What is the recommended treatment for relapsed acute lymphoblastic leukemia (ALL) using the ALL REZ BFM90 protocol?

Treatment of Relapsed Acute Lymphoblastic Leukemia Using the ALL-REZ BFM90 Protocol

The ALL-REZ BFM90 protocol is the recommended treatment for relapsed acute lymphoblastic leukemia (ALL) in pediatric patients, with treatment stratification based on time and site of relapse, and includes intensive multichemotherapy blocks followed by hematopoietic stem cell transplantation (HSCT) for high-risk patients. 1

Risk Stratification in ALL-REZ BFM90

The protocol stratifies patients into three main risk groups:

1. Group A (High Risk): Early bone marrow relapses (<36 months from initial diagnosis)
2. Group B (Intermediate Risk): Late bone marrow relapses (≥36 months from initial diagnosis)
3. Group C (Standard Risk): Isolated extramedullary relapses (≥18 months from initial diagnosis)
4. Poor Prognosis Group (PPG): Early bone marrow or T-ALL relapse

Treatment Components of ALL-REZ BFM90

Induction and Consolidation

• Alternating short-course intensive polychemotherapy blocks (R1, R2, R3)
• Block R3 includes high-dose cytarabine and etoposide
• Cranial/craniospinal irradiation for CNS prophylaxis
• Maintenance therapy following intensive blocks

Response Assessment

• Complete remission (CR2) rates vary by risk group: Group A (83%), Group B (94%), Group C (100%) 1
• MRD assessment is critical for determining subsequent therapy and prognosis

Post-Remission Therapy

• High-risk patients (Groups A and PPG): Allogeneic HSCT is strongly recommended after achieving CR2
• Intermediate and standard-risk patients: May continue with chemotherapy alone, especially for late relapses

Outcomes by Risk Group

The protocol demonstrates significant differences in event-free survival (EFS) between risk groups 1, 2:

• Group A (early BM relapses): 17% ± 3%
• Group B (late BM relapses): 43% ± 4%
• Group C (isolated extramedullary relapses): 54% ± 6%
• Poor prognosis group: 15% ± 3%

Role of HSCT in ALL-REZ BFM90

HSCT plays a crucial role in the management of relapsed ALL:

• High-risk patients (Groups A and PPG) show significantly better outcomes with HSCT compared to chemotherapy alone (33% ± 5% vs. 20% ± 5%) 2
• HSCT is the only known curative therapy for early relapse of B-ALL 1
• For late relapses of B-ALL or late isolated CNS relapses of T-ALL, chemotherapy alone may be sufficient 1

Important Considerations

• Timing of relapse: The most significant prognostic factor is time from initial diagnosis to relapse
• Site of relapse: Isolated extramedullary relapses have better outcomes than bone marrow relapses
• Immunophenotype: T-cell ALL relapses generally have poorer outcomes
• MRD status: Achievement of MRD negativity before HSCT significantly improves outcomes

Treatment Algorithm

1. Initial assessment:

   • Determine time from initial diagnosis to relapse
   • Identify site(s) of relapse (bone marrow, extramedullary, or combined)
   • Confirm immunophenotype (B-ALL vs. T-ALL)

2. Risk stratification:

   • Assign to Group A, B, C, or PPG based on criteria above

3. Treatment implementation:

   • Begin intensive multichemotherapy blocks (R1, R2, R3)
   • Administer CNS prophylaxis with cranial/craniospinal irradiation
   • Assess response after induction (CR2 rate, MRD status)

4. Post-remission decision:

   • For high-risk groups (A and PPG): Proceed to allogeneic HSCT if donor available
   • For intermediate/standard risk (B and C): Continue chemotherapy followed by maintenance

Newer Therapeutic Options

While the ALL-REZ BFM90 protocol remains important, newer approaches for relapsed ALL include:

• Immunotherapy: Blinatumomab for CD19+ B-ALL and inotuzumab ozogamicin for CD22+ B-ALL 1
• CAR T-cell therapy: May maintain long-term remission without subsequent HSCT in some patients 1
• Targeted therapies: TKIs for Philadelphia chromosome-positive ALL 3

Pitfalls and Caveats

• Early identification of high-risk features is critical for timely HSCT referral
• Delayed HSCT can result in poor outcomes due to disease progression or cumulative toxicity
• MRD status before HSCT significantly impacts post-transplant outcomes
• Treatment-related mortality remains a significant concern, especially in heavily pretreated patients

The ALL-REZ BFM90 protocol has demonstrated that more than one-third of patients with relapsed ALL can be cured with this risk-stratified approach, though high-risk patients continue to have poor outcomes despite intensive therapy and HSCT 2.