“I’ve been diagnosed with CML. What’s the best initial treatment for me?”
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Transcript of “I’ve been diagnosed with CML. What’s the best initial treatment for me?”
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“I’ve been diagnosed with CML. What’s the best initial
treatment for me?”
Dr N M ButtConsultant Haematologist
Royal Liverpool University Hospital11th October 2014
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CML: cause treatment
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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
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Imatinib
Dasatinib
Nilotinib
Bosutinib
Ponatinib
2000 2010 20152005
Development License NICE approved
Off patent2016
TKIs in CML
CDF(radotinib)
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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.
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Phases of disease at diagnosis
• Chronic phase
• Accelerated phase
• Blast crisis
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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.
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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.
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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.
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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• ………
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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)
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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.
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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.
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Imatinib?
Bosutinib?
Dasatinib?
Nilotinib?
Ponatinib?
In the absence of a clinical trial, which drug?
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Which drugs are routinely funded for newly diagnosed CML?
• Currently – Accelerated / Blast crisis phase CML :
- Imatinib (high dose)
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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
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Imatinib
Dasatinib
Nilotinib
Bosutinib
Ponatinib
2000 2010 20152005
Development License NICE approved
Off patent2016
TKIs in CML
CDF(radotinib)
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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)
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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)
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Of drugs which are routinely funded for newly diagnosed CML….
Imatinib versus Nilotinib?
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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.
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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*
Nilotinib 400 mg BID (n=281)• N = 846• 217 centers• 35 countries
Follow-up 5 years
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Nilotinib is Superior to Imatinib: CCyR Rates
p<0.0001
p=0.0005
% C
CyR
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Nilotinib Leads to Faster / Deeper Responses
9
33
43 44
5
30
3843
1
12
1822
0
10
20
30
40
50
60
Month 3 Month 6 Month 9 Month 12
Per
centa
ge
Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD
% M
MR
p<0.0001
p<0.0001
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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
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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, nb
Y5, nc
Total, n (%)
Y1-4, nb
Y5, nc
Total, n (%)
Y1-4, nb
Y5, nc
Total patients with CVEs
21 (7.5)
18 437
(13.4)24 14
6 (2.1)
4 2
Ischemic heart disease
11 (3.9)
11 024 (8.7)
14 10 5 (1.8)
3 2
Ischemic cerebrovascular events
4 (1.4)
3 1 9 (3.2)
5 4 1 (0.4)
1 0
Peripheral artery disease
7 (2.5)
4 3 7 (2.5)
5 2 0 0 0
26
Data cutoff: September 30, 2013
CVE, cardiovascular event.
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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.
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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
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Thank You