ACUTE LEUKEMIA

Leukaemias are malignant disorders of the haematopoietic stem cell  compartment,characteristically associated with increased numbers of white cells in the bone marrow and/or peripheral blood. The course of leukaemia may vary from a few days or weeks to many years, depending on the type.
Epidemiology
The incidence of leukaemia of all types in the population is approximately 10/100 000 per annum, of which just under 

half are acute leukaemia. Males are affected more frequently than females, the ratio being about 3:2 in acute leukaemia, 2:1 in chronic lymphocytic leukaemia and 1.3:1 in chronic myeloid leukaemia. Geographical variation in incidence does occur, the most striking being the rarity of chronic lymphocytic leukaemia in the Chinese and related races. Acute leukaemia occurs at all ages. Acute lymphoblastic leukaemia shows a peak of incidence in the 1-5 age group. All forms of acute myeloid leukaemia have their lowest incidence in young adult life and there is a striking rise over the age of 50. Chronic leukaemias occur mainly in middle and old age.
Aetiology
The cause of the leukaemia is unknown in the majority of patients. Several factors, however, are associated with the development of leukaemia and these are listed in Box 24.36.
i Terminology and classification
In acute leukaemia there is proliferation of primitive stem cells leading to an accumulation of blasts, predominantly in the bone marrow, which causes bone marrow failure. In chronic leukaemia the malignant clone is able to differen¬tiate, resulting in an accumulation of more mature cells.
Leukaemias are traditionally classified into four main groups:
• acute lymphoblastic leukaemia (ALL) • acute myeloid leukaemia (AML)
• chronic lymphocytic leukaemia (CLL) • chronic myeloid leukaemia (CML).
The diagnosis of leukaemia is usually suspected from an abnormal blood count, often a raised white count. The
24.36 FACTORS ASSOCIATED WITH THE
DEVELOPMENT OF LEUKAEMIA
lanising radiation
• A significant increase in myeloid leukaemia followed the atomic
bombing of Japanese cities
• An increase in leukaemia was observed after the use of
radiotherapy for ankylosing spondylitis and diagnostic X-rays of
the fetus in pregnancy
Cytotoxic drugs
• These, particularly alkylating agents, may induce myeloid
leukaemia, usually after a latent period of several years
• Exposure to benzene in industry
Retroviruses
~ One rare form of T-cell leukaemia/lymphoma appears to be
associated with a retrovirus similar to the viruses causing
leukaemia in cats and cattle
Genetic
• There is a greatly increased incidence of leukaemia in the
identical twin of patients with leukaemia
• Increased incidence occurs in Down s syndrome and certain
other genetic disorders
Immunological
9 Immune deficiency states (e.g. hypogammaglobulinaemia) are
associated with an increase in haematological
 
 
 
 
BLOOD DIS ORDERS
diagnosis is made from examination of the bone marrow. This includes the morphology of the abnormal cells. analysis of cell surface markers (immunophenotyping). clone-specific chromosome abnormalities and molecular changes. Not only does this allow an accurate diagnosis but also gives valuable prognostic information, allowing therapy to be tailored to the patient s disease.
The World Health Organization (W1-10I classification of tumours of haematopoietic and lymphoid tissues divides these diseases into lineaaes and incorporates results from immunophenon-ping, genetic and molecular analysis. The subclassification of acute leukaemias is shown in Box 24.3%.
 

ACUTE LEUKAEMIA
There is a failure of cell maturation in acute leukaemia. Proliferation of cells which do not mature leads to an accumulation of useless cells which take up more and more marrow space at the expense of the normal haematopoietic elements. Eventually, this proliferation spills into the blood. Acute myeloid leukaemia is about four times more common than acute lymphoblastic leukaemia in adults. In children the proportions are reversed, the lymphoblastic variety being more common. The clinical features are usually those of bone marrow failure (anaemia, bleeding or infection¬pp. 1012, 1016 and 1018).
Investigations
Blood examination usually shows anaemia with a normal or raised MCV The leucocyte count may vary from as low as 1 x 109/1 to as high as 500 x 109/1 or more. In the majority of patients the count is below 100 x 109/1. Severe thrombocytopenia is usual but not invariable. The appear¬ance of blast cells in the blood film is usually diagnostic.
24.37 WHO CLASSIFICATION OF ACUTE LEUKAEMIA
i
Acute myeloid leukaemia with recurrent genetic abnormalities
• AML with t(8;21) gene product AML/ETO
• AML with eosinophilia inv(16) or t(16;16), gene product
CBF(3/MYH11
• Acute promyelocytic leukaemia t(15;17), gene product PML/RARA
• AML with 11 q23 abnormalities (MLL)
Acute myeloid leukaemia with multilineage dysplasia
0 e.g. Following a myelodysplastic syndrome
Acute myeloid leukaemia and myelodysplastic syndromes,
therapy-related
~ e.g. Alkylating agent or topoisomerase II inhibitor
I
Acute myeloid leukaemia not otherwise specified
~ e.g. AML with or without differentiation, acute myelomonocytic
leukaemia, erythroleukaemia, megakaryoblastic leukaemia;
myeloid sarcoma
Acute lymphoblastic leukaemia
• Precursor BALL
• Precursor T ALL
Fig. 24.27 Acute myeloid leukaemia. Bone marrow aspirate showing infiltration with large blast cells which display nuclear folding and prominent nucleoli.
Sometimes the blast cell count may be very low in the peripheral blood and a bone marrow examination is necessary to confirm the diagnosis.
The bone marrow is the most valuable diagnostic inves¬tigation and will provide material for cytology (Fig. 24.27), cytogenetics and immunological phenotyping. A trephine biopsy should be taken if no marrow is obtained (dry tap). The marrow is usually hypercellular, with replacement of normal elements by leukaemic blast cells in varying degrees (but more than 20% of the cells). The presence of Auer rods in the cytoplasm of blast cells indicates a myelo¬blastic type of leukaemia. Illustrations of immunopheno¬typing and chromosome analysis are shown in Figure 24.2&.
Management
The general strategy for acute leukaemia is given in Figure 24.29. The first decision must be whether or not to give specific treatment. This is generally aggressive_ has a number of side-effects, and may not be appropriate for the very elderly or patients with other serious disorders (Chs 7 and 11). In these patients supportive treatment on15- should be offered; this can effect considerable improvement in well-being.
Specific therapy
If a decision to embark on specific therapy has been taken, the patient should be prepared in the ways listed in Box 24.38. It is unwise to attempt aggressive management of acute leukaemia unless adequate sersices are available for the provision of supportive therapy.
The aim of treatment is to destrov the leukaemic clone of cells without destroying the residual normal stem cell compartment from which repopulation of the haemato¬poietic tissues will occur. There are three phases:
• Remission induction. In this phase, the bulk of the tumour is destroyed by combination chemotherapy. The patient goes through a period of severe bone marrow hypoplasia, requiring intensive support and inpatient care from specially trained medical and nursing staff.
• Remission consolidation. If remission has been achieved by induction therapy, residual disease is attacked by therapy during the consolidation phase. This consists of a number of courses of chemotherapy, again resulting in
 
 
Fig. 24.28 Investigation of acute lymphoblastic leukaemia (ALL). [nl Flow cytometric analysis of blasts labelled with the fluorescent antibodies anti-CD19 (y axis) and anti-CD10 (x axis). ALL blasts are positive for both CD19 and CD10 (arrow). © Chromosome analysis (karyotype) of blasts showing additional chromosomes X, 4, 6, 7, 14. 18 and 21.
Supportive therapy only
No further treatment
Fig. 24.29 Treatment strategy in acute leukaemia.
periods of marrow hypoplasia. In poor prognosis leukaemia this may include a stem cell transplant.
0 Remission maintenance. If the patient is still in remission after the consolidation phase for acute lymphoblastic leukaemia, a period of maintenance therapy is given, consisting of a repeating cycle of drug administration. This may extend for up to 3 years if relapse does not occur and is usually given on an outpatient basis.
 
Maintenance Bone marrow therapy transplantation
i 24,38 MANAGEMENT OF ACUTE LEUKAEMIA: ; SPECIFIC THERAPY
~ Existing infections identified and treated (e.g. urinary tract infection, oral candidiasis, dental, gingival and skin infections) ~ Anaemia corrected with red cell concentrate infusion
~ Thrombocytopenic bleeding controlled with platelet transfusion
~ If possible, central venous catheter (e.g. Hickman line) inserted to facilitate access to the circulation for delivery of chemotherapy 9 Therapeutic regimen carefully explained to the patient and informed consent obtained
Thereafter, specific therapy is discontinued and the patient observed. (This maintenance phase is not thought to be of benefit in most patients with AML who have been brought into complete remission by induction and consolidation therapy.)
In patients with ALL it is necessary to give prophylactic treament to the central nervous system as this is a sanctuary site where standard therapy does not penetrate. This usually consists of a combination of cranial irradiation, intrathecal chemotherapy and high-dose methotrexate which crosses the blood-brain barrier.
The detail of the schedules for these treatments will be found in specialist texts. The drugs most commonly employed for the two main varieties of acute leukaemia are given in Box 24.39. Generally, if a patient fails to go into remission with induction treatment, alternative drug combinations may be tried but the outlook is poor unless remission can be achieved. Disease which relapses during treatment or soon after the end of treatment carries a poor prognosis and is difficult to treat. The longer after the end of treatment that relapse occurs, the more likely it is that further treatment will be effective.
Supportive therapy
Aggressive and potentially curative therapy which involves periods of severe bone marrow failure would not be possible
 
 
24.39 DRUGS COMMONLY USED IN THE TREATMENT
OF ACUTE LEUKAEMIA At
Phase ALL AML
Induction Vincristine (i.v.) Daunorubicin (i.v.)
 Prednisolone (oral) Cytarabine (i.v.)
 L-asparaginase (i.m.) Etoposide (i.v. and oral)
 Daunorubicin (i.v.) 
 Methotrexate (intrathecaq 
Consolidation Daunorubicin (i.v.) Cytarabine (i.v.)
 (,ytarabine (i.v.) Amsacrine (i.v.)
 Etoposide (i.v.) Mitoxantrone (i.u.)
 Methotrexate (i.v.) 
Maintenance Prednisolone (oral) 
 Vincristine (ix.) 
 Mercaptopurine (oral) 
 Methotrexate (oral) 
without adequate and skilled supportive care. The following problems commonly arise.
Anaemia. Anaemia is treated with red cell concentrate infusions to maintain a haemoglobin above 100 g/1. Bleeding. Thrombocytopenic bleeding requires platelet transfusions unless the bleeding is trivial. Prophylactic platelet transfusion should be given to maintain the platelet count above 10 x 109/1. Coagulation abnormalities occur and need accurate diagnosis and treatment as appropriate, usually with fresh frozen plasma.
Infection. Fever (> 38°C) lasting over 1 hour in a neutro¬penic patient (absolute neutrophil count < 1.0 x l0y/1) indicates possible septicaemia. Parenteral broad-spectrum antibiotic therapy is essential. Empirical therapy is given with a combination of an aminoglycoside (e.g. gentamicin) and a broad-spectrum penicillin (e.g. piperacillin/tazobactam). This combination is synergistic and bactericidal and should be continued for at least 3 days after the fever has resolved. The organisms most commonly associated with severe neu¬tropenia are Gram-positive bacteria such as Staphylococcus aureus and Staph. epidermidis which are present on the skin and gain entry via cannulae and central lines. Gram-negative infections often originate from the gastrointestinal tract, which is affected by chemotherapy-induced mucositis; organisms such as Escherichia eoli, Pseudomonas and Klebsiella are more likely to cause rapid clinical deterioration and must be covered with the initial empirical therapy. Gram-positive infection may require vancomycin therapy.
Patients with lymphoblastic leukaemia are susceptible to infection with Pneumocystis carinii (now jirovecii, p. 389), which causes a severe pneumonia. Prophylaxis with co¬trimoxazole is given during chemotherapy. Diagnosis may be difficult and may require either bronchoalveolar lavage or open lung biopsy. Treatment is with high-dose co¬trimoxazole, initially intravenously, with change to oral treatment as soon as possible.
Oral and pharyngeal monilial infection is common. Fluconazole is effective for the treatment of established local infection. Prophylaxis against systemic fungal infections with either fluconazole or itraconazole is usual practice during intensive chemotherapy.
For systemic fungal infection with Candida or asper¬gillosis, intravenous amphotericin is required for at least 3 weeks, but is nephrotoxic and hepatotoxic. Renal and hepatic function should therefore be monitored closely, particularly if the patient is receiving antibiotics which are also nephrotoxic. Potassium supplementation is usually required. For patients who experience nephrotoxicity with standard amphotericin. or who require high-dose therapy for aspergillosis, lipid formulations of amphotericin can be administered without further renal deterioration. New antifungal agents such as caspofungin and voriconazole are now available in addition for treatment of fungal infection (p. 154).
Herpes simplex infection (p.303) occurs frequently round the lips and nose during ablative therapy for acute leukaemia and is treated with aciclovir. This may also be prescribed prophylactically to patients with a history of cold sores or elevated titres to herpes simplex. Herpes zoster manifesting as chicken pox or, after reactivation, as shingles (p. 305) should be treated in the early stage with high-dose aciclovir as this can be fatal in immunocompromised patients.
The value of isolation facilities. such as laminar flow rooms, is debatable but may contribute to staff awareness of careful reverse barrier nursing practice. The isolation is often psychologically stressful for the patient.
Metabolic problems. Continuous monitoring of renal, hepatic and haemostatic function is necessary, together with fluid balance monitoring. Patients are often severely anorexic as a consequence of the side-effects of therapy; they may find drinking difficult and hence require intravenous fluids and electrolytes. Renal toxicity occurs with some antibiotics (e.g. aminoglycosides) and antifungal agents (amphotericin). Cellular breakdown during induction therapy increases uric acid production, which may cause renal failure. Allopurinol and intravenous hydration are given to try to prevent this, along with close monitoring of biochemistry. Occasionally dialysis may be required.
Psychological support. This is a key aspect of care. Patients should be kept informed. and their questions answered and fears allayed as far as possible. An optimistic attitude from the staff is vital. Delusions. hallucinations and paranoia are not uncommon during periods of severe bone marrow failure and septicaemic episodes, and should be met with patience and understanding.
Alternative chemotherapy Gentle chemotherapy not designed to achieve remission may be used to curb excessive leucocyte proliferation. Drugs used for this purpose include hydroxycarbamide and mercaptopurine. The aim is to reduce the leucocyte count without inducing bone marrow failure.
Prognosis
Without treatment the median survival of patients with acute leukaemia is about 5 weeks. This may be extended to a number of months with supportive treatment. Patients who achieve remission with specific therapy have a better outlook. Around 80% of adult patients under 60 years of age with ALL or AML achive remission. Remission rates are lower for older patients. However, the relapse rate continues
24.40 OUTCOME IN ADULT ACUTE LEUKAEMIA
Disease/risk Risk factors 5-year overall
survival
AML  
Good risk Promyelocytic leukaemia: 76%
 t(15;17) 
 t(8;21) 
 inv 16 or t(16;16) 
Poor risk Cytogenetic abnormalities 21%
 -5,-7,del 
 5q, abn(3q), complex (? 5 ) 
Intermediate risk AML with none of the above 48%
ALL  
Poor risk Philadelphia chromosome 20%
 High white count 
 > 100 x 109/I 
 Abnormalities short arm 
 of chromosome 11 
 t(1;19) 
Standard ALL with none of the above 37%
to be high. Box 24.40 shows the survival in ALL and AML and the influence of prognostic features.
National and international studies have led to steady improvement in survival from leukaemia. Advances include the introduction of drugs such as ATRA (all transretinoic acid) in acute promyelocytic leukaemia; which has greatly reduced induction deaths from bleeding in this good-risk leukaemia. Current trials aim to improve survival, especially in standard and poor-risk disease, and also investigate the place of transplantation.