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The Treatment Continuum for Patients with CML

The Treatment Continuum for Patients with CML. Jorge Cortes, MD Department of Leukemia MD Anderson Cancer Center Houston, Texas. Survival in Early Chronic Phase CML. MDACC 2009. Results with Imatinib in Early CP CML – The IRIS Trial at 8-Years. 304 (55%) patients on imatinib on study

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The Treatment Continuum for Patients with CML

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  1. The Treatment Continuum for Patients with CML Jorge Cortes, MD Department of Leukemia MD Anderson Cancer Center Houston, Texas

  2. Survival in Early Chronic Phase CML MDACC 2009

  3. Results with Imatinib in Early CP CML – The IRIS Trial at 8-Years 304 (55%) patients on imatinib on study Projected results at 8 years: CCyR 83% 82 (18%) lost CCyR, 15 (3%) progressed to AP/BP Event-free survival 81% Transformation-free survival 92% If MMR at 12 mo: 100% Survival 85% (93% CML-related) Annual rate of transformation: 1.5%, 2.8%, 1.8%, 0.9%, 0.5%, 0%, 0%, & 0.4% Deininger et al; Blood 2009; 114: Abst# 1126

  4. IRIS 8-Year Update 37% Deininger et al; Blood 2009; 114: Abst# 1126

  5. Improving Frontline Therapy in CML • Standard-dose imatinib • High-dose imatinib • Imatinib-based combinations • Second generation TKI • Dasatinib • Nilotinib • Bosutinib

  6. TOPS - Rate of MMR Over Time by Imatinib Dose (ITT) Baccarani et al. Blood 114; Abst# 337

  7. Significance of OCT-1 Activity in Response to Imatinib White et al. Blood 2009; 114: Abst# 507

  8. Imatinib vs Imatinib Combinations in CML ECP Hehlmann et al. Blood 2009; 114: Abst# 339

  9. Imatinib vs Imatinib Combinations in CML ECP Guilhot et al. Blood 2009; 114: Abst# 340

  10. 2nd Generation TKI in Newly Dx CML Dasatinib • 72 pts with previously untreated CML CP • Dasatinib 100mg SD or 50mg BID • Median FU 25 mos Nilotinib • 67 pts with CML CP previously untreated • Nilotinib 400 mg BID • Median FU 21 mos Cortes et al. Blood 2009; Abst# 338 & 341

  11. Complete Cytogenetic Response in Early CP CML by Treatment Cortes et al. Blood 2009; Abst# 338 & 341

  12. Event-Free Survival by Treatment in ECP CML Probability Event-Free Months Cortes et al. Blood 2009; Abst# 338 & 341

  13. R A N DO M I Z ED • Newly Dx CML-CP: • > 200 centers • 34 countries • N = 771 • FU for 5 yrs • FPFV 3Q 07 • LPFV 3Q 08 Nilotinib 400 BID (n=257) Nilotinib 300 BID (n=257) Imatinib 400 QD (n=257) Nilotinib vs Imatinib in Newly Dx CML (ENESTnd) • Open label, randomized, multi-center • Primary objective: MMR at 12 mos • Secondary objective: CCyR by 12 mos • Other: time/duration of MMR and CGCR, EFS, PFS, time to AP/BP, OS Extension study for pts failing therapy Futility and Safety IA built into study • Stratification by Sokal risk scores Saglio et al. Blood 2009; 114: abst# LBA-1

  14. Nilotinib vs Imatinib in Newly Diagnosed Chronic Phase CML Saglio et al. Blood 2009; 114: abst# LBA-1

  15. Nilotinib vs Imatinib in Newly Dx CML Events and Transformation by 12 Months P=0.0898 P=0.0095 P=0.0012 P=0.0037 Number of patients with event • None of 14 pts who progressed to AP/BC had achieved MMR Saglio et al. Blood 2009; 114: abst# LBA-1

  16. Nilotinib vs Imatinib in Newly Dx CMLDrug-Related AEs Saglio et al. Blood 2009; 114: abst# LBA-1

  17. Events and Transformation by Treatment in Frontline CML Trials Deininger et al. ASH 2009. Abs# 1126; Saglio et al. Blood 2009; 114: abst# LBA-1; Cortes et al. JCO 2010; 28: 424-30

  18. EFS Drug X EFS Drug Y EFS Drug X  Y Frontline Therapy for CMLThe Road from A to B A B % • Conditions: • Low mortality upon relapse • Effective salvage therapy Imatinib  2nd generation TKI Time

  19. “Current EFS” with TKI in CML • 281 pts with frontline imatinib Rx (73 SD, 208 HD) • CCyR 88%  75 stopped IM • 41 events  14 (5%) CCyR CLFS at 7 yrs = 88% EFS at 7 yrs = 81% Al-Kali et al. Blood 2009; 114: abst# 2197

  20. Significance of Sustained CMR in CML • 261 pts treated with frontline imatinib • Sustained CMR in 32% [undetectable (sensitivity ≥4.5-log) in ≥ 2 consecutive assays over ≥6 mo] • Median time to sustained CMR 30 mo (6-84 mo) Event-Free Survival Transformation-Free Survival Verma et al. Blood 2009; 114; Abst# 505

  21. Imatinib Treatment DiscontinuationsThe French Experience • 69 pts treated with imatinib for ≥3 yrs with CMR (≥5-log ) sustained for ≥2 yrs • 34 prior IFN, 35 no prior IFN • Median follow-up 21 mo (11-29 mo) • 41 (59%) pts relapsed; all within 7 mo • 53% prior IFN, 66% no prior IFN • Probability of CMR 12 mo after stop: 47% post IFN, 34% no prior IFN • Peripheral NK cells significantly lower in relapse pts at imatinib discontinuation • All patients responded after imatinib re-start Mahon et al. Blood 2009; 114: Abst# 859

  22. BCR-ABL Vaccine in CML (GIMEMA) • CML VAX 100 (5 p210 b3a2 peptides) + GM-CSF • 6 vaccinations QOW, then Q mo x3, then Q 3 mos x2 (Boosts optional Q6 mo) • 46 evaluable pts (≥18 mo on imatinib, CCyR, persistence molecular disease) • Median 55 mo imatinib therapy • 19 IM post IFN; 27 imatinib frontline •  BCR-ABL/ABL 50% at 6 mo 51% • Undetectable at least once 41% Bocchia et al. Blood 2009; 114:abst# 648

  23. Adherence to Imatinib Bazeos et al. Blood 2009; 114: abst# 3290

  24. Criteria for Failure and Suboptimal Response to Imatinib Lack or loss of molecular response is not a criterion for failure Baccarani et al. JCO 2009; 27: 6041-51

  25. Dasatinib in CML Chronic Phase After Imatinib Failure (START-C) 387 pts; IM resistance 74%; dasatinib 70 mg BID; minimum follow-up 24 mo Baccarani et al. Blood 2008; 112: abst# 450

  26. Nilotinib in CML Chronic Phase Post Imatinib Failure 321 pts with imatinib resistance (71%) or intolerance (29%) Median age 58 yrs; median exposure 19 mo Nilotinib 400 mg PO BID ≥ 6 mos • Median dose intensity 789 mg/d • Grade 3-4 ↓ plts 31%, neut 31%; lipase elevation 17% (pancreatitis <1%), bilirubin 8% Kantarjian et al. Blood 2009 (Abst# 1129)

  27. Predictive Factors of Outcome with 2nd Generation TKI • 123 pts treated with dasatinib (n=78) or nilotinib (n=45) after imatinib failure • Multivariate analysis for predictors of outcome • Adverse factors: PS ≥ 1 and lack of CG response to imatinib Jabbour et al. Blood 2009; 114 (abst# 509)

  28. Similar Efficacy & Safety with 2nd Generation TKI in Older Pts • Dasatinib • 97 pts age >60 yr • Dasatinib 140 mg/d (n=47) or 100 mg/d (n=44) • CCyR 48%, MMR 32% • Pleural effusion 25%, G3-4 myelosuppression 22% at 10mg/d • Nilotinib • 452 pts age ≥60 yrs • CCyR 31%, 24mo PFS 81% • QTc >500msec 1%, G3-4 myelosuppression 14% Le Coutre et al. ASH 2009; 114: Abst# 3286; Latagliata et al. Blood 2009; 114: Abst# 2211

  29. Outcome of Patients who Fail ≥2 TKI or with T315I T315I Overall Survival ≥2 TKI Failure (CP) Failure-Free Survival CML AP (n=38, dead=16) CML CP (n=82, dead=37) Ph+ ALL (n=46, dead=32) CML BP (n=56, dead=48) Nicolini et al. Blood 2009; 114: 5271-8 Garg et al. Blood 2009; 114; 4361-8

  30. Treatment Options for CML with T315I or After ≥2 TKI Multi-kinase inhibitors MK-0457 AP24534 XL228 PHA-739358 DCC-2036 KW-2449 Omacetaxine (Homoharringtonine) Histone deacetylase inhibitors Stem cell transplant

  31. AP24534 – Summary of Preclinical Profile • Potent inhibitor of native Bcr-Abl, T315I, and other mutants • Once-daily oral dosing effective in multiple mouse models • Inhibits emergence of resistance in mutagenesis screen • Induces apoptosis within 24 hrs (BCR-ABL with or without mutations) I315 E255 Y253 AP24534 O’Hare et al. Cancer Cell 2009; 16: 401-12

  32. Phase I Study of AP24534 Best Response to Therapy (Ph+) * 10 additional pts entered in CHR and maintained CHR Cortes et al. Blood 2009; 114: Abst# 643

  33. Omacetaxine for CML with T315I Mechanism of Action 1Chen et al. Cancer Res 2006; 66: 9059-66; 2Tang et al. Mol Cancer Ther 2006; 5: 723-31; 3Allan et al. EHA 2009 (Abstract# 1052); 4Quintas-Cardama et al. Cancer 2007; 109: 248-55 First-in-class cetaxine, inhibitor of protein elongation1 Potent inhibitory activity against leukemic cells, including T315I+ cells1 Activity independent of Bcr-Abl binding Induces apoptosis by inhibiting the anti-apoptotic oncoprotein Mcl-12 Inhibits cell growth and induces apoptosis in CD34+ cells3 Clinical activity in CML after imatinib failure4

  34. Omacetaxine for CML with T315IResponse to Therapy Data independently adjudicated by Data Monitoring Committee Cortes et al. Blood 2009; 114: Abst# 644

  35. Take Home Message – CML 2010 Imatinib effective in most patients Dose optimization matters 2nd generation TKI: the future standard? CMR advantage: IFN? Vaccines? Sub-optimal responses:  dose imatinib (400mg → 800mg) New TKI? Failure: dasatinib, nilotinib, bosutinib Early intervention High risk patients: individualize approach T315I: SCT, HHT, AP24534, PHA-739538, XL-228, DCC-2036

  36. Questions? jcortes@mdanderson.org 713-794-5783

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