Acute leukaemia

Epidemiology

The incidence of acute leukaemia is 4-7 cases per 100 000. The peak incidence of acute lymphoblastic leukaemia (ALL) is 3-4 years and of acute myeloid leukaemia (AML) is over 60 years.

Aetiology

The cause of most cases is unknown. Some inherited diseases carry an increased risk:

♦ Fanconi's anaemia

♦ Bloom's syndrome

♦ Klinefelter's syndrome

♦ Ataxia telangiectasia

There is a 3-5 times increased risk in identical twins.

Environmental factors such as ionizing radiation, chemical carcinogens, or chemotherapeutic drugs, and infectious agents (e.g. T-cell leukaemia virus 1 in the Caribbean or Japan) or more subtle mechanisms such as exposure in the very young of naive immune systems to infections, have all been implicated as rare causes.

Diagnosis and classification

Peripheral blood pancytopenia is the commonest finding, but a minority have an elevated white blood cell count (WBC) which may be a clinical manifestation of anaemia, bleeding, or infection. There may be associated adenopathy or hepatosplenomegaly, which is more likely in lymphoid disease.

A marrow examination using morphology, immunophenotyping, and cytogenetics will allow classification into myeloid or lymphoid leukaemia, with morphological subtypes related to cell maturity (designated FAB 0-7 for myeloid and L1-3 for lymphoid disease). CNS infiltration can be a feature of ALL and requires a diagnostic lumbar puncture.

Acute lymphoblastic leukaemia (ALL)

ALL is the commonest cancer in children but is responsive to effective treatment, with a 70% cure rate. Adult disease responds less well, with only 30% long-term survivors.

Chemotherapy

Induction of remission is routinely achieved by combining vincri-stine, prednisolone, and L-asparaginase. Additional anthracycline is used in adults. Remission rates are 90-95% in children and a little less in adults. Initial response to treatment can predict outcome e.g. remission within two weeks has a favourable outlook whereas failure to gain remission by four weeks of chemotherapy predicts a poor prognosis. Such findings reflect the use of more sophisticated molecular methods.

Consolidation is a crucial phase during which exposure to new drugs (e.g. cyclophosphamide, thioguanine, cytosine arabinoside) is a key strategy as is clearance of the CNS as a sanctuary site. This may be achieved by CNS irradiation or MTX intra-thecally or in high-dose IV.

In high-risk cases there remains a 10% risk of CNS relapse and there are concerns about the long-term effects of different treatment modalities.

Maintenance

For about two years patients in remission continue on a cyclical schedule of methotrexate, 6 thioguanine, vincristine, and prednisolone.

Prognostic factors

♦ Adverse factors—male sex

—older age —age <1 year —high blast count —hypodiploidy

—Philadelphia chromosome positive

♦ Good prognostic factors—cure rate 50%

♦ Bad prognostic factors—cure rate 20%

Treatment of high-risk disease

Various approaches are in use for high-risk disease. Intensification in consolidation with cyclophosphamide or methotrexate in higher dosage has brought some success. Stem cell transplantation in first remission will cure 50% (allograft) or 30% (autograft)—but insufficient prospective comparisons with intensified conventional chemotherapy have been undertaken. When treatment fails, outcome depends on age and length of first remission. In children with long remissions, further chemotherapy may achieve salvage, for others stem cell transplant is indicated.

Acute myeloid leukaemia (AML)

In clinical practice, three factors will be taken into account in establishing the diagnosis:

♦ Acute promyelocytic leukaemia must be identified at diagnosis to ensure that retinoic acid is included in the treatment schedule.

♦ The clinical condition or performance score. It is now usual that patients under 60 years are given intensive treatment that may include stem cell transplantation. Older patients constitute the majority, and some patients are not considered suitable for intensive treatment and are offered a palliative approach.

Chemotherapy

Anthracycline and cytosine arabinoside, given over 7-10 days, has been the backbone of treatment for 30 years. The addition of a third drug (thioguanine or etoposide) is widely used, but there is little evidence that one or other is superior. There is recent interest in giving higher ara-C doses in induction but without definite evidence of benefit.

Successful induction depends on patient age (90% in children, 75% 50-60 years, 65% 60-70 years)—70-80% of all patients achieve complete response with the first course. Three or four further intensive courses incorporating other drugs (e.g. amsacrine, etoposide, idaru-bicin, mitoxantrone, and araC at higher doses) are usually given. It is not at present clear how many courses of consolidation is optimum. Older patients seldom tolerate more than two.

Maintenance treatment has become unfashionable—but may become of renewed interest for the elderly.

Prognostic factors

A number of characteristics can identify different risks of relapse and therefore survival. Most powerful of these are cytogenetics, patient age, and initial response of marrow blasts to treatment. Other factors are also important:

♦ High WBC on presentation

♦ Less cellular differentiation

♦ Leukaemia secondary to prior chemotherapy

♦ Myelodysplasia

Favourable cytogenetics are t(8:21), t(15:17), inv(16) that tend to be associated with young age and comprise about 25% of patients under 60 years. Adverse cytogenetics are abnormalities of chs 5 or 7 3q- or more complex abnormalities that tend to be more frequent in older patients and are associated with therapy-related leukaemia and prior MDS. A chemoresistance phenotype of P-glycoprotein overexpression occurs particularly in the elderly and is associated with a lower rate of remission and higher relapse risk.

Stem cell transplantation

If the patient is under 45 years and has an HLA-matched sibling, allo-geneic transplantation of blood or bone marrow stem cells will be considered. In good-risk patients this is only used when patients fail first-line treatment, but is given as consolidation in other groups.

Acute promyelocytic leukaemia

This is a separate entity having FAB-M3 morphology, the t(15:17) rearrangement creating the PML-RAR fusion gene. All-transretinoic acid (ATRA) used alone can induce remission by differentiation without hypoplasia but is not curative. Additional chemotherapy, either given with or subsequent to chemotherapy, remains essential. The level of the WBC at diagnosis is of key importance. Low count patients given ATRA and chemotherapy will have 80% survival. The 25% of patients who present with higher WBC have a high risk of early death and only 60% survival.

Autologous transplantation has been widely used to consolidate first remissions with results almost equivalent to allogeneic BMT. It is available to older patients (up to 60 years) and those without donors. It appears to be superior to chemotherapy, except in children, where it adds little.

Treatment outcome

Remission is achieved in 80% of patients under 60 years, and 60-65% of patients over 60 years. Survival is age-related and will depend on prognostic factors. Most patients will relapse, but the patient's age, length of first CR, and initial cytogenetic risk group will dictate outcome. If first remission is short and cytogenetics are not favourable in older patients, the outlook is grave.

Future prospects

AML is a heterogenous disease and it is likely that subtypes require risk-directed therapy. Arsenic compounds may find a role in AML; there will be refinements in the techniques of stem cell transplantation; and immunologically based approaches will be evaluated. The disease in the elderly remains a major challenge. It must be established which patients benefit from an intensive approach and improved nonintensive treatment is needed. Modulation of molecular resistance is theoretically possible and will be evaluated in the next few years.

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