Epidemiology

Leukaemias are relatively common with a preponderance of men affected (Table 28.1). In the United Kingdom, 8616 people were diagnosed with leukaemia and 4603 died of the disease in 2011.

The leukaemias are described generally as either acute or chronic. The main variants are lymphoid and myeloid leukaemia, which account for almost 95% of leukaemia. Myeloid neoplasms are derived from bone marrow progenitor cells that normally develop into erythrocytes, granulocytes (neutrophils, basophils and eosinophils), monocytes or megakaryocytes. The myeloid proliferations are divided into four groups:

• acute myeloid leukaemia (AML) defined as >20% myeloid blast cells in the blood or bone marrow, often associated with chromosomal rearrangements;
  
• myeloproliferative neoplasms are a group of clonal proliferations of one or more myeloid lineages, often associated with tyrosine kinase mutations;
  
• myelodysplastic syndromes are disorders with ineffective production of blood cells and a variable risk of transformation to acute leukaemia;
  
• myelodysplastic/myeloproliferative neoplasms are disorders sharing dysplastic and proliferative features.

Examples of each group are shown in Figure 28.1.

Lymphoid neoplasms derive from cells that develop into B lymphocytes or T lymphocytes and are further divided into those originating from lymphoid precursors (such as acute lymphoblastic leukaemia (ALL)) and those deriving from mature lymphocytes and plasma cells. ALL is far more common in childhood than acute myeloid leukaemia (AML); whilst in adults approximately 80% of all the acute leukaemias are myeloid. In adults, chronic lymphocytic leukaemia (CLL) outnumbers chronic myeloid leukaemia (CML).

Pathogenesis

Hybrid fusion genes caused by reciprocal chromosomal translocations that join half a gene from one chromosome to half a gene from another chromosome occur relatively commonly in leukaemias. For example, acute promyelocytic leukaemias (APMLs) are characterized by a translocation between chromosomes 15 and 17. The resultant fusion gene is formed between part of the promyelocytic leukaemia (PML) gene on chromosome 15 and the retinoic acid alpha receptor gene (RARA) on chromosome 17. This hybrid gene interacts with histone deacetylase complexes that regulate gene transcription (see Chapter 3). Treatment with retinoic acid leads to dissociation of this complex and a transient remission of the leukaemia. Some examples of the fusion genes seen in leukaemia are described in Table 28.2.

Point mutations and gene deletions are also seen in leukaemias involving oncogenes such as p53 and RAS. P53 mutations are seen in ALL and blast crisis of CML, and N-RAS and c-KIT mutations are found in AML. Similarly, the myeloproliferative neoplasms are associated with mutations of tyrosine kinase genes. For example, polycythemia rubra vera, essential thrombocythemia and primary myelofibrosis are associated with mutations of JAK-2 (Janus kinase 2). It should be noted that the predominant molecular change in leukaemia is chromosomal translocation. This is in contrast with solid tumours, where the predominant changes are gene deletions and amplifications.

Although there is a greater understanding of the molecular biology of leukaemia, the reason for the genetic changes observed is not known. The exceptions are those rare leukaemias that occur in the context of exposure to radiation or as secondary events following chemotherapy. Such secondary leukaemias are commonly associated with chromosomes 5, 7 or 11 abnormalities (see Figure 3.25).

Presentation

The presentation of patients with acute leukaemia is remarkable in its dramatic onset. It is usual to obtain a history that dates back only a few days, with features of anaemia, thrombocytopenia and leucopenia, although some people date their symptoms back for much longer periods. Chronic leukaemia may be diagnosed as an incidental finding, for example, when a blood count is performed as part of a routine screen for another medical problem. Patients with chronic leukaemia may have abdominal discomfort due to splenomegaly or present with anaemia or lymphadenopathy (Figure 28.2). Such presentations generally tend to be insidious; this is particularly the case for CLL. The situation is a little different for CML, which progresses from a chronic to an accelerated to a blast phase. The diagnosis can be made at any point in this clinical course.

Investigations and classification

The diagnosis of acute leukaemia is made by an examination of the peripheral blood and bone marrow (Figures 28.3, 28.4, 28.5, 28.6). In ALL, a lumbar puncture will be performed in order to investigate the possibility of CNS infiltration. Two common cytochemical stains are used to distinguish between AML and ALL. These are the Sudan black, which is usually positive in AML and negative in ALL, and the periodic acid–Schiff (PAS) test, which is usually positive in ALL and negative in AML. These stains are outmoded and have been largely replaced by immunophenotyping.

The classification of acute leukaemias usually follows the French–American–British (FAB) classification, which essentially describes the degree of differentiation and maturation. AML are described as M1 to M7, and ALL as L1 to L3 (Table 28.3).

Immunophenotyping is also carried out in suspected ALL, where the presence of B- and T-cell markers is sought out. More than 70% of adult ALL are of B-cell origin. Following immunophenotyping, cytogenic and molecular analysis is carried out in order to define chromosomal and molecular abnormalities, which provide prognostic information (Figure 28.7). Cytogenetic analysis is useful in the diagnosis of CML and the prognosis of CLL.

The t(8;21) translocation in AML is associated with a good prognosis and occurs in about 8% of patients. The inversion or reciprocal translocation t(16;16) of chromosome 16 is associated with the M4 phenotype and again confers a favourable response. Translocations with an 11q23 breakpoint is a poor prognostic feature. The presence of the Philadelphia chromosome is found in about 5% of childhood and 25% of adult ALL, and is thought to perhaps indicate transformation from CML: this is an adverse prognostic feature.

CLL is a tumour of B-cell origin in 95% of patients (Table 28.4 and Figures 28.8, 28.9 and 28.10). Cytogenetic changes are described in up to 80% of patients with CLL. Although there is no particular pattern that emerges to characterize this leukaemia, five or six abnormalities are usually observed. Trisomy 12, for example, the most common cytogenetic abnormality, is found in just one-third of patients. Patients with CLL are classified using a number of different systems, most of which are helpful in describing survival related to lymphocytosis, lymph node involvement and the presence or absence of anaemia or thrombocytopenia.

Treatment

Acute leukaemia

The management of acute leukaemia is complex. It requires psychological support of the individual and of the family, and active and urgent treatment, particularly for the acute leukaemias. Initial treatment involves attempts to stabilize the patient by transfusion of red cells and platelets, combined with treatment of infection by antibiotics to limit the complications that may occur with the initiation of chemotherapy. These mainly revolve around the tumour lysis syndrome. Rehydration is required, and the patient is started on allopurinol and rasburicase to prevent the metabolic abnormalities that are described in detail in Chapter 40.

The chemotherapy that is given to patients with leukaemia has evolved as a result of many clinical trials over very many years, involving the Medical Research Council (MRC) in the United Kingdom, and the Cancer and Leukaemia Group B in the United States. The mainstay of induction chemotherapy in adult has been the use of daunorubicin and cytosine arabinoside given in a daily schedule, the dosage and duration of which is varied and repeated upon recovery of haematological parameters.

B-cell	T-cell
B-cell chronic lymphocytic leukaemia/small lymphocytic lymphoma	T-cell chronic lymphocytic leukaemia (large granular lymphocytic leukaemia)
B-cell prolymphocytic leukaemia	T-cell prolymphocytic leukaemia
Hairy-cell leukaemia and variant	Adult T-cell leukaemia/lymphoma
Splenic marginal zone lymphoma, including splenic lymphoma with villous lymphocytes	Leukaemic phase of mycosis fungoides/Sézary syndrome
Leukaemic phase of mantle cell lymphoma
Leukaemic phase of follicular lymphoma
Leukaemic phase of lymphoplasmacytoid lymphoma

During treatment, patients require supportive therapies with blood products such as platelets and red cells. Platelet support is given to keep platelet counts above 10 × 10⁹/L, which limits the risk of spontaneous haemorrhage (Figure 3.22). There is a risk of immunization against platelets, which may require human leucocyte antigen (HLA) matched transfusions rather than random donor platelet transfusion. There is also a risk of graft versus host reactions in these heavily immunosuppressed patients who are also candidates for stem cell transplantation (Figure 28.19). This risk, from lymphocytes in blood donations, is reduced by irradiating blood prior to transfusion. Patients are of course at risk from neutropenic sepsis, which is treated with intravenous antibiotics. Prolonged neutropenia may be associated with fungal infection. In the context of persistent fever, particularly following transplantation, antifungal therapy is instituted. CT scanning may be appropriate in order to diagnose Aspergillus pneumonia. There is little evidence to suggest that any prophylactic antifungal treatment is of value, but randomized studies have shown that prophylaxis with antibiotics such as co-trimoxazole reduces the risk of Pneumocystis infection.

With recovery of the marrow, a further bone marrow examination is carried out. The majority of patients will have entered complete remission just before the second course of chemotherapy. Generally, four to six cycles of treatment are given in all, and this may be followed by post-remission treatment using an allogenic stem cell transplant ideally from a closely matched relative. These approaches are used in younger patients who have entered their first remission. Approximately 50–55% of patients who receive a transplant will be cured, but there is no evidence of better survival after transplantation in the good-prognosis patients.

The management of patients in transplant programmes is, of course, highly specialized, and medical training is focussed on the recognition of the problems associated with profound and prolonged immunosuppression (see Box 28.1). The management of transplant patients has completely changed in recent years, because of the availability of recombinant growth factors. The use of granulocyte colony-stimulating factor (G-CSF) in transplant programmes has reduced the period of profound neutropenia such that the average duration of stay on a transplant ward has decreased from 28 to 17 days. One of the major complications of allogeneic transplantation is the development of graft versus host disease (GVHD), which is associated with a significant morbidity and mortality rate (Figure 28.19). New drugs to suppress GVHD have been developed, which include sirolimus, tacrolimus and mycophenolate. Sirolimus, also known as rapamycin, was first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample from Rapa Nui, one of the Easter Islands. Both sirolimus and tacrolimus inhibit mTOR (mammalian target of rapamycin), which is a cellular protein kinase that acts as a common step in many signal transduction pathways.