Myeloablative therapy is the term used for treatment that employs high-dose chemotherapy or chemotherapy plus radiation, with the aim of clearing the bone marrow completely of both benign and malignant cells. Without bone marrow replacement or ‘transplantation', the patient would die of bone marrow failure. Approaches to restore bone marrow function include the following:
■ Allogeneic bone marrow transplantation (BMT): Bone marrow or periph-eral blood stem cells from another individual, usually a human leucocyte antigen (HLA)-identical sibling, are infused intravenously following myelo-ablative therapy. Immunosuppression is required to prevent host rejection and graft-versus-host disease (GVHD). The latter is a syndrome in which donor T lymphocytes infiltrate the skin, gut and liver, causing a maculo-papular rash, diarrhoea and liver necrosis. This occurs in 30-50% of transplant recipients and is potentially fatal in some cases. Following allogeneic BMT the blood count usually recovers within 3-4 weeks. The mortality rate is 20-40%, depending on the person's age, and is often a result of infection or GVHD.
■ Autologous (the patient acts as his or her own source) stem cells: These are collected from bone marrow or peripheral blood before myeloablative chemotherapy and stored and reinfused afterwards. The main advantage is the short time for blood count recovery because peripheral blood progenitor cells are more differentiated. This technique has been particu-larly effective in relapsed leukaemias, lymphomas, myeloma and germ cell tumours.
■ Syngeneic: Donor cells are taken from an identical twin.
■ From umbilical cord blood. This is increasingly being used for adult and childhood leukaemia.
These arise as a result of the tumour itself or as a complication of treatment.
Superior vena cava syndrome can arise from any upper mediastinal mass but is most commonly associated with lung cancer and lymphoma. Presentation is with dit^iculty breathing and/or swallowing, oedematous facies and arms, and venous congestion in the neck with dilated veins in the upper chest and arms. Treatment is with immediate steroids, vascular stents, radiotherapy and chemotherapy for sensitive tumours.
Acute tumour lysis syndrome occurs as a result of treatment producing massive and rapid breakdown of tumour cells, leading to increased serum level of urate, potassium and phosphate but with hypocalcaemia. It is most commonly seen as a complication of treatment of acute leukaemia and high-grade lymphoma unless preventive measures are taken. Hyperuricaemia and hyperphosphataemia result in acute kidney injury through urate and calcium phosphate deposition in the renal tubules. Prevention and treatment is with allopurinol (p. 295), rasburicase (urate oxidase) and high fluid loads e.g. 4-5 litres daily by intravenous infusion prior to, and continuing during chemotherapy.
Spinal cord compression (p. 779), neutropenic sepsis (p. 205), hyper-calcaemia (p. 651) and raised intracranial pressure (p. 715) are discussed elsewhere.
The leukaemias are malignant neoplasms of the haemopoietic stem cells, characterized by diffuse replacement of the bone marrow by neoplastic cells. In most cases, the leukaemic cells spill over into the blood, where they may be seen in large numbers. The cells may also infiltrate the liver, spleen, lymph nodes and other tissues throughout the body. They are relatively rare dis-eases with an overall incidence of 10 per 100 000 per year.
General classitication The characteristics of leukaemic cells can be assessed by light microscopy, expression of cytosolic enzymes and expres-sion of surface antigens. These will reflect the lineage and degree of maturity of the leukaemic clone. Thus, 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:
■ Acute myeloid leukaemia (AML)
■ Acute lymphoblastic leukaemia (ALL)
■ Chronic myeloid leukaemia (CML)
■ Chronic lymphocytic leukaemia (CLL).
In most cases the aetiology is unknown though several factors are associated.
Genetic factors Genetic factors are suggested by the increased incidence in patients with chromosomal disorders (e.g. Down's syndrome) and in identi-cal twins of affected patients. Chromosomal abnormalities have been described in patients with leukaemia. The earliest described was the Phila-delphia (Ph) chromosome, found in 95% of cases with CML and some patients with ALL. In the Ph chromosome the long arm of chromosome 22 is shortened by reciprocal translocation to the long arm of chromosome 9 (t(9;22)). The protein product of the resulting ‘fusion' gene, BCR-ABL, has tyrosine kinase activity, and enhanced phosphorylating activity compared with the normal protein, resulting in altered cell growth, stromal attachment and apoptosis.
The leukaemic cells of most patients with acute promyelocytic leukaemia (APML) have the translocation t(15;17) involving the retinoic acid receptor alpha (RARa) on chromosome 17 and the promyelocytic leukaemia gene (PML) on chromosome 15. The resulting PML-RARa fusion protein shows reduced sensitivity to retinoic acid and prevents differentiation of myeloid cells.
■ Chemicals, e.g. benzene compounds used in industry.
■ Drugs, e.g. AML occurs after treatment with alkylating agents e.g. melphalan.
■ Radiation exposure can induce genetic damage to haemopoietic precur-sors and increased incidences of leukaemia have been seen in survivors of Hiroshima and Nagasaki and in patients treated with ionizing radiation.
The acute leukaemias are characterized by a clonal proliferation of myeloid or lymphoid precursors with reduced capacity to differentiate into more mature cellular elements. There is accumulation of leukaemic cells in the bone marrow, peripheral blood and other tissues with a reduction in red cells, platelets and neutrophils.
Both types of acute leukaemia can occur in all age groups, but ALL is pre-dominantly a disease of childhood, whereas AML is seen most frequently in older adults (middle-aged and elderly).
These are the result of marrow failure: anaemia, bleeding and infection, e.g. sore throat and pneumonia. Sometimes there is peripheral lymphadenopathy and hepatosplenomegaly.
A definitive diagnosis is made on the peripheral blood film and a bone marrow aspirate. The various subtypes (Table 6.2) are classified on the basis of morphology and immunophenotyping, and cytogenetic studies of blast cells. Auer rods (a rod-like conglomeration of granules in the cytoplasm) within blast cells are pathognomonic of AML. If the patient has a fever, blood cul-tures and chest radiograph are essential.
■ Blood count shows anaemia and thrombocytopenia. The white cell count is usually raised, but may be normal or low.
■ Blood film shows characteristic leukaemic blast cells.
|Table 6.2 World Health Organization classification of acute leukaemia|
|a. AML (acute myeloid leukaemia)|
1. AML with recurrent cytogenetic abnormalities (including acute promyelocytic leukaemia with t(15;17) or variants
2. AML with multilineage dysplasia (often secondary to a pre-existing MDS)
3. AML and MDS, therapy-related, occurring after chemotherapy or radiotherapy
4. AML - not otherwise categorized
|b. ALL (acute lymphoblastic leukaemia)|
1. Precursor B cell acute lymphoblastic leukaemia
2. Burkitt cell leukaemia
3. Precursor T cell acute lymphoblastic leukaemia
|MDS, myeỉodyspỉastic syndromes.|
■ Bone marrow aspirate usually shows increased cellularity, with a high percentage of abnormal lymphoid or myeloid blast cells.
■ Lumbar puncture and cerebrospinal fluid examination are performed after blasts have been cleared from peripheral blood in all patients with ALL and AML with monoblast/monocytic component as the risk of central nervous system (CNS) involvement is high.
The initial requirement of therapy is to return the peripheral blood and bone marrow to normal (complete remission) with ‘induction chemotherapy' tailored to the particular leukaemia and the individual patient's risk factors. The risk of failure of treatment is based on the cytogenetic pattern. Successful remission induction is always followed by further treatment (consolidation), the details being determined by the type of leukaemia and the patient's risk factors (and the patient's tolerance of treatment). Recurrence is almost invari-able if ‘consolidation' therapy is not given.
Supportive care Before starting treatment the following need to be performed:
■ Correction of anaemia and thrombocytopenia by administration of blood and platelets
■ Treatment of infection with intravenous antibiotics
■ Prevention of the acute tumour lysis syndrome (p. 256).
Acute myeloid leukaemia
Treatment with curative intent is undertaken in the majority of adults below the age of 60 years, provided there is no significant comorbidity.
■ Low risk of treatment failure (based on the cytogenetic pattern) A moderately intensive combination of intravenous chemotherapy, e.g. cytosine arabinoside (cytarabine) and daunorubicin is given at intervals to allow marrow recovery in between. This is followed by consolidation therapy with a minimum of four cycles of treatment given at 3-4-week intervals.
■ Intermediate risk Consolidating chemotherapy to induce remission fol-lowed by sibling matched allogeneic bone marrow transplantation, despite its attendant risks.
■ High risk of treatment failure. This is only curable with allogeneic trans-plantation but unfortunately ‘high risk' is commoner with advancing age when the toxicity of this treatment increases greatly.
Acute promyelocytic leukaemia
APML is specifically associated with disseminated intravascular coagulation (DIC), which may worsen when treatment is started. Management of DIC is discussed on page 235. The empirical discovery that all-Érans-retinoic acid (ATRA) causes differentiation of promyelocytes and rapid reversal of the bleeding tendency was a major breakthrough. It is now conventional to treat APML with ATRA combined with chemotherapy and to follow successful remission induction with maintenance ATRA. Remission induction therapy as in other forms of AML is also necessary for long-term survival.
Prognosis Complete remission will be achieved in about three-quarters of patients under the age of 60, failure being due to either resistant leukaemia or death due to infection or (rarely) bleeding. About 50% of those entering complete remission will be cured. (i.e. approximately 30% overall). The management of recurrence is undertaken on an individual basis, since the overall prognosis is very poor despite the fact that second remissions may be achieved. Long survival following recurrence is rarely achieved without allogeneic transplantation.
Acute lymphoblastic leukaemia
The principles of treatment differs in detail from that for AML. Remission induction is undertaken with combination chemotherapy including vincristine, dexamethasone, asparaginase and daunorubicin. Details of consolidation will be determined by the anticipated risk of failure but is usually with intensive chemotherapy and then maintenance therapy for two years to reduce the risk of disease recurrence. ALL has a propensity to involve the CNS, so treatment also includes prophylactic intrathecal drugs, methotrexate or cytosine arabi-noside (cytarabine). Cranial irradiation is used in those at very high risk or in those with symptoms.
The prognosis in children with ALL is excellent with almost all achieving complete remission and with 80% being alive and disease free at 5 years. The results in adults are not so good, the prognosis getting worse with advancing years. Overall about 70-80% achieve complete remission with only about 30% being cured.
Chronic myeloid leukaemia
CML occurs most commonly in middle age and is characterized by the pres-ence of the Philadelphia (Ph) chromosome. There is an insidious onset, with fever, weight loss, sweating and symptoms of anaemia. Massive spleno-megaly is characteristic.
Untreated, this chronic phase lasts 3-4 years. This is usually followed by blast transformation, with the development of acute leukaemia (usually acute myeloid) and, commonly, rapid death. Less frequently, CML transforms into myelofibrosis, death ensuing from bone marrow failure.
■ Blood count usually shows anaemia and a raised white cell count (often >100 X 109/L). The platelet count may be low, normal or raised.
■ Bone marrow aspirate shows a hypercellular marrow with an increase in myeloid progenitors. The Ph chromosome and the BCR-ABL oncogene are shown by cytogenetics and reverse transcriptase polymerase chain reaction (RT-PCR).
Imatinib, a tyrosine kinase inhibitor that specifically blocks the enzymatic action of the BCR-ABL fusion protein, is first-line treatment for the chronic phase. Imatinib produces a complete haematological response in over 95% of patients, and 70-80% of these have no detectable BCR-ABL transcripts in the blood. Event-free, and overall, survival appear to be better than for other treatments. Imatinib can be continued indefinitely.
In the acute phase (blast transformation) most patients have only a short-lived response to imatinib, and other chemotherapy as for acute leukaemia is used in the hope of achieving a second chronic phase.
Chronic lymphocytic leukaemia
CLL is an incurable disease of older people, characterized by an uncontrolled proliferation and accumulation of mature B lymphocytes (although T cell CLL does also occur).
CLL usually follows an indolent course. Early CLL is generally asymptomatic and isolated peripheral blood lymphocytosis is frequent. Symptoms are a consequence of bone marrow failure: anaemia, infections and bleeding. An autoimmune haemolysis contributes to the anaemia. Some patients may be asymptomatic, the diagnosis being a chance finding on the basis of a blood count done for a different reason. There may be lymphadenopathy and, in advanced disease, hepatosplenomegaly.
■ Blood count shows a raised white cell count with lymphocytosis (>5 X 109/L). There may be anaemia and thrombocytopenia.
■ Blood film shows small lymphocytes of mature appearance with ‘smear or smudge cells', an artefactual finding due to cell rupture while the film is being made.
■ Bone marrow reflects peripheral blood usually heavily infiltrated with lymphocytes.
■ Immunophenotyping is essential to exclude reactive lymphocytosis and other lymphoid neoplasms.
■ Cytogenetics to characterize the specific mutation can be helpful in assessing prognosis.
The decision to treat depends on the stage of the disease and more recently on cytogenetic markers. Early-stage disease is treated expectantly whereas advanced-stage disease is always treated immediately. Other indications for treatment include anaemia, recurrent infections, splenic discomfort and pro-gressive disease.
Oral chlorambucil, with or without prednisolone, reduces the blood count and decreases lymphadenopathy and splenomegaly, and successfully palli-ates the disease. The bone marrow rarely returns to normal.
The purine analogue fludarabine in combination with cyclophosphamide and/or rituximab (p. 254) has a greater impact on the bone marrow and can induce complete remission. Alemtuzumab (p. 254) is used in patients in whom there is disease progression after treatment with fludarabine.
The median survival from diagnosis is very variable and correlates closely with disease stage at diagnosis and cytogenetic findings, e.g. patients with either 11q or 17p deletions (the sites of two tumour suppressor genes) are at high risk of not responding to initial treatment and rapid progression. In other patients there is near normal life expectancy.
1. Ethics and communication
2. Infectious diseases
3. Gastroenterology and nutrition
4. Liver, biliary tract and pancreatic disease
Liver, biliary tract and pancreatic disease
LIVER BIOCHEMISTRY AND LIVER FUNCTION TESTS
SYMPTOMS AND SIGNS OF LIVER DISEASE
NON - ALCOHOLIC FATTY LIVER DISEASE (NAFLD)
COMPLICATIONS AND EFFECTS OF CIRRHOSIS
TYPES OF CHRONIC LIVER DISEASE AND CIRRHOSIS
PRIMARY SCLEROSING CHOLANGITIS
BUDD - CHIARI SYNDROME
LIVER DISEASE IN PREGNANCY
CARCINOMA OF THE PANCREAS
NEUROENDOCRINE TUMOURS OF THE PANCREAS
5. Haematological disease
Assessment and treatment of suspected neutropenic sepsis
INHERITED HAEMOLYTIC ANAEMIAS
ACQUIRED HAEMOLYTIC ANAEMIA
THE WHITE CELL
HAEMOSTASIS AND THROMBOSIS
6. Malignant disease
COMMON INVESTIGATIONS IN MUSCULOSKELETAL DISEASE
COMMON REGIONAL MUSCULOSKELETAL PROBLEMS
THE SERONEGATIVE SPONDYLOARTHROPATHIES
Clinical features, Investigations
INFECTION OF JOINTS AND BONES
AUTOIMMUNE RHEUMATIC DISEASES
SYSTEMIC INFLAMMATORY VASCULITIS
DISEASES OF BONE
8. Water, electrolytes and acid–base balance
WATER AND ELECTROLYTE REQUIREMENTS
BODY FLUID COMPARTMENTS
REGULATION OF BODY FLUID HOMEOSTASIS
PLASMA OSMOLALITY AND DISORDERS OF SODIUM REGULATION
DISORDERS OF POTASSIUM REGULATION
DISORDERS OF MAGNESIUM REGULATION
DISORDERS OF ACID - BASE BALANCE
9. Renal disease
INVESTIGATION OF RENAL DISEASE
URINARY TRACT INFECTION
HYPERTENSION AND THE KIDNEY
RENAL CALCULI AND NEPHROCALCINOSIS
URINARY TRACT OBSTRUCTION
ACUTE RENAL FAILURE/ACUTE KIDNEY INJURY
CHRONIC KIDNEY DISEASE
RENAL REPLACEMENT THERAPY
CYSTIC RENAL DISEASE
TUMOURS OF THE KIDNEY AND GENITOURINARY TRACT
DISEASES OF THE PROSTATE GLAND
10. Cardiovascular disease
COMMON PRESENTING SYMPTOMS OF HEART DISEASE
INVESTIGATIONS IN CARDIAC DISEASE
ISCHAEMIC HEART DISEASE
VALVULAR HEART DISEASE
PULMONARY HEART DISEASE
ARTERIAL AND VENOUS DISEASE
DRUGS FOR ARRHYTHMIAS
DRUGS FOR HEART FAILURE
DRUGS AFFECTING THE RENIN - ANGIOTENSIN SYSTEM
NITRATES, CALCIUM - CHANNEL BLOCKERS AND POTASSIUM - CHANNEL ACTIVATORS
11. Respiratory disease
12. Intensive care medicine
13. Drug therapy, poisoning, and alcohol misuse
14. Endocrine disease
PITUITARY HYPERSECRETION SYNDROMES
THE THYROID AXIS
MALE REPRODUCTION AND SEX
FEMALE REPRODUCTION AND SEX
THE GLUCOCORTICOID AXIS
THE THIRST AXIS
DISORDERS OF CALCIUM METABOLISM
DISORDERS OF PHOSPHATE CONCENTRATION
ENDOCRINOLOGY OF BLOOD PRESSURE CONTROL
DISORDERS OF TEMPERATURE REGULATION
15. Diabetes mellitus and other disorders of metabolism
16. The special senses
COMMON NEUROLOGICAL SYMPTOMS
COORDINATION OF MOVEMENT
THE CRANIAL NERVES
COMMON INVESTIGATIONS IN NEUROLOGICAL DISEASE
UNCONSCIOUSNESS AND COMA
STROKE AND CEREBROVASCULAR DISEASE
EPILEPSY AND LOSS OF CONSCIOUSNESS
NERVOUS SYSTEM INFECTION AND INFLAMMATION
HEADACHE, MIGRAINE AND FACIAL PAIN
SPINAL CORD DISEASE
DEGENERATIVE NEURONAL DISEASES
DISEASES OF THE PERIPHERAL NERVES