Overview
Definition:
Acute Lymphoblastic Leukemia (ALL) is a heterogeneous lymphoid malignancy characterized by the uncontrolled proliferation of immature lymphoid precursor cells (lymphoblasts) in the bone marrow, peripheral blood, and other organs
It is the most common childhood cancer and a significant cause of cancer-related mortality in children
Risk stratification is crucial for tailoring treatment intensity and intensity, while Central Nervous System (CNS) prophylaxis aims to prevent or treat leukemic infiltration of the CNS.
Epidemiology:
ALL accounts for approximately 25% of all pediatric cancers
The incidence peaks between 2 and 5 years of age
While common in children, it can also occur in adolescents and adults
Incidence rates vary geographically, with higher rates observed in developed countries
Certain genetic syndromes like Down syndrome and Li-Fraumeni syndrome are associated with an increased risk of ALL.
Clinical Significance:
Accurate risk stratification guides therapeutic decisions, balancing the need for intensive treatment to achieve cure with minimizing treatment-related toxicity
CNS involvement in ALL is a major challenge, as the CNS is a sanctuary site for leukemic cells, leading to relapse if not adequately treated
Effective CNS prophylaxis is paramount to improving long-term outcomes and preventing life-threatening neurological complications.
Risk Stratification
Initial Risk Factors:
Age at diagnosis (infants and older children have poorer prognosis)
White blood cell count at diagnosis (<50,000/µL is favorable, >50,000/µL is unfavorable)
Cytogenetics and molecular abnormalities (e.g., Philadelphia chromosome, hypodiploidy, hyperdiploidy, MLL rearrangements)
Immunophenotype (B-ALL vs
T-ALL)
Presence of extramedullary disease
Initial response to therapy (day 7/15 blast reduction).
Risk Groups Classification:
Standard-risk, High-risk, Very high-risk
These categories are defined by specific combinations of the initial risk factors and early treatment response
For example, infants with ALL often fall into a very high-risk category
Patients with specific high-risk cytogenetic abnormalities like t(9;22) (BCR-ABL) are also classified as high-risk
Early achievement of MRD (Minimal Residual Disease) negativity is a key determinant of response and prognosis.
Molecular And Genetic Markers:
High-resolution genomic studies are increasingly important
Key markers include Philadelphia chromosome (BCR-ABL1 fusion gene), KMT2A (MLL) rearrangements, ETV6-RUNX1 fusion, TCF3-PBX1 fusion, iAMP21, and ploidy status (hypodiploid, diploid, hyperdiploid)
These markers significantly influence treatment protocols and outcomes.
Minimal Residual Disease Mrd:
MRD assessment by flow cytometry or PCR is a critical component of risk stratification and treatment response monitoring
MRD negativity at specific time points (e.g., end of induction, after consolidation) indicates a favorable prognosis and may allow for de-escalation of therapy in some protocols
Persistent MRD is a strong predictor of relapse.
Central Nervous System Prophylaxis
Rationale For Cns Prophylaxis:
The CNS is a sanctuary site for leukemic cells, meaning standard systemic chemotherapy may not reach adequate concentrations in the cerebrospinal fluid (CSF)
Untreated CNS leukemia leads to high rates of relapse and significantly poorer survival
Prophylaxis aims to eradicate or prevent leukemic infiltration of the brain and meninges.
Methods Of Cns Prophylaxis:
Intrathecal (IT) chemotherapy: administration of cytotoxic agents directly into the CSF via lumbar puncture or Ommaya reservoir
Systemic chemotherapy: certain agents like high-dose methotrexate can achieve therapeutic CSF levels
Cranial radiation therapy (CRT): historically used, now reserved for high-risk cases or established CNS disease due to long-term neurocognitive sequelae, particularly in young children.
Agents And Dosing:
Commonly used IT agents include methotrexate (MTX), cytarabine (Ara-C), and corticosteroids (e.g., hydrocortisone)
Standard IT methotrexate dose for prophylaxis in children is typically 10-12 mg in infants and 12-15 mg in older children, administered every 1-4 weeks depending on the treatment phase and risk group
Doses are adjusted based on age and weight
Systemic high-dose methotrexate (HD-MTX) protocols also contribute to CNS control.
Timing And Frequency:
CNS prophylaxis is initiated early in treatment, often during induction chemotherapy, and continues throughout the multi-phase treatment course (induction, consolidation, interim maintenance, delayed intensification, maintenance)
Frequency varies by risk group and treatment phase, typically administered monthly or bi-monthly during maintenance
For very high-risk patients or those with CNS involvement at diagnosis, it may be given more frequently.
Cns Prophylaxis In Specific Scenarios
High Risk Patients:
Patients classified as high-risk or very high-risk receive more intensive CNS prophylaxis, often with more frequent IT chemotherapy, potentially higher doses, or addition of other agents
Systemic HD-MTX is a cornerstone for many high-risk protocols.
Patients With Cns Leukemia At Diagnosis:
Patients presenting with symptomatic CNS leukemia (e.g., cranial nerve palsies, seizures, increased intracranial pressure) require therapeutic intrathecal chemotherapy
This often involves more aggressive protocols, including multiple IT injections, sometimes combined with systemic chemotherapy and potentially cranial irradiation in select cases
Response is monitored by CSF cytology.
Infants And Young Children:
Special considerations are given to infants (<1 year) and very young children due to increased susceptibility to neurotoxicity from IT chemotherapy and especially cranial radiation
Protocols aim to minimize or avoid CRT
Lower doses of IT agents and careful monitoring for adverse effects are employed
Some protocols utilize systemic agents with good CNS penetration.
Complications Of Cns Prophylaxis
Neurotoxicity:
Common side effects include chemical meningitis (headache, nausea, vomiting, back pain after lumbar puncture), arachnoiditis (inflammation of the arachnoid mater causing neurological deficits), cranial nerve palsies, and seizures
Long-term sequelae from repeated IT chemotherapy and especially cranial radiation can include cognitive impairment, learning disabilities, endocrine dysfunction, and secondary malignancies.
Leukoencephalopathy:
With high-dose systemic methotrexate and cranial radiation, leukoencephalopathy (damage to the white matter of the brain) can occur, leading to neurological deficits
This is more common with combined modality treatment.
Infection:
Immunosuppression from chemotherapy and the invasive nature of lumbar punctures increase the risk of CNS infections, including bacterial and viral meningitis, and cerebral abscesses.
Prevention And Management:
Dose adjustments, careful monitoring of CSF cytology, serial neurological assessments, and judicious use of cranial radiation are key
Prompt management of side effects, including hydration and supportive care for chemical meningitis, and close follow-up for long-term neurocognitive function are essential.
Key Points
Exam Focus:
Understand the criteria for risk stratification (age, WBC, cytogenetics, MRD)
Recall the agents, doses, and routes of CNS prophylaxis (IT MTX, Ara-C, steroids)
Differentiate between CNS prophylaxis and CNS therapy
Recognize the importance of MRD in treatment response and prognosis
Be aware of the long-term toxicities, particularly neurocognitive deficits from cranial radiation.
Clinical Pearls:
Always assess for CNS involvement in ALL at diagnosis
Ensure proper technique for lumbar puncture to minimize complications
Monitor for signs of neurotoxicity closely, especially in younger children
Discuss the implications of treatment toxicity with parents
Embrace the evolving landscape of targeted therapies and immunotherapy in ALL treatment.
Common Mistakes:
Overlooking CNS prophylaxis in standard-risk patients
Underestimating the risk of CNS relapse in certain genetic subsets
Inadequate monitoring of MRD
Prescribing cranial radiation without strict indication due to long-term sequelae
Misinterpreting CSF cytology findings in the context of IT chemotherapy administration.