What are the phases of treatment for acute lymphoblastic leukemia (ALL)?

Treatment Phases of Acute Lymphoblastic Leukemia (ALL)

ALL treatment is organized into three major phases—induction, consolidation, and maintenance—with all regimens incorporating mandatory CNS prophylaxis throughout therapy. 1

Overview of Treatment Structure

The treatment approach to ALL represents one of the most complex and intensive programs in cancer therapy, with phases that can be further subdivided into more detailed components including induction IA and IB, CNS phase, early intensification, delayed intensification, continuation, consolidation IA/IB/IC/II, reinduction I and II, and interim maintenance I and II. 1 While specific regimens differ among pediatric, adolescent/young adult (AYA), and adult patients, the fundamental treatment principles remain consistent across age groups. 1

Phase 1: Induction Therapy

The goal of induction is to rapidly reduce tumor burden by clearing as many leukemic cells as possible from the bone marrow to achieve complete remission. 1

Standard Induction Regimens:

• 4-drug backbone (BFM/COG regimens): Vincristine + anthracycline (daunorubicin or doxorubicin) + corticosteroid (prednisone or dexamethasone) + asparaginase 1

• 3-drug regimen for standard-risk pediatric patients: Vincristine + corticosteroid + asparaginase (without anthracyclines) 1

• 5-drug regimen (CALGB for AYA/adults): The above 4-drug combination plus cyclophosphamide 1

• T-ALL patients: Typically receive the 4-drug regimen 1

Corticosteroid Selection:

Dexamethasone significantly decreases isolated CNS relapse risk and improves event-free survival compared to prednisone, likely due to superior CNS penetration. 1 However, dexamethasone carries significant toxicities including osteonecrosis and infection, particularly at high doses (10 mg/m²/day), and no conclusive overall survival advantage has been demonstrated except in T-ALL patients with prednisone good response. 1 COG uses a dexamethasone schedule of 6 mg/m²/day for 28 days to balance efficacy and toxicity. 1

Age-Specific Modifications:

• Adults <65 years with Ph-negative ALL: Multiagent regimens based on vincristine, anthracyclines, corticosteroids, and L-asparaginase 2

• Adults ≥65 years or with substantial comorbidities: Low-intensity options (vincristine + prednisone or POMP) or moderate-intensity options (ALLOLD07, EWALL, GMALL, or GRAALL regimens) 2

Phase 2: Consolidation/Intensification Therapy

Consolidation therapy intensifies treatment after achieving remission to eliminate residual disease and prevent relapse. 2

Key Components:

• High-dose methotrexate 2
• Cytarabine 2
• Additional chemotherapy agents in various combinations 2
• Continued asparaginase administration 3

MRD-Guided Therapy:

Minimal residual disease (MRD) assessment at end of induction is the most critical prognostic factor. 3 MRD positivity at end of induction in B-ALL and end of consolidation in T-ALL predicts high relapse rates and should prompt evaluation for allogeneic hematopoietic cell transplantation (HCT). 1 Patients with MRD ≥0.01% require intensified therapy, while those with MRD <0.01% follow standard consolidation and maintenance. 3

Phase 3: Maintenance Therapy

Maintenance therapy continues for approximately 2-3 years total from diagnosis to prevent relapse. 3

Standard Maintenance Regimen:

• Daily oral mercaptopurine 2, 3
• Weekly oral methotrexate 2, 3
• Monthly vincristine pulses 2, 3
• Pulse dexamethasone 2, 3

Maintenance therapy with mercaptopurine and methotrexate is essential based on worse outcomes in patients where such maintenance was omitted. 4

CNS Prophylaxis (Integrated Throughout All Phases)

All treatment regimens for ALL must include CNS prophylaxis and/or treatment, as CNS involvement significantly impacts prognosis. 1

CNS-Directed Therapy Components:

• Intrathecal chemotherapy: Methotrexate, cytarabine, and dexamethasone (triple intrathecal therapy) beginning during induction and continuing throughout treatment 3

• Systemic high-dose methotrexate: Incorporated during consolidation phases 3

• CNS boost consideration: For patients with CNS involvement at relapse, consider CNS boost with total body irradiation (TBI); however, no clear evidence supports CNS boost for preventing subsequent CNS relapse in those without CNS involvement at relapse 1

Role of Hematopoietic Cell Transplantation

Indications for HCT in First Remission (B-cell ALL):

• Unfavorable cytogenetics (consider HCT for MLL/KMT2A mutation in infants <6 months with high-risk features) 1
• MRD ≥0.01% post-consolidation (week 9-12 from diagnosis) 1

Indications for HCT in Non-First Remission:

• Induction failure (M3 marrow): Recommend HCT after achieving MRD-negative status 1
• CR2: Consider HCT based on timing of relapse and leukemic phenotype 1
• CR3: Recommend HCT 1

Critical Pitfalls to Avoid

The role of HCT for patients with hypodiploid ALL in first remission has not been established, even in MRD-positive patients at end-induction. 1 This represents an area where clinical judgment must guide decisions in the absence of definitive evidence.

Treatment should be administered at specialized centers with expertise in ALL management given the complexity of therapy and need for intensive supportive care. 3