What is the management of Acute Lymphoblastic Leukemia (ALL) in pediatric and adult patients?

Management of Acute Lymphoblastic Leukemia (ALL)

ALL management requires intensive, risk-stratified multiagent chemotherapy delivered in sequential phases (induction, consolidation, and maintenance), with treatment at specialized cancer centers strongly recommended given the complexity and toxicity of therapy. 1

Treatment Framework by Phase

Induction Therapy (Weeks 1-4)

The standard induction regimen consists of a 4-drug backbone:

• Vincristine at 1.4 mg/m² IV weekly (maximum 2 mg) 2
• Corticosteroid (prednisone or dexamethasone) - prednisone preferred in young children to minimize osteonecrosis risk, though dexamethasone provides superior CNS penetration 2
• Anthracycline (daunorubicin 25-30 mg/m² IV weekly) 2
• L-asparaginase/pegaspargase (2,500 IU/m² IV, 1-3 doses during induction) 2, 3

Complete remission rates exceed 90% with modern induction regimens. 1

CNS Prophylaxis (Initiated During Induction)

CNS-directed therapy must begin during induction and continue throughout treatment:

• Triple intrathecal therapy (methotrexate, cytarabine, dexamethasone) administered during induction and continued through consolidation 2
• Systemic high-dose methotrexate incorporated during consolidation phases 1, 2
• Cranial irradiation is NOT routinely recommended - reserved only for high-risk CNS involvement at diagnosis/relapse, as it causes serious complications without convincingly improving survival when effective systemic and intrathecal therapy is used 1, 4

Consolidation/Intensification Therapy

After achieving complete remission, consolidation includes:

• High-dose methotrexate for high-risk and T-cell ALL 1
• Cyclophosphamide, cytarabine, and mercaptopurine in various combinations 2
• Delayed intensification phase with dexamethasone, vincristine, and asparaginase 1
• Additional pegaspargase doses during consolidation 2
• Continued intrathecal chemotherapy 2

MRD response during consolidation is the most important prognostic factor - MRD ≥0.01% requires treatment intensification, while MRD <0.01% follows standard consolidation and maintenance 2

Maintenance Therapy (2-3 Years Total Duration)

Standard maintenance consists of:

• Daily oral mercaptopurine 1, 2
• Weekly oral methotrexate 1, 2
• Monthly vincristine pulses 2
• Pulse dexamethasone 2

Continuation therapy for 2 to 2.5 years is essential to prevent relapse. 1

Risk-Stratified Approaches

High-Risk Features Requiring Intensification

High-risk ALL is defined by:

• Age ≥35 years 5
• Elevated WBC (>30 × 10⁹/L for B-ALL; >100 × 10⁹/L for T-ALL) 5
• Time to complete remission >4 weeks 5
• Philadelphia chromosome positivity 5
• MRD ≥0.01% at end of induction 2

Philadelphia Chromosome-Positive ALL

For Ph+ ALL, tyrosine kinase inhibitors are mandatory:

• Adding TKI to chemotherapy improves 3-year event-free survival from 35% to 80% without transplantation 1, 5
• Allogeneic HSCT should be considered in first complete remission for Ph+ ALL 5
• If TKI unavailable, use most intensive chemotherapy and transplant if poor response to induction 1

Allogeneic Hematopoietic Stem Cell Transplantation

HSCT is a key component for transplant-eligible adult patients with high-risk ALL:

• Recommended for 2-6% of very high-risk patients (T-cell ALL, Ph+ ALL with poor early response) 1
• For patients with MRD-positive second CR, give 1-2 additional courses to achieve MRD negativity before HSCT 1
• Some patients cannot achieve MRD negativity - proceed to HSCT regardless 1
• 5-year overall survival for high-risk Ph-negative ALL is only 29%, highlighting need for intensive approaches 5

Relapsed/Refractory Disease

For multiple relapse or refractory B-ALL, treatment options include:

• Clinical trial (preferred) 1
• Blinatumomab for B-ALL 1
• Tisagenlecleucel for B-ALL - 3-year relapse-free survival 52%, with only 22% proceeding to HCT 1
• Inotuzumab ozogamicin for relapsed/refractory CD22-positive B-cell precursor ALL in adults and pediatric patients ≥1 year 6
• Goal is achieving second remission followed by allogeneic HSCT 7

Isolated extramedullary relapse (CNS or testicular) requires systemic therapy to prevent marrow relapse. 1

Special Population Considerations

Pediatric Patients

Pediatric ALL has dramatically improved outcomes with 5-year OS up to 96%:

• Cure rates 80-90% with modern protocols 8, 9
• Treatment must be delivered at specialized pediatric cancer centers given complexity and need for supportive care 1, 2
• Infants (<1 year) have higher incidence of KMT2A rearrangements and may require dose modifications 2

Adult Patients

Adults have worse outcomes than children due to higher-risk features and reduced chemotherapy tolerance:

• Complete remission rate 85-93% but 5-year survival only 38-41% 1
• Common adult regimens include UKALL XII/ECOG 2993 and hyperCVAD protocols 1
• HSCT is key for most transplant-eligible adults with enhanced/maximum resources 1
• For patients ≥65 years or substantial comorbidities, reduce treatment intensity, but chronologic age alone should not determine fitness 5

Critical Pitfalls to Avoid

Common errors in ALL management:

• Failing to initiate CNS prophylaxis during induction - must start early 2
• Using routine cranial irradiation when not indicated - causes serious complications without survival benefit in most cases 1, 4
• Not monitoring MRD to guide therapy intensification - MRD is the most critical prognostic factor 2
• Treating complex ALL cases at non-specialized centers - complexity demands expertise 1, 2
• Omitting TKI in Ph+ ALL when available - dramatically improves outcomes 1, 5
• Proceeding to HSCT with MRD-positive status without attempting additional therapy to achieve MRD negativity 1