Management and Treatment of Acute Lymphoblastic Leukemia (ALL)
ALL requires intensive multiagent chemotherapy administered in three distinct phases—induction, consolidation, and maintenance—with treatment intensity and drug selection determined by age, Philadelphia chromosome status, risk stratification, and minimal residual disease (MRD) response. 1, 2
Risk Stratification Before Treatment
Risk assessment must be completed immediately to guide treatment intensity and determine candidacy for allogeneic hematopoietic cell transplantation (HCT). 1, 3
High-risk features requiring treatment intensification include: 3
- Age ≥35 years
- WBC >30 × 10⁹/L for B-cell lineage or >100 × 10⁹/L for T-cell lineage 1, 2
- Time to complete remission >4 weeks
- Hypodiploidy 1, 2
- MLL/KMT2A rearrangements 1, 2
- Poor-risk cytogenetics and molecular alterations 3
Phase 1: Induction Therapy
Adults <65 Years with Ph-Negative B-cell ALL
The standard approach uses a 4-drug backbone consisting of vincristine, anthracycline (daunorubicin or doxorubicin), corticosteroid (prednisone or dexamethasone), and L-asparaginase/pegaspargase. 1, 2, 3
High-intensity regimen options include CALGB 9111, ECOG 1910, or dose-adjusted Hyper-CVAD. 3 Moderate-intensity alternatives include modified DFCI 91-01, GMALL, GRAALL, or EWALL regimens. 3
For CD20-positive disease, add rituximab to the GMALL regimen. 3
Regarding corticosteroid selection: Dexamethasone provides superior CNS penetration and reduces CNS relapse risk compared to prednisone, but carries higher risks of induction mortality, neuropsychiatric events, and myopathy, with no conclusive overall survival advantage demonstrated. 2, 3 The choice depends on balancing CNS protection against toxicity risk in each patient.
Adults ≥65 Years or with Substantial Comorbidities
Use reduced-intensity regimens rather than full-dose therapy, as chronologic age alone is a poor surrogate for determining fitness. 1, 2
Low-intensity options include vincristine and prednisone or POMP. 1 Moderate-intensity options include ALLOLD07, EWALL, GMALL, or GRAALL regimens. 1
Pediatric Patients
Standard-risk patients receive 3-drug induction without anthracyclines. 1, 2 High-risk patients receive 4-drug induction including anthracyclines. 1
CNS Prophylaxis from Day 1
Initiate intrathecal chemotherapy immediately at induction start—triple intrathecal therapy (methotrexate, cytarabine, hydrocortisone) is preferred over methotrexate alone. 3, 4
Prophylactic cranial irradiation is not recommended for B-ALL when effective systemic and intrathecal therapy is provided. 3
For intrathecal dosing, use age-based rather than body surface area-based dosing to avoid underdosing in children and overdosing in adults: 4
- Age <1 year: 6 mg
- Age 1 year: 8 mg
- Age 2 years: 10 mg
- Age ≥3 years: 12 mg
Phase 2: MRD Assessment and Treatment Modification
MRD assessment after induction is mandatory and determines all subsequent treatment decisions. 1, 3
MRD-Negative Patients
Proceed with standard consolidation and maintenance therapy. 3
MRD-Positive or Rising MRD Patients
Add blinatumomab or inotuzumab ozogamicin before consolidation. 3 Blinatumomab achieves 88% complete MRD response in patients with MRD ≥10⁻³. 3
Common pitfall to avoid: Never delay MRD assessment, as this prevents timely treatment intensification and consideration for stem cell transplantation. 3
Phase 3: Consolidation Therapy
Consolidation typically includes high-dose methotrexate, cytarabine, and other agents. 1, 4 Continue intrathecal chemotherapy throughout consolidation as CNS prophylaxis is essential in all treatment regimens. 1
For patients with high-risk features or persistent MRD positivity, consider allogeneic HCT in first complete remission. 3
Phase 4: Maintenance Therapy
Standard maintenance consists of: 1, 5
- Daily mercaptopurine (1.5-2.5 mg/kg orally once daily)
- Weekly methotrexate
- Monthly vincristine
- Pulse dexamethasone
Maintenance therapy extends over 2-3 years total treatment duration. 6, 7
Critical dosing considerations for mercaptopurine: 5
- Take consistently either with or without food
- Monitor CBC and adjust dose to maintain desirable ANC
- Test for TPMT and NUDT15 deficiency in patients with severe or repeated myelosuppression
- Patients with homozygous TPMT or NUDT15 deficiency require 10% or less of standard dosing
- When coadministered with allopurinol, reduce mercaptopurine dose to one-third to one-quarter of current dosage
Special Populations and Modifications
Renal Impairment
Use the lowest recommended starting dosage for mercaptopurine in patients with CLcr <50 mL/min. 5
Hepatic Impairment
Use the lowest recommended starting dosage for mercaptopurine and adjust based on tolerability. 5
Philadelphia Chromosome-Positive ALL
The combination of BCR::ABL1 tyrosine kinase inhibitors (TKIs) with chemotherapy or blinatumomab has dramatically improved outcomes, with 5-year survival rates now exceeding 80%. 6, 7 Current approaches using more potent TKIs (ponatinib, dasatinib) with blinatumomab achieve 4-year survival rates of 85-90%. 7
T-cell ALL
Combination chemotherapy incorporating pegylated asparaginase and nelarabine is standard. 6 Early T-cell precursor (ETP) ALL is high-risk and allogeneic SCT should be considered. 6
Mature B-ALL
Survival rates exceed 80% with short intensive chemotherapy combined with rituximab. 8, 9
Ongoing Monitoring Throughout Treatment
MRD monitoring guides therapy intensification and consideration for stem cell transplantation throughout all treatment phases. 1 Achieving complete molecular remission, particularly by next-generation sequencing, is an important prognostic indicator that may identify patients who can avoid allogeneic SCT. 6
Monitor CBC regularly and evaluate bone marrow in patients with prolonged or repeated myelosuppression to assess leukemia status and marrow cellularity. 5