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Resistance to Imatinib in Chronic Myelogenous Leukemia (CML): Mutations and Beyond

Resistance to Imatinib in Chronic Myelogenous Leukemia (CML): Mutations and Beyond Dr. Lambert Busque. Potential Conflict of Interest. Consultant - Fonds de recherche / 2004 – 2009 Novartis Ad Board / 2008 Brystol Myers Squibb. Q-CROC Résistance à l’Imatinib et leucémie myéloïde chronique.

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Resistance to Imatinib in Chronic Myelogenous Leukemia (CML): Mutations and Beyond

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  1. Resistance to Imatinib in Chronic Myelogenous Leukemia (CML): Mutations and Beyond Dr. Lambert Busque

  2. Potential Conflict of Interest • Consultant - Fonds de recherche / 2004 – 2009 • Novartis • Ad Board / 2008 • Brystol Myers Squibb

  3. Q-CROCRésistance à l’Imatinib et leucémie myéloïde chronique Resistance to Imatinib in Chronic Myelogenous Leukemia (CML): mutations and beyond Lambert Busque MD FRCPC Hôpital Maisonneuve-Rosemont Université de Montréal

  4. CML epidemiology • Global incidence of CML: 1.6/100,000 • Canada: ~ 500 new cases/year • Median age at presentation • 53 years • Incidence increases with age • Up to 30% of patients >60 years of age • Slightly higher incidence in men (male:female 1.3:1) • At presentation • 50% diagnosed by routine laboratory tests • 85% diagnosed during chronic phase

  5. 1 2 3 4 5 9 6 7 8 10 11 12 13 14 15 16 17 18 22 19 20 21 x Y CML cytogenetic abnormality:The Philadelphia chromosome • Discovery, Nowell (1960) • t(9;22), Rowley (1973) • BCR-ABL, Collins (1984) • Imatinib, Druker (1996)

  6. Functional activation of Ras Inhibition of apoptosis Kinase Domain Kinase Domain DNA BD Actin BD DD SH3 SH2 BCR ABL Downregulation of cell adhesion molecules Defective response to genotoxic stress Signal transduction pathways

  7. Chronic phase Blast crisis Rate of transformation ~ 10-15%/year CML evolution (accelerated) Survival : 4 years (Hydrea)

  8. CML treatment • Bone marrow transplantation • 25% have a familal HLA identical donor • 80% disease free survival at 5 years • 10% early mortality • 30% chronic graft versus host disease • Interferon • 20% complete cytogenetic response • Imatinib: molecular targeted therapy

  9. Imatinib targets the cause of CML Imatinib: a specific inhibitor of a small family of tyrosine kinases, including Bcr-Abl

  10. 100 90 80 70 60 %responding 50 40 30 CHR 20 MCyR 10 CCyR 0 0 6 12 18 24 30 36 42 48 54 60 66 Months since randomization to Imatinib Cumulative Best Response at 12 and 60 months on First-line Imatinib 96% 98% 92% 85% 84% 87% 80% 69%

  11. 100 90 80 70 60 % without event 50 Survival without AP/BC 40 Event-free Survival 30 20 10 0 0 6 12 18 24 30 36 42 48 54 60 66 Months since randomization Event-free Survival and Survival Without AP/BC on First-line Imatinib Estimated rate at 60 months (with 95%CI) (90-96) 93% 83% (80-87) Actual Events 6.3% AP/BC (n=35) 5.1% loss of MCyR (n=28)2.5% loss of CHR (n=14)1.6% CML-unrelated deaths (n=9)

  12. Resistance occurs Patient - Imatinib Blast crisis Primary and secondary resistance Therapeutic alternatives 20%

  13. Documenting resistance by monitoring of the Philadelphia chromosome • t(9;22) • Karyotype • FISH • RT-PCR • Qualitative • Quantitative (Q-PCR) • Resistance • Mutation analysis • Imatinib blood level

  14. Quantitating Leukemic Cell Load 1012 CHR Cytogenetic response MCR 1010 CCR Q-PCR response 108 3 log reduction Number of leukemic cells 4 log reduction 106 Nested PCR Limits of detection 104 102 1 100% disease free progression CHR: complete hematologic responseMCR: major cytogenetic response

  15. Primary resistance Patient not achieving specific therapeutical milestones

  16. Milestones 3 Months 12 Months 18 Months 24 Months Response Hematological Major Cytogenetic (MCR) (<35% PH+ cells) Complete Cytogenetic (CCR) Major Molecular (> 3 log)

  17. Secondary resistance Loss of response

  18. **CML progression** • Transformation (accelerated; blastic phase) • Clonal evolution (supplementary cytogenetic abnormalities) • Loss of CCR (FISH) • > 0.5 log (Q-PCR) increase in transcript level • Detection of ABL mutation

  19. Causes of resistance Janet Apperley, Lancet Oncology 2007

  20. Imatinib Adherence 3500 2921 3000 2500 2000 Patients 1500 1000 685 500 0 0-1 1-2 2-3 3-4 4-5 5-6 6-7 7-8 8-9 9-10 10-11 11-12 12-13 13+ Months Tsang J et al. J Clin Oncol. 2006;24:330s. Abstract 6119.

  21. Quartiles 2 and 3≥ 647-1170 ng/mLN = 178 Quartile 4> 1170 ng/mLN = 86 Quartile 1< 647 ng/mLN = 87 > 2000 ng/mL (n = 19) Imatinib 400 mg daily (N = 351) Mean = 979 ng/mL, Median = 879 ng/mL Larson et al. Blood, 108 (11): Abstract 0429 Imatinib PK Trough Levels at Day 29

  22. Higher CCyR Rates With Higher Imatinib PK Trough Levels 89% 84% 87% 80% 73% 71% P = 0.005 (Q1 vs others) 81% 73% 59% P = 0.0125 (overall) (N = 87) (N = 178) (N = 86) Larson et al. Blood, 108 (11): Abstract 0429

  23. (N = 51) (N = 126) (N = 65) 86% P = 0.08 (overall) 79% 63% 53% P = 0.03 (Q1 vs others) 50% 38% Higher MMR Rates (in CCyR Patients) With Higher Imatinib PK Trough Levels Larson et al. Blood, 108 (11): Abstract 0429

  24. Intracellular level Oct-1: influences outcome (T. Hughs) MDR Drug metabolism: CYP3A4-5/2D6) CRKL Intracellular level: Optimization Oct-1 Functional testing: Target inhibition (CRKL) JCO oct 2007

  25. kinase BCR ABL Mutation detection in ABL gene of bcr-abl • Specific amplification of bcr-abl transcripts • Very specific • 2. Sequence exons 4-9 • Low sensitivity Mutation Detection: 25% of cells need to harbor the mutation

  26. P-loop Mutations associated with drug resistance >90 different mutations in 50 residues M351T Y253F Y253H E255K E255V E355G L248V F359V F359C T315I G250E F317L Q252H E279K M388L S417Y E450G E459K F486S H396R M244V ATP binding site carboxy terminal activation loop BCR-ABL Kinase Domain

  27. 2007 >90 mutations at 57 residues T315I 2001 - P loop poorer prognosis M351T increased dose Schindler et al, Science 2000, 289, 1938 Imatinib binding mode can help explain resistance S. Branford

  28. 15 T315I M351T G250E M244V F359V Y253H E255K H396R F317L 10 5 0 Q252H M244V D276G M351V Y253H D276N M351T E453G E459Q G250E Y320C E355G A397P E450G L273M M388L E450D T277N L387M Y253F T277A H396R E450K E255K T277S T315P S417Y E453K E459K E255V E292V F359C S417F F486S E279K F359V F376V L248V L298V L387F L387F M472I F317L L387L V379I T315I I418V F311I F317I F359I L364I T277P Mutations are not born equal…. High insensitivity Low insensitivity Frequency of mutations % S. Branford

  29. Clinical impact of mutations • The biological impact of most mutations is unknown. • There are >40 mutations that we have not detected after 6 years of testing and have not been characterised in terms of sensitivity to imatinib • The clinical outcomes of patients with most mutation is poorly characterized. • Need for international registry of mutations

  30. Therapeutic Alternatives for Patients with CML and Imatinib Resistance

  31. Nilotinib, Imatinib and Dasatinib: Preferential Binding of Tyrosine Kinases • The balance between preferential targeting and potency for BCR-ABL1 may prove to be beneficial in providing activity against point mutations and retaining a favourable tolerability profile. • Nilotinib has no significant effect on other kinases evaluated (including SRC, FLT3, VEGFR, EGFR, InsR, RET, MET, IGFR, etc.) at concentration <3000 nM 1. Mestan J et al. Blood. 2004;104(546a):Abstract 1978. 2. Weisberg E et al. Cancer Cell. 2005;7:129.

  32. Profiles for Kinase Inhibition:Nilotinib and Dasatinib Giles F, et al: Presented at ASH 2006. Poster #2170.

  33. Pharmacokinetic Properties

  34. T315 /I/V/C/S F317 V299 V299L L248V L248 /R Q252H E255K Predictions for dasatinib treated patients /A T315I S. Branford V F317L P-loop T315I, T315A, and F317V should account for most cases of clinical resistance

  35. START-C: Efficacy of Dasatinib at 15 Months CHR MCR 100 80 90 80 5 PCR 70 59 CCR 60 52 11 CHR % with Response 50 91 13 40 75 30 49 20 40 10 0 Total Total Imatinib- Imatinib- intolerant rResistant Stone RM et al. Presented at ASH 2007. Presentation 734.

  36. START-C: PFS With Dasatinib at 2 Years PFS, Progression-free survival Stone RM et al. Presented at ASH 2007. Presentation 734.

  37. T315I 10,000 sensitive 1,500 E255V Y253H E255K IC50 Cell Proliferation (nM) 1,000 500 0 Q252H M244V D276G G250V M351T E355G G250A G250E H396R M388L E255D E255R K285N Y253H F317C F317V E275K E355A E281K F486S E292K F311V F359V A380S F359C E255K E255V S348L L248V L387F F317L M237I T315I Sensitivity to Nilotinib of 33 Mutants

  38. Nilotinib – Phase II: Response Rates in Patients With CP CML *In patients without CHR at baseline. 1. Rosti G et al. Presented at: 43rd ASCO Annual Meeting; June 1-5, 2007; Chicago, Ill. Abstract 7007. 2. Martinelli G et al. Presented at: 12th Congress of the European Hematology Association; June 7-10, 2007; Vienna, Austria. Abstract 0555. 3. Kantarjian HM et al. Oral presentation at the 49th ASH Annual Meeting; December 8-11, 2007; Atlanta, Georgia. Blood. 2007;110(11):Abstract 735.

  39. Bosutinib (SKI-606) Orally bioavailable dual Src/Abl inhibitor Shows inhibitory activity against Bcr-Abl 200 times more potent than imatinib Minimal inhibitory activity against platelet-derived growth factor receptor (PDGFR) or c-kit Inhibits a wide variety of Bcr-Abl kinase domain mutants, except T315I 500-mg daily dose showed efficacy in phase I study

  40. Bosutinib in CP CML: Responses Among Patients Previously Treated with Imatinib Cortes J et al. Presented at ASH 2007. Oral presentation 733.

  41. GIMEMA CML WP Nilotinib in early CP-CML (GIMEMA)Complete Cytogenetic Response (ITT) GIMEMA Protocol CML 0307 Rosti et al. Blood 2008;112(11). Abstract #181 – Oral

  42. CML resistance overview • Paradigm for cancer targeted therapy • Simplest oncologic disorder??? • Resistance occurs and is multifactorial • Strategies to overcome resistance • Drug level optimization • Intracellular?? • More potent TKI early? • Combination therapy?

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