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

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: 6041-6051 TKI: tyrosine kinase inhibitor

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

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: 6041-6051

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: 6041-6051

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

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

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

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

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

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: 6041-6051

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

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: 3395-3400

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

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

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: 513-521 Baccarani et al. JCO 2009; 27: 6041-6051

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