What is the BFM (Berlin-Frankfurt-Munster) regimen for Acute Lymphoblastic Leukemia (ALL)?

Berlin-Frankfurt-Münster (BFM) Regimen for Acute Lymphoblastic Leukemia (ALL)

The BFM regimen is a cornerstone multiagent chemotherapy protocol for ALL that includes a 4-drug induction regimen with vincristine, an anthracycline (daunorubicin/doxorubicin), a corticosteroid (prednisone/dexamethasone), and L-asparaginase, followed by structured consolidation and maintenance phases. 1

Core Components of the BFM Regimen

Induction Phase

• The primary goal is to reduce tumor burden by clearing leukemic cells from bone marrow 1
• Standard 4-drug backbone includes:
  • Vincristine
  • Anthracycline (daunorubicin or doxorubicin)
  • Corticosteroid (prednisone or dexamethasone)
  • L-asparaginase/pegaspargase 1
• For standard-risk pediatric patients, a 3-drug induction (without anthracyclines) may be used 1
• Antimetabolites (methotrexate, cytarabine, mercaptopurine) are often included for CNS prophylaxis 1

Consolidation Phase

• Designed to eliminate residual leukemic cells after induction 1
• Intensity varies based on risk stratification - lower-risk patients receive less intensive consolidation while higher-risk patients receive more intensive therapy 1
• May include high-dose methotrexate and cytarabine 1

Maintenance Phase

• Long-term therapy to prevent relapse 1
• Typically continues for a total treatment duration of 24 months 2

CNS Prophylaxis

• All BFM regimens include CNS-directed therapy 1
• May include intrathecal methotrexate and cranial radiation (dose reduced to 12 Gy in more recent protocols) 3

Risk Stratification in BFM Protocols

• Risk stratification guides treatment intensity and has evolved over time 4
• Modern risk assessment includes:
  • Clinical factors: age, WBC count, extramedullary involvement 4
  • Biological characteristics: immunophenotype, cytogenetics 4
  • Early treatment response: prednisone response, minimal residual disease (MRD) 4
• Poor prognostic factors include:
  • Elevated WBC count (≥30×10⁹/L for B-cell lineage; ≥100×10⁹/L for T-cell lineage)
  • Hypodiploidy
  • MLL/KMT2A rearrangements 1

Evolution and Modifications of BFM Regimen

• Originally developed for pediatric patients but has been adapted for adolescent and young adult (AYA) patients 1
• The Cancer and Leukemia Group B (CALGB) modified the BFM approach for adults by adding cyclophosphamide to the 4-drug induction regimen 1, 2
• Recent modifications include:
  • More rapid drug sequencing during induction 3
  • Incorporation of MRD assessment to guide therapy intensity 1, 4
  • Reduced use of anthracyclines and cranial radiation to minimize toxicity 3

Clinical Outcomes

• The BFM approach has significantly improved survival rates in pediatric ALL 3
• In children, 6-year event-free survival rates of approximately 78-85% have been reported 3
• Outcomes are less favorable in adults, with 5-year overall survival rates of 32-39% in Ph-negative ALL 5
• Treatment abandonment (15%) and infectious complications (19.5%) are significant challenges in resource-constrained settings 6

Important Considerations and Pitfalls

• Dexamethasone versus prednisone:
  • Dexamethasone significantly reduces CNS relapse risk and improves event-free survival 1
  • However, dexamethasone is associated with higher risks of induction mortality, neuropsychiatric events, and myopathy 1
  • No conclusive advantage for overall survival has been demonstrated 1
• Early response assessment is critical:
  • Poor response to prednisone pre-phase (>1,000 blasts/μL after 7 days) identifies high-risk patients with only 35% survival 4
  • MRD assessment provides more refined risk stratification 1, 4
• Age-specific considerations:
  • Treatment intensity is typically reduced for patients ≥65 years or those with substantial comorbidities 1
  • Chronologic age alone is a poor surrogate for determining fitness for therapy 1