What are the current guidelines for prophylactic radiotherapy in Acute Lymphoblastic Leukemia (ALL)?

Current Guidelines for Prophylactic Radiotherapy in Acute Lymphoblastic Leukemia (ALL)

According to the most recent NCCN Guidelines (2025), cranial radiotherapy is no longer routinely recommended for CNS prophylaxis in ALL and is often avoided in favor of intrathecal chemotherapy and systemic therapy due to concerns about late effects. 1

CNS Prophylaxis Approach

Classification of CNS Status

• CNS-1: No lymphoblasts in CSF regardless of WBC count
• CNS-2: WBC count <5/μL in CSF with presence of lymphoblasts
• CNS-3: WBC count ≥5/μL in CSF with presence of lymphoblasts, or clinical symptoms (facial nerve palsy, brain/eye involvement, CNS hemorrhage, hypothalamic syndrome) 1

Current Recommendations for CNS Prophylaxis

Standard Approach (All Patients)

• All patients with ALL should receive CNS prophylaxis regardless of CNS involvement at diagnosis 1
• Without CNS-directed therapy, >50% of patients will eventually develop CNS leukemia 1

Preferred CNS-Directed Therapy

1. Intrathecal (IT) chemotherapy:

   • Methotrexate, cytarabine, corticosteroids
   • Typically begins at diagnostic workup with lumbar puncture 1

2. Systemic chemotherapy with CNS penetration:

   • High-dose methotrexate
   • Cytarabine
   • Pegaspargase/calaspargase 1

Cranial Radiotherapy Guidelines

• For CNS-3 disease at diagnosis: If cranial radiation is used, recommended dosing is 18 Gy at 1.5–1.8 Gy/fraction 1
• For T-ALL: Timing of cranial radiation is less clear; follow specific treatment protocol in its entirety 1
• General approach: Cranial RT is often avoided in favor of IT chemotherapy and systemic therapy due to concern for late effects 1, 2

Evidence Supporting Current Approach

Efficacy of Non-Radiation Approaches

• The St. Jude Total XV Study demonstrated that prophylactic cranial irradiation could be safely omitted in all patients without compromising overall survival 1
• A meta-analysis of 16,623 patients showed that CRT does not impact relapse risk in children with ALL treated on contemporary protocols 2

Specific Indications for Cranial Radiotherapy

• CNS-3 disease at diagnosis: Significantly lower risk of isolated CNS relapse (4% with CRT vs 17% without CRT) 2
• High-risk features: Patients with mature B-cell immunophenotype, T-cell immunophenotype, high leukocyte counts, or elevated serum LDH may require more intensive prophylaxis 3

Late Effects of Cranial Radiotherapy

• Even with lower dose (18 Gy) cranial irradiation, studies have shown:
  • Pituitary hormone abnormalities 4
  • Gradual decrease in height SDS, particularly in patients irradiated at a young age 4
  • Potential cognitive sequelae requiring neuropsychological monitoring 3

Protocol-Based Approach

For Pediatric ALL

• Follow specific treatment protocol in its entirety 1
• The ALL-BFM 90 trial demonstrated that 12-Gy preventive cranial radiotherapy provided sufficient CNS prophylaxis with isolated CNS relapse rates of only 0.8% in medium-risk and 1.6% in high-risk groups 5

For Adult ALL

• Similar approach to pediatric ALL but with drug dosages tailored to adult tolerance 1
• The Hyper-CVAD regimen with early intrathecal therapy has significantly reduced CNS relapses (3% vs 17-31% with other regimens) 3

Algorithm for CNS Prophylaxis Decision-Making

1. Assess CNS status (CNS-1, CNS-2, or CNS-3)
2. Evaluate risk factors:
   • T-cell phenotype
   • High WBC count
   • Elevated LDH
   • Mature B-cell immunophenotype
3. Standard approach (all patients):
   • Intrathecal chemotherapy (methotrexate, cytarabine, corticosteroids)
   • Systemic chemotherapy with CNS-penetrating agents
4. Consider cranial radiotherapy only for:
   • CNS-3 disease at diagnosis (18 Gy at 1.5–1.8 Gy/fraction)
   • Protocol-specific indications for T-ALL

Common Pitfalls and Caveats

• Overuse of cranial radiotherapy: Modern protocols have demonstrated excellent CNS control without routine use of cranial RT
• Undertreatment of CNS-3 disease: Patients with overt CNS disease still benefit from cranial RT
• Inconsistent protocol adherence: Follow the chosen treatment protocol in its entirety rather than mixing approaches
• Inadequate monitoring: Close neurological monitoring is essential during and after treatment, especially with neurotoxic agents like vincristine and blinatumomab 3

In summary, the current approach to CNS prophylaxis in ALL has shifted away from routine cranial radiotherapy toward effective intrathecal and systemic chemotherapy regimens, reserving radiation primarily for patients with CNS-3 disease at diagnosis.