significantly improves outcomes

LAR with DLI represents an important therapeutic option for relapsed hematologic malignancies after allogeneic HSCT, with effectiveness varying significantly by disease type, disease burden, and timing of intervention.