1. Dr Nauman Butt – Royal Liverpool University Hospital CML Patient Seminar - 14 th November 2015 What is CML? How do we treat it? Get up to speed…

2. Chronic Myeloid Leukaemia (CML) Basic biology Clinical assessment – symptoms / diagnosis / staging / prognosis Treatment –Short term considerations –Long term management Monitoring disease Assessing response to treatment (milestones) Role of stem cell transplantation

3. What is CML? CML is an overactive bone marrow disorder associated with an increase in white cells in the blood Characterised by the presence of the Philadelphia chromosome in the bone marrow

4. The Philadelphia chromosome

5. Regulating normal cell growth Molecules bind to a cell receptors. These activate chemicals (or enzymes) called tyrosine kinases (e.g. ABL) which control cell signalling.

6. Cell growth in CML The Ph chromosome contains the BCR-ABL ‘fusion’ gene. The resulting BCR-ABL tyrosine kinase is permanently switched ‘on’ - promoting uncontrolled cell growth. X

7. Symptoms None or Abdominal discomfort (caused by an enlarged spleen) Fever, night sweats, weight loss Aching joints and bones Tired, weak Breathless Unusual bleeding / easy bruising Infections Visual disturbance

8. Diagnosis FBC (WCC often in the >100x10 9 /l) –Blood film (and bone marrow) Cytogenetics (BM) –including tests for Philadelphia chromosome / translocation (FISH) Molecular testing –measure BCR-ABL transcript levels by polymerase chain reaction [PCR]

9. Staging – CML is a ‘triphasic’ disease Chronic phase (90%+ cases) –mainly excess of mature BM (myeloid) cells Accelerated phase –associated with more primitive cells (blasts) in BM Blast crisis –akin to acute leukaemia

10. Prognosis - predictors of treatment response / outcome Scoring systems to utilise combinations of some or all of the following : age, spleen size, individual cell counts Sokal score (1984) –Predictive of survival with ‘older’ therapies – low, intermediate, high risk Euro (or Hasford) score (1998) –Predictive of survival with ‘newer’ therapies – low, intermediate, high risk EUTOS score (2011) –Predictive of complete cytogenetic response and subsequent progression free survival to ‘modern therapies’ – low, high risk

11. How do we treat CML? –Short term considerations Urgent / early interventions –Long term management Drug therapies –availability of clinical trials Role of stem cell (‘bone marrow’) transplant

12. How do we treat CML? Short term considerations -Immediate intervention to control white cell count -Physical / mechanical removal (leucoreduction) -Medication – hydroxycarbamide -Stem cell collection (future potential transplant candidate) -Fertility

13. How do we treat CML? Long term management Drug therapies availability of a clinical trial Stem cell (‘bone marrow’) transplant

14. Initial treatment (based on outcome of trials – including IRIS, SPIRIT 1 & 2 studies) Traditional therapies Mostly historical (as initial therapy) –Busulphan –Hydroxycarbamide* –Interferon* –Cytarabine *have a current role in the management of some cases of CML Modern ‘targeted’ therapies Tyrosine kinase inhibitors (TKIs) Selectively ‘switch off’ BCR- ABL tyrosine kinase –Imatinib –Dasatinib –Nilotinib –Bosutinib –Ponatinib

15. Which TKI is best for me? Role of clinical trials forthcoming SPIRIT 3 trial commercial studies What’s new? (Prof Steve O’Brien) / Involvement in clinical trials (Prof Jane Apperley) Choice of first line therapy (Prof Mhairi Copland)

16. Measuring response to treatment Full blood count (FBC) – haematological response Bone marrow - cytogenetic response (measure Ph+ chromosomes in marrow) Molecular response - measure BCR-ABL transcript levels by PCR in blood

17. Goals of treatment Haematologic remission (normal blood cell count and physical examination (ie no spleen) Cytogenetic remission (normal chromosomes - 0% Philadelphia positive cells in marrow) Molecular remission (negative PCR for BCR/ABL)

18. Assessing response to treatment (milestones)

19. Measuring response to treatment Peripheral blood - molecular response (measure BCR- ABL – transcript levels by PCR) –Understand your PCR and ask some questions (Prof Letizia Foroni)

20. Duration of therapy Traditionally treatment is indefinite / long term Unclear if this is necessary in the ‘best’ responders Trials evaluating dose reduction / stopping Prospects for stopping? Should this be in a clinical trial? (Prof Richard Clark)

21. When should we switch treatment? –Intolerant to treatment Side effects –Common side effects and how can they be managed? (Dr Dragana Milojkovic ) ; Long term side effects: to include fertility & parenting (Dr Graeme Smith) –Refractory (or unresponsive) to treatment Failure to achieve recommended milestones

22. Alternative therapies Choice of second and third line therapies –Dependent on what agent was used first line Choosing second and third line drugs. How do we choose?(Dr Jenny Byrne)

23. Role of stem cell transplantation Those failing (or at highest risk of failing) standard TKI therapy (based on risk group / treatment response) Some patients presenting with or progressing to more advanced phase disease (accelerated / blast crisis) Transplant eligibility is dependent on patient fitness and donor availability –What happens if you need a transplant? Dr Hugues de Lavallade

24. Summary Basic biology Clinical assessment – symptoms / diagnosis / staging / prognosis Treatment –Short term considerations –Long term management Monitoring disease Assessing response to treatment (milestones) Role of stem cell transplantation