1 Blood count and film

The white cell count may be raised, normal or low. Only 20% have white cell counts greater than 50 × 10⁹/L. Anaemia and thrombocytopenia are common. The proportion of blast cells in the white cell count varies from 0% to 100%.

2 Bone marrow aspirate and trephine

This is essential to confirm the diagnosis and for classification.

3 Cytochemistry

Stains which classically show positivity in AML – Sudan black and myeloperoxidase – are negative in ALL. Cytochemistry is useful in distinguishing precursor B and B-ALL from T-ALL. Reactivity with the acid phosphatase stain is seen in malignant T-lymphocytes but not in B-cells which may show periodic acid Schiff (PAS) block positivity.

4 Immunophenotyping

Useful reagents for establishing the diagnosis and identifying the immunological subtype include antibodies to CD19, CD79A and CD22 (found in most B-lineage ALLs), CD10 (the ‘common ALL antigen’), CD3 and CD7 (found in T-lineage ALLs).

5 Cytogenetics

Cytogenetic analysis is doubly useful as structural abnormalities correlate with particular subtypes of ALL and both structural and numerical abnormalities give prognostic information (see Table 21.2). Varying patterns of cytogenetic abnormality may partly explain the different prognosis in children and adults. The Philadelphia chromosome, regarded as a marker of ‘incurability’ by chemotherapy, is found in 20–30% of adult cases but in only 2% of children.

6 Molecular techniques

Molecular analysis yields complementary and additional information to conventional cytogenetics (see Table 21.2). The cryptic t(12;21) creates a TEL-AML1 (ETV6-RUNX1) fusion gene – this is the commonest genetic rearrangement in childhood ALL and it can only be detected by molecular techniques. Although not yet routinely available in most laboratories, global gene expression profiling reveals distinct patterns in specific subtypes of ALL (see p. 100).

General principles

Patients with ALL require supportive care. Chemotherapy is the mainstay of treatment. Drug schedules vary but remission induction classically relies on three agents: vincristine, a glucocorticoid (e.g. prednisolone) and asparaginase. The anthracycline daunorubicin may be included in the induction regimen and other drugs, notably methotrexate, cyclophosphamide and cytosine arabinoside, then added in ‘intensification’ (‘consolidation’) (see p. 54 for more detail of individual drugs). The rationale for early intensification of treatment is to reduce the leukaemic cell population quickly and reduce the likelihood of drug resistance. Therapy is usually completed with a period of ‘maintenance’ using methotrexate and mercaptopurine. The greater chance of CNS disease in ALL (than in AML) necessitates prophylactic treatment to prevent CNS relapse. The usual method is intrathecal and systemic chemotherapy with the possible addition of cranial irradiation in those at highest risk.

The ultimate choice of management is influenced by a number of prognostic factors which have changed with improving treatment (Table 21.3). Where clinical and laboratory features predict a poor response to chemotherapy alone, more intensive treatments such as allogeneic stem cell transplantation (SCT) are considered. Of all the prognostic indices the most influential is age.

ALL in children

The majority of children are curable with current chemotherapy regimens. The standard strategy is intensive induction therapy, CNS prophylaxis, and maintenance treatment for 2–2.5 years. In children receiving the most intensive protocols, 5-year disease-free survivals of nearly 90% are now achievable. Autologous and allogeneic SCT is best reserved for relapse after chemotherapy or for patients with poor prognostic features. New methods for detecting minimal residual disease during treatment (e.g. after induction) allow early identification of patients at high risk of relapse. Mature B-ALL is a special case best treated with short-term fractionated intensive chemotherapy. With improved cure rates the long-term side-effects of the drugs, including endocrine problems, secondary leukaemia and cardiotoxicity, are becoming increasingly relevant. Wherever feasible, the use of agents with the safest profiles is desirable.

ALL in adults

The majority of adult patients enter remission but are not curable with chemotherapy alone and less than 40% will become long-term survivors. Most chemocurable patients are aged between 16 and 25 years with other good prognostic features. This ‘good risk’ subgroup resembles childhood ALL and chemotherapy alone is a reasonable initial policy with cure rates of around 75%. For adults with higher-risk disease the hope of cure is likely to depend on even more intensive therapy with either autologous or allogeneic SCT. Allogeneic SCT from an HLA-matched family donor performed in first remission gives long-term survival of around 50%. SCT using an unrelated HLA-’matched’ donor is more risky but can be successful. In Philadelphia chromosome positive ALL the tyrosine kinase inhibitor imatinib is useful adjunctive therapy (see p. 45). Optimum management of adult ALL has yet to be defined and there is a need for careful consideration of all the known prognostic factors in each case. More elderly patients (over 60 years) tolerate chemotherapy less well and cure rates are very low. In these cases it is often kinder to concentrate on palliation of symptoms and provision of a short period of good quality life rather than undertaking aggressive chemotherapy with a negligible chance of success.