Chronic leukaemias: 1.

CLL

Will I see one? Will I get it?

Incidence: UK 3/100,000 (40% of leukaemia)
15,000 new cases each year one new case per GP practice each 5-6yrs

Mean age at diagnosis 65-70yrs BUT, 30% occur 55yrs Occasionally seen <35yrs Oddities 1
M:F 2:1: and females have milder disease; why??? Rare in Asians wherever they live! ? a genetic component

What is CLL?
An accumulation of mature B lymphocytes:
Unusually for cancer: Due to inappropriately prolonged survival of the cells, not because of rapid production

Because these are immunological cells:

Accumulate in lymph organs and bone marrow Suppress normal immune function

Oddities2
Often cause disturbed immune function: autoimmune disease; this is almost always targeted against blood cells why?

Presentations of CLL
Incidental: About 40%-60% of patients with CLL are diagnosed in the
absence of disease-related symptoms, even with very high numbers of circulating lymphocytes >100 x 109/l.

Nodal: Frequently, the presence of lymphadenopathy during a routine medical

examination is the only reason to consider the diagnosis

Immunological: e.g. haemolysis or thrombocytopenia Marrow failure Manifestations of bone marrow (BM) involvement,
particularly significant anemia (hemoglobin <11g/dl) or thrombocytopenia (platelets count <100 x 109/l), are noted at presentation in 15% of CLL patients.

The remaining patients may present with weakness, fatigue, night sweats, fever, or infections

What they look like CLL

AML

Note the cells are small and mature compared with typical blast cells

Incidental finding

As cells are small, non-functional and largely inert, CLL in blood counts of 50x109/l (or more) are often without symptoms

Accumulation in lymph glands

Lymph gland involvement may be subtle or spectacular, but generally it is only within nodes: unsightly or uncomfortable; but not invasive

Autoimmune disease in CLL (1)

Where are the platelets??

Autoimmune disease in CLL (2)

Worse still why are some red cells dense and stuck to each other??

Bone marrow failure in CLL

CLL cells accumulate in marrow, but many normal cells persist (arrows); even when infiltration is severe blood counts may be normal. Ultimately though the marrow fails.

What can we do about CLL?

The arrows indicate new treatment options and number of complete remissions in each decade.

Treatment: over the years things are improving

But this is complicated, complete remission does not mean cure. People who enter remission may not survive longer! Also these are older patients Can everyone tolerate these new treatments?

Approaches to treatment 1.
TRADITIONAL: DO NO HARM Most patients are old and tolerate intensive treatment poorly Watch and wait MRC showed early treatment with alkylating agents did not extend life, and caused more secondary skin cancer Give treatment only to reduce symptoms

Approaches to treatment 2.
ENFORCED: EXPENSIVE TREATMENT MUST DO GOOD NICE say fludarabine is expensive, with no proof of improved survival over other treatments it is not funded (even though more CR)

Approaches to treatment 3.
TRIALS of treatment: Patients in CR feel better in quality of life assessment Some patients e.g. 11q have such a short survival that intensive treatment may be needed

Trials aim to answer the question of how best to treat patients

Clever Bits: All CLL is not the same

WHY?

It is now clear that not all CLL is the same disease. Certain cytogenetic lesions cause some cases to have a much shorter survival
Particularly: 17p deletion 11q deletion

Why do 17p and 11q do so badly??

 11q encodes the ATM gene (ataxia telangectasia mutation) gene 17p encodes the p53 gene Both are closely related and control cell death!

Action of the ATM and p53 genes:

DNA damage
Normal karyotype

ATM gene is activated

Severe damage Less severe damage

p53 activation

DNA repair

APOPTOSIS

SURVIVAL

In 11q deletion ATM is missing!

DNA damage
CLL 11q deletion

ATM gene

Neither death nor repair are initiated

When patients are treated, the CLL cells are protected from death because the p53 gene is not activated. The time from diagnosis to death is reduced from 11.5 years to 6.5 years

In 17p deletion p53 is missing!

DNA damage e.g. chemothera

17p deletion

ATM gene
Severe damage Less severe damage

p53 activation
Programmed death does not occur

DNA repair
Instead cells undergo repair

Now treatment is even less effective: mean survival is reduced from 11.5 years to less than 3 years!