HAEMATOLOGICAL

MALIGNANCIES
Dr Hassan Abshir MBBS, MPH
 Leukaemias
• 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 and aetiology
• The incidence of leukaemia of all types in the
population is approximately 10/100 000 per
annum, of which just under half are cases of
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 children aged 1-5 years.
• 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.
• The cause of the leukaemia is unknown
in the majority of patients.
• Several risk factors, however, are known
(Box 24.46).
 24.46 Risk factors for leukaemia
• Ionising radiation
• After atomic bombing of Japanese cities (myeloid leukaemia)
• Radiotherapy for ankylosing spondylitis
• Diagnostic X-rays of the fetus in pregnancy
• Cytotoxic drugs
• Especially alkylating agents (myeloid leukaemia, usually after a latent period
of several years)
• Industrial exposure to benzene
• 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 : Identical twin of patients with leukaemia
• Down's syndrome and certain other genetic disorders
• Immunological : Immune deficiency states (e.g. hypogammaglobulinaemia)
• Leukaemias are traditionally classified into four main groups:
• Leukaemias are traditionally classified into
four main groups:
• acute lymphoblastic leukaemia (ALL)
• acute myeloid leukaemia (AML)
• chronic lymphocytic leukaemia (CLL)
• chronic myeloid leukaemia (CML).
• 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 differentiate, resulting in an accumulation of
more mature cells.
• Lymphocytic and lymphoblastic cells are those
derived from the lymphoid stem cell (B cells and T
cells).
• Myeloid refers to the other lineages, i.e.
precursors of red cells, granulocytes, monocytes
and platelets (see Fig. 24.2, p. 989).
• The diagnosis of leukaemia is usually
suspected from an abnormal blood count,
often a raised white count, and is
confirmed by 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.
• These results are incorporated in the World
Health Organization (WHO) classification of
tumours of haematopoietic and lymphoid
tissues; the subclassification of acute
leukaemias is shown in Box 24.47.
• The features in the bone marrow not only
provide an accurate diagnosis but also give
valuable prognostic information, allowing
therapy to be tailored to the patient's
disease
 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 (AML) is about four
times more common than acute lymphoblastic
leukaemia (ALL) 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. 997, 1002 and 1004).
 Investigations
• Blood examination usually shows anaemia with a
normal or raised MCV.
• The leucocyte count may vary from as low as 1 × 109/L
to as high as 500 × 109/L or more.
• In the majority of patients the count is below 100 ×
109/L.
• Severe thrombocytopenia is usual but not invariable.
• The appearance of blast cells in the blood film is usually
diagnostic.
• 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 usually hypercellular, with
replacement of normal elements by leukaemic
blast cells in varying degrees (but more than 20%
of the cells)(Fig. 24.26).
• The presence of Auer rods in the cytoplasm of
blast cells indicates a myeloblastic type of
leukaemia.
• Illustrations of immunophenotyping and
chromosome analysis are shown in Figure 24.27.
• The general strategy for acute leukaemia is
shown in Figure 24.28.
• 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 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 as recommended in Box
24.48.
• It is unwise to attempt aggressive management
of acute leukaemia unless adequate services are
available for the provision of supportive therapy.
 24.48 Preparation for specific therapy in
acute leukaemia
• Existing infections identified and treated (e.g. urinary
tract infection, oral candidiasis, dental, gingival and
skin infections)
• Anaemia corrected with red cell concentrate tranfusion
• Thrombocytopenic bleeding controlled with platelet
transfusions
• If possible, central venous catheter (e.g. Hickman line)
inserted to facilitate access to the circulation for
delivery of chemotherapy
• Therapeutic regimen carefully explained to the patient
and informed consent obtained
• The aim of treatment is to destroy the leukaemic
clone of cells without destroying the residual
normal stem cell compartment from which
repopulation of the haematopoietic 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 a specially trained
multidisciplinary team.
• Remission consolidation. If remission has been
achieved, residual disease is attacked by therapy during
the consolidation phase.
• This consists of a number of courses of chemotherapy,
again resulting in periods of marrow hypoplasia.
• In poor-prognosis leukaemia this may include bone
marrow transplantation.
• Remission maintenance. If the patient is still in
remission after the consolidation phase for ALL, 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.
• In patients with ALL it is necessary to give
prophylactic treatment 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.
• Thereafter, specific therapy is discontinued and
the patient observed.
 Supportive therapy
• The following problems commonly arise.
• Anaemia. Anaemia is treated with red cell
concentrate transfusions.
• Bleeding. Thrombocytopenic bleeding requires
platelet transfusions, unless the bleeding is trivial.
• Prophylactic platelet transfusion should be given to
maintain the platelet count above 10 × 109/L.
• Coagulation abnormalities occur and need accurate
diagnosis and treatment as appropriate (p. 1049).
 Infection.
• Fever (> 38 °C) lasting over 1 hour in a neutropenic
patient 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 neutropenia 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 coli, Pseudomonas and Klebsiella spp.
are more likely to cause rapid clinical deterioration
and must be covered with the initial empirical
therapy.
• Gram-positive infection may require vancomycin
therapy.
 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 achieve remission, although
remission rates are lower for older patients.
• However, the relapse rate continues to be high.
Box 24.50 shows the survival in ALL and AML and
the influence of prognostic features. Advances in
treatment 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, with strategies that
include allogeneic BMT.