Basic Sciences
Before the advent of immunohistochemistry, lymphoblastic leukaemias were given a morphological classification - L1 (small round blue cells), L2 (increased cytoplasm, nucleioli) and L3 (mature-appeariang cells). This classification was thought to carry prognostic significance but with the exception of L3 disease (which is consistent with advanced stage Burkitt lymphoma) it is no longer used to determine therapy.
Immunohistochemistry has allowed the distinction of precursor B and T cell leukaemia, consistent with transformation at particular stages of lymphocyte development. Precursor B cell leukaemias are most common (80-85%), followed by precursor T cell leukaemia (10-15%). Rare forms include early pre-T cell leukaemia and mature B cell leukaemia, both associated with worse prognosis.
Cytogenetics have allowed further stratification of the precursor B cell leukaemias; the presence of any translocation (eg. BCR/ABL gene fusion known as Philadelphia chromosome) is associated with poorer prognosis.
Diagnosis
Patients are usually children; B cell leukaemia presents earlier than T cell leukaemia in general. Patients usually present with vague symptoms with no apparent cause (eg. fever, bleeding, aches/pains or lymphadenopathy). Less common presentations include those specific to extramedullary sites - CNS involvement may lead to headaches, nausea and vomiting; testicular involvement may lead to orchidomegaly.
Diagnosis may be confirmed on peripheral blood examination but bone marrow biopsy is almost always required.
Management
Initial supportive care to correct any abnormalities in full blood count or electrolyte disturbance is essential. Some patients may develop effusions (eg. pleural or pericardial) that may require drainage. Treatment of the leukaemia is divided into induction, consolidation and maintenance periods. Radiotherapy is often incorporated in high risk disease either for CNS prophylaxis or as total body irradiation as a component of allogenic haematopoietic stem cell transplantation.
Chemotherapy
Induction Therapy
Regardless of the type of leukaemia, the initial goal of treatment is to induce remission. This is usually easy to achieve using vincristine, steroid, asparaginase and occasionally additional cytotoxics for higher risk disease.
About 5% of patients fail induction (ie. morphologically detectable disease in bone marrow or peripheral blood). This is a very poor prognostic feature requiring intensification of therapy.
Consolidation Therapy
After successful induction, patients go on to receive 6 months of ongoing intensive therapy aimed at eliminating subclinical disease. This usually involves methotrexate at high dose, asparaginase, and 6-mercaptopurine.
Maintenance Therapy
Maintenance therapy continues for 2 years after diagnosis, usually as weekly methotrexate and 6-mecraptopurine. This treatment eliminates slowly dividing cells which may have escaped the intensive period of treatment.
Radiotherapy
Prophylactic CNS treatment
Relapse in the central nervous system is a common event without prophylactic therapy. In the past, craniospinal irradiation was used, but this was associated with long term neurocognitive and malignant complications. This has been largely replaced by intrathecal methotrexate. Radiotherapy is indicated for:
- Patients with high risk (WCC > 100) T cell leukaemia
- Patients with B cell leukaemia and elevated minimal residual disease (> 0.1%) at end of induction
The typical dose is 12 Gy in 6 fractions delivered to the brain only. Intrathecal methotrexate provides sufficient treatment to the spinal cord.
CNS Leukaemia
About 5% of patients present with CNS leukaemia (positive CSF cytology, WCC > 5, also called 'CNS 3'). These patients all require cranial radiotherapy; again, intrathetcal methotrexate is sufficient to treat the spinal cord. This treatment is delivered at the end of consolidation (6 months post diagnosis). Unlike prophylactic treatment, a total dose of 18 Gy is used (1.5-1.8 Gy #)
CNS Relapse
Isolated relapse in the CNS occurs in < 5% of patients, requiring re-induction chemotherapy as well as radiotherapy. For those relapsing after 18 months, cranial irradiation is sufficient (18 Gy in 1.5 Gy #). Early relapse requires craniospinal irradiation (24 Gy to cranium, 15 Gy to spine).
