What is the treatment for lymphoblastic leukemia?

Treatment of Lymphoblastic Leukemia

Treatment Approach Based on Age and Disease Subtype

Treatment for lymphoblastic leukemia consists of multi-phase chemotherapy including induction, consolidation, CNS prophylaxis, and maintenance therapy, with specific regimens determined by age (pediatric vs. adult), Philadelphia chromosome status, and risk stratification based on minimal residual disease (MRD). 1

Pediatric B-Cell ALL Treatment

Standard-Risk Pediatric Patients (Age 1-10 years, WBC <50×10⁹/L)

• Induction therapy uses a 3-drug regimen without anthracyclines: dexamethasone, vincristine, and pegaspargase 2
• For infants and very young children (age <1 year or weight <17 kg), a 4-drug induction is preferred: corticosteroid (prednisone preferred over dexamethasone to minimize toxicity), vincristine (1.4 mg/m² IV weekly, max 2 mg), anthracycline (daunorubicin 25-30 mg/m² IV weekly), and pegaspargase (2,500 IU/m² IV) 3
• CNS prophylaxis with triple intrathecal therapy (methotrexate, cytarabine, dexamethasone) must begin during induction 3, 2

Post-Induction Risk Stratification by MRD

• MRD <0.01% at end of induction (Day 29): Standard consolidation with 6-mercaptopurine, vincristine, and intrathecal methotrexate 2
• MRD 0.01% to <0.1%: Standard consolidation therapy 2
• MRD ≥0.1%: Intensified consolidation with cyclophosphamide, cytarabine, 6-mercaptopurine, vincristine, pegaspargase, and intrathecal methotrexate 2

Maintenance Therapy (2-3 years total from diagnosis)

• Daily oral mercaptopurine (1.5-2.5 mg/kg) 4
• Weekly oral methotrexate 3, 2
• Monthly vincristine pulses 3, 2
• Pulse dexamethasone 3, 2

Adult ALL Treatment (Age ≥40 years)

Philadelphia Chromosome-Negative ALL

Induction Regimens:

• CALGB 8811 (Larson regimen): Daunorubicin, vincristine, prednisone, asparaginase, and cyclophosphamide (for patients >60 years, use reduced doses) 1
• Hyper-CVAD ± rituximab: Hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine (add rituximab for CD20-positive disease) 1
• Linker 4-drug regimen: Daunorubicin, vincristine, prednisone, and asparaginase 1

Risk Stratification for Adults <65 years:

• High-risk features: WBC ≥30×10⁹/L (B-cell) or ≥100×10⁹/L (T-cell), hypodiploidy, or MLL rearrangements 1
• High-risk patients should be considered for allogeneic stem cell transplantation in first remission 1

Philadelphia Chromosome-Positive ALL

• Tyrosine kinase inhibitors (TKIs) combined with chemotherapy: Imatinib or dasatinib with hyper-CVAD 1
• Alternative: TKIs with multiagent chemotherapy (daunorubicin, vincristine, prednisone, cyclophosphamide) 1
• For elderly patients (>60 years): TKIs with corticosteroids alone (imatinib and prednisone) 1
• Recent advances show 4-year survival rates of 85-90% with ponatinib or dasatinib combined with blinatumomab 5

Maintenance for Ph-Positive ALL:

• Weekly methotrexate plus daily 6-mercaptopurine plus monthly vincristine/prednisone pulses (2-3 years) 1
• Add TKIs (imatinib or dasatinib) to maintenance regimen 1

CNS Prophylaxis and Treatment (All Patients)

• All patients require CNS-directed therapy regardless of CNS involvement at diagnosis 1
• CNS-3 disease (overt CNS leukemia) at diagnosis requires cranial irradiation 18 Gy 1
• Intrathecal chemotherapy dosing based on age (not body surface area): Age <1 year: 6 mg; Age 1 year: 8 mg; Age 2 years: 10 mg; Age ≥3 years: 12 mg 6
• High-dose systemic chemotherapy (methotrexate, cytarabine) can substitute for cranial irradiation in most cases except overt CNS disease 1

Novel Immunotherapy Approaches (2024 Update)

For B-lineage ALL:

• Blinatumomab (CD3-CD19 bispecific T-cell engager) combined with standard chemotherapy achieves 80-85% 4-year survival in B-cell ALL 5
• Inotuzumab ozogamicin (CD22 antibody-drug conjugate) as alternative or combination therapy 1, 5
• These targeted therapies have lower treatment-related mortality (~1%) compared to traditional chemotherapy (10-20% in adults) 1

Critical Treatment Modifications

TPMT/NUDT15 Deficiency:

• Homozygous deficiency: Reduce mercaptopurine dose to 10% or less of standard dosing 4
• Heterozygous deficiency: Most tolerate standard dosing, but some require reduction; patients heterozygous for both genes require substantial dose reductions 4

Allopurinol Interaction:

• Reduce mercaptopurine dose to one-third to one-quarter when coadministered with allopurinol 4

Renal/Hepatic Impairment:

• Use lowest recommended starting dosage and adjust based on ANC and toxicity 4

Common Pitfalls to Avoid

• Never use preserved methotrexate formulations for intrathecal or high-dose therapy (contains benzyl alcohol) 6
• Dexamethasone provides superior CNS penetration but carries higher risk of osteonecrosis in patients ≥10 years old 2
• Chronologic age alone is inadequate for determining treatment fitness in adults; individual assessment of comorbidities is essential 1
• Treatment must be administered at specialized centers with expertise in ALL management due to complexity and supportive care requirements 3, 2
• Monitor CBC frequently and adjust dosing to maintain adequate ANC while avoiding excessive myelosuppression 4