Acute leukaemia is a malignant disorder of white cells caused by a failure of normal differentiation of haemopoietic stem cells and pro- genitors into mature cells. This results in the accumulation of primitive leukaemic cells within the bone marrow cavity, causing bone marrow failure, and as a consequence patients typically present with anaemia, thrombocytopenia or neutropenia (Box 6.1).
Much progress has been made in understanding the pathogenesis of the acute leukaemias, and it is now clear that they occur because of the acquisition of distinct genetic abnormalities in haemopoietic stem cells or committed progenitors. These molecular abnormalities frequently occur as the result of chromosomal translocations or the loss of chromosomal material. In addition, activating mutations in genes regulating cellular proliferation, such as tyrosine kinase genes, are commonly identified. Malignant transformation of primitive cells with the capacity to develop into cells of the myeloid lineage results in acute myeloid leukaemia (AML), while acquired genetic
abnormalities in lymphoid progenitors result in acute lymphoblas- tic leukaemia (ALL).
In the past 30 years there has been a steady improvement in survival rates in patients presenting with acute leukaemia, most dramatically in childhood ALL. This progress has occurred as a result of the rigor- ous evaluation of chemotherapeutic drugs and supportive care in the setting of large-scale randomized studies. The recent identification of specific molecular abnormalities associated with the pathogenesis of acute leukaemia now also offers the prospect of designing new therapies that target the underlying molecular lesion.
Classification
The acute leukaemias are subdivided into (i) AML and (ii) ALL. AML is a disease of myeloid progenitors (cells from which neu- trophils, eosinophils, monocytes, basophils, megakaryocytes and erythrocytes are derived) and is characterized by the accumulation of myeloblasts within the bone marrow (Fig. 6.1). ALL, in contrast, is a disease of lymphoid progenitors (immature lymphocytes) resulting in infiltration of the bone marrow by lymphoblasts (Fig. 6.2).
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| Figure 6.1 Myeloblasts and pathognomonic Auer rod in a patient with acute myeloid leukaemia. |
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| Figure 6.2 Lymphoblasts in a patient with acute lymphoblastic leukaemia |
For nearly three decades, the French–American–British (FAB) classi- fication was used to subdivide AML and ALL based on morphological criteria. The recent identification of non-random cytogenetic abnormalities in AML has been incorporated into the new World Health Organization (WHO) classification, which includes karyotypic as well as morphological abnormalities (http://www3.who.int/ icd/vol1htm2003/fr-icd.htm).
ALL is the commonest cancer of childhood. The highest incidence is in the age range 0–4 years (5.2 cases per 100 000 per annum) falling to 1.9 cases per 100 000 per annum in the 10–14-year age group. After 40 years of age, there is a secondary rise in incidence but not to the levels seen in childhood. US data suggest that ALL is more common in white than in African American children. Conversely, AML is more common in adulthood, with an overall incidence of 3.4 per 100 000 per annum, and nearly two-thirds of cases occurring in patients over the age of 60 years.
Although the great majority of cases of acute leukaemia are sporadic, a number of factors associated with an increased risk of developing leukaemia have been identified (Box 6.2).
Clinical features of acute leukaemia
Acute leukaemia can present with a wide range of symptoms and signs reflecting infiltration of the bone marrow or other organs with leukaemic blasts or the systemic consequences of advanced malignancy. It should be considered in the differential diagnosis of a number of common clinical presentations (Box 6.3).
Infection
Neutropenia (reduced neutrophil count) is common at diagnosis, and results in an increased risk of both bacterial and fungal infec- tion. Bacterial infection in the throat, skin or perianal region is com- monly seen and may be missed unless the relevant areas are carefully examined. Fungal infections most commonly present either as oral candidiasis or invasive intrapulmonary aspergillosis. Even if the neutrophil count appears normal, neutrophil function can often be poor, particularly in patients with a prior history of myelodysplastic syndrome in which neutrophils are usually dysfunctional.
Bleeding
Bleeding can occur as a consequence of thrombocytopenia or abnormal coagulation. Spontaneous bruising, gingival bleeding, palatal and retinal haemorrhages, epistaxis, menorrhagia and prolonged bleeding after venepuncture are all relatively common.
Infiltration
Leukaemic blasts can infiltrate any organ. Bone pain is a direct con- sequence of marrow disease. Infiltration of the meninges, resulting in headache or cranial nerve palsies, is particularly common in ALL and consequently lumbar puncture is mandatory in newly diagnosed patients with ALL. Hepatosplenomegaly is frequently present at diagnosis in ALL, and mediastinal enlargement is well documented in T-cell ALL. ALL can also involve the testes, presenting with a painful testicular mass. Skin and gum infiltration also occur: most com- monly in AML.
Diagnosis of acute leukaemia
A diagnosis of acute leukaemia is confirmed by the demonstration of an infiltrate of leukaemic blasts in the bone marrow. In all patients in whom intensive treatment is planned, the following investigations are mandatory.
Full blood count
The blood count is nearly always abnormal in acute leukaemia. Patients with acute leukaemia commonly present with circulating leukaemic blasts in the peripheral blood resulting in a raised white blood count. This will usually be accompanied by thrombocytopenia, neutropenia and anaemia. In a proportion of patients, the white blood count will be normal or reduced.
Coagulation
Thrombocytopenia is a common cause of petechial bleeding or bruising. Disseminated intravascular coagulation (DIC) is often present in newly diagnosed patients with acute leukaemia and may result in life-threatening bleeding complications. DIC is either triggered directly by the underlying leukaemia [acute promyelocytic leukaemia (APL) is typically associated with DIC] or can be second- ary to sepsis. Consequently, measurement of the platelet count, prothrombin time, activated partial thromboplastin time and fibrinogen and, if abnormal, prompt correction, is essential in all newly diagnosed patients.
Biochemistry
Abnormal renal function can occur secondary to hyperuricaemia (particularly in association with a high white blood cell count) and sepsis. Infiltration of the liver can cause abnormal liver function tests.
Bone marrow aspirate and trephine biopsy
A diagnosis of leukaemia can usually be made from a bone marrow aspirate alone. Slides from a bone marrow aspirate are air-dried and stained within the haematology laboratory, making it possible to confirm the diagnosis on the same day as the test is performed. In patients with a heavy infiltrate of leukaemic cells, a bone marrow aspirate may sometimes fail to yield sufficient marrow cells (a ‘dry tap’) or only result in a haemodilute sample. In such circumstances, a trephine biopsy is needed, which requires a number of days to proc- ess in the laboratory.
Immunophenotyping
Leukaemic blasts are characterized by the aberrant expression of haemopoietic antigens on their cell surface. Distinct patterns of an- tigen expression permit accurate discrimination between myelob- lasts and lymphoblasts, allowing confident distinction between AML and ALL. Current guidelines for immunophenotyping are available online (http://www.blackwell-synergy.com/links/doi/10.1046/j.1365– 2257.2002.00135.x/full/;jsessionid=aTVogw Pie66BGY5K).
Cytogenetic and molecular studies
The demonstration that specific chromosomal abnormalities are as- sociated with distinct subtypes of acute leukaemia has had enormous implications for the diagnosis and management of acute leukaemia and it is now clear that distinct cytogenetic abnormalities present in newly diagnosed patients with acute leukaemia provide vitally im- portant prognostic information. In AML, cytogenetic examination at diagnosis can be used to classify patients into three prognostic risk groups. Patients with the chromosomal abnormalities t(8;21) (Fig. 6.3), inv(16) or t(15;17) have a relatively good prognosis when treated with intensive chemotherapy, whereas patients with abnor- malities of chromosomes 3, 5 or 7 or complex karyotypic abnor- malities respond poorly to chemotherapy. In ALL, cytogenetics also provides important prognostic information with the presence of the Philadelphia chromosome [t(9;22)] predicting poor long-term disease-free survival, whereas hyperdiploid karyotypes are associated with an improved outcome.
Many of the common translocations present in AML or ALL result in the formation of a novel gene, which can be detected in the bone marrow by the polymerase chain reaction (PCR). This allows con- firmation of diagnosis and permits the monitoring of the response to treatment. This is best illustrated by APL, a particular subtype of AML, which is associated with the presence of the t(15;17) trans- location (Fig. 6.4), which results in the formation of a novel gene, PML:RARA. Detection of the t(15;17) translocation or the PML: RARA transcript by PCR can be used both to confirm a diagnosis of APL and to monitor for the presence of minimal residual disease (MRD). Several other non-random chromosomal abnormalities,
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| Figure 6.3 Karyotypic analysis in a patient with acute myeloid leukaemia associated with t(8;21). |
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| Figure 6.4 Fluorescence in situ hybridization study in a patient with acute promyelocytic leukaemia demonstrating t(15;17). |
such as t(8;21) and inv(16), and their associated transcripts AML: ETO and CBFb:MYH11, are classically seen in AML and assist both in assigning patients with AML to a particular molecular subgroup and in monitoring MRD.
Chest radiography
A mediastinal mass may be present, particularly in T-cell ALL.
Lumbar puncture in patients with ALL
The presence of leukaemia in the central nervous system (CNS) should be suspected if there are symptoms of headache, visual disturbance or abnormalities such as blurred disc margins or retinal haemorrhage on fundoscopy. It is common at diagnosis and relapse in ALL but only rarely occurs in AML.
Principles of treatment
Acute leukaemia is a life-threatening, but potentially curable, disease and should be managed by a specialist multidisciplinary team. All patients in whom acute leukaemia is suspected or has been confirmed should be urgently referred to a specialist haematology unit. The essential early principles of management are summarized in Box 6.4. The most important prognostic factors in AML are patient age, performance status and presentation cytogenetics. It is important to assess whether patients have a significant chance of benefit from intensive chemotherapy. In patients whose outcome with chemotherapy is likely to be poor (such as patients over the age of 70 years with poor risk cytogenetics), palliative therapy with blood and platelet support may be the best treatment (Box 6.5 and Table 6.1). Such decisions are clearly complex and must be taken in careful consultation with the patients and their families.
Supportive care
Treatment and prevention of the complications caused by neutropenia and thrombocytopenia are vital both at diagnosis and during intensive treatment of acute leukaemia. This includes transfusion of platelet concentrates and prompt treatment of infection (Box 6.6).
Careful examination and thorough investigation of neutropenic patients with a temperature > 38°C is critical, since these patients are immunocompromised and susceptible to life-threatening infections. Particularly important sources of infection in neutropenic patients include bacterial and fungal pneumonias, infections associated with indwelling central lines and infections of the sinuses and perineum. Early institution ofbroad spectrum antibiotics after appropriate investigations (blood cultures, chest X-ray and swabs of potentially infected sites) is vital. If patients are hypotensive, aggressive treatment of possible septic shock including aggressive fluid resuscitation and, if necessary, transfer to the intensive care unit are critical.
General principles of management
The initial aim of treatment is to achieve a complete remission (CR), which is defined as the reduction of leukaemic blasts within the bone marrow to < 5% and recovery of neutrophil and platelet counts.
Once achieved, patients then receive further courses of chemotherapy with or without adjunctive stem cell transplantation with the aim of securing long-term disease erradication. The side effects of
chemotherapy are varied (Box 6.7) but can be profound. It is most important to consider these when deciding whether to institute treat
ment in older patients in whom the prospects for long-term survival with conventional chemotherapy are poor.
Specific management of AML
Chemotherapy
Effective chemotherapeutic agents in AML include the anthracyclines (daunorubicin and idarubicin), cytosine arabinoside and etoposide. A new drug currently being examined in the UK National Cancer Research Network (NCRN) AML studies is gemtuzumab ozogamicin, an immunoconjugate of the toxin calicheamycin and an antibody to CD33 – an antigen expressed on leukaemic cells.
These drugs are administered in combination in order to increase their activity and reduce the risk of the emergence of drug resistance. CRs can be achieved in 70–80% of newly diagnosed adults using one or two cycles of induction chemotherapy. Once CR has been achieved, the majority of patients receive a further two cycles of chemotherapy. In APL, treatment with myelosuppressive drugs, particularly anthracyclines, is combined with all-trans-retinoic acid, which is very active in this disease and has substantially improved outcome.
Role of stem cell transplantation
Allogeneic stem cell transplantation using an HLA identical sibling has the capacity to reduce the relapse rate and improve disease-free survival in patients with AML. Allogeneic transplantation is not indicated in patients with good risk cytogenetics, whose outcome with chemotherapy alone is encouraging, but is an important treatment modality in patients under the age of 45 years with standard or poor risk cytogenetics in first CR.
One of the frustrations of stem cell transplantation has been the fact that the toxicity associated with conventional myeloablative conditioning regimens has precluded the use of this highly effective anti-leukaemia therapy in older patients. The recent demonstration that it is possible to significantly reduce the toxicity of allogeneic transplantation through the use of less intensive chemotherapy regimens (‘reduced intensity’ or ‘mini’ transplants) has made it feasible to extend the curative potential of allogeneic stem cell transplantation to patients up to the age of 65 years – a remarkable breakthrough.
Preliminary results using such reduced intensity transplants suggest that they may possess the capacity to improve the outcome of older patients with AML and this is currently being tested in national studies.
Management of relapse
Despite intensive treatment, leukaemic relapse occurs in the majority of adults with AML. Reinduction treatment and subsequent transplantation using a sibling or an unrelated donor represent the only curative treatment in the great majority of patients. The success of such an intensive treatment strategy is predictable at the time of relapse by three main factors: patient age, cytogenetics and duration of first remission. In patients whose duration of first remission is < 1 year, long-term survival rates even with intensive treatment are < 10%, and this information is clearly important when coming to a decision with the patient on whether to proceed down such an arduous road.
Novel therapies
There is clearly a need for the development of new treatments in AML. The success of imatinib (Glivec®; Novartis) in patients with chronic myeloid leukaemia (CML) has led to the hope that it may be possible to identify similar targets in AML. Although there has been some encouraging preliminary experience in AML with drugs which target dysregulated genes, such as flt 3or ras, in AML these agents have not as yet fulfilled their promise.
Specific management of ALL
Treatment of ALL follows the same principles as for AML with three main exceptions. Firstly, treatment directed at treating or preventing the seeding of the CNS with leukaemic blasts forms a central part of ALL regimens. Treatment takes three forms: (i) regular intrathecal administration of chemotherapy agents which are both active and non-toxic (such as methotrexate, cytosine arabinoside or steroids); (ii) the systemic administration of high-dose methotrexate; and (iii) cranial radiotherapy.
Secondly, several additional drugs including vincristine and Lasparaginase are highly active in ALL. In addition, imatinib is highly active in patients with Philadelphia-positive ALL and an important adjunct to conventional chemotherapy in this subgroup of usually adult patients.
Lastly, maintenance treatment for up to 2 years with oral drugs such as 6-mercaptopurine and methotrexate has been shown to improve overall survival in adults and children with ALL.
Allogeneic stem cell transplantation has an important role in the management of ALL. Although usually reserved for children and for patients who have previously relapsed, it plays an important role in preventing relapse and improving overall survival in adults with ALL in first CR. In adults lacking a sibling donor, unrelated donor transplantation is indicated, particularly in those deemed to be at high risk of relapse, such as patients with the Philadelphia chromosome.
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