What is the initial treatment for a patient with acute lymphoblastic leukemia (ALL)?

Initial Treatment for Acute Lymphoblastic Leukemia

The initial treatment for ALL consists of intensive multiagent induction chemotherapy using a backbone of vincristine, corticosteroids, and asparaginase with or without anthracyclines, followed by CNS prophylaxis, consolidation, and maintenance therapy. 1, 2

Induction Therapy Regimens

Pediatric Patients

• Standard-risk patients receive a 3-drug induction regimen without anthracyclines (vincristine, corticosteroid, and asparaginase). 1, 3
• High-risk patients receive a 4-drug induction regimen that adds an anthracycline (daunorubicin or doxorubicin) to the standard backbone. 1, 3
• The BFM/COG regimens form the cornerstone of pediatric ALL treatment, with structured phases including induction, consolidation, and maintenance. 3

Adult Patients (<65 years)

• Ph-negative ALL requires multiagent regimens based on vincristine, anthracyclines, corticosteroids, and L-asparaginase. 2
• Some protocols add cyclophosphamide to create a 5-drug regimen, particularly for adolescent and young adult (AYA) patients. 3
• Common regimens include Hyper-CVAD and MRC UKALL XII/ECOG E2993 protocols. 4

Older Adults (≥65 years) or Patients with Comorbidities

• Low-intensity options include vincristine and prednisone or POMP regimens. 2
• Moderate-intensity options include ALLOLD07, EWALL, GMALL, or GRAALL regimens. 2
• Chronologic age alone should not determine fitness for therapy; functional status and comorbidities must be considered. 3, 4

Corticosteroid Selection: Critical Decision Point

Dexamethasone is preferred over prednisone for its superior CNS penetration and reduced CNS relapse risk, though it carries higher toxicity. 1, 3

• Dexamethasone significantly decreases isolated CNS relapse and improves event-free survival compared to prednisone. 1
• However, dexamethasone increases risks of osteonecrosis, infection, induction mortality, neuropsychiatric events, and myopathy. 1, 3
• No conclusive overall survival advantage has been demonstrated for dexamethasone versus prednisone except in T-ALL patients with prednisone good response. 1, 3
• COG uses dexamethasone 6 mg/m² per day for 28 days rather than the higher 10 mg/m² per day for 21 days to balance efficacy and toxicity. 1

Asparaginase Formulations

• Pegaspargase has a longer half-life and decreased immunogenicity compared to native E. coli-derived L-asparaginase. 1
• Calaspargase is an alternative formulation with enhanced pharmacokinetics. 1
• Asparaginase Erwinia chrysanthemi (recombinant)-rywn (ERW-rywn) serves as an alternative for patients with hypersensitivity reactions. 1

Essential Concurrent Therapies

CNS Prophylaxis

• Intrathecal chemotherapy with methotrexate, cytarabine, and corticosteroids is mandatory in all ALL treatment regimens. 1, 2
• High-dose methotrexate and cytarabine during consolidation provide additional CNS protection. 2

Antimicrobial Prophylaxis

• Trimethoprim-sulfamethoxazole (Bactrim) for Pneumocystis prophylaxis is recommended. 1

Treatment Phases Beyond Induction

Consolidation Therapy

• Includes high-dose methotrexate, cytarabine, and other agents to eliminate residual disease. 2
• MRD assessment at end of induction guides therapy intensification decisions. 2, 4

Maintenance Therapy

• Standard regimens include daily mercaptopurine, weekly methotrexate, monthly vincristine, and pulse dexamethasone. 2
• Duration typically extends 2-3 years from diagnosis. 2

Risk-Adapted Treatment Modifications

High-Risk Features Requiring Intensification

• Age ≥35 years (adults) or unfavorable age in pediatrics. 4
• Elevated WBC count (≥30×10⁹/L for B-cell lineage; ≥100×10⁹/L for T-cell lineage). 2, 4
• Hypodiploidy or MLL/KMT2A rearrangements. 2, 3
• Time to complete remission >4 weeks. 4
• MRD positivity at end of induction (B-ALL) or end of consolidation (T-ALL). 1, 2

Philadelphia Chromosome-Positive ALL

• Add tyrosine kinase inhibitor to standard chemotherapy backbone, which improves 3-year event-free survival from 35% to 80%. 4
• Consider allogeneic hematopoietic stem cell transplantation in first complete remission. 4

Allogeneic Stem Cell Transplantation Indications

• Induction failure (M3 marrow): Recommend HCT after achieving MRD-negative status. 1
• High-risk features in first remission, particularly with persistent MRD. 1, 4
• Second complete remission (CR2): Consider based on timing of relapse and leukemic phenotype. 1
• Third complete remission (CR3): Recommend HCT. 1
• Young patients with HLA-identical donors should be referred for allogeneic HCT except those achieving complete response on specific regimens with excellent outcomes. 1

Critical Pitfalls to Avoid

• Do not delay CNS prophylaxis—it must begin during induction therapy, as CNS relapse is a major cause of treatment failure. 1, 2
• Do not use chronologic age alone to determine treatment intensity; assess functional status and comorbidities comprehensively. 3, 4
• Do not ignore MRD status—MRD positivity at end of induction predicts high relapse rates and should prompt evaluation for allogeneic HCT. 1, 2
• Do not interrupt treatment in responding patients outside clinical trials, as continuous therapy is essential for maintaining remission. 1
• Do not use high-dose dexamethasone (10 mg/m² per day) without considering toxicity risks; the COG schedule of 6 mg/m² per day for 28 days balances efficacy and safety. 1