“I’ve been diagnosed with CML.
What’s the best initial
treatment for me?”
Dr N M Butt
Consultant Haematologist
Royal Liverpool University Hospital
11th October 2014
CML: cause  treatment
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
TKIs in CML
Off patent
2016
Imatinib
Development License
NICE approved
Dasatinib
Nilotinib
Bosutinib
Ponatinib
(radotinib)
CDF
2000
2005
2010
2015
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.
Phases of disease at diagnosis
• Chronic phase
• Accelerated phase
• Blast crisis
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.
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.
Clinical Trials
Benefits / Advantages
Risk / Disadvantages
• 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
• 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.
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
………
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)
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.
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.
In the absence of a clinical trial,
which drug?
Imatinib?
Nilotinib?
Dasatinib?
Bosutinib?
Ponatinib?
Which drugs are routinely funded for
newly diagnosed CML?
• Currently – Accelerated / Blast crisis phase
CML :
- Imatinib (high dose)
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
TKIs in CML
Off patent
2016
Imatinib
Development License
NICE approved
Dasatinib
Nilotinib
Bosutinib
Ponatinib
(radotinib)
CDF
2000
2005
2010
2015
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)
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)
Of drugs which are routinely funded
for newly diagnosed CML….
Imatinib versus Nilotinib?
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.
ENESTnd Study Design and Endpoints
• N = 846
• 217 centers
• 35 countries
R
Nilotinib 300 mg BID (n=282)
A
N
D
O Nilotinib 400 mg BID (n=281)
M
I
Z
Imatinib 400 mg QD (n=283)
E
D*Stratification by Sokal risk score
*
• Primary endpoint:
• Secondary endpoint:
• Other endpoints:
Follow-up 5 years
MMR at 12 months
CCyR by 12 months
time to and duration of MMR and
CCyR, EFS, PFS, time to AP/BC, OS
Nilotinib is Superior to Imatinib: CCyR Rates
p<0.0001
% CCyR
p=0.0005
Nilotinib Leads to Faster / Deeper
p<0.0001
Responses
60
p<0.0001
% MMR
Percentage
50
44
43
38
40
33
30
30
22
18
20
10
43
12
9
5
1
0
Month 3
Nilotinib 300 mg BID
Month 6
Month 9
Nilotinib 400 mg BID
Month 12
Imatinib 400 mg QD
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
ENESTnd (nilotinib)
Cardiovascular Events by 5 Years
Nilotinib
300 mg BID
(n = 279)
Total,
Y1-4,
Y5,
b
n (%)
n
nc
Nilotinib
400 mg BID
(n = 277)
Total,
Y1-4,
Y5,
b
n (%)
n
nc
Imatinib
400 mg QD
(n = 280)
Total,
Y1-4,
n (%)
nb
Total patients with
CVEs
21
(7.5)
37
(13.4)
6
(2.1)
Ischemic heart
disease
18
4
11
(3.9)
11
0
Ischemic
cerebrovascular events
4
(1.4)
3
1
Peripheral artery
disease
7
(2.5)
4
3
24
14
14
10
9
(3.2)
5
7
(2.5)
5
24 (8.7)
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.
CVE, cardiovascular event.
Y5,
nc
4
2
5
(1.8)
3
2
4
1
(0.4)
1
0
2
0
0
0
Data cutoff: September 30, 2013
26
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.
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
Thank You