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Treatment Approaches in Relapsed CML

Treatment Approaches in Relapsed CML

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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