Leukaemia, lymphoma and myeloma constitute only a small proportion of all malignant diseases. They share common origins in the myeloproliferative and lymphoproliferative systems but are a heterogeneous group, with a natural history resulting in survival ranging from a few months to several years. Their importance lies in their responsiveness to both chemotherapy and radiotherapy, so that many patients with acute leukaemia, Hodgkin’s disease, and high grade non-Hodgkin’s lymphoma, can now be cured. However, the majority of patients with haematological malignancy still die as a consequence of the illness, it is therefore essential to explain the disease, its treatment and the chance of success to the patient and to the family.
Leukaemia is rare, with an annual overall incidence of 5 per 100000. Both subtypes of acute leukaemia can occur in all age groups but acute lymphoblastic leukaemia (ALL) is predominantly a disease of childhood, whereas acute myelogenous leukaemia (AML) is most frequently seen in older adults.
In the majority of cases, the aetiology is unknown. Feline leukaemia virus has been shown to cause the disease in cats; there is, however, no evidence for a viral aetiology in humans apart from the association of a specific subtype of T-cell leukaemia, found predominantly in the Southern Island of Japan and the Caribbean, with the retrovirus HTLV-l. However, many people in the endemic areas have antibodies to the virus, implying past infection, but may never develop leukaemia.
Many patients with acute leukaemia have a chromosomal abnormality. When complete remission (CR) is achieved, the chromosomal translocation/deletion often becomes undetectable, but returns at recurrence. Such a cytogenetic change usually implies a worse prognosis but not always: 99% of patients with acute promyelocytic leukaemia (APML) have the (15;17) translocation; the latter and the t(8;21) translocation in AML in fact confer a better long-term prognosis once CR has been achieved.
The first non-random chromosomal abnormality to be described was the Ph chromosome which is associated in 95% of cases with chronic myeloid leukaemia (CML). The Ph chromosome is also found in some patients with ALL, the incidence in the latter increasing with age. The translocation is shown schematically. The Ph chromosome is an abnormal chromosome 22, resulting from a reciprocal translocation between part of the long arm of chromosome 22 and chromosome 9. The resulting karyotype is described as t(9;22)(q34;qll). The molecular consequences of the translocation have been defined as follows: the oncogene C-ABL) normally present on chromosome 9 is translocated to chromosome 22, where it comes into juxtaposition with a region of chromosome 22 named the ‘breakpoint cluster region’ (BCR). The translocation thus creates a hybrid transcription unit consisting of the 5′ end of the BCR gene and the C-ABL proto-oncogene. The new gene is capable of being expressed as a chimeric mRNA which has been identified in cells from patients with CML. When translated, this produces a fusion protein that has tyrosine kinase activity and enhanced phosphorylating activity compared to the normal C-ABL protein. The contribution of these molecular events to the disease process is at present unclear. The precise breakpoint differs in CML and Ph-positive ALL, leading to the production of two different tyrosine kinase proteins.
1 Chemicals, e.g. benzene compounds used in industry.
2 Drugs, e.g. cytotoxic agents such as chlorambucil and procarbazine.
3 Radiation-the evidence for radiation causing leukaemia comes from three sources:
(a) The atomic bombs exploded in Hiroshima and Nagasaki resulted in an increased incidence of both AML and, in particular, CML in people living in surrounding areas. There is therefore concern about the population living round Chernobyl.
(b) In the past, patients with ankylosing spondylitis were treated with radiotherapy, leading to an increased incidence of secondary AML.
(c) A small proportion of patients with Hodgkin’s disease receiving (usually) both chemotherapy and radiotherapy will develop secondary AML. Unlike de novo AML which is potentially curable, AML developing in relation to previous cytotoxic chemotherapy is nearly always resistant to treatment.
Leukaemia can be divided on the basis of the speed of evolution of the disease into acute or chronic. Each of these is then further subdivided into myeloid or lymphoid, according to the cell type involved, hence the terms:
• Acute myelogenous leukaemia
• Acute lymphoblastic leukaemia
• Chronic myeloid leukaemia
• Chronic lymphocytic leukaemia
ACUTE LEUKAEMIA (AML and ALL)
The symptoms of acute leukaemia are a consequence of bone marrow failure:
• Symptoms of anaemia, e.g. tiredness, weakness, shortness of breath on exertion
• Repeated infections, e.g. sore throat, pneumonia
• Bruising and/or bleeding
• Occasionally, lymph node enlargement and/or symptoms relating to enlargement of the liver and spleen There may be few or no signs; commonly patients have:
• Signs of anaemia
• Bruises, petechial haemorrhages, purpura, fundal haemorrhages
• Signs of infection
• Sometimes peripheral lymphadenopathy and/or hepatosplenomegaly
The definitive diagnosis is made on the peripheral blood film and a bone marrow aspirate. Additional investigations such as cytogenetic analysis and immunophenotyping of the leukaemic blast cells are not mandatory but can be helpful. If the patient has a fever, blood cultures and a chest X-ray are essential.
A low haemoglobin (Hb).
White cell count (WCC) usually raised, but can be decreased or normal.
Platelets usually reduced.
PERIPHERAL BLOOD FILM shows characteristic leukaemic blast cells.
BONE MARROW ASPIRATE usually shows increased cellularity with a high percentage of abnormal lymphoid or myeloid blast cells.
The decision to treat a patient with curative intent will depend on the person’s age, their general state of health, the point in the course of the illness (presentation or recurrence), and the person’s wishes. The use of intensive combination chemotherapy may, for example, be entirely inappropriate at the time of recurrence in an older person.
The diagnosis, its implications, the treatment options and the likely outcome of such treatment, together with its side-effects, need to be explained to the patient and to the family. People often find it difficult to assimilate all of this information on one occasion; it is therefore essential to give them the opportunity to ask questions, particularly as circumstances change. Before starting treatment, the following need to be considered:
CORRECTION OF ANAEMIA AND THROMBOCYTOPENIA by administration of blood and platelets.
TREATMENT OF INFECTION with intravenous antibiotics.
LEUKAEMIC BLAST CELLS can infiltrate the brain and the lungs resulting in coma and respiratory failure respectively. If the blast cell count in the peripheral blood is very high (>100 x 109/litre) the patient may need leucophoresis (i.e. blood is collected from a vein and centrifuged so as to remove some of the leukaemic cells; the red cells and plasma are then returned to the patient via another vein). Leucophoresis can be life saving; an alternative is to use high doses of the drug hydroxyurea.
ADMINISTRATION OF ALLOPURINOL, a xanthine oxidase inhibitor to treat and prevent hyperuricaemia. In certain types of leukaemia where the rate of cell division is very fast, e.g. B-ALL, T-ALL, patients may develop the ‘tumour lysis’ syndrome when chemotherapy is given. The latter is characterized by hypercalcaemia and high serum levels of phosphate and potassium resulting from a high rate of cellular breakdown. This is a potentially life-threatening situation and difficult to treat once it has happened. It can usually be prevented by making sure that chemotherapy is not given whilst the uric acid level is high, by giving intravenous fluids before starting chemotherapy and monitoring the relevant biochemical parameters at regular intervals. Patients may require haemodialysis to correct the metabolic imbalance. Specific treatment programmes for the different subtypes of leukaemia will be mentioned only briefly since treatment regimens are evolving. Good ‘supportive care’ in terms of antibiotics and blood products is as important as the specific combination of drugs used; patients with acute leukaemia should therefore be treated in specialist centres where the medical and nursing staff are familiar with the management of neutropenia and thrombocytopenia.
Patients need to be informed of what is going on as the situation changes.
Acute myelogenous leukaemia
AML is a potentially curable disease. The aim of treatment is to restore the bone marrow to normal and the patient to a normal state of health, i.e. complete remission (CR). AML is classified on the basis of the morphological appearance of the bone marrow into seven subtypes, FAB M1-M7, which differ depending on the predominant cell type involved.
Treatment has traditionally been regarded in two parts:
remission/induction and postremission/consolidation therapy. The rationale for going on with treatment beyond the point of CR is based on data from an experimental mouse model (L1210 leukaemia) and from children with ALL in whom it has been calculated that, at the time of presentation, the number of leukaemic blast cells is of the order of 1012 or 1013.At the point of CR, i.e. when there is no morphologically detectable leukaemia, there are still 108 or 109 leukaemic blast cells present. It is therefore not surprising that if no postremission therapy is given, the majority of patients develop recurrent leukaemia.
Remission/induction therapy usually includes an anthracycline drug such as daunorubicin or doxorubicin, given in conjunction with cytosine arabinoside. The first cycle of treatment is given in hospital; the patient needs to stay for about 4 weeks due to the risk of infection and bleeding consequent upon neutropenia and thrombocytopenia. Subsequent cycles of treatment are given as much as possible on an outpatient basis. There is much debate as to the best postremission therapy. Alternatives include:
• Further cycles of chemotherapy which is the same as that given to induce remission
• Chemotherapy different from that given to induce remission
• Myeloablative therapy with allogeneic/autologous bone marrow transplantation (BMT).
With modern combination chemotherapy, approximately -0% of younger people (aged <60 years) would be expected to return to normal health. However, within 1- 3 years, the disease will recur in at least 60% of the latter, the remainder almost certainly having been cured. In general, treatment has become more intensive over the last _0 years with a concomitant improvement in overall suviral. Survival curves for patients treated at St Bartholomew’s Hospital during three consecutive time periods are shown.
Following recurrence, it is possible to give further treatment in an attempt to induce secondary remission but such remissions are rarely durable, hence the use of very intensive treatment involving BMT.