Chronic leukaemias 2.

1. Chronic leukaemias 2. Myeloproliferative disorders

2. What is Myeloproliferation?

3. 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!

4. 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.

5. 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.

6. Uncontrolled Growth Stem cells Proliferating/maturing cells If the capacity to fully mature is lost than primitive cells accumulate: an acute leukaemia

7. Stem cells Proliferating/maturing cells CML ET MF If the capacity to mature is retained a myeloproliferation results PRV

8. 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

9. CML is a classic example in haematology • 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

10. The Philidelphia Chromosome (described Nowell and Hungerford in 1960 Material is exchanged between chromosomes 9 and 22 Reciprocal translocation

11. The BCR-ABL tyrosine kinase (described 1983) The chromosomal translocation causes the formation of a fusion between two gene: BCR and ABL. This activates ABL activating many signalling pathways:

12. Why does this cause increased white blood cells? • The problem arises in normal bone marrow and affects normal blood cell formation

13. This is how normal haematopoiesis proceeds: Those cells mature CML Disturbs this whole process Daughter cells are formed Stem cells self-renew Some die during maturation

15. Why does this cause increased white blood cells? • The problem arises in normal bone marrow and affects normal blood cell formation • The mutation begins in the stem cell

16. Normal haematopoiesis * * * * 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

17. Why does this cause increased white blood cells? • 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

18. If cells don’t die as easily: Greater numbers of early and mature cells are formed

19. Why does this cause increased white blood cells? • 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

20. If cells differentiate more slowly Even greater numbers of early and mature cells are formed

21. Why does this cause increased white blood cells? • 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

22. If cells self-renew more often: Many more early and mature cells are formed!!

23. The result: 1. Excess white cells in blood (counts up to 500x109/l)

24. The result: 2. Massive infiltration of bone marrow

25. The result: 3. Excess white cells “spill over” into spleen and liver; circulating cells may block vessels

26. The result: 4. 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.

27. Treatment over the years • 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

28. Year 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

29. The newest arrival, targeted treatment! 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

30. Mechanism of action of Imatinib (Glivec) Imatinib

31. Does it work?

32. Year 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