What is the best approach for a patient with a history of malignancy, such as acute lymphoblastic leukemia (ALL), experiencing an early relapse isolated to the central nervous system (CNS)?

Management of Early Isolated CNS Relapse in Acute Lymphoblastic Leukemia

For early isolated CNS relapse of ALL (occurring <18 months from diagnosis), hematopoietic stem cell transplantation (HSCT) is the only known curative therapy and should be pursued after achieving second remission with intensive systemic chemotherapy plus intrathecal therapy. 1

Treatment Algorithm Based on Timing of Relapse

Early Relapse (<18 months from diagnosis)

Immediate Induction Therapy:

• Initiate intensive systemic chemotherapy with CNS-penetrating agents (high-dose methotrexate ≥3 g/m² or high-dose cytarabine) alternating with standard blocks 1
• Begin intrathecal chemotherapy twice weekly (methotrexate 12 mg or triple therapy: methotrexate 15 mg, cytarabine 40 mg, hydrocortisone 20 mg) until CSF clears of blasts 1, 2
• Age-based intrathecal dosing is superior to body surface area dosing: age <1 year = 6 mg; age 1 year = 8 mg; age 2 years = 10 mg; age ≥3 years = 12 mg 2

Definitive Therapy:

• Proceed to allogeneic HSCT as soon as second complete remission (CR2) is achieved 1
• HSCT is the only known curative option for early relapse, with event-free survival (EFS) of only 17% ± 3% without transplant 1
• Include total body irradiation (TBI) in the conditioning regimen, with consideration of cranial boost of 6 Gy 1

Late Relapse (≥18 months from diagnosis)

Chemotherapy-Based Approach:

• Late isolated CNS relapse can be treated with chemotherapy alone without mandatory HSCT 1
• Intensive systemic chemotherapy with CNS-penetrating agents for 12 months followed by reduced-dose cranial radiation (18 Gy) achieves 4-year EFS of 77.7% ± 6.4% 3
• Continue intrathecal therapy during the 12-month intensive phase, then maintenance chemotherapy until 104 weeks post-diagnosis 4, 3

Radiation Timing and Dosing:

• Delay cranial radiation until 12 months after starting therapy to allow intensive systemic chemotherapy to work 3
• For late relapse (CR1 ≥18 months): 18 Gy cranial radiation only 3
• For early relapse (CR1 <18 months): 24 Gy cranial with 15 Gy spinal radiation 3

Critical Prognostic Factors

Duration of First Complete Remission:

• CR1 <18 months: 4-year EFS 51.6% ± 11.3% with chemotherapy alone 3
• CR1 ≥18 months: 4-year EFS 77.7% ± 6.4% with chemotherapy alone 3
• This distinction determines whether HSCT is mandatory versus optional 1

NCI Risk Group at Initial Diagnosis:

• Standard-risk patients: 4-year EFS 80.2% ± 6.3% 3
• High-risk patients: 4-year EFS 51.4% ± 10.8% 3
• High-risk patients with early relapse have particularly poor outcomes (EFS 15% ± 3%) and require HSCT 1

Systemic Therapy Regimens

COG AALL01P2 Approach:

• Three blocks of reinduction chemotherapy with early introduction of high-dose cytarabine for CNS disease 1
• Patients with CNS leukemia non-randomly assigned to receive high-dose cytarabine in block 2 1
• CR2 rate of 81.2% overall, but only 68% ± 6% for early relapses 1

MRD Monitoring:

• Absence of minimal residual disease (MRD) after first month of reinduction predicts better outcomes 1
• Subsequent therapy blocks reduce MRD burden in 71% of patients who remain MRD-positive after block 1 1

Common Pitfalls and How to Avoid Them

Do Not Delay HSCT for Early Relapse:

• Early isolated CNS relapse has dismal outcomes without HSCT (EFS 17%) 1
• Begin HLA typing and donor search immediately upon diagnosis of early relapse 1
• HSCT should occur as soon as CR2 is achieved, not after prolonged chemotherapy 1

Do Not Rely on Systemic Chemotherapy Alone for CNS Disease:

• Blood-brain barrier prevents adequate CNS penetration of most systemic agents 5
• Intrathecal chemotherapy must be given concurrently with systemic therapy 1
• Even high-dose methotrexate requires intrathecal supplementation for documented CNS involvement 1, 5

Do Not Use Standard Body Surface Area Dosing for Intrathecal Therapy:

• Age-based dosing produces more consistent CSF concentrations and less neurotoxicity 2
• Body surface area dosing of 12 mg/m² results in low CSF concentrations in children and high concentrations with neurotoxicity in adults 2

Monitor for Second Relapse Patterns:

• 46% of second relapses after late isolated CNS relapse include the CNS again 4
• Most relapses after early CNS relapse involve bone marrow 3
• Perform regular bone marrow assessments during CNS-directed therapy to detect combined relapse 1

Avoid Premature Reduction in Cranial Radiation Dose:

• Reduction from 18 Gy to 12 Gy resulted in inferior EFS (64.3% vs 77.7%) despite more intensive chemotherapy 4
• The optimal dose for late isolated CNS relapse remains 18 Gy delivered at 12 months 3

Alternative Approaches for Specific Scenarios

CAR T-Cell Therapy:

• Patients achieving remission with CAR T cells can maintain long-term remission without subsequent HSCT 1
• Consider for patients who achieve MRD-negative CR2 but lack suitable HSCT donor 1

Blinatumomab as Bridge to Transplant:

• Effective for achieving MRD-negative status before HSCT in B-cell precursor ALL 1
• FDA-approved for B-cell precursor ALL in first or second CR with MRD ≥0.1% 1