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Treatment Approaches in Relapsed CML

Treatment Approaches in Relapsed CML. Jorge Cortes, MD Professor of Medicine Deputy Chair, Department of Leukemia The University of Texas MD Anderson Cancer Center Houston, TX   .

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Treatment Approaches in Relapsed CML

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  1. Treatment Approaches in Relapsed CML Jorge Cortes, MD Professor of Medicine Deputy Chair, Department of Leukemia The University of Texas MD Anderson Cancer Center Houston, TX   

  2. A 50-year old female presented with LUQ pain and splenomegaly 10 cm/BCM. Her WBC was 105 x 109/L, Plts 800 x 109/L. BM shows 5% blasts, 4% basophils. CG show 100% Ph, no clonal evolution. She has a perfect match brother. Your treatment plan is: Allogeneic BMT ASAP Imatinib 400 mg QD Imatinib 400 mg BID Dasatinib 100 mg QD Nilotinib 400 mg BID Case Study: Question 1

  3. Patient has now received imatinib 400 mg QD for 12 months. CG at 12 months shows Ph+ 10%. You would now proceed to: Allogeneic BMT Continue Imatinib 400 mg QD Imatinib 400 mg BID Dasatinib 100 mg QD Nilotinib 400 mg BID Case Study: Question 2

  4. Patient has now received imatinib for two years, the second year at imatinib 800 mg/D. Repeat CG show Ph+ 0%, QPCR is .15%. You would now proceed with: Allogeneic BMT ASAP Send sample for mutation studies and decide accordingly Continue Imatinib 400 mg BID Dasatinib 100 mg QD Nilotinib 400 mg BID Case Study: Question 3

  5. Patient is now on imatinib 800 mg/D for the past 40 months. Repeat CG shows Ph+ 40%, and a mutation screen identifies the T359C mutation. Your next approach is: Allogeneic BMT ASAP Consider MK 0457 Continue Imatinib 400 mg BID Dasatinib 100 mg QD Nilotinib 400 mg BID Case Study: Question 4

  6. The patient achieved a compete cytogenetic response. One year later, cytogenetic analysis shows 50% Ph+ metaphases. A T315I mutation is detected. Your approach now is: Allogeneic SCT Imatinib 400 mg BID Increase Dasatinib to 140 mg QD Change to Nilotinib 400 mg BID Consider Homoharringtonine Case Study: Question 5

  7. Results with Imatinib in Early CP CML – The IRIS Trial • 364 (66%) patients on imatinib on study • Projected results at 6 years: • CCyR 87% • Event-free survival 83% • Transformation-free survival 93% • If MMR at 12 mos: 100% • If CCyR, no MMR: 98% • Survival 88% • Annual rate of transformation: 1.5%, 2.8%, 1.6%, 0.9%, 0.6%, and 0% Hochhaus et al; Blood 2007; 110: abst# 25

  8. Criteria for Failure to Imatinib Baccarani et al. Blood 2006; 108: 1809-20

  9. Survival Post Imatinib Failure by CML Phase Kantarjian et al. Cancer 2007; 109: 1556-60

  10. Inhibition of Bcr-Abl

  11. Outcome After Imatinib Dose Increase Jabbour et al. Blood 2007; 110: abst# 1035

  12. Dasatinib in CML Chronic Phase After Imatinib Failure (START-C) • 387 pts; IM resistance 74%; median CML duration 61 mos; dasatinib 70 mg BID • Dose reductions 73%; median dose 101 mg/d • Grade 3-4 ↓ plts 49%, neuts 50%; pleural effusions 26% (grade 3-4 9%) Stone et al. Blood 2007; 110: abst# 734

  13. 100 80 60 40 20 0 100 80 60 40 20 0 97% 84% % without loss of MCyR 24-month response rates 24-month response rates MCyR CCyR MMR MCyR CCyR MMR 55% 45% 37% 82% 78% 78% 0 3 6 9 12 15 18 21 24 27 30 Months Months Duration of MCyR to Dasatinib in CML CP Imatinib Resistance Imatinib Intolerance 0 3 6 9 12 15 18 21 24 27 30 Stone et al. Blood 2007; 110: abst# 734

  14. 100% 100% 100 80 60 40 20 0 96% 100 80 60 40 20 0 92% 98% 94% 88% 75% 0 3 6 9 12 15 18 21 24 27 30 33 0 3 6 9 12 15 18 21 24 27 30 33 Months Months PFS and Overall Survival with Dasatinib in CML CP by Imatinib Failure Imatinib Resistance Imatinib Intolerance Overall Survival Progression-Free Survival Progression was defined as increasing WBC count, loss of CHR / MCyR, AP / BP, or death Stone et al. Blood 2007; 110: abst# 734

  15. Phase II Studies of Dasatinib After Imatinib Failure ASH 2007; abst# 470, 734

  16. PFS with Dasatinib in CML After Imatinib Failure 100 80 60 40 20 0 CP AP 100 80 60 40 20 0 88% 75% 64% 46% 0 3 6 9 12 15 18 21 24 27 30 33 0 3 6 9 12 15 18 21 24 27 30 33 Months 100 80 60 40 20 0 Months 100 80 60 40 20 0 ALL BP MyBP (Median 5.6 mo) Non T315I (Median 5.7 mo) All (Median 3.3 mo) LyBP (Median 3.1 mo) 0 3 6 9 12 15 18 21 24 27 30 0 3 6 9 12 15 18 21 24 27 30 Months Months

  17. Dasatinib vs HD Imatinib in CML (START-R) • 150 pts post failure of IM 400-600 mg/d • Randomized (2:1) to dasatinib 70 mg BID vs IM 400 mg BID; median FU 15 mos • Endpoint: CG response at 12 weeks  crossover • PFS better with dasatinib (HR 0.14; p<0.0001) • More grade 3-4  plts (57% vs 14%) and neuts (63% vs 39%), and pl. effusions (17% vs 0%) with dasatinib Kantarjian et al. Blood 2007; 110: abst# 736

  18. PFS with Dasatinib vs HD IM by Prior Imatinib Dose Dasatinib Imatinib 100 80 60 40 20 0 P=0.0562 P=0.0033 Per cent PFS Prior imatinib dose: 400 mg Prior imatinib dose: 600 mg 0 3 6 9 12 15 18 21 24 27 30 33 Months Kantarjian et al. Blood 2007; 110: abst# 736

  19. Optimal Dose and Schedule of Dasatinib IN CML CP after Imatinib Failure Shah et al. JCO 2007; 25; (Abst # 7004)

  20. Better Outcome on Dasatinib with Earlier Intervention • Patients on dasatinib studies analyzed by failure status on imatinib: loss of CG response vs loss of CHR Kantarjian et al. Blood 2007; 110: abst# 1036

  21. Nilotinib in CML Chronic Phase Post Imatinib Failure • 320 pts with imatinib resistance (71%) or intolerance (29%) • Median age 58 yrs; median CML duration 58 mo • Nilotinib 400 mg PO BID ≥ 6 mos • Median dose 790 mg/d • Grade 3-4 ↓ plts 28%, neuts 30%; lipase elevation 15% (pancreatitis <1%), bilirubin 8% Kantarjian et al. Blood 2007; 110: abst# 735

  22. 89% 84% Without Loss of MCyR, % Total = 184 Failed = 23 lll = Censored observations Months Nilotinib in CML-CP Duration of Major CG Response Kantarjian et al. Blood 2007; 110: abst# 735

  23. Phase II Studies of Nilotinib After Imatinib Failure ASH 2007

  24. Time to Progression with Nilotinib in CML After Imatinib Failure CP AP 78% 70% 64% 57% Months Months le Coutre et al. Blood 2007; 110: abst# 471

  25. Bosutinib (SKI–606) in CML and Ph+ ALL • Src-Abl inhibitor; 30x more potent than IM • No inhibition of PDGFR, c-kit • 152 CP pts; median time from Dx 65 mos; 76% IM resistant • Bosutinib 400-600 mg/d; Phase II 500 mg/d • Response in CP (N=56) % • CHR 89 • Cytogenetic 81 • Major 41 • Complete 30 • G 3-4 toxicity: rash 7%, thrombocytopenia 14%, neutropenia 9% Cortes et al. Blood 2007; 110: abst# 733

  26. Phase I INNO-406 • Abl/Lyn kinase inhibitor 25-55x more potent than imatinib • Inhibits 17/18 Bcr-Abl mutants • Not MDR dependent; good CNS penetration; active against F317C/L/V • 41 pts: 21 CP, 7 AP, 6 BP, 7 ALL • 32 pts received ≥ 2 TKIs • INNO-406 30 mg SD → 480 mg BID • Responses: • 2 CG CR + 1 CG major + 1 CG minor / 7 CP post IM failure • 1 CG CR + 2 HR in ≥ 2 TKI failures • DLT transient LFT ; phase II 240 mg P.O. BID Kantarjian et al. Blood 2007; 110: abst# 469

  27. Survival Post Imatinib Failure in CP by Treatment Kantarjian et al. Cancer 2007; 109: 1556-60

  28. Survival Post Imatinib Failure in AP by Treatment Kantarjian et al. Cancer 2007; 109: 1556-60

  29. Time to Response to 2nd Generation TKI P = 0.003 mCyR or CHR (27) MCyR or CCR (59) • 113 pts with CML CP receiving nilotinib (N = 43) or dasatinib (N = 70) after imatinib failure. • Failure to achieve mCyR by 3 or 6 mos = 3-7% chance of reaching MCyR at 12 mo (vs > 50% if mCyR at 3-6 mos). Tam et al. Blood 2007; 110: abst# 1931

  30. Hematologic Response to 2nd Generation TKI in Advanced Stage CML After IM Failure • 136 pts: CML AP (N = 87), BP (N = 60) or Ph+ ALL (N = 7) treated with dasatinib (N = 73) or nilotinib (N = 81) after imatinib failure • MCyR 35%; 46% no CHR at time of MCyR • Most common causes of no CHR: thrombocytopenia (88%), neutropenia (35%), immature cells (31%) Fava et al, Blood 2007; 110: abst# 1944

  31. Response to Dasatinib by BCR-ABL Mutation in CML CP After Imatinib Failure Complete CyRPartial CyR Complete HR No response Stone et al. Blood 2007; 110: abst# 734

  32. Response to Nilotinib in CML CP after Imatinib Failure by Mutation Hughes et al. Blood 2007; 110: abst# 320

  33. EFS by Mutations in CML CP Treated with 2nd Generation TKI after IM Failure Low IC50 P = 0.43 No Mutation P = 0.0004 Intermediate IC50 • 87/169 (51%) pts treated had mutation • CP 31, AP 41, BP 15 • Mutations classified into high, intermediate, and low sensitivity to dasatinib or nilotinib based on IC50 • No significant difference in AP or BP Jabbour et al, Blood 2007; 110: abst# 1941

  34. Inducible Mutations in Mutagenesis Studies with AMN and BMS Bradeen et al. Blood. 2006; 108: 2332-8; Ray et al. Blood. 2007; epub ahead of print; von Bubnoff et al. Blood. 2006; 108: 1328-33. Burgess et al. PNAS. 2005; 102: 3395-400.

  35. NILOTINIB This series N=15 In vitro models* DASATINIB This series N=10 In vitro models* M244V (1) Q252H (1) + Y253H (3) + G250E (1) E255K (1) + V299L (3) + D276G (1) F317L (5) + F311I/L (2) + T495R (1) F359V/C (3) + Total match E453K (1) 80% patients H396P/R (2) Total match 67% patients Occurrence of Mutations Predicted from In Vitro Models Cortes et al. Blood 2007 [e-pub ahead of print] *Burgess et al. PNAS 2005; 102: 3395-400; von Bubnoff et al. Blood 2006; 108: 1328-33; Bradeen et al. Blood 2006; 108: 2332-8.

  36. Impact of Clonal Evolution in Response to Dasatinib or Nilotinib • CE in 60/242 pts (25%) with CML AP treated with nilotinib (30) or dasatinib (30) after IM failure • Double Ph 28%, chr 8 (17%), chr 17 (17%), other 35%) • Response: CHR 80%, CCyR 40%, PCyR 6% Verma et al, Blood 2007; 110: abst# 2949

  37. 2nd Generation TKI in Newly Dx CML Dasatinib • 37 pts with previously untreated CML CP • Dasatinib 100 mg SD or 50mg BID • Median FU 18 mos Nilotinib • 32 pts with CML CP previously untreated • Nilotinib 400 mg BID • Median FU 6.5 mos Cortes et al. Blood 2007; 110: abst# 29 & 30

  38. TKI in Newly Diagnosed CML Cortes et al. Blood 2007; 110: abst# 29 & 30

  39. HHT in CML with Mutation T315 I • 19 pts: 11 CP, 4 AP, 4 BP • Failure on IM (19), dasatinib (10), nilotinib (8), MK457 (3) • HHT 1.25 mg SQ BIDx14 Q4 wks until CHR → x 7 Q4 wks • T315I undetectable in 4 CP and 1 AP • Responses: • CP: 5 CHR, 1 mCyR, 2 CCyR • AP: 1 HI, 2 PHR, 1 mCyR Khoury et al. Blood 2007; 110: abst# 1050

  40. A 50-year old female presented with LUQ pain and splenomegaly 10 cm/BCM. Her WBC was 105 x 109/L, Plts 800 x 109/L. BM shows 5% blasts, 4% basophils. CG show 100% Ph, no clonal evolution. She has a perfect match brother. Your treatment plan is: Allogeneic BMT ASAP Imatinib 400 mg QD Imatinib 400 mg BID Dasatinib 100 mg QD Nilotinib 400 mg BID Case Study: Question 1

  41. A 50-year old female presented with LUQ pain and splenomegaly 10 cm/BCM. Her WBC was 105 x 109/L, Plts 800 x 109/L. BM shows 5% blasts, 4% basophils. CG show 100% Ph, no clonal evolution. She has a perfect match brother. Your treatment plan is: Allogeneic BMT ASAP Imatinib 400 mg QD Imatinib 400 mg BID Dasatinib 100 mg QD Nilotinib 400 mg BID Recommended approach: Imatinib 400 mg QD Case Study: Question 1

  42. Patient has now received imatinib 400 mg QD for 12 months. CG at 12 months shows Ph+ 10%. You would now proceed to: Allogeneic BMT Continue Imatinib 400 mg QD Imatinib 400 mg BID Dasatinib 100 mg QD Nilotinib 400 mg BID Case Study: Question 2

  43. Patient has now received imatinib 400 mg QD for 12 months. CG at 12 months shows Ph+ 10%. You would now proceed to: Allogeneic BMT Continue Imatinib 400 mg QD Imatinib 400 mg BID Dasatinib 100 mg QD Nilotinib 400 mg BID Recommended approach: Imatinib 400 mg BID Case Study: Question 2

  44. Patient has now received imatinib for two years, the second year at imatinib 800 mg/D. Repeat CG show Ph+ 0%, QPCR is .15%. You would now proceed with: Allogeneic BMT ASAP Send sample for mutation studies and decide accordingly Continue Imatinib 400 mg BID Dasatinib 100 mg QD Nilotinib 400 mg BID Case Study: Question 3

  45. Patient has now received imatinib for two years, the second year at imatinib 800 mg/D. Repeat CG show Ph+ 0%, QPCR is .15%. You would now proceed with: Allogeneic BMT ASAP Send sample for mutation studies and decide accordingly Continue Imatinib 400 mg BID Dasatinib 100 mg QD Nilotinib 400 mg BID Recommended approach: Continue imatinib 400 mg BID Case Study: Question 3

  46. Patient is now on imatinib 800 mg/D for the past 40 months. Repeat CG shows Ph+ 40%, and a mutation screen identifies the T359C mutation. Your next approach is: Allogeneic BMT ASAP Consider MK 0457 Continue Imatinib 400 mg BID Dasatinib 100 mg QD Nilotinib 400 mg BID Case Study: Question 4

  47. Patient is now on imatinib 800 mg/D for the past 40 months. Repeat CG shows Ph+ 40%, and a mutation screen identifies the T359C mutation. Your next approach is: Allogeneic BMT ASAP Consider MK 0457 Continue Imatinib 400 mg BID Dasatinib 100 mg QD Nilotinib 400 mg BID Recommended approach: Dasatinib 100 mg QD Case Study: Question 4

  48. The patient achieved a compete cytogenetic response. One year later, cytogenetic analysis shows 50% Ph+ metaphases. A T315I mutation is detected. Your approach now is: Allogeneic SCT Imatinib 400 mg BID Increase Dasatinib to 140 mg QD Change to Nilotinib 400 mg BID Consider Homoharringtonine Case Study: Question 5

  49. The patient achieved a compete cytogenetic response. One year later, cytogenetic analysis shows 50% Ph+ metaphases. A T315I mutation is detected. Your approach now is: Allogeneic SCT Imatinib 400 mg BID Increase Dasatinib to 140 mg QD Change to Nilotinib 400 mg BID Consider Homoharringtonine Recommended approach: Allogeneic SCT or Homoharringtonine Case Study: Question 5

  50. Take Home Message – CML 2008 • Imatinib effective in most patients • High-dose? • Dose optimization and adequate monitoring more important then ever • Sub-optimal responses: •  dose imatinib (400 mg → 800 mg) • New TKI? • Failure: • Dasatinib, nilotinib • Others (Bosutinib, INNO 406) • Frontline use of new TKI? • T315I: HHT, XL-228, PHA-739538

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