Chronic leukaemias 2
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Chronic leukaemias 2. Myeloproliferative disorders. What is Myeloproliferation?. Stem cells. Proliferating/maturing cells. Mature cells. monocytes. neutrophils. megakaryocytes. red cells. This is normal myeloid cell production (hopelessly simplified).

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Chronic leukaemias 2

Chronic leukaemias 2.

Myeloproliferative disorders



Chronic leukaemias 2

Stem cells

Proliferating/maturing cells

Mature cells

monocytes

neutrophils

megakaryocytes

red cells

This is normal myeloid cell production (hopelessly simplified)

Myeloproliferation arises when normal blood cell production goes wrong!


Chronic leukaemias 2

Stem cells

Proliferating/maturing cells

Mature cells

monocytes

neutrophils

megakaryocytes

red cells

Uncontrolled

Growth

It arises when stem cells begin to grow in an uncontrolled fashion.


Chronic leukaemias 2

Stem cells

Proliferating/maturing cells

Mature cells

monocytes

neutrophils

megakaryocytes

red cells

Uncontrolled

Growth

What happens next depends on whether those cells retain the capacity to mature.


Chronic leukaemias 2

Uncontrolled

Growth

Stem cells

Proliferating/maturing cells

If the capacity to fully mature is lost than primitive cells accumulate: an acute leukaemia


Chronic leukaemias 2

Stem cells

Proliferating/maturing cells

CML

ET

MF

If the capacity to mature is retained a myeloproliferation results

PRV


Symptoms then depend on the type of mature cell that is formed
Symptoms then depend on the type of mature cell that is formed

  • Primary polycythaemia: effects of excess red cell growth

  • Primary thrombocythaemia: effects of excess platelets

  • Chronic myeloid leukaemia: effects of white cell accumulation

  • Myelofibrosis: bone marrow failure, massive spleen enlargement

    Additionally, at any point in the disease the ability to differentiate may be lost and transformation to acute leukaemia may result


Cml is a classic example in haematology
CML is a classic example in haematology formed

  • Distinctive natural history

  • First “chromosomal” malignancy

  • Massive research interest – some understanding of how it forms

  • Real effectiveness of biological therapies: bone marrow transplant; interferon; donor lymphocyte infusion

  • First targeted malignancy: Glivec


Chronic leukaemias 2

The Philidelphia Chromosome formed

(described Nowell and Hungerford in 1960

Material is exchanged between chromosomes 9 and 22

Reciprocal translocation


Chronic leukaemias 2

The BCR-ABL tyrosine kinase (described 1983) formed

The chromosomal translocation causes the formation of a fusion between two gene: BCR and ABL.

This activates ABL activating many signalling pathways:


Why does this cause increased white blood cells
Why does this cause increased white blood cells? formed

  • The problem arises in normal bone marrow and affects normal blood cell formation


Chronic leukaemias 2

This is how normal haematopoiesis proceeds: formed

Those cells mature

CML Disturbs this whole process

Daughter cells are formed

Stem cells self-renew

Some die

during maturation


Why does this cause increased white blood cells1
Why does this cause increased white blood cells? formed

  • The problem arises in normal bone marrow and affects normal blood cell formation

  • The mutation begins in the stem cell


Chronic leukaemias 2

Normal haematopoiesis formed

*

*

*

*

Stem cells self-renew

*

*

*

*

*

*

*

*

Since this cell self-renews and generates all mature cells the abnormality persists and affects not just the stem cell but is also passed on to it’s daughter cells


Why does this cause increased white blood cells2
Why does this cause increased white blood cells? formed

  • The problem arises in normal bone marrow and affects normal blood cell formation

  • The mutation begins in the stem cell

  • The mutation reduces cell death


Chronic leukaemias 2

If cells don’t die as easily: formed

Greater numbers of early and mature cells are formed


Why does this cause increased white blood cells3
Why does this cause increased white blood cells? formed

  • The problem arises in normal bone marrow and affects normal blood cell formation

  • The mutation begins in the stem cell

  • The mutation reduces cell death

  • The mutation slow maturation allowing more cycles of cell division


Chronic leukaemias 2

If cells differentiate more slowly formed

Even greater numbers of early and mature cells are formed


Why does this cause increased white blood cells4
Why does this cause increased white blood cells? formed

  • The problem arises in normal bone marrow and affects normal blood cell formation

  • The mutation begins in the stem cell

  • The mutation reduces cell death

  • The mutation slow maturation allowing more cycles of cell division

  • These same processes also affect stem cells causing their numbers to increase


Chronic leukaemias 2

If cells self-renew more often: formed

Many more early and mature cells are formed!!


Chronic leukaemias 2

The result: 1. formed

Excess white cells in blood

(counts up to 500x109/l)


Chronic leukaemias 2

The result: 2. formed

Massive infiltration of bone marrow


Chronic leukaemias 2

The result: 3. formed

Excess white cells “spill over” into spleen and liver; circulating cells may block vessels


Chronic leukaemias 2

The result: 4. formed

Inevitable and in all cases the disease transforms as new mutations arise; transformation to acute leukaemia occurs at a rate of 10% a year. Traditionally survival was around 3.5 years from diagnosis.


Treatment over the years
Treatment over the years formed

  • CML has been a “test bed” for many new treatment approaches:

    • Many have shown success:

      • Interferon

      • Bone marrow transplant

      • Donor lymphocyte infusion

        This has slowly translated to improved survival


Survival in early chronic phase cml

Year formed

Total

Dead

1990-2000

960

357

1982-1989

365

266

1975-1981

132

127

1965-1975

123

122

Survival in Early Chronic-Phase CML

1.0

0.8

0.6

Proportion Surviving

0.4

0.2

0.0

0

3

6

9

12

15

Years From Referral

University of Texas M.D. Anderson Cancer Center Database 1965-2005


The newest arrival targeted treatment
The newest arrival, targeted treatment! formed

CML has recently become a huge area of interest as the first example of a truly effective “targeted” drug therapy: a compound has been developed that binds to BCR/ABL (mimicking ATP) and blocks its action:

IMATINIB




Survival in early chronic phase cml1

Year formed

Total

Dead

Imatinib

276

14

1990-2000

960

357

1982-1989

365

266

1975-1981

132

127

1965-1975

123

122

Survival in Early Chronic-Phase CML

1.0

0.8

0.6

Proportion Surviving

0.4

0.2

0.0

0

3

6

9

12

15

Years From Referral

University of Texas M.D. Anderson Cancer Center Database 1965-2005