Haematological malignancies account for only 5% of all cancers; of these, CLL is the most common form of leukaemia. UK incidence data are presented in Table 50.1. CLL mainly affects an older age group: 90% of patients are over the age of 50 and nearly two-thirds are over 60 years old at diagnosis. It rarely occurs in young people and is twice as common in men as in women. CML is primarily a disease of middle age with the median onset in the 40–50 year old age group, but it can occur in younger people.

Table 50.1 Incidence of leukaemia in the UK (Leukaemia and Lymphoma Research, 2010)

	New cases/year	Incidence per 100,000 of the population
CLL	2750	4.58
CML	750	1.5
ALL	650	1.00
AML	1950	3.25

Acute leukaemia is rare, with a total annual incidence of approximately 4 per 100,000 population. The more common form of the disease is AML, which accounts for 75% of cases. The incidence of AML rises steadily with age, occurring only rarely in young children. In contrast, ALL is predominantly a childhood disease, with the peak incidence in the 3–5 year age group, and is the most common childhood cancer.

Aetiology

In common with other cancers, the aetiology of leukaemia is not fully understood. Leukaemia is thought to result from a combination of factors that induce genetic mutations which allow mutated cells to proliferate faster than normal cells and/or to fail to die in response to normal apoptotic signals. Epidemiological studies have, however, identified a number of specific risk factors for the development of leukaemia, which are described as follows.

Radiation

The association between the ionising radiation and the development of leukaemia is evident from nuclear disasters such as Hiroshima and more recently Chernobyl. Long-term follow-up of survivors of Nagasaki and Hiroshima has shown an increase in all forms of leukaemia other than CLL. The link is also apparent for patients who received radiotherapy for the treatment of malignant and non-malignant conditions such as Hodgkin’s disease or ankylosing spondylitis. The effect of chronic low-level exposure to radiation is less certain.

Exposure to chemicals and cytotoxic drugs

There is a small but definite risk of acute leukaemia occurring in patients successfully treated for other malignancies with cytotoxic and immunosuppressive agents. The combination of chemotherapy, especially alkylating agents such as cyclophosphamide and radiotherapy, presents the highest risk. This has practical implications as an increasing number of patients achieve a ‘cure’ as a result of combination therapy, while occupational exposure of health professionals to these agents is also an area of concern. Occupational exposures to paint, insecticides and solvents, in particular, the aromatic solvent benzene, have all been associated with the development of leukaemia, but it is difficult to be certain whether such exposures genuinely cause the disease.

Viruses

Human T-cell lymphotrophic virus, an RNA retrovirus endemic in Japan and the West Indies, has been linked to a rare T-cell leukaemia/lymphoma.

Genetic factors

Down’s syndrome, constitutional trisomy of chromosome 21, is associated with an increased risk of leukaemia. Disorders that predispose to chromosomal breaks such as Fanconi’s anaemia and ataxia telangectasia are also associated with an increased risk of developing acute leukaemia. These alterations may permit the expression of oncogenes, which promote malignant transformation.

Haematological disorders

Many patients with other haematological disorders have a greatly increased risk of developing leukaemia, particularly AML. These disorders include the myelodysplastic syndromes, the non-leukaemic myeloproliferative disorders, aplastic anaemia and paroxysmal nocturnal haemoglobinuria.

Pathophysiology

In leukaemia, the normal process of haemopoiesis is altered (Fig. 50.1). Transformation to malignancy appears to occur in a single cell, usually at the pluripotential stem cell level, but it may occur in a committed stem cell with capacity for more limited differentiation. Accumulation of malignant cells leads to progressive impairment of the normal bone marrow function.

Fig. 50.1 Haemopoiesis.

Acute leukaemias

In acute leukaemia, the normal bone marrow is replaced by a malignant clone of immature blast cells derived from the myeloid (in AML) or lymphoid (in ALL) series. More than 20% of the cellular elements of the bone marrow are replaced with blasts. This is usually associated with the appearance of blasts in the peripheral circulation accompanied by worsening pancytopenia as a result of the marrow’s reduced ability to produce normal blood cells as the proportion of malignant cells increases. In ALL, the blasts may infiltrate lymph nodes and other tissues such as liver, spleen, testis and the meninges, in particular. In AML, blasts tend to infiltrate skin, gums, liver and spleen.

Classification of acute myeloblastic leukaemia

AML has traditionally been classified on the basis of morphological features of the disease. Subtypes displaying granulocytic, monocytic, erythroid and megakaryocytic differentiation can be demonstrated. Recently, the World Health Organization (WHO) has updated this system (Table 50.2). AML is now classified using a combination of morphological, genetic and immunological cell marker features (surface antigen expression) in an attempt to define disease groups of greater prognostic significance (Swerdlow et al., 2008).

Table 50.2 WHO classification of AML

Subgroup	Examples
AML with recurrent genetic abnormalities	Inversion chromosome 16 (inv 16)
	t(15;17)
	t(8;21)
AML with multilineage dysplasia
Therapy-related AML
AML not otherwise classified	AML without maturation
	AML with granulocytic maturation
	AML with granulocytic and monocytic differentiation
	AML with monocytic differentiation
	AML with erythroid differentiation
	AML with megakaryocytic differentiation

Classification of acute lymphoblastic leukaemia

As with AML, the WHO classification system takes account of morphological, genetic and immunological features. The disease is, however, mainly classified immunologically, based on the presence or absence of B- or T-cell markers (Table 50.3). Each subtype displays different clinical presentations, response to treatment and, ultimately, prognosis, with pre-B having the best prognosis and B-ALL the worst. It is worth noting that B-ALL (Burkitt’s type), which is associated with translocations of the myc gene normally located on chromosome 8, seems to be a morphologically and biologically distinct form of leukaemia.

Table 50.3 Classification of ALL

Pre-B ALL	Possessing the common ALL antigen CD 10
B cell type	B-ALL of Burkitt’s type
T cell type	T-ALL
Null	Non-B, non-T and lacking the common ALL antigen CD 10

Chronic leukaemias

In chronic leukaemia, the normal bone marrow is replaced by a malignant clone of maturing haemopoietic cells.

Chronic lymphocytic leukaemia

CLL is characterised by a clonal expansion of morphologically mature lymphocytes of B-cell origin. These cells accumulate in the peripheral blood and give rise to a lymphocytosis that may be very marked. Lymphocytes accumulate in lymph nodes and spread to the liver and spleen, which become enlarged. The bone marrow is progressively infiltrated. Although the malignant lymphocytes appear morphologically normal, they are functionally deficient.

Chronic myelocytic leukaemia

The characteristic feature of CML is the predominance of maturing myeloid cells in blood, bone marrow, liver, spleen and other organs. CML was the first cancer to be associated with a specific chromosomal abnormality: the Philadelphia chromosome translocation (Ph) seen in over 90% of cases. This is a translocation of genetic material between the long arms of chromosome 22 and chromosome 9. This results in the apposition of the BCR gene (chromosome 22) and the ABL gene (chromosome 9). This novel BCR-ABL gene encodes a fusion protein which has tyrosine kinase activity. This genetic event is believed to be crucial in the pathogenesis, or perhaps even to initiate the development, of CML since overactivity of the tyrosine kinase results in the uncontrolled growth characteristic of leukaemic cells (Cilloni and Saglio, 2009).

Clinical manifestations

Acute leukaemia

Most of the clinical manifestations of acute leukaemia are related to bone marrow failure. The disease commonly presents with a short history, and left untreated, it is rapidly fatal. Symptoms of infection, anaemia and bleeding are common and life-threatening presenting problems. Bleeding may be particularly severe in one subtype of AML, acute promyelocytic leukaemia (APL). This condition is associated with a translocation of genetic material between chromosomes 15 and 17, t(15;17). Disseminated intravascular coagulation (DIC) is commonly the presenting feature of this disease. Some patients with AML develop symptoms and signs due to infiltration of major organs by leukaemic cells.

The involvement of other tissues such as spleen, liver, lymph nodes and meninges is more common in ALL than AML. Involvement of the central nervous system (CNS) may give rise to headaches, vomiting and irritable behaviour. CNS disease is rare at presentation, but develops in up to 75% of children with ALL unless specific prophylactic treatment is given. Less commonly, patients present with features of hypermetabolism, hyperuricaemia or generalised aches and pains.

Chronic leukaemia

Chronic myelocytic leukaemia

Patients with CML commonly present with non-specific symptoms, such as malaise, weight loss and night sweats. The main physical sign is an enlarged spleen that may give rise to abdominal discomfort. Hepatomegaly is also detected in approximately 40% of newly diagnosed patients. Neutropenia and thrombocytopenia are uncommon at presentation. Thus, unlike the acute leukaemias, patients with CML rarely present with symptoms of infection or haemorrhage. In up to 30% of cases, patients are asymptomatic and the disease is detected as a result of a routine blood test performed for other reasons.

CML is a triphasic disease. The initial chronic phase may last from several months to 20 years; the median is around 5 years. During this time, treatment can alleviate symptoms and reduce the white blood count (WBC) and spleen size, allowing patients to lead near normal lives. An accelerated phase eventually occurs where the disease becomes more aggressive with progressively worsening symptoms: unexplained fevers, bone pain, anaemia, thrombocytopenia or thrombocytosis. Finally, after a period of weeks or months, a blast crisis occurs, resembling fulminating acute leukaemia. In a small percentage of patients, this occurs abruptly with no prior accelerated phase.

Chronic lymphocytic leukaemia

An increasing number of patients are diagnosed as having CLL by chance, when a full blood count is performed for an unrelated reason. Symptomatic patients often suffer B symptoms: night sweats, unexplained fever and weight loss. At diagnosis, findings may include generalised lymphadenopathy and some enlargement of the liver and spleen. The course of CLL is variable; in some patients, the disease may remain indolent for many years, while others experience a steady deterioration in their health. Survival typically varies from 2 to 20 years depending on the extent of disease. Patients are immunocompromised with a reduction in serum gammaglobulin and are at increased risk of bacterial and viral infections. There is an increased susceptibility to autoimmune disease, particularly immune haemolytic anaemias and thrombocytopenia. With progressive disease, bone marrow failure becomes apparent, resulting in fatigue, infection and bleeding, and the disease becomes less responsive to treatment. Patients with CLL also have an increased risk of developing a more aggressive malignancy such as high-grade non-Hodgkin’s lymphoma (known as Richter’s transformation) or prolymphocytic leukaemia (PLL).

Investigations

Examinations of peripheral blood and bone marrow are the key laboratory investigations carried out in cases of suspected leukaemia. However, some additional investigations can help in the diagnosis and classification of this group of diseases. Some of the main findings at diagnosis are presented in Table 50.4.

Table 50.4 Findings at diagnosis in leukaemia

In acute leukaemia, leukaemic blast cells are usually seen on the peripheral blood film. The blasts of ALL and AML are distinguished using morphology, cytochemical stains, cytogenetics and cell surface antigen analysis. In CML, the principal feature is a leucocytosis with WBC usually ranging from 10 × 10⁹ L⁻¹ to 250 × 10⁹ L⁻¹ and comprising the complete spectrum of myeloid cells. In CLL, it is lymphocytes, in particular, which are increased, with clonal lymphocyte counts exceeding 5 × 10⁹ L⁻¹. Non-random chromosome abnormalities are increasingly being identified in patients with leukaemia. The information obtained from cytogenetic analysis of bone marrow or peripheral blood cells can be used to confirm the diagnosis and classification of leukaemia and may provide a guide to the likely response to treatment and prognosis.

Treatment

Although significant progress has been made in the treatment of leukaemia, work continues to further improve prognosis. As leukaemias are rare malignancies, the most important studies are undertaken on a national or international basis. In addition to the specific anti-leukaemia treatment, general supportive therapy is vital to manage both the disease and the complications of therapy.

Acute leukaemia

At the outset, intensive combination chemotherapy is given in the hope of achieving a complete remission (CR). This initial phase of treatment is termed induction or remission induction chemotherapy. A CR can only be achieved by virtual ablation of the bone marrow, followed by recovery of normal haemopoiesis. If two cycles of therapy fail to induce CR, an alternative drug regimen can be used. If this is unsuccessful, it is unlikely that CR will be achieved. The subsequent duration of the first remission is closely linked to survival.

Remission is defined as the absence of all clinical and microscopic signs of leukaemia, less than 5% blast forms in the bone marrow and return of normal cellularity and haemopoietic elements. Despite achieving CR, occult residual disease (also termed minimal residual disease or MRD) will persist, and further intensive therapy is given in an attempt to sustain the remission. This post-remission consolidation therapy may comprise chemotherapy or a combination of chemotherapy and bone marrow transplantation.

Acute lymphoblastic leukaemia

Treatment of ALL in childhood has been one of the success stories of the past 3 decades. Over 80% of children will achieve a remission lasting more than 5 years, and current studies are often focused on trying to identify the 20% of children with poor risk disease and treating them more aggressively (Vrooman and Silverman, 2009). Unfortunately, the results in adults are not so impressive. The combination of vincristine, prednisolone, anthracyclines and asparaginase induces CR in about 90% of children with ALL and 80% of adults, although sadly relapse is far more common in adults (Table 50.5). Other active drugs in the treatment of ALL include methotrexate, 6-mercaptopurine, cyclophosphamide and mitoxantrone.

Table 50.5 Treatment of ALL (adapted from MRC protocol UKALL 12-2005)

Patients with ALL are at a high risk of developing CNS infiltration. Cytotoxic drugs penetrate poorly into the CNS which thus acts as a sanctuary site for leukaemic cells. For this reason, all patients with ALL receive CNS prophylaxis. Cranial irradiation plus intrathecal methotrexate or high-dose systemic methotrexate can be used.

Maintenance treatment is important to sustain a CR. It is usually milder than induction or consolidation chemotherapy, but is carried on for at least 18 months. Treatment usually consists of weekly methotrexate and daily 6-mercaptopurine with intermittent vincristine and prednisolone.

The treatment of relapsed disease varies with the site of relapse. Isolated CNS or testicular relapse may be successfully treated with radiation and reinduction therapy. Cure can still be achieved for some patients. Bone marrow relapse is much more difficult to cure, especially if it occurs early.

A small proportion of paediatric patients and a larger proportion of adult patients have the Philadelphia chromosome translocation within their ALL blasts. Such patients have a relatively poor prognosis and therefore require more intensive therapy. There is some evidence that drug combinations including imatinib may enhance the response of these leukaemias to therapy.

Acute myeloblastic leukaemia (non-acute promyelocytic leukaemia)

As for ALL, the treatment of AML involves induction and consolidation chemotherapy. In AML therapy, however, the chemotherapy regimens used to achieve remission are much more myelotoxic, and patients require intensive supportive care to survive periods of bone marrow aplasia (Fig. 50.2). The pyrimidine analogue cytarabine has formed the basis of treatment for AML for 20 years. The addition of daunorubicin and oral thioguanine has achieved a CR rate of 75% in patients under the age of 60 years and about 50% in those over 60 years (Dohner et al., 2010). The precise dose and scheduling of these agents is continually being refined in order to improve the response rates. Despite the numbers of patients who achieve CR following induction therapy, the majority relapse, with only about 25% becoming long-term disease-free survivors (Stone et al., 2004). Thus, in common with ALL, additional post-remission therapy is required. Intensive consolidation chemotherapy with high-dose cytarabine and daunorubicin or amsacrine appears to improve survival rates to approximately 50% after 3 years, with even more encouraging results being obtained in patients under 25 years of age (Dohner et al., 2010; Robak and Wierzbowska, 2009). There is generally no role for maintenance therapy in AML. Similarly, CNS prophylaxis is not routinely indicated though patients thought to be at particularly high risk of CNS disease, such as those with testicular or sinus involvement, should receive prophylactic therapy.

Fig. 50.2 One example of a possible treatment regimen for AML. The figure demonstrates that patients are treated with initial induction therapy, then remission is consolidated with at least two courses of chemotherapy. This figure provides a summary only and should not be used as a guide to prescribing or dispensing therapy.

An alternative approach to post-remission therapy is stem cell transplantation. In patients under 40 years of age, allogeneic bone marrow transplantation has resulted in disease-free survival of 45–65% at 5 years post-transplant. These patients are considered cured of their disease. Only about 10% of patients are suitable for allogeneic bone marrow transplants, and there is little evidence to suggest that autologous stem cell transplantation improves the outcome for patients with AML in first CR. It is always worth remembering that AML is most common in the elderly, and intensive intravenous chemotherapy regimens are not always appropriate for this population of patients.

Treatment of AML in relapse is difficult and the prognosis is generally poor. Encouraging results have been seen using a combination of fludarabine, cytosine arabinoside and granulocyte colony-stimulating factor (G-CSF). Novel approaches in AML therapy are often piloted in this group of poor-risk patients. A combination of anti-CD33 antibody, which targets myeloid blasts, with calicheamicin, an anthracycline antibiotic, is a promising and effective approach (Stone et al., 2004), but appears most effective when given in combination with conventional chemotherapy. A newly developed purine analogue, clofarabine, has also been shown to have activity against AML. This drug is a promising agent, particularly in the treatment of older patients, as pilot studies suggest that its toxic effects may be less severe than those associated with other chemotherapy regimens (Robak and Wierzbowska, 2009). 5-Azacytidine is also of interest, especially in older patients and those whose disease has evolved from myelodysplastic syndrome MDS. This agent inhibits DNA methyltransferase resulting in DNA hypomethylation. This process is thought to increase activity of some tumour suppressor genes resulting in anti-tumour effects. The agent has been shown to slow the rate of progression to AML in patients with high-risk myelodysplastic syndrome and is currently the subject of clinical trials in AML.