1. Imatinib – where are we now. What about generic imatinib
Imatinib – where are we now? What about generic imatinib? CML patient & carer meeting 2016 Manchester, 24th September Richard Clark Royal Liverpool University Hospital 1

2. Audience participation! Please stand up if you have ever had CML
No pressure! 2

3. Please sit down if diagnosed before 1953
You predated modern treatment which can readily control the blood count 3

4. Please sit down if diagnosed between 1953 & 1983!
Please sit down if diagnosed between 1953 & 1983
You had treatment which can readily control the blood count, but no prospect of clearing the marrow 4

5. Please sit down if diagnosed between 1983 & 1999 !
Please sit down if diagnosed between 1983 & 1999
You probably initially had interferon. This can readily control the blood count, and may partially clear the marrow; completely in 5% of cases.
Given by injection.
Many side effects! 5

6. Please sit down if diagnosed between 1999 & 2003 !
Please sit down if diagnosed between 1999 & 2003
You probably had imatinib (maybe after initial interferon).
Imatinib readily controls the blood, and completely clears the marrow in at least 70% of patients.
Some side effects……………………… 6

7. Please sit down if diagnosed between 2003 & 2012 !
Please sit down if diagnosed between 2003 & 2012
You probably had imatinib though might have had one of the newer ‘TKIs’ in a clinical trial.
All the TKIs readily control the blood, and completely clear the marrow in at least 70% of patients.
Some side effects……………………… 7

8. Please sit down if diagnosed from 2013 onward !
Please sit down if diagnosed from 2013 onward
You could have had either imatinib or nilotinib on the NHS, though might have had one of the 3 other TKIs in a clinical trial.
All the TKIs readily control the blood, and completely clear the marrow in at least 70% of patients.
Some side effects……………………… 8

9. CML: Natural history (1980s)
Initial chronic phase
Accelerated phase
Blast crisis

10. CML: Natural history (2016)
After 2-3 years: ~93% still fine in
chronic phase
After ~10 years: ~almost all still
well in chronic phase
Initial chronic phase
Accelerated phase
~ 7% in blast crisis

11. PRIMARY GOAL of treatment: No More Progression Can we reliably predict those who will progress?

12. Disease Burden and Cytogenetic Response
Number of Leukaemic Cells
1012
1011
1010
109
108
107
106
RUGBY BALL
Complete haematological response
Normal blood count
GrapeFruit
Walnut
Overall survival
Complete cytogenetic response
No Ph+ chromosomes

13. Event-free Survival in IRIS by Molecular Response: 18-Month Landmark Analysis
BCR-ABLIS ≤ 0.1% (MMR) at 18 months predicted for prolonged Event-free Survival at 84 months
≤ 0.1% (n = 164)
>0.1-1% (n = 47)
>1-10% (n = 25)
>10% (n = 13)
BCR-ABL % (IS)
Without Event, % 10 20 30 40 50 60 70 80 90
100
Months Since Start of Treatment 12 24 36 48 72 84
* MMR defined as BCR-ABL% (IS) ≤ 0.1.
IRIS, International Randomized Study of Interferon and STI571; MMR, major molecular response.
Hughes et al., Blood (19):

14. Achieving Complete Cytogenetic Response
Complete cytogenetic response is a surrogate marker for the clinical outcome

15. Moving to molecular response

16. Disease Burden and Molecular Response
Number of Leukaemic Cells
1012
1011
1010
109
108
107
106
RUGBY BALL
GrapeFruit
Complete cytogenetic response
Walnut
Overall survival
Grain of rice
Major molecular response
BCR-ABL 0.1% or less
Stable response
No risk of progression

17. Event-free Survival in IRIS by Molecular Response: 18-Month Landmark Analysis
BCR-ABLIS ≤ 0.1% (MMR) at 18 months predicted for prolonged Event-free Survival at 84 months
≤ 0.1% (n = 164)
>0.1-1% (n = 47)
>1-10% (n = 25)
>10% (n = 13)
BCR-ABL % (IS)
Without Event, % 10 20 30 40 50 60 70 80 90
100
Months Since Start of Treatment 12 24 36 48 72 84
* MMR defined as BCR-ABL% (IS) ≤ 0.1.
IRIS, International Randomized Study of Interferon and STI571; MMR, major molecular response.
Hughes et al., Blood (19):

18. Overall Survival by Landmark Analysis of Molecular Response by 12 Months
Hehlmann et al., J Clin Oncol. 2011;29(12):

19. Survival for 282 Patients Treated with Imatinib First Line According to Molecular Response Achieved at 3 Months
BCR-ABL/ABL<9.8% OS= 93.3%
Probability of survival
BCR-ABL/ABL>9.8% OS= 54%
p<0.0001
Time from onset of imatinib therapy (years)
Marin et al, JCO 2011

20. 8-year cumulative incidence of CMR on imatinib therapy according to the BCR-ABL transcript level at 3 months
3-month transcript ratio ≤0.61% (n=57)
8-year CI of CMR of 84.7%,
Cumulative incidence of CMR
p<0.0001
3-month transcript ratio >0.61% (n=222)
8-year CI of CMR of 1.5%
Time from onset of imatinib therapy (years)
Marin et al, JCO 2011

21. BCR-ABL transcript levels at 3 months predicts 2 year cumulative incidence of CCyR and MMR
BCR-ABL/ABL <10%, n=117
BCR-ABL/ABL <10%, n=117
BCR-ABL/ABL >10%, n=11
Cumulative incidence of CCyR
Cumulative incidence of MMR
BCR-ABL/ABL >10%, n=11
p<0.001
p<0.001
Time from start of therapy (months)
Time from start of therapy (months)
Marin et al, Blood 2012

22. Disease Burden and Molecular Response
Number of Leukaemic Cells
1012
1011
1010
109
108
107
106
RUGBY BALL
GrapeFruit
Complete cytogenetic response
Overall survival
Walnut
Stable response
No risk of progression
Grain of rice
Major molecular response
Less than grain of sand
‘MR4’
BCR-ABL less than 0.01% (or undetectable)
Possibility to discontinue therapy

23. The ‘Glivec’ imatinib UK patent expires in December 2016.
Generic imatinib
A generic drug = ‘equivalent to a brand-name product in dosage, strength, route of administration, quality, performance, and intended use’.
The ‘Glivec’ imatinib UK patent expires in December 2016.
To get a licence, it is not necessary to carry out clinical trials – just to demonstrate equivalence. 23

24. How to make imatinib
Making it suitable for clinical use requires crystallisation.

25. Imatinib crystallisation
The easy way of crystallisation creates an ‘α stereoisomer’.
Glivec is a ‘β stereoisomer’; the patent covers its synthesis
Several α stereoisomers have been widely used in India, Turkey, etc.
There are no clinical trials of α stereoisomers.
DOES ALL THIS MATTER?
Possibly not …… 25

26. The generic imatinibs from:
Accord Teva
CIPLA Sandoz
Mylan Wockhardt
all have ‘approved marketing authorisation’ (i.e. a licence), though they may not necessarily all manufacture imatinib long-term.
Each will cost well under £2000 a year (‘Glivec’ costs ~£21,000 a year (400mg per day).
NHS England and Scotland are tendering to procure generic imatinib for a Jan 2017 start .
Colleagues in Canada and Poland are ~ 2 years ahead of us and report no problems with several of the generics 26

27. Changing Goals of Treatment
1960
1970
1980
1990
2000
2010
Typ ? e
Busulphan
IFN
Imatinib
2nd Gen TKIs
Optimal
Treatment
Aim
MCyR
Improved OS ~ 1.5Y
MMR
Optimal OS in some
Deeper/faster MR
Optimal OS in more?
“Cure” ?
CHR
Improved QoL
No effect on OS
Tumour Reductiona
≤10% ≈ 1-log
≤1% ≈ 2-log
Tumour Burden
MR4 and beyond
≤0.1%IS ≈ 3-log
≤0.01%IS ≈ 4-log
≤0.0032%IS ≈ 4.5-log
≤0.001%IS ≈ 5-log
a Compared with baseline levels.
CMR, complete molecular response; IFN, interferon; IS, international scale.

28. GOALS of treatment Prevention of progression: Of course Essential
Normal (low) blood count by 3 months:
Molecular (PCR) less than 10% at 3 months:
Might be important
Cytogenetic response/less than 1% by 12 months:
Definitely Important
MMR is a “safe haven”, but is CCyR enough?
Probably useful
Is a deeper response (MR4 or better) essential?
Maybe not