00:01
Hello, In other lectures, we focused on leukaemia
and lymphoma, but now I want to focus on other
haemopoietic malignancies and aplastic anaemia.
We will learn in this lecture, the myelodysplasia
and myeloproliferative disease are clonal
disorders of the myeloid lineage within the
bone marrow. Myeloma is a malignant disorder
of plasma cells and is treated with a wide
range of novel therapies. And finally aplastic
anaemia results in the loss of stem cells
in the bone marrow and may result
from an autoimmune process.
00:43
Let us start with myelodysplasia, break the
word down myeloid bone marrow, dysplasia dysplastic
or deficient function of the bone marrow.
This is a group of disorders, which are clonally
derived of a haemopoietic stem cell and they
are characterized by bone marrow failure in
association with dysplastic features in one
or more cell lineages. What do I mean by that?
What does dysplastic mean? It means that the
cells when we look at them at the microscope
display abnormal features. Let me show you
by moving to the right-hand side of the screen,
you will see three figures there. On the top
left, believe it or not, these are neutrophils,
but they do not look like normal neutrophils,
I hope you agree. They are hypergranule.
01:39
We do not see the granules that you see in the
normal neutrophil and they are also not so
heavily lobed, just two lobes. So these are
dysfunctional neutrophils. On the top right
an unusual cell is a megakaryocyte in the
bone marrow, but again very abnormal looking
not enough nuclei much small of the normal
of the very prominent cytoplasm. And at the
bottom, that is a special stain for iron in
erythroblasts in the bone marrow and you will
see around the red nucleus ring of iron material
sideroblasts and we will talk about that in
the next couple of slides. You can see this
is a disorder characterized by a very proliferative
bone marrow producing very abnormal cells.
This is due to the accumulation of a range
of DNA mutations and epigenetic modifications
in the haemopoietic stem cells. It is often
seen in people who are quite elderly and therefore
it can be regarded as a premalignant and also
. . . malignant in some cases disorder of
the haemopoietic stem cell.
03:01
The classification of myelodysplasia is really
quite complicated. We do not need to go into
it in great detail in this lecture, but there
are a few points to help you. You may get
these dysplastic changes just in one lineage
down the red cells leading to refractory anaemia
or in the neutrophils or platelets or there
may be two or more lineages involved and I
think you can understand that the more lineages
involved the worst the outlook is liked to
be. Occasionally this erythroid dysplasia
can be associated with those ring sideroblasts
that I showed you on the previous sites surrounding
the nucleus. That is the specific type of
disease with a very common mutation in the
gene SF3B1. If the blast cell count or the
leukaemia count is increased in the bone marrow,
then the diagnosis is called refractory anaemia
with excess blasts and that is moving towards
acute myeloid leukaemia that is very worrying
because that is a difficult disease to treat.
A special subtype is the 5q- syndrome.
04:16
This
is more common in women and typically there
is a macrocytic anaemia or red cells with
increased platelet count and as the name suggests
this disorder is diagnosed by having a karyotype
or a chromosomal spread of the tumor and recognizing
loss of the long arm of chromosome 5 and finally
if the monocyte count is raised above the
level of 1 x 10 9 it is a chronic myelomonocytic
leukaemia. So I do not think you need to retain
all the details of this classification, but
you can see some of the principles of this
quite heterogenous disorder. Now how this
disorder is were presented clinically? How
is it present within patients? I said already
that it is mainly a disorder of all the patients
and the main clinical problems arise because
the blood count is reduced. The haemoglobin
is down leading to anaemia. The white cells
are down leading to infection and the platelets
are dysfunctional leading to bleeding.
05:24
I have just brought two slides there to show you
the top you can see small bruises or purpura,
very characteristic of people with low platelet
counts or dysfunctional platelets and on the
right a chest x-ray showing an area of infection.
So like many hematological disorders, myelodysplasia
is diagnosed on the basis of the histoexamination
together with the blood count and the bone
marrow and cytogenic analysis. Now we tend
to divide myelodysplasia into patients low
risk on patients at high risk. What do we
mean by this? Well, low risk patients are
likely to survive longer. We do not need to
treat them quite as rapidly and in fact we
often use different therapies whereas high-risk
disease is very worrying, which I will show
you in the next slide and scores were revolved
where we use a range of different measurements
to divide patients into these risk groups
as you will see at the top. Patients with
less than 5 percent blasts or leukaemic cells
in the bone marrow and only one cytopenia
and relatively feeble genetic damage are diagnosed
as low-grade myelodysplasia. We tend to use
supportive treatment, blood transfusions.
We can give erythropoietin and similar drugs
as well as growth factors such as Granulocyte-colony
stimulating factor. The 5q- syndrome is well
treated by a drug called lenalidomide and
that is interesting in a special case.
07:16
At the bottom those, one example of these risk
scores that can be used to assign patients
to low or high risk group and you will see
on the left the prognostic variables that
are used the percentage of bone marrow blasts,
the type of karyotype or chromosomal damage
and also the cytogenetic. High-risk myelodysplasia
is seen in patients
who have very poor prognostic genetic change
or they have a high number of blast counts
in the bone marrow and are progressing towards
the acute myeloid leukaemia. This is high-risk
disease and the outlook is poor. Intensive
chemotherapy such as it is used for acute
myeloleukaemia can be used although the outlook
with that is not very good because it tends
to only control the disease for short periods
of time. Azacytidine is an interesting demethylating
therapy, which is valuable in some cases and
finally we will only achieve cure really through
the use of an allogeneic stem cell transplant
particularly in the younger patients.