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Haematological disorders
packed RBCs and, where possible, should be appropriately cross-matched. In cases of emergency, type O RhDnegative blood can be given. Regular blood transfusion
may be necessary for chronic anaemia which is not corrected by supplements. Table36.1 summarizes the compli-
cations of transfusion.
Splenectomy
Splenectomy is useful in cases of anaemia related to sickle
cell disease, thalassaemia and essential thrombocytopenia. Anaemias related to lymphoproliferative disease (myelofibrosis, lymphoma and leukaemia) also respond well
to the procedure. Complications of splenectomy include
thrombocytosis and increased susceptibility to infection with encapsulated bacteria (mainly pneumococcus,
Table36.1 Complications associated with blood
transfusion
Complication Cause
Haemolytic reaction ABO incompatibility (acute,
Anaphylaxis Hypersensitivity to plasma
Febrile reaction Antibodies to white cells
Volume overload Particularly the elderly and in
Coagulopathies Platelets and clotting factors
Infection Virus (HIV, hepatitis B virus,
Haemosiderosis With repeated transfusions
Alloimmunization Antibodies may develop into
Graft-versus-host
disease
Air embolism Particularly if given via central
Thrombophlebitis At cannula site
Transfusion-associated
lung injury
CMV, Cytomegalovirus; EBV, Epstein–Barr virus; HIV, human
immunodeficiency virus.
severe), extravascular
haemolysis (delayed by 3days
to 3weeks, mild/clinically
silent)
proteins
megaloblastic anaemia
are reduced by a dilutional
effect in massive transfusion
hepatitis C virus, EBV, CMV),
gram-negative bacteria
(uncommon)
red cells, leucocytes, platelets
and plasma proteins despite
compatible blood being
received; this may cause
problems the next time the
patient receives a transfusion
Uncommon: preventable
by use of irradiated blood
(important in transplant
recipients)
lines
Unpredictable, noncardiogenic
pulmonary oedema
meningococcus and Haemophilus influenzae type b).
Patients should be immunized with vaccines against these
organisms 4–6weeks before elective splenectomy, if possible. Lifelong daily treatment with penicillin or macrolides
for prophylaxis is often started after splenectomy.
Erythropoietin
Erythropoietin (EPO)-stimulating agents are recommended
for use in the management of anaemia associated with
chronic renal failure. The response is dependent on the individual patient, the degree of anaemia, the stage of kidney
disease and the presence of adverse factors (e.g. iron deficiency). Close monitoring of therapy is needed, and complications include hypertension, increase in the number of
platelets, thromboembolic events and pure RBC aplasia.
Causes of anaemia
Some other causes of anaemia commonly seen in daily
practice are described next.
Anaemia of chronic disease
Clinical features
Many chronic diseases, particularly infective, inflammatory
or malignant conditions, are associated with anaemia. The
pathogenesis is multifactorial, with an inappropriate utilization of adequate iron stores, reduced EPO production
and response and reduced survival of RBCs. Anaemia of
chronic kidney disease is thought to be caused by slightly
different processes. Here anaemia arises due to a proportional decrease in EPO production with a decline in glomerular filtration rate. Increase in bleeding tendency due
to uraemia-mediated platelet dysfunction, the presence of
uraemic inhibitors (e.g. parathyroid hormone, cytokine inhibitors) and no reticulocyte response are also present.
The presentation can be subtle in people who already
have chronic disease. Typical symptoms and signs include
pallor, tiredness, breathlessness and tachycardia.
Blood tests usually show:
• Normochromic normocytic anaemia (may also be
hypochromic microcytic).
• Low serum iron level but normal/high serum ferritin
level.
• Increased iron stores in bone marrow.
• Low total iron-binding capacity. This helps differentiate
anaemia of chronic disease from iron-deficiency
anaemia when total iron-binding capacity is raised.
COMMON PITFALLS
Remember that ferritin is an acute phase protein
and should not be used to diagnose anaemia in
acute illness.
358
Anaemia
3636
Management
Treatment of the underlying condition should normalize
the Hb level. If anaemia is mild, no treatment is necessary.
Iron supplements should be used only if iron deficiency has
been established.
If the anaemia is severe enough to be symptomatic, or if the
patient’s Hb level is below a ‘transfusion trigger’ of between
60 and 80 g/L according to which protocol is being used,
transfusion with packed RBCs is recommended. Novel EPOstimulating proteins or recombinant human EPO have also
been recommended for use in some other conditions. These
include anaemia of chronic kidney disease, chemotherapyinduced anaemia, anaemia associated with rheumatoid
arthritis, heart failure, inflammatory bowel disease and cancer.
Haemolytic anaemia
Clinical features
In haemolytic anaemias the normal RBC lifespan of
120days is reduced. RBC lysis can occur in two ways:
• Intravascular: in peripheral circulation, most
commonly due to complement activation, trauma
or extrinsic factors. Examples include glucose
6-phosphate dehydrogenase deficiency, prosthetic
cardiac valves, thrombotic thrombocytopenic
purpura and disseminated intravascular coagulation
(DIC).
• Extravascular: in the monocyte–macrophage system
(liver, spleen and lymph nodes). This method is most
common and most likely to occur because of surface
antibodies on RBCs or intrinsic RBC defects (e.g.
hereditary spherocytosis).
Anaemia can be genetic (e.g. sickle cell disease, glucose
6-phosphate dehydrogenase deficiency, hereditary spherocytosis) or acquired. Acquired anaemias can be further divided into:
• immune (e.g. haemolytic disease of the newborn,
blood transfusion-related haemolysis);
• autoimmune:
○
warm antibody type: severer with a positive
Coombs test result (lymphoma, leukaemia);
○
cold antibody type: usually mild (paroxysmal cold
haemoglobinuria, infections, e.g. Mycoplasma
pneumoniae, or infectious mononucleosis;
lymphoma);
○
drug related (penicillins, sulphonamides).
• nonimmune (trauma, e.g. haemolytic uraemic
syndrome, DIC; infection, liver disease).
The signs and symptoms are due to both anaemia and underlying disease. Jaundice can be present because of raised
unconjugated bilirubin level and gallstones can occur.
Blood investigations show:
• low Hb level
• spherocytes, fragmented and nucleated RBC on
blood film
• raised lactate dehydrogenase (LDH) level
• raised reticulocyte count
• reduced level of or absent haptoglobin
Management
General measures include folic acid administration (haemolysis may cause deficiency) and transfusion therapy for
severe cases (as the risk of acute haemolysis of transfused
blood is high). Iron replacement is needed in cases of severe
intravascular haemolysis where persistent haemoglobinuria
causes iron loss. Immunosuppressive therapies with steroids and biological agents and splenectomy are indicated
for severe cases.
Sickle cell anaemia
Sickle cell anaemia is an inherited (autosomal recessive)
condition that most commonly affects Afro-Caribbeans but
is also found in the Middle East and Mediterranean. A single base mutation in the DNA on chromosome 11 causes
substitution of glutamic acid for valine at position 6 in the
Hb beta chain, causing the formation of HbS. When the patient is heterozygous for the gene, it provides an advantage
in infection with Plasmodium falciparum (falciparum malaria). If the patient is homozygous for the gene, it is a cause
of sickle cell disease. Sickle cell disease can also be caused by
other inherited disorders which result in the production of
the defective Hb: HbS.
Clinical features
When HbS becomes deoxygenated, it aggregates in an organized fashion, forming polymers within the RBCs that are
less soluble and less deformable. As a result, the erythrocyte shape becomes distorted and changes from a biconcave
disc to a ‘sickle’ shape; the sickle cells cannot readily pass
through the microcirculation and become trapped in small
vessels (causing infarction) and in the spleen, where they
are destroyed.
In the homozygous patient (HbSS), severity is variable
and dependent on factors such as the level of fetal Hb (HbF)
and the coinheritance of the α-thalassaemia trait. It may
present from the third month of life onwards, when levels
of HbF start to fall. There is chronic haemolysis, with intermittent crises and complications. The most common types
of sickle cell anaemia crisis are:
• Aplastic: temporary cessation of erythropoiesis causing
anaemia. Commonly precipitated by parvovirus
B19 infection. Profound anaemia usually requires
transfusion.
• Sequestration: sudden enlargement of spleen
causing a drop in Hb level, circulatory collapse and
hypovolemic shock. Occurs mainly in young children
and babies. If unrecognized or left untreated, the
condition has high mortality. Transfusion is the
treatment of choice.
• Vasoocclusive: due to vascular occlusion. Can be
precipitated by dehydration, hypoxia, infections or cold
359
Haematological disorders
exposure. Almost any organ can be affected. Swollen,
painful joints, lung involvement and acute abdomen
are common. Large-vessel occlusion can cause serious
complications, including thromboembolic stroke or
acute sickle chest syndrome.
• Hyperhaemolytic: excessive haemolysis causing a fall in
Hb levels.
The investigations are similar to those described for haemolytic anaemias but additionally should include a blood
film to search for sickle cells, target cells and nucleated
RBCs. Hb electrophoresis or chromatography demonstrates the presence of HbS and HbSS and their relative
proportions.
Management
Patients should be appropriately educated regarding precipitating factors and complications. Management and regular
review by a multidisciplinary specialist team is necessary.
Immunization against encapsulated bacteria and prompt
treatment of infection is extremely important. During episodes of crisis, supportive care must include effective analgesia as well as optimization of hydration and oxygenation.
Transfusion therapy is the key intervention to reduce mortality and morbidity. Other treatments include:
• Hydroxycarbamide (hydroxyurea): indicated in
patients with painful crises, significant anaemia or
other complications. It increases HbF levels and
reduces the frequency of crises. It causes a macrocytosis
and myelosuppression in a dose-dependent manner,
and there may be a risk of leukaemia with long-term
treatment.
• Folate and zinc replacement.
• Prophylactic penicillin at diagnosis.
Haematopoietic stem cell transplantation is the only curative treatment but is reserved for those with a severe clinical
course and an HLA-matched sibling donor.
The prognosis of the condition differs because of variable clinical presentations. Median life expectancy is estimated between 40 and 60years of age, with death most
commonly due to infection.
Table36.2 Summary of normal haemoglobin synthesis
Haemoglobin
feature Characteristic
Structure Composed of four polypeptide
chains (tetramer)
At various stages of development,
different polypeptide chains are
produced (ζ, ε, α, δ and β)
HbF is composed of two α chains
and two γ chains (α2, γ2) and is the
major haemoglobin of intrauterine
life. Its level declines rapidly around
birth and it constitutes less than 1%
of haemoglobin by 6months of age.
HbF is produced predominantly by
the liver until 30weeks, after which
the bone marrow takes over. It has
an avid affinity for oxygen
Production of β chains increases
rapidly at 36weeks’ gestation; 96%
of adult haemoglobin is HbA (α2,
β2)., 3.5% is HbA2 (α2, δ 2), with the
remainder being HbF
Genetics The genes for the globin chains
α and ζ are found clustered on
chromosome 16. The genes for the
remaining chains are located in a
cluster on chromosome 11
Each person has four α genes
(two on each chromosome 16)
and two β genes (one on each
chromosome 11)
HbA, Haemoglobin A; HbF, fetal haemoglobin.
according to which Hb chain they affect, and the two types
are α-thalassaemia and β thalassaemia. α-Thalassaemia
affects those in Southeast Asia, Africa and India, whereas
β-thalassaemia is found in China, the Mediterranean and
the Middle East. Thalassaemia also provides an advantage
in infection with P. falciparum (falciparum malaria).
HINTS AND TIPS
Do not deny sickle cell patients adequate analgesia
during a crisis through a misplaced fear of drug
dependency. Most patients nowadays will have a
personalized crisis management plan that states
preferred analgesia.
Thalassaemia
Thalassaemias are a group of autosomal recessive diseases of defective Hb production. Normal Hb synthesis
is summarized in Table 36.2. Thalassaemias are classified
360
Clinical features
The clinical presentation depends on the underlying abnormality, as described in Tables 36.3 and 36.4. Carriers
with only one defective copy of the gene (or two in α-
thalassaemia) are usually asymptomatic. Reduced production of one or more of the Hb chains (most importantly α or
β) results in a relative excess and accumulation of the other
chain (‘imbalanced globin chain synthesis’). The unstable
Hb precipitates ineffective erythropoiesis and haemolysis.
Other features include:
• skeletal change due to the expansion of erythropoietic
bone marrow
• aplastic crises with parvovirus B19 infection
Anaemia
Table36.3 Characteristics of thalassaemia
Silent carrier α-Thalassaemia trait HbH disease Hydrops fetalis
Genetic abnormality One α gene
Clinical features Asymptomatic Usually asymptomatic Haemolytic anaemia
Haematological
findings
Survival Normal Normal Variable Stillborn or death
HbH, Haemoglobin H.
deleted
Usually no
abnormality
Two α genes deleted Three α genes deleted Four α genes deleted
Hepatosplenomegaly
Gross oedema
Hypoalbuminaemia
Extramedullary
haematopoiesis
Hypochromia
Microcytosis
Reticulocytosis
Target cells
Nucleated red cells
Haemoglobin Bart’s on
electrophoresis
shortly after birth
Hypochromia
Microcytosis
Splenomegaly
Bone changes
May be symptomatic at
birth
Hypochromia
Microcytosis
Reticulocytosis
HbH (β4) on electrophoresis
Inclusion bodies with cresyl
blue
3636
Table36.4 Clinical features of β-thalassaemias
β-Thalassaemia minor β-Thalassaemia intermedia β-Thalassaemia major
Genetic abnormality Heterozygous abnormality in
β-globin gene
Clinical features Usually asymptomatic
Splenomegaly on imaging
Haematological findings Mild anaemia
Microcytosis with normal
RDW Hypochromia
Target cells
Poikilocytosis
HbA2 level high
HbF level may be raised
Survival Normal Variable. Usually survive
HbA, Haemoglobin A; HbF, fetal haemoglobin; RBC, red blood cell; RDW, red blood cell distribution width.
Homozygous or mixed
heterozygous abnormality in
β-globin gene
Variable – possible
features: extramedullary
haematopoiesis,
hepatosplenomegaly,
skeletal deformity,
gallstones, leg ulcers,
thrombosis, pulmonary
hypertension
Moderate anaemia but
usually not transfusion
dependent
Microcytosis
Hypochromia
Target cells
Poikilocytosis
to adulthood even without
treatment
Homozygous abnormality in
β-globin gene
Failure to thrive (3–6months)
Jaundice
Extramedullary
haematopoiesis
Hepatosplenomegaly
Skeletal deformity
Haemosiderosis
Recurrent infections
Cardiac failure
Gallstones
Leg ulcers
Transfusion-dependent severe
anaemia
Microcytosis
Hypochromia
Target cells
Anisopoikilocytosis
Reticulocytosis
Nucleated RBCs
Basophilic stippling
Inclusion bodies on supravital
staining with methyl violet
HbA absent or very low level
HbF level high
Death in childhood without
treatment; bone marrow
transplantation may be
curative
361
Haematological disorders
Management
• Asymptomatic carriers do not generally require
treatment.
• All patients should be offered disease education and
psychological support.
• Transfusion to maintain an adequate Hb level (>95 g/L)
especially in periods of rapid growth, infection or
pregnancy is recommended.
• In cases of hypersplenism, splenectomy should be
considered.
• Iron chelation to prevent haemosiderosis using
desferrioxamine.
• The only treatment for the disease is stem cell
transplantation.
• Prenatal diagnosis and genetic counselling is
available.
Aplastic anaemia
This refers to failure of haemopoiesis and pancytopenia (i.e. deficiency of all three marrow cell lines) due to
the hypocellular bone marrow. Most cases are acquired
and immune mediated, but inherited causes also exist
(Table36.5).
Clinical features
Most commonly patients will present with symptoms of
anaemia (pallor, fatigue, dyspnoea and palpitations) and
thrombocytopenia (skin or mucosal haemorrhage, petechial
rashes). Susceptibility to infection due to leucopenia is a less
common presenting feature.
Investigations in a suspected patient will show pancytopenia in the absence of compensatory reticulocytosis and
hypocellular bone marrow on biopsy.
Management
• Treatment is based on the degree of cytopenia and not
marrow cellularity (asymptomatic individuals may not
need treatment).
• Supportive measures include platelet and blood
transfusion, and prompt treatment of infection.
Table36.5 Causes of aplastic anaemia
Acquired Congenital
Idiopathic
Infection (5%–10% of cases are
preceded by hepatitis infection)
EBV, HIV, mycobacteria
Toxic exposure (e.g. benzene)
Drugs (chloramphenicol, gold,
sulphonamides, penicillamine,
chloroquine, carbamazepine)
EBV, Epstein–Barr virus; HIV, human immunodeficiency virus.
Fanconi anaemia
Diamond–Blackfan
syndrome
• Bone marrow stem cell transplantation is
recommended, especially for younger patients.
• Immunosuppressive therapy is usually combined and
can include antithymocyte globulin or antilymphocyte
globulin and ciclosporin.
LEUKAEMIA
The leukaemias are a group of conditions characterized by
malignant proliferation of leucocytes in the bone marrow.
In the acute leukaemias, there is a proliferation of early
lymphoid and myeloid precursors (blasts), which do not
mature. The clinical course is very aggressive, and they are
rapidly fatal without treatment. The chronic leukaemias
have a more indolent course and are characterized by proliferation of lymphoid and myeloid cells that would have
reached maturity.
COMMUNICATION
Leukaemia is a frightening diagnosis for most
patients. Clear communication about disease
prognosis and treatment is essential.
Acute lymphoblastic leukaemia
Aetiology
Acute lymphoblastic leukaemia (ALL) is the most common
malignancy in children, with about three in four cases occurring in children below the age of 6years. It represents
12% of all leukaemias but 80% in children. Peak incidence
is between 2 and 4years of age.
Its cause is unknown but is thought to be multifactorial.
Genetic, environmental and infectious predispositions have
been suggested.
Pathology
This leukaemia results from malignant transformation of
a clone of lymphoid progenitor cells. In most cases, it is
from B-cell precursors (80%). Produced lymphoblasts replace normal marrow components, resulting in a marked
decreased production of normal blood cells, which then
causes anaemia, thrombocytopenia and neutropenia.
Abnormal blasts can spill out of bone marrow and infiltrate other structures. In the case of ALL this is particularly
visible in the spleen, lymph nodes and liver.
Clinical features
The history is short and usually the initial complaint is
fatigue and generalized malaise that quickly progresses to
362
Leukaemia
3636
bone marrow failure (Table36.6). The signs and symptoms
can include:
• fatigue, dizziness, palpitations
• joint and bone pain
• recurrent and severe infections
• fever without obvious infection
• haemorrhagic or thrombotic complications due to low
platelet levels or DIC, including frequent nosebleeds,
menorrhagia and petechial rash
• lymphadenopathy and hepatosplenomegaly on
examination
• symptoms or signs due to involvement of other organs
(e.g. meningism or cranial neuropathies with central
nervous system (CNS) involvement)
Investigations will show:
• normochromic normocytic anaemia with low
reticulocyte count
• normal, high or low white cell count but there is usually
neutropenia
• thrombocytopenia
• hypercellular bone marrow dominated by lymphoblasts
(>20% required for diagnosis)
Immunophenotyping (e.g. using flow cytometry) will reveal
the subtype of leukaemia.
Treatment and prognosis
Patients with ALL are typically treated with staged chemotherapy, except for mature B-cell ALL (Burkitt lymphoma),
for which the chemotherapy is typically short. The stages of
a typical regimen include:
• Remission induction: elimination of 99% of leukaemic
cells and restoration of normal haemopoiesis. Usually,
therapy is with steroids, chemotherapy medication and
antimicrobials.
• Consolidation: intensifies remission induction.
• Maintenance: usually with weekly or daily cytotoxic
medication.
Generalized maintenance measures should be available to support cytotoxic treatment and usually include
replacement of blood cells and antibiotics. CNS prophylaxis is very important, and includes intrathecal methotrexate therapy, intrathecal triple therapy (methotrexate,
steroids and a cytotoxic drug) or systemic combination
therapy.
Table36.6 Symptoms of bone marrow failure
Cells affected Result Manifestation
Red cell
precursors
White cell
precursors
Platelet
precursors
Anaemia Lethargy,
dyspnoea, pallor
Neutropenia Recurrent
infections, fever
Thrombocytopenia Bleeding, bruising,
purpura
Allogeneic bone marrow transplantation often improves
outcomes and can be curative. It is usually reserved for patients with high-risk ALL.
Prognosis is strictly related to the age of the patient. Cure
rates reach 90% in children and drop to 10% in frail and
elderly patients. Adverse prognostic characteristics include:
• age less than 1year or more than 10years
• presenting leucocyte count greater than 50 × 109/L
• male sex
• CNS involvement
An important good prognostic indicator is an early
response to chemotherapy. The overall 10-year survival
rate for ALL is about 63% in children and 25%–35% in
adults.
Acute myeloid leukaemia
Acute myeloid leukaemia (AML) results from a malignant
arrest of bone marrow cells in early stages of development.
It is the most common form of leukaemia in adults.
Aetiology
Most cases arise with no clear cause, although many risks
are recognized:
• ionizing radiation and chemical exposure (e.g.
survivors of the atomic bomb dropped on
Hiroshima);
• previous chemotherapy: alkylating agents;
• predisposing diseases: myeloproliferative diseases,
aplastic anaemia and myelodysplasia can transform
to acute leukaemia; congenital disease, including
Down syndrome, and neurofibromatosis are risk
factors.
Pathology
The malignant cells in AML are myeloblasts. Accumulation
of these immature haematopoietic blast cells in the bone
marrow can cause marrow failure (>20% leukaemic cells is
diagnostic). Immature cells can arrest at various stages of
differentiation, giving rise to heterogenicity of the condition
(Table36.7). Blasts can infiltrate the liver, spleen, skin, gums
and, less commonly, the CNS.
Clinical features
The presentation may be related to bone marrow failure
(see Table36.6) or to organ infiltration. In young patients
the course is usually more acute when compared with older
adults, who present with more chronic fatigue and malaise.
Characteristic features include:
• Median age at presentation is 67years (the incidence
rises with increasing age).
• Bone pain, joint pain and malaise.
• Significant hepatomegaly and splenomegaly
(lymphadenopathy is rare).
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Haematological disorders
Table36.7 World Health Organization classification of
acute myeloid leukaemia
AML with recurrent
genetic abnormalities
AML with multilineage
dysplasia
AML/MDS related to t
therapy
AML not otherwise
categorized
AML, Acute myeloid leukaemia; DIC, disseminated intravascular
coagulation; MDS, myelodysplastic syndrome.
Generally better prognosis.
Includes t(8:21), Auer
rods seen; t(15:17),
promyelocytic leukaemia.
DIC may occur
With or without preceding
myeloproliferative disorder
or myelodysplasia
Following alkylating agents
or radiation
• Bleeding that may be caused by thrombocytopenia,
coagulopathy and resulting DIC (haemorrhage in
the CNS, lungs or gastrointestinal systems can be
life-threatening).
• On the skin, there may be petechial rash or larger
ecchymoses and leukaemia cutis.
• Gums are commonly involved, resulting in gingivitis
and swollen bleeding gums that may lead to initial
presentation at a dentist.
• White blood cells (WBCs) count can be high and,
even in presence of neutropenia, cause persistent
fever. If WBC counts are extremely elevated (>100 ×
109/L) leucostasis (a hyperviscosity state), respiratory
distress and altered mental status can occur, which is
considered a medical emergency.
Investigating the patient with suspected AML requires
a blood film and bone marrow analysis for diagnosis.
Cytochemistry will allow classification into subtypes. Bone
marrow is hypercellular with blasts that may contain Auer
rods (characteristic of AML). Cytogenetic studies can be
performed to further assess prognosis and consider individually tailored treatment.
Treatment and prognosis
Treatment should be managed in a specialized unit. A good
response to treatment is blast clearance in the bone marrow
to less than 5%, morphologically normal haemopoiesis and
normal peripheral blood count. Broad principles of management include:
• Supportive care as for all leukaemias (see ALL).
• Intensive cytotoxic chemotherapy: induction of
remission and postremission (consolidation) therapy.
The exact regimen is determined by patient factors and
AML subtype.
• Stem cell transplantation, which has been shown
to have high survival benefits in patients with
intermediate-risk and high-risk AML.
Prognosis is patient and AML subtype dependent. In children, around 80% of patients achieve remission following
induction chemotherapy, and overall survival rates are
around 70%. In younger adults, the survival rate is about
40% at 5years, and in those older than 60years the survival
rate is less than 10%.
Other poor prognostic factors include very high white
cell count, secondary leukaemia (e.g. previous myelodysplasia), certain cytogenetic abnormalities and the presence of
DIC.
Chronic lymphocytic leukaemia
Aetiology
Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in the developed world, representing about
a quarter of all leukaemias. It is largely a disease of the elderly, with incidence that increases with age. The median
age of diagnosis is 72years, and the incidence is only about
10% in those younger than 55years. Genetic correlations of
CLL are seen, with a sevenfold increase in the risk of CLL
development in first-degree relatives of CLL patients, but
the mechanisms of that are unknown.
Pathology
This leukaemia comprises malignant monoclonal expansion of B lymphocytes. Abnormal cells can accumulate in
the blood, bone marrow, lymph nodes, liver and spleen.
These cells morphologically have a normal appearance but
are not reactive and immature, and therefore lead to immunological compromise of an individual.
Diagnosis is made when:
monoclonal B-cell lymphocyte count in peripheral
blood is 5000/μL or greater for at least 3months with
clonality confirmed by flow cytometry
blood smear shows characteristically small, mature
lymphocytes with a dense nucleus lacking nucleoli and
partially aggregated chromatin
Clinical features
The presentation can be variable, with it being an incidental finding for some asymptomatic patients, whereas others
may describe malaise, weight loss, night sweats, recurrent
infections, bleeding or symptoms of anaemia:
• Symmetrical lymphadenopathy is usually found.
• Hepatosplenomegaly can cause abdominal pain.
• Skin involvement is common with pallor or
thrombocytopenic rash.
Investigations are with simple blood tests:
• Lymphocytosis is seen on full blood count (FBC), with
peripheral blood smear showing ‘smudge’ cells.
• Autoimmune haemolysis anaemia can be present, and
should be investigated with a direct antiglobulin test
(direct Coombs test) which is positive.
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Multiple myeloma
3636
• Lymph node biopsy is necessary to establish the
possibility of transformation to high-grade lymphoma.
• All patients should be tested for the presence of tumour
protein 53 gene (TP53) mutation before treatment.
This tumour suppressor gene deletion is associated with
lower response to treatment and a worse prognosis.
Treatment and prognosis
Except for stem cell transplantation there is no curative
treatment for CLL currently. Treatment is based on disease
stage, with only early disease being monitored. For symptomatic disease (e.g. weight loss, persistent fever, marrow
failure) treatment is with standard chemotherapy (alkylating agents, monoclonal antibodies, purine analogues).
Steroids may be used to treat autoimmune complications
and improve marrow function.
Relapse is managed only if the disease is symptomatic.
Chemotherapy can be then repeated or the regimen can be
changed.
CLL is usually associated with long overall survival. The
median survival differs depending on the disease stage and
extent of the disease. Patients with TP53 gene deletion have
the worst prognosis.
Chronic myeloid leukaemia
Chronic myeloid leukaemia (CML) accounts for about 15%
of adult leukaemias. It can present at any stage of life but is
uncommon in the young. The median age at diagnosis is
estimated at between 60 and 65years. CLL typically progresses through three stages:
• Chronic phase (where 90% of patients present):
competent immune system with patient asymptomatic
for prolonged periods (4–5years).
• Accelerated phase: 15%–29% of blasts present in
patient’s marrow, causing marrow failure and resistance
to treatment. About two-thirds of chronic phase
patients will transform into accelerated phase patients
at some stage.
• Blast crisis or blastic phase: usually results from a
transformation of the accelerated phase but in about
25% of patients, transformation is from the chronic
phase. This is an aggressive acute leukaemia with
marrow arrest that is resistant to treatment and has
high mortality.
lines (erythroid, platelet and myeloid). The process is
due to failed apoptosis and increased production but
the detailed mechanisms are unknown. More than 90%
of cases have been shown to result from cytogenetic abnormality known as Philadelphia chromosome. This is
a chromosome 9 to 22 (9:22) reciprocal translocation
which results in fusion gene (BCR/ABL1). This gene
possesses high tyrosine kinase activity that alters cellular properties.
Clinical features
The signs and symptoms can differ and can be insidious in
onset. Most commonly they include:
• lethargy, weight loss, sweats and abdominal discomfort
(enlarging spleen)
• symptoms of anaemia or thrombocytopenia
• on examination, splenomegaly, which may be massive
• lymphadenopathy and hepatomegaly
Investigations will show:
• leucocytosis with granulocytes in various stages of
development on FBC and blood film
• normocytic normochromic anaemia and thrombocytosis
Bone marrow aspiration is crucial to determine the percentage of blasts and basophils and for cytogenetic analysis.
Treatment and prognosis
Good supportive therapy is needed. Desired treatment results in haematological remission (i.e. normal FBC, no organomegaly and no cytogenic or molecular abnormalities).
As first-line treatment, chemotherapy is considered to be
superior to stem cell transplantation because of mortality
associated with transplantation. Current drug treatment
concentrates around tyrosine kinase inhibitors (e.g. imatinib, but newer tyrosine kinase inhibitors are continuously
being developed). Frequent monitoring of response to treatment is extremely important.
Prognosis of CML is dependent on the phase of CML
at presentation, but has significantly improved with the use
of tyrosine kinase inhibitors. Observational and follow-up
studies are currently in progress, but it is estimated that the
5-year survival rate is 89% with the use of imatinib.
MULTIPLE MYELOMA
Aetiology
The cause is unknown. There are no obvious familial, geographic, economic or ethnic associations. Some sources
suggest higher risk to be associated with atomic bombs and
exposure to radiation (e.g. in Hiroshima and Nagasaki).
Pathology
CML is a myeloproliferative disorder of pluripotent haemopoietic stem cells. It can affect one or all stem cell
Aetiology
Myeloma is the second most common haematological cancer. It is responsible for about 2% of all deaths from cancer. It
is usually a disease of the elderly, and the median age at presentation is 70years. It is more common in Afro-Caribbean
patients and in men.
It results from the accumulation of neoplastic plasma
cells in bone marrow. These produce a monoclonal protein
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Haematological disorders
that causes tissue and organ impairment. This process seems
to be proceeded by monoclonal gammopathy of undetermined significance (MGUS). Plasma cells produce various
levels of monoclonal free light chains. They are then filtered
and reabsorbed in the kidneys. If reabsorption capacity is
exceeded, light chains (Bence Jones proteins) will accumulate in the kidneys as casts and cause acute kidney injury.
Its cause is thought to be due to a genetic mutation occurring before the terminal differentiation of B cells into
plasma cells. As myeloma develops, further genetic mutations occur.
It is one of a number of diseases associated with abnormal proliferation of a clone of plasma cells (terminally differentiated B cells), including:
• MGUS: paraprotein is less than 5% of plasma cells in
the marrow and no end-organ damage. A minority of
patients with MGUS will progress to myeloma.
• Asymptomatic multiple myeloma: greater than 10%
plasma cells in the bone marrow but no end-organ
damage.
• Primary systemic amyloidosis: production of light
chain fibrils which are deposited in organs.
Pathology
Myeloma results from the neoplastic proliferation of plasma
cells. This leads to diffuse bone marrow infiltration and
failure. The malignant cells oversecrete a monoclonal immunoglobulin (paraprotein) that is detectable in serum and
urine. Osteoclast activity is increased, resulting in osteolytic
bone lesions and hypercalcaemia. Renal failure and immunodeficiency are also caused by paraprotein. Myelomas are
classified by the type of antibody they produce, and the
most common form is immunoglobulin G myeloma.
Clinical features
A variety of signs and symptoms can be a feature of
myeloma:
• Symptoms of anaemia may be present.
• Bone pain due to osteolytic lesions and pathological
fractures.
• Hypercalcaemia is often present, causing typical
symptoms (see Chapter33).
• Renal impairment is due to light chain or amyloid
deposition, hypercalcaemia and dehydration.
• Recurrent infections.
• Spinal cord and nerve compression.
• Polymerization of the monoclonal antibody can result
in hyperviscosity syndrome.
Investigations commonly show:
• normochromic normocytic anaemia
• leucopenia
• hypercalcaemia
• impaired renal function
• persistently raised plasma viscosity and erythrocyte
sedimentation rate
• a monoclonal paraprotein as demonstrated by serum
protein electrophoresis and which is used to assess
response to treatment
• free light chains in the urine (Bence Jones protein) as
detected by urine electrophoresis, or in the serum as
detected with a serum-free light chain assay
• generalized osteopenia, ‘punched-out’ lytic lesions and
pathological fractures as revealed by a skeletal survey
with X-rays
Bone marrow aspirate is diagnostic when plasma cells account for more than 10% of bone marrow cells.
HINTS AND TIPS
Psychological care of very sick or terminally ill
patients is an important part of their management,
and referral to a clinical psychologist may help
patients cope with their illness.
Treatment and prognosis
Myeloma is a chronic, relapsing and remitting illness that
is currently incurable. Treatment is aimed at disease control and improvement of survival. Patients with MGUS
and asymptomatic myeloma are monitored only. Currently
there is no intervention that would delay or prevent progression of MGUS to myeloma.
In elderly patients, treatment is with steroids and chemotherapy. Multiple agents have been approved for treatment,
including thalidomide and cyclophosphamide. In younger
patients, where prognosis is better, stem cell transplantation
is considered first-line treatment.
In cases of relapse, secondary stem cell transplantation
or chemotherapy can be considered.
Follow-up is with 2–3monthly FBC, blood and urine
electrophoresis and renal and bone profiles.
Prognosis of the disease is variable but is improving with the
development of new treatments. In some patients, survival
exceeds 8years, whereas in aggressive disease, death usually
occurs within 24 months. Response to treatment and the
patient’s age are independent prognostic factors.
LYMPHOMA
Lymphomas are blood cell tumours that result from the
neoplastic proliferation of lymphocytes. They are split into
two broad categories on the basis of histological findings:
Hodgkin disease (Reed–Sternberg (RS) cells present) and
non-Hodgkin lymphoma (NHL; all others). The WHO also
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Lymphoma
extralymphatic
3636
includes two other categories of lymphoma: myeloma and
immunoproliferative disorder.
Hodgkin disease
Aetiology
Hodgkin disease is one of the most common malignancies
in young adults. There is a bimodal age distribution with
peaks at 20–34years and above 70years, with a male preponderance. Its cause is unknown but there is a link with
Epstein–Barr virus (EBV), which is found in about 50% of
RS cells of patients with Hodgkin lymphoma. Other risk
factors include immunodeficient states (e.g. HIV infection,
immunosuppressant therapy).
Pathology
This is a malignant tumour of the lymphatic system characterized by presence of RS cells in a background of inflammatory infiltrate. There are also associated abnormal
mononuclear cells that are smaller and originating from B
cells in germinal centres.
Hodgkin lymphoma is further classified into subgroups
(Table36.8), with classic Hodgkin lymphomas being seen in
95% of patients. This divide is important as accurate classification will determine management and prognosis.
more than 10% over 6months. Hepatosplenomegaly or features of paraneoplastic syndrome can also occur.
Diagnosis requires lymph node biopsy, and excision of
a whole node is performed if possible to provide adequate
structural information. A CT scan of the chest, abdomen
and pelvis is performed to stage the disease (Fig. 36.1).
Other useful tests include FBC, ESR, blood chemistry and
HIV, hepatitis B and hepatitis C tests.
Treatment and prognosis
Before treatment, staging and assessment of risk factors is
essential. Radiotherapy, chemotherapy and combined therapies are used in disease management. Both radiotherapy
and chemotherapy have been found to increase the risk of
developing secondary solid tumours such as cancers of the
breast or lung. Chemotherapy itself is effective, but carries
Clinical features
The most common presentation is with enlarged, otherwise asymptomatic lymph nodes typically in the cervical or
supraclavicular area. Mediastinal nodes are also common,
and can result in dyspnoea and a dry cough. Affected lymph
nodes feel rubbery and are nontender. Pruritus is common,
and alcohol-induced lymph node pain can occur. Systemic
symptoms are termed ‘B-cell symptoms’ and include nightsweats, temperature of more than 38°C and weight loss of
Table36.8 Classification of Hodgkin lymphoma
Subtype Feature
Classic Hodgkin
lymphoma
Nodular
lymphocytepredominant
Hodgkin
lymphoma
EBV, Epstein–Barr virus; RS, Reed–Sternberg.
Lymphocyte rich More common in
Lymphocyte
depleted
Nodular sclerosis Most common
Mixed nodularity Most common in
No RS cells
males
Associated with
EBV
worldwide
older adults
Stage I
One lymph
node site
only
Stage III
Lymph node
involvement
on both sides
of the
diaphragm
Fig.36.1 Ann Arbor staging of malignant lymphomas.
Stages I–IV are shown. When you stage a lymphoma,
you give a number (I–IV) and a letter (A or B). The letter
A denotes the absence of B symptoms and the letter B
denotes the presence of B symptoms. For example, stage
IIA corresponds to stage II lymphoma without B symptoms.
Stage II
Two lymph
node sites,
but on the
same side
of the
diaphragm
Stage IV
Disseminated
disease
involving one
or more
organs
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