“I’ve been diagnosed with CML. What’s the best initial treatment for me?”

1. “I’ve been diagnosed with CML. What’s the best initialtreatment for me?” Dr N M Butt Consultant Haematologist Royal Liverpool University Hospital 11th October 2014

2. CML: cause  treatment

3. Tyrosine Kinase Inhibitors (TKI’s) • Ph+ chromosome • Abnormal BCR-ABL fusion gene  abnormal fusion protein • This protein – “enzyme” - Tyrosine Kinase (TK) • TKs control cell growth • BCR-ABL protein has abnormal tyrosine kinase (TK) activity. • Produces unregulated growth of white blood cells which is typical for CML. • Treatment targeted to block (inhibit) TK activity (TKIs) of BCR-ABL has revolutionized the treatment of CML in the past 15 years

4. TKIs in CML Off patent 2016 Imatinib Development NICE approved License Dasatinib Nilotinib Bosutinib Ponatinib (radotinib) CDF 2000 2005 2010 2015

5. What’s the best initial treatment for me? • It depends… • …on the phase of disease at diagnosis**. • …on the availability of a clinical trial. • …on what drugs are funded**. • …on clinician / patient choice.

6. Phases of disease at diagnosis • Chronic phase • Accelerated phase • Blast crisis

7. What’s the best initial treatment for me? • It depends… • …on the phase of disease at diagnosis**. • …on the availability of a clinical trial. • …on what drugs are funded**. • …on clinician / patient choice.

8. What’s the best initial treatment for me? • It depends… • …on the phase of disease at diagnosis**. • …on the availability of a clinical trial. • …on what drugs are funded**. • …on clinician / patient choice.

9. Clinical Trials Benefits / Advantages Risk / Disadvantages You cannot be sure of the outcome. New treatment may not be as effective as standard treatments. It is possible that you will experience unexpected, serious or life threatening side effects. Likely to involve more frequent hospital visits, more tests, more monitoring than you would if you were receiving the standard treatment in usual care. • Gain access to new drugs that may be better for your condition than standard treatments. • Treatment and progress may be monitored more closely than if you were receiving the usual treatment. • Help others in contributing to medical research

10. Clinical trials in newly diagnosed CML • IRIS – IFN V IM • SPIRIT – IM with / without IFN , Ara-C • SPIRIT2 – IM V DAS • DASISION – IM V DAS • ENESTnd - IM V NIL • BELA – BOS V IM • EPIC – PON V IM • ………

11. Clinical trials • Currently no national CML trials open • SPIRIT3 in pipeline…. • Liverpool – BFORE study – BOS V IM (similar to BELA – BOS dose reduced  reduced side effects maintain positive features / advantages over IM)

12. What’s the best initial treatment for me? • It depends… • …on the phase of disease at diagnosis**. • …on the availability of a clinical trial. • …on what drugs are funded**. • …on clinician / patient choice.

13. What’s the best initial treatment for me? • It depends… • …on the phase of disease at diagnosis**. • …on the availability of a clinical trial. • …on what drugs are funded**. • …on clinician / patient choice.

14. In the absence of a clinical trial, which drug? Imatinib? Nilotinib? Dasatinib? Bosutinib? Ponatinib?

15. Which drugs are routinely funded for newly diagnosed CML? • Currently – Accelerated / Blast crisis phase CML : - Imatinib(high dose)

16. Which drugs are routinely funded for newly diagnosed CML? • Currently – Chronic phase CML - only two drugs are approved for funding by National Institute for Health and Care Excellence (NICE) for newly diagnosed CML: - Imatinib • Nilotinib

17. TKIs in CML Off patent 2016 Imatinib Development NICE approved License Dasatinib Nilotinib Bosutinib Ponatinib (radotinib) CDF 2000 2005 2010 2015

18. Which drugs are not routinely funded for newly diagnosed CML? • Dasatinib - no trials directly comparing DAS and NIL - indirect comparisons between DAS and NIL suggest equally as effective - DOH and the manufacturer of NIL agreed to provide the drug to the NHS at a discounted price. • Cost reduction enabled NICE approval NIL for use on the NHS. • (NB DAS is funded via Cancer Drug Fund (CDF) for IM/NIL failure or intolerant)

19. Which drugs are not routinely funded for newly diagnosed CML? • Bosutinib (NICE – only review for previously treated CML – [not approved Nov 2013] – not newly diagnosed); CDF funded – CML failed NIL or DAS) • Ponatinib (not reviewed NICE ; CDF funded for CML with specific mutation - T315I – makes condition resistant to other TKIs)

20. Of drugs which are routinely funded for newly diagnosed CML…. Imatinib versus Nilotinib?

21. What’s the best initial treatment for me? • It depends… • …on the phase of disease at diagnosis**. • …on the availability of a clinical trial. • …on what drugs are funded**. • …on clinician / patient choice.

22. ENESTnd Study Design and Endpoints Nilotinib 300 mg BID (n=282) R A N DO M I Z ED * • N = 846 • 217 centers • 35 countries Nilotinib 400 mg BID (n=281) Imatinib 400 mg QD (n=283) *Stratification by Sokal risk score Follow-up 5 years • Primary endpoint: MMR at 12 months • Secondary endpoint: CCyR by 12 months • Other endpoints: time to and duration of MMR and CCyR, EFS, PFS, time to AP/BC, OS

23. Nilotinib is Superior to Imatinib: CCyR Rates p<0.0001 p=0.0005 % CCyR

24. Nilotinib Leads to Faster / Deeper Responses p<0.0001 p<0.0001 % MMR

25. BUT…. • the trade off…?? • IM (once daily)versus NIL (twice daily**) • Dietary restriction** NIL - No food should be consumed for 2 hours before the dose is taken and no food should be consumed for at least one hour after the dose is taken. • Poor compliance** affects response

26. ENESTnd (nilotinib)Cardiovascular Events by 5 Years Y, year. a All events, regardless of relationship to study drug. b Data cutoff: July 27, 2012 (minimum follow-up of 48 cycles). c Events reported between the 48-cycle and 60-month data cutoffs. Data cutoff: September 30, 2013 CVE, cardiovascular event. 26

27. What’s the best initial treatment for me? • It depends… • …on the phase of disease at diagnosis**. • …on the availability of a clinical trial. • …on what drugs are funded**. • …on clinician / patient choice.

28. What’s the best initial treatment for me? • It depends… • …on the phase of disease at diagnosis**. • …on the availability of a clinical trial. Liverpool – BFORE study; SPIRIT3 in due course • …on what drugs are funded**. UK – AP/BC – Imatinib; UK – CP - Imatiniband Nilotinib • …on clinician / patient choice. Liverpool - Favour Imatinib with very close response monitoring

29. Thank You