What is the initial approach to treating acute lymphoblastic leukemia (ALL) in the relapsed setting?

Initial Approach to Treating Relapsed Acute Lymphoblastic Leukemia

For patients with relapsed acute lymphoblastic leukemia (ALL), the treatment approach should be based on the timing of relapse, with clinical trial participation as the preferred option when available, followed by targeted therapies such as blinatumomab for B-cell ALL or appropriate salvage chemotherapy regimens, with subsequent allogeneic hematopoietic stem cell transplantation for eligible patients. 1

Risk Stratification of Relapsed ALL

The approach to relapsed ALL depends on several key factors:

• Timing of relapse:

  • Early relapse: <36 months from initial diagnosis for bone marrow relapse or <18 months for isolated extramedullary relapse 1
  • Late relapse: ≥36 months from initial diagnosis for bone marrow relapse or ≥18 months for isolated extramedullary relapse 1

• Site of relapse:

  • Bone marrow (isolated or combined)
  • Extramedullary (CNS, testicular, other)
  • Combined (bone marrow plus extramedullary)

• Immunophenotype:

  • B-cell ALL
  • T-cell ALL
  • Philadelphia chromosome status

Treatment Algorithm for Relapsed ALL

Step 1: Initial Assessment

1. Determine timing of relapse (early vs. late)
2. Identify site of relapse (bone marrow, extramedullary, combined)
3. Confirm immunophenotype and genetic profile
4. Assess patient's age and comorbidities
5. Evaluate prior treatment history and response

Step 2: Reinduction Therapy

For B-cell ALL:

• Preferred option: Clinical trial participation 1
• If no trial available:
  • Blinatumomab (for CD19+ B-cell precursor ALL) 1
  • Inotuzumab ozogamicin (for CD22+ B-cell precursor ALL) 1
  • Salvage chemotherapy regimens:
    • FLAG-IDA (fludarabine, cytarabine, G-CSF, idarubicin)
    • Clofarabine-based combinations
    • Augmented hyper-CVAD
    • MOpAD regimen 1
    • UKALL R3 protocol (mitoxantrone-based) 1

For T-cell ALL:

• Preferred option: Clinical trial participation
• If no trial available:
  • Nelarabine-containing regimens 1
  • Other salvage chemotherapy options

Step 3: Response Assessment

• Evaluate minimal residual disease (MRD) status after reinduction
• MRD negativity is a critical prognostic factor for subsequent treatment success 1

Step 4: Post-Reinduction Strategy

For patients achieving second remission:

• Early relapse: Allogeneic hematopoietic stem cell transplantation (HSCT) is generally recommended as the only known curative therapy 1
• Late relapse:
  • For B-ALL: Consider chemotherapy alone or HSCT based on MRD status 1
  • For T-ALL with isolated late CNS relapse: Chemotherapy alone may be sufficient 1

For patients with persistent disease:

• Consider additional novel agents or experimental therapies
• CAR T-cell therapy (tisagenlecleucel) for eligible patients 1, 2

Evidence-Based Outcomes

The prognosis for relapsed ALL varies significantly based on timing and response to reinduction:

• Second remission rates:

  • UKALL R3 trial: High second remission rates with mitoxantrone-based therapy (superior to idarubicin) 1
  • ALL-REZ BFM 90 trial: 84% overall second remission rate (83% in early bone marrow relapse group, 94% in late bone marrow relapse group) 1
  • COG AALL01P2 study: 81.2% second remission rate overall (68% for early relapses, 96% for late relapses) 1

• Long-term outcomes:

  • 5-year progression-free survival after HSCT: 56% in UKALL R3 trial 1
  • Patients who received CAR T-cells can maintain long-term remission without subsequent HSCT in some cases 1

Special Considerations

CNS-Directed Therapy

• For CNS involvement: Intrathecal chemotherapy with methotrexate, cytarabine, and hydrocortisone 3
• Consider CNS boost radiation for patients with CNS involvement who will undergo HSCT 1

MRD Monitoring

• MRD assessment after reinduction is critical for determining subsequent therapy 1
• MRD negativity before HSCT significantly improves outcomes 1

Common Pitfalls to Avoid

1. Delaying HSCT evaluation for patients achieving second remission
2. Underestimating the importance of MRD in guiding post-reinduction therapy
3. Failing to consider novel agents like blinatumomab or inotuzumab ozogamicin for relapsed B-cell ALL
4. Not screening for extramedullary relapse sites, particularly CNS involvement

Remember that the prognosis for relapsed ALL remains poor, particularly for early relapses, making clinical trial participation and consideration of novel therapies crucial for improving outcomes.