Now let us turn to the second major
subset of leukaemias. We move from acute leukaemia
into chronic leukaemia and I will start with
chronic lymphoid leukaemia. This is the most
common leukaemia in many societies. Interestingly
not all societies because there seems to be
a genetic predisposition to CLL. That is more
common in those of Caucasian and Asian origin.
CLL develops from the accumulation of a clone
of B cells, which you can see on the blood
film there in the bone marrow in the blood
and in the lymph nodes. On that blood film,
you will see many lymphocytes. You will see
many purple smears and indeed very cells are
lymphocytes, which have undergone destruction
during the preparation of the blood film. Smear cells
are a characteristic feature of CLL.
Now the B cells in CLL are very interesting.
They have a number of unusual proteins on
the surface, unusual for B cell. I have put
two there, CD5 and CD23 and it is the presence
of those proteins that we look for when are
making a diagnosis of CLL in a patient who
has too many lymphocytes within the blood.
Now, CLL is quite slowly progressive.
It developed over many years and now from 90 percent of
patients are diagnosed with CLL simply because
they have blood taken for another reason.
They may go for a health check or they may
go as the doctor saying that I feel quite
so well or dizzy or whatever it is, a blood
test is done and we notice that there are
too many lymphocytes. So it can be what we
call an indolent disease slowly progressive
and not needing any treatment. Indeed, treatment
is generally only started when the patient needs
it. We call this as a watch and wait policy.
So when do patients need treatment,
if they develop anaemia, when the CLL crowd
out the normal cells and the bone marrow and
lead to anaemia or perhaps when the lymph
nodes in the neck swell up and cause problems
or the spleen, which can also be involved.
So it may seem unusual that we make the diagnosis
of leukaemia, but don´t treat it. But certainly
results from several years ago showed that
if one treats too early, you can actually
have a worse outcome than watching and waiting.
What about the treatment of this condition?
Over 30 years, doctors have been studying
different combinations of treatment for CLL
and at the current time, a combination of
chemotherapy with injection of an antibody
targeted against the B cells through CD20
is a standard treatment. So younger patient
would get CD20 specific antibody with more
intensive chemotherapy and all the patients
will get an antibody with perhaps less intensive
chemotherapy and those are effective in the
majority of patients although they are never
in themselves curative. The disease always
has the risk of coming back and these combinations
of chemotherapy and antibody are usually given
for around 4 to 6 courses perhaps every month
if possible and the patient may well obtain
a remission for several years before they
need treatment again. But in fact in CLL as
in many areas of haematology, there has been
some interesting new developments and tablets
have recently been developed that specifically
target B-cell receptor signalling that are
very effective in CLL. There are two major
pathways that we can inhibit mentioned on
the slide, BTK Bruton's tyrosine kinase and
PI3K delta, PI3kinase delta subunit.
These are two proteins, which are involved in signalling
when a B-cell sees its antigen through the
immunoglobulin on the cell surface and they
send survival signals and proliferative signals
to the tumor cell and tablets, which block
those signalling pathways lead to the death
of the CLL tumor cells. Now these have only
been around for 2 or 3 years, but they may
well come to represent the new standard of
care in chronic lymphocytic leukaemia and
now drug studies are being designed and started
which compare chemotherapy with oral medication.
Finally a fourth subset of leukaemia, chronic
myeloid leukaemia. This is a relatively rare
disorder but is seen in people of all ages
and is remarkable because we know so much
about its etiology and it lead to the introduction
of a new treatment that is changed our
approach to cancer. In many cases, it is caused by
a translocation. This was the first translocation
to be identified in cancer called the Philadelphia
chromosome between chromosomes 9 and 22. Just
look at that cartoon on the right and you
will see those pink chromosomes. On the left
of those pink diagrams, you will see the normal
chromosome 9 and below it the normal chromosome
22. But if those break at ABL and BCR, they
can stop that genetic material and lead to
those pink chromosomes on the right, 9q+,
22q-. Now, what is fascinating about this
translocation is it leads to the formation
of a new protein, a fusion protein that is
shown in the top right? BCR and ABL come together
to form a new fusion protein only present
within the tumor cells. As you will see on
the right-hand side of the diagram, this protein
encodes an enzyme, which has tyrosine kinase
activity and this tyrosine kinase activity
is overactive within the tumor cells and through
a range of mechanism that leads to proliferation
of this myeloid cell and generation of the
leukaemia and as you will see, it drives the
bone marrow to access proliferation of the
myeloid compartment. The clinical features
of CML reflect that myeloid proliferation.
Let us look down the left-hand side first
of all splenomegaly often you will see a very
large spleen under the left-hand side of the
ribs and patients with CML. Fevers, sweats
and indeed gout because the patient is making
so many cells and also many of these cells
are dying and gout interestingly is precipitated
by the formation of uric acid from DNA of
cells that have been broken down. Let us look
now on the right-hand side. You will see on
the right the particular blood film of the
patient with chronic myeloid leukaemia. Lots
of neutrophils, but also earlier and more
primitive cells that we should not see in
the blood, promyelocytes and myelocytes and
in those two tubes, we see the startling feature
of CML that we see in some patients, very
high numbers of leukaemic cells. Let me explain.
On the left-hand side of those two tubes,
you will see normal blood. It has been placed
in the centrifuge and the bottom of the red
cells or the top is the plasma and in between
those two, there would normally be a very
thin layer of white cells sometimes known
as the buffy coat whereas in the right-hand
tube, you can see that enormous white area
that is the huge buffy coat of the malignant
white cells within the blood of this patient.
So if you ever wanted to see an example of
how leukaemia really does mean white blood
that is a typical picture.
Now, the treatment of chronic myeloid leukaemia
is one of the fascinating areas of medicine.
Imatinib is a drug that was designed specifically
treat chronic myeloid leukaemia and it can
specifically block the BCR-ABL protein. You
can already see how exciting that is because
that fusion protein is only in the tumor cells.
It is exactly the sort of drug that we have
been looking for when it comes to specifically
affecting the tumor cells as opposed to chemotherapy.
It is highly effective and simple oral medication
can control the disease in most cases.
Now it is true that the disease can get resistant
in some cases or the patient might perhaps
be intolerant of Imatinib, but there are now
several new drugs, which also inhibit BCR-ABL
in different ways and indeed some evidence
that they may be more effective than Imatinib
as a first line of therapy. So there are many
trials now seeing if these different drugs
are effective at different stages and to bring
about a more rapid and complete control of
CML. But the treatment of this disease has
been transformed. Treatment is now monitored
by looking at the percentage of the BCR-ABL
messenger RNA in the blood and so we will
see patients in the clinic perhaps every three
months and will see how rapidly we are killing
off the tumor with the tablet combination.
If it is not quickly enough, we will switch
to another agent, which is more effective.
The success with Imatinib has changed the
general approach to treatment of cancer and
many types of cancer now even the common sorts,
lung cancer, breast cancer we are starting
to look away from the old fashion chemotherapy,
which affects many rapidly dividing cells
and we are looking into the genome of the
tumor cell finding the specific mutation that
cause that cancer and looking for tablet that
can specifically block that and that is how
cancer will be treated in the 21st century.
So In summary, leukaemia can be classified
into four different subtypes. Now each of
these four is very different and you need
a very thorough diagnostic approach to making
right diagnosis of the subtype and I hope
that you have seen and enjoyed from this talk
that these leukaemias are treated by a variety
of therapies, chemotherapy antibodies and
drugs that inhibit signalling pathways. As
is often the case in hematology, the development
of these drugs has led to improvements in
many areas of medicine.
Thank you very much for watching.