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

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Presentation on theme: "“I’ve been diagnosed with CML. What’s the best initial treatment for me?” Dr N M Butt Consultant Haematologist Royal Liverpool University Hospital 11 th."— Presentation transcript:

1 “I’ve been diagnosed with CML. What’s the best initial treatment for me?” Dr N M Butt Consultant Haematologist Royal Liverpool University Hospital 11 th 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 Imatinib Dasatinib Nilotinib Bosutinib Ponatinib Development License NICE approved Off patent 2016 TKIs in CML CDF (radotinib)

5 What’s the best initia l 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 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 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.

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

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 Imatinib Dasatinib Nilotinib Bosutinib Ponatinib Development License NICE approved Off patent 2016 TKIs in CML CDF (radotinib)

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 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 *Stratification by Sokal risk score Imatinib 400 mg QD (n=283) Nilotinib 300 mg BID (n=282) RANDOMIZED*RANDOMIZED* Nilotinib 400 mg BID (n=281) N = centers 35 countries Follow-up 5 years

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

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

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. Nilotinib 300 mg BID (n = 279) Nilotinib 400 mg BID (n = 277) Imatinib 400 mg QD (n = 280) Total, n (%) Y1-4, n b Y5, n c Total, n (%) Y1-4, n b Y5, n c Total, n (%) Y1-4, n b Y5, n c Total patients with CVEs 21 (7.5) (13.4) (2.1) 42 Ischemic heart disease 11 (3.9) (8.7) (1.8) 32 Ischemic cerebrovascular events 4 (1.4) 319 (3.2) 541 (0.4) 10 Peripheral artery disease 7 (2.5) 437 (2.5) Data cutoff: September 30, 2013 CVE, cardiovascular event.

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 - Imatinib and Nilotinib – …on clinician / patient choice. Liverpool - Favour Imatinib with very close response monitoring

29 Thank You


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