1. HOW TO TREAT FIRST LINE FAILURE?
Dr Delphine Rea
Pôle Hématologie, Oncologie, Radiothérapie
Hôpital Saint-Louis
Paris, France
CML Horizons
Münich, May 12, 2012

2. CURRENT MANAGEMENT OF CML
Newly diagnosed CP-CML
I: imatinib
D: dasatinib
N: nilotinib
A: allografting
E: experimental drug
First-line TKI I D N
Acceptable safety profile
AND
optimal response
Intolerance OR
treatment failure
Continue First-line TKI
Stop First-line TKI
Start 2nd-line therapy I A E D N
Never stop medication therapy1
1Baccarani et al. JCO 2009; 27:
TKI: tyrosine kinase inhibitor

3. TOOLS FOR MONITORING THE RESPONSE AND DETECTING TREATMENT FAILURE
Hematologic (blood drawn by venipuncture): blood cell counts
Cytogenetic (bone marrow aspiration): karyotype
Molecular (blood drawn by venipuncture): RTQ-PCR
Molecular (blood drawn by venipuncture): mutational analysis

4. IMATINIB FAILURE: ELN DEFINITION
Evaluation time, months
Failure 3
Less than complete hematologic response 6
No cytogenetic response (Ph+ > 95%) 12
Less than partial cytogenetic response (Ph+>35%) 18
Less than complete cytogenetic response (Ph+ ≥ 1%)
Any time during treatment
Loss of complete hematologic response; loss of complete cytogenetic response; mutations; Ph+ clonal evolution
Baccarani et al. JCO 2009; 27:

5. IMATINIB FAILURE: SECOND LINE TREATMENT OPTIONS
Second generation TKI in the absence of a T315I mutation
dasatinib or nilotinib
Allogeneic SCT (whenever possible1):
in case of progression to advanced phase CML
in case of a T315I mutation
New drugs under development
1Age, eligibility, matched donor availability
SCT: stem cell transplantation
Baccarani et al. JCO 2009; 27:

6. FACTORS DRIVING THE CHOICE OF THE BEST SECOND LINE THERAPY
Type of first line therapy
Phase of CML at the time of treatment failure
Mechanisms for treatment failure
Poor compliance
Drug-drug interactions substantially decreasing TKI plasma level
Clonal evolution
BCR-ABL mutations
Efficacy of the available drugs in the second line setting
EBMT score and matched-donor availability
Safety profile of the available drugs
Age, performance status and comorbidities

7. PATIENT CASE Man aged 69 years at CP-CML diagnosis
Significant comorbidity: type 2 diabetes treated by metformine
Frontline therapy: imatinib 400mg/d 6 12 18 24 30 36
0.001
0.01
0.1 1 10
100
Months from TKI therapy
BCR-ABL/ABL IS %
MMR
MR4.5
CHR
56% Ph+
CCA: trisomy 8
Mut = 0
Failure
No compliance issues
Indication for dasatinib or nilotinib
CHR
CHR
40% Ph+
Mut = 0
Suboptimal response
Compliance issues
Dr Delphine Rea, Hôpital Saint-Louis

8. DASATINIB AFTER IMATINIB RESISTANCE OR INTOLERANCE IN CP-CML (PHASE III STUDY BMS CA180034): RESPONSES BY 24 MONTHS
Patients with baseline mutations with IC50 > 3 nM had lower responses rates to dasatinib
L248V, G250E, Q252H, E255K/V, L384M, F317L, L384M, F386F
V299L, F317L, T315I 10 20 30 40 50 60 70 80 90
100
All
Resistant
Intolerant
MCgR
CCgR
MMR
Dasatinib 100 mg QD 63 37 59 44 35 77 67 43
Percentage
Shah et al. Haematologica 2010;95: 232−240.
Muller et al, Blood 2009;114: 4944−4953.
MCgR: major cytogenetic response

9. NILOTINIB AFTER IMATINIB RESISTANCE OR INTOLERANCE IN CP-CML (STUDY CAMN107A2101): RESPONSES BY 24 MONTHS
Patients with baseline mutations with IC50 > 150 nM had lower responses rates to nilotinib2
Y253H, E255K/V, F359C/V, T315I 10 20 30 40 50 60 70 80 90
100
All
Resistant
Intolerant
Nilotinib 400 mg BID 59 44 28 56 41 66 51
MCgR
Percentage
CCgR
MMR
Kantarjian et al. Blood 2011;117:1141−1145
Hughes et al. JCO 2009;27:4204−4210
MCgR: major cytogenetic response

10. PATIENT CASE: OUTCOME Man aged 69 years at CP-CML diagnosis
Significant comorbidity: type 2 diabetes treated by metformine
Frontline therapy: imatinib 400mg/d
Second line therapy: dasatinib 100mg/d 6 12 18 24 30 36
0.001
0.01
0.1 1 10
100
Months since TKI treatment
BCR-ABL/ABL % IS
MMR
MR4.5
Switch to
Dasatinib
CHR
14% Ph+
CHR
0% Ph+
Dr Delphine Rea, Hôpital Saint-Louis

11. ELN PROVISIONAL DEFINITIONS OF RESPONSE TO 2nd LINE TKI
Provisional definitions of response to nilotinib and dasatinib, as second-line therapy in patients with imatinib-resistant CML-CP
Evaluation time
Response
Suboptimal
Failure
Baseline −
3 months
Minor CgR
No CgR; new mutations
6 months
PCgR
Minimal CgR; new mutations
12 months
< MMR
< PCgR; new mutations
CgR: cytogenetic response
PCgR: partial cytogenetic response
MMR: major molecular response
Baccarani et al. JCO 2009; 27:

12. PATIENT CASE Man aged 55 years at CP-CML diagnosis
Significant comorbidity: none
Frontline therapy: imatinib 400mg/d in the context of a clinical trial
CHR
0% Ph+
Mut: F317L
CHR
0% Ph+ 6 12 18 24 30 36 42 48 54 60
Months since imatinib treatment
0.001
0.01
0.1 1 10
100
MMR
MR4.5
BCR-ABL/ABL % IS
Mut: F317L
Dr Delphine Rea, Hôpital Saint-Louis

13. DEALING WITH BCR-ABL MUTATIONS
T315I/A T315I
Dasatinib
Nilotinib
Q252H
Q252H
V299L
F317V/L/I/S
Y253H
S349L
F359I
F311I
L248R
E255K/V
E255K
BCR-ABL Kinase Domain P A
M278L
G250E/R
F359C
H396R/P
M343T
E373K
E279K
E281K
V338G
V339A/G
I360F
V379E/A
G398R
D276V
M244V
L248R/V
E255K
T315I/S/G
Y253H/C/F
Imatinib
Adapted from: Burgess et al PNAS 2005;102:

14. PATIENT CASE Man aged 55 years at CP-CML diagnosis
Significant comorbidity: none
Frontline therapy: imatinib 400mg/d in the context of a clinic al trial
CHR
0% Ph+
Mut: F317L 6 12 18 24 30 36 42 48 54 60
Months since imatinib treatment
0.001
0.01
0.1 1 10
100
MMR
MR4.5
BCR-ABL/ABL % IS
Imatinib failure
dasatinib-resistant mutation
Switch to nilotinib
Dr Delphine Rea, Hôpital Saint-Louis

15. DEALING WITH A T315I MUTATION
The T315I mutation precludes the access of all approved TKIs to the ATP binding pocket of BCR-ABL
New drugs capable of targeting the BCR-ABL T315I mutation are currently under development
eg: omacetaxine
eg: ponatinib
BCR-ABL
T315
BCR-ABL
unmutated
Inib
Inib
Nanda et al, Haematologica 2011; 96: S2 abstract 1011
Cortes et al, Blood 2011; 118: abstract 109

16. ALLOGENEIC SCT AFTER 1rst LINE TREATMENT FAILURE
The numbers of allogeneic transplants for CML have substantially declined over the years due to the availability and efficacy of TKIs but allogeneic SCT remains an important salvage therapy
Current indications for allogeneic SCT are:
After first line TKI in patients who progressed to advanced phase CML and in patients who carry the T315I mutation
In case of failure of imatinib and dasatinib or nilotinib
In patients with advanced phase CML at diagnosis after a pretreatment with TKI
Feasibility of allogeneic SCT depends on age, general health status and matched-donor availability
Risks and benefits must be carefully evaluated
Gratwohl et al. Haematologica 2006;91:
Baccarani et al. JCO 2009; 27:

17. CONCLUSIONS
Failure to first line therapy requires a treatment change, with the goal to restore an optimal response
Best second line treatment choice is guided on disease characteristics at the time of treatment failure, patients medical background, safety and efficacy profile of available drugs
New drugs in development like ponatinib may further improve outcomes of patients who fail currently approved TKIs especially those who develop a T315I mutation and in whom allogeneic stem cell transplantation is not possible
Allogeneic stem cell transplantation is an option in case of progression to advanced phase disease, emergence of a T315I mutation or in case of failure of at least 2 TKIs