Describe the current standard of care for acute lymphoblastic leukaemia (ALL) in adults and children.

Current Standard of Care for Acute Lymphoblastic Leukaemia (ALL)

The standard of care for ALL involves a multi-phase, intensive treatment regimen designed to achieve complete remission, eradicate residual leukemia cells, and prevent relapse. While the overarching principles are similar, significant differences exist in treatment intensity, specific agents, and duration between pediatric and adult protocols due to varying disease biology, tolerance to therapy, and prognostic factors.

Treatment Phases in ALL

Standard ALL treatment typically follows distinct phases:

• Steroid Pre-phase (Optional): A short course of steroids (e.g., prednisolone, dexamethasone) to reduce tumor burden quickly, often preceding chemotherapy.
• Induction Therapy: The initial intensive phase aimed at achieving complete remission (no detectable leukemia cells in bone marrow or blood). This usually lasts 4-6 weeks.
• Consolidation/Intensification Therapy: Follows induction, designed to eliminate any remaining leukemia cells (minimal residual disease, MRD) and prevent relapse. This phase involves multiple cycles of different chemotherapy drugs. In some protocols, this may include "interim maintenance" and "delayed intensification."
• Maintenance Therapy: A longer, less intensive phase (typically 2-3 years) to sustain remission and prevent recurrence. This often involves oral chemotherapy and intermittent intravenous treatments.
• Central Nervous System (CNS) Prophylaxis/Treatment: Administered throughout treatment to prevent or treat the spread of leukemia cells to the brain and spinal cord, typically via intrathecal chemotherapy and/or cranial radiation.

Standard of Care in Children

Children with ALL generally have a better prognosis and higher cure rates compared to adults. Treatment protocols are highly risk-adapted, based on factors such as age, initial white blood cell count, immunophenotype, cytogenetics, and early response to therapy (MRD status).

Key Components of Childhood ALL Treatment:

• Chemotherapy: This is the cornerstone of treatment and often involves a combination of drugs such as vincristine, corticosteroids (prednisone or dexamethasone), asparaginase (e.g., pegaspargase), and anthracyclines (e.g., daunorubicin, doxorubicin). High-risk groups may receive additional drugs like cyclophosphamide, cytarabine, and etoposide. Methotrexate and 6-mercaptopurine (6-MP) are crucial in consolidation and maintenance phases.
• Targeted Therapy: For children with Philadelphia chromosome-positive (Ph+) ALL, tyrosine kinase inhibitors (TKIs) like imatinib or dasatinib are integrated into chemotherapy regimens, significantly improving outcomes.
• Immunotherapy: Newer immunotherapies, such as blinatumomab (a bispecific T-cell engager antibody targeting CD19) and CAR T-cell therapy (e.g., tisagenlecleucel), are increasingly used for relapsed/refractory B-cell ALL and are being investigated in frontline settings for high-risk patients.
• Stem Cell Transplant (SCT): Allogeneic stem cell transplantation may be considered for children with high-risk ALL, those with poor response to initial therapy, or those who relapse, particularly in specific subtypes like T-cell ALL or Ph+ ALL not responding to TKIs.
• CNS Prophylaxis: Intrathecal chemotherapy (methotrexate, cytarabine, or hydrocortisone) is standard. Cranial radiation therapy is now less frequently used but may be considered in very high-risk cases or for CNS relapse.

Standard of Care in Adults

Adult ALL presents greater challenges due to more aggressive disease biology, higher rates of adverse genetic features (e.g., Philadelphia chromosome), and reduced tolerance to intensive chemotherapy, especially in older patients. Adult regimens often mimic pediatric-inspired protocols for younger adults (15-39 years) to improve outcomes.

Key Components of Adult ALL Treatment:

• Chemotherapy: Regimens are typically very intensive and include agents like vincristine, corticosteroids (dexamethasone), anthracyclines (daunorubicin, doxorubicin), cyclophosphamide, and asparaginase. High-dose methotrexate and cytarabine are common in consolidation. Maintenance therapy is similar to pediatric protocols but may be adapted for adult tolerance.
• Targeted Therapy: TKIs (imatinib, dasatinib, ponatinib) are essential for Ph+ ALL in adults, combined with chemotherapy or, in some cases, blinatumomab. They have revolutionized the prognosis for this subtype.
• Immunotherapy:
  • Blinatumomab: Approved for CD19-positive B-cell precursor ALL, particularly in minimal residual disease (MRD)-positive patients in remission, or for relapsed/refractory disease.
  • Inotuzumab Ozogamicin: An antibody-drug conjugate targeting CD22, used for relapsed/refractory B-cell ALL.
  • CAR T-cell Therapy: Tisagenlecleucel and other CAR T-cell therapies are approved for relapsed/refractory B-cell ALL and are being explored in earlier lines of therapy.
• Stem Cell Transplant (SCT): Allogeneic SCT is a critical treatment option for many adult ALL patients, particularly those with high-risk features, Ph+ ALL who achieve remission with TKI therapy, or those experiencing relapse. It aims for a deeper and more durable remission.
• CNS Prophylaxis: Intrathecal chemotherapy is standard, and high-dose systemic chemotherapy (e.g., methotrexate, cytarabine) that penetrates the CNS is also used.

Comparative Overview of ALL Treatment

The table below highlights key differences in the standard of care between children and adults with ALL:

Feature	Children with ALL	Adults with ALL
Prognosis	Generally excellent (5-year survival ~90%)	Less favorable (5-year survival ~30-40% overall, better for younger adults)
Chemotherapy Intensity	High, generally well-tolerated. Pediatric-inspired regimens for young adults.	Very intensive, higher toxicity, especially in older adults. Dosage reduction often required for older patients.
Ph+ ALL Treatment	TKI + Chemotherapy	TKI + Chemotherapy (often less intense) or Blinatumomab
Immunotherapies	Blinatumomab, CAR T-cell therapy primarily for relapsed/refractory, increasingly in high-risk frontline.	Blinatumomab, Inotuzumab Ozogamicin, CAR T-cell therapy for relapsed/refractory, and increasingly integrated into frontline.
Stem Cell Transplant	For high-risk, poor responders, or relapse.	More frequently considered, especially for high-risk or Ph+ ALL in first remission, or for relapse.
Risk Stratification	Sophisticated genetic and MRD-based stratification guides treatment intensity.	Similar, but with a higher prevalence of adverse genetic features (e.g., Ph-like ALL, Ph+ ALL) impacting stratification.

Recent Advances and Future Directions

Recent years have seen a revolution in ALL treatment, particularly with the advent of targeted therapies and immunotherapies.

• Minimal Residual Disease (MRD) Monitoring: Highly sensitive techniques to detect residual leukemia cells after treatment are crucial for guiding therapeutic decisions, risk stratification, and early intervention for impending relapse.
• Novel Targeted Agents: Beyond TKIs, new agents targeting specific genetic alterations (e.g., BCL-2 inhibitors like venetoclax for ETP-ALL) are under investigation.
• CAR T-cell Therapy Expansion: Chimeric Antigen Receptor (CAR) T-cell therapy is being explored in earlier lines of treatment and for more ALL subtypes.
• Less Toxic Regimens: Efforts are ongoing to integrate immunotherapies and targeted agents to reduce reliance on highly cytotoxic chemotherapy, especially for older and frail patients.