Treatment Guidelines for Relapsed Acute Lymphoblastic Leukemia Using ALL-REZ BFM90 Protocol
The ALL-REZ BFM90 protocol is a risk-stratified, multichemotherapy block approach that remains a cornerstone treatment for relapsed pediatric ALL, with hematopoietic stem cell transplantation (HSCT) recommended for high-risk patients who achieve second complete remission.
Risk Stratification in ALL-REZ BFM90
The protocol stratifies patients into three main risk groups based on timing and site of relapse:
- Group A (High Risk): Early bone marrow relapses (<36 months from initial diagnosis)
- Group B (Intermediate Risk): Late bone marrow relapses (≥36 months from initial diagnosis)
- Group C (Standard Risk): Isolated extramedullary relapses (CNS or testicular)
Additionally, patients with early bone marrow relapse or T-ALL relapse are classified as "poor prognosis group" (PPG) and may be eligible for experimental regimens 1.
Treatment Components of ALL-REZ BFM90
Induction and Consolidation
The protocol consists of alternating short-course intensive polychemotherapy blocks:
- Block R1: Multi-agent chemotherapy
- Block R2: Multi-agent chemotherapy
- Block R3: High-dose cytarabine and etoposide (introduced to improve outcomes)
These blocks are followed by:
- Cranial/craniospinal irradiation
- Maintenance therapy
Response Assessment
- Second 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
Outcomes by Risk Group
Event-free survival (EFS) rates differ significantly between risk groups:
Role of Hematopoietic Stem Cell Transplantation
HSCT is strongly recommended for high-risk patients (Group A and poor prognosis group) who achieve CR2, as it significantly improves outcomes compared to chemotherapy alone (EFS 33% vs 20%, p=0.005) 1, 2.
Key considerations:
- HSCT is the only known curative therapy for early relapse of B-ALL 1
- For late relapses (Group B) or isolated extramedullary relapses (Group C), chemotherapy alone may be sufficient 1
- Patients should achieve MRD negativity before proceeding to HSCT when possible
Special Considerations
T-ALL Relapse
For relapsed T-ALL, treatment options include:
- Clinical trials (preferred)
- Nelarabine-containing regimens
- Bortezomib-containing regimens
- UKALL R3 Block 1 or BFM Intensification Block 1 1
CD20+ B-ALL
Consider adding rituximab to chemotherapy regimens for CD20+ B-ALL relapse, as it has shown improved outcomes in adult studies 1.
MRD-Positive Disease
For patients with persistent MRD positivity:
- Consider blinatumomab before proceeding to HSCT 1
- Additional therapy should be considered to eliminate MRD before transplant 1
Pitfalls and Caveats
- Timing is critical: Delay in initiating relapse therapy can worsen outcomes
- CNS prophylaxis: Inadequate CNS prophylaxis can lead to CNS relapses (reported incidence of 19% following bone marrow relapse) 3
- Age considerations: Treatment-related mortality increases with age, particularly in patients >60 years 1
- Transplant timing: Early transplant is preferred to avoid cumulative toxicities and reduce risk of relapse before transplant 1
Algorithm for Decision Making
- Determine risk group based on time and site of relapse
- Initiate ALL-REZ BFM90 protocol with alternating blocks of chemotherapy
- Assess response after induction (CR2 and MRD status)
- Proceed to HSCT for:
- All Group A patients who achieve CR2
- Poor prognosis group patients who achieve CR2
- Group B patients with persistent MRD positivity
- Continue chemotherapy alone for:
- Group B patients with MRD negativity
- Group C patients (isolated extramedullary relapse)
- Consider novel agents (blinatumomab, inotuzumab ozogamicin, CAR-T) for patients with persistent MRD or those who fail to achieve CR2
The ALL-REZ BFM90 protocol has demonstrated that more than one-third of patients with relapsed ALL can be cured with this approach, with HSCT offering significant benefit for high-risk patients 2.