1. Treatment of CML Transplant or Imatinib? Mark B Juckett MD Section of Hematology/BMT University of Wisconsin

2. CML - Age specific incidence BMT Candidates

3. Clinical Course: Phases of CML Chronic phase Median 5–6 years stabilization Accelerated phase Median duration 6–9 months Blast crisis Median survival 3–6 months Advanced phases

4. Cytogenetic Response and Survival With IFN-  Guilhot F et al. N Engl J Med. 1997;337:223-229. Major response Proportion Surviving 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0.01224364860 Minor or no response P <.001 Months After Treatment CCR – 70% OS at 10 yrs

5. Cytogenetic Abnormality of CML: The Philadelphia Chromosome Discovered in 1960 by Nowell and Hungerford First consistent genetic “lesion” in human cancer

6. Mechanism of Action of Imatinib Mesylate Goldman JM, Melo JV. N Engl J Med. 344:1084-1086.

7. Imatinib for Chronic Phase CML Cytogeneic and Hematologic Responses NEJM 346:645, 2002 Median time on treatment was 17.5 months

8. Accelerated Disease Study: Responses Talpaz, et al, 2002 Blood 99: 1928, 2002

9. Blast Crisis Study: Responses Median time to major cytogenetic response was 3 months Most patients treated with 600mg

10. Gleevec vs. Interferon for new CML International Randomized Study (IRIS) 1,106 patients, 177 center, 16 countries Gleevec 400 mg/day vs INF 5 MIU/M2/day with Ara-C 20mg/M2/day 10 days per month Median follow-up 19 months Analysis from July 2002 O’Brien S.G. N Engl J Med. 348:994.

11. Design IFN-  + Ara-C Imatinib Crossover for: Lack of response Loss of response Intolerance of treatment Crossover RANDOMIZERANDOMIZE O’Brien S.G. N Engl J Med. 348:994.

12. Primary Endpoints Time to Progression, defined by: Death from any cause Accelerated phase or blast crisis Loss of complete hematologic response (CHR) Loss of major cytogenetic response (MCR :  35% Ph positive) Increasing WBC in patients without a CHR O’Brien S.G. N Engl J Med. 348:994.

13. Inclusion Criteria Age 18 to 70 Ph positive CML (other cytogenetic abnl OK) Within 6 months of diagnosis Chronic phase of disease No prior therapy except hydroxyurea & anagrelide O’Brien S.G. N Engl J Med. 348:994.

14. Patient Status ImatinibIFN + Ara-C Randomized553 Continued initial treatment 474 (86%)60 (11%) Discontinued initial treatment 68 (12%)175 (32%) Crossed Over11 (2%)318 (58%) O’Brien S.G. N Engl J Med. 348:994.

15. Complete Hematologic Responses 96% 67% p<0.001 O’Brien S.G. N Engl J Med. 348:994.

16. Best Cytogenetic Response p<0.001 O’Brien S.G. N Engl J Med. 348:994.

17. Major Cytogenetic Responses 84% 30% p<0.001 22% 85% O'Brien, S. G. et al. N Engl J Med 2003;348:994-1004

18. Patients Without Progression Estimated rate at 12 months Imatinib 97.2% (p<0.001) IFN+Ara-C 80.3%

19. Summary of 18 Month Data <0.001 O’Brien S.G. N Engl J Med. 348:994.

20. Quality of Life Hahn, E.A. et al. JCO 2003;21:2138-46 Imatinib vs. INF/ARAC

21. Does higher dose improve outcome? Phase II study of 400mg twice daily 114 patients within 12 mo of Dx Compared to historical controls Median follow-up 15 months Results CHR 98% CCR 90% (52% by 3 months) Sokal high risk – 76% vs. 95% Complete PCR response 28% (18 mo) – Compared to 7% historically Kantarjian H. Blood. 103:2873, 2004.

22. Results After High Dose Imatinib Complete Cytogenetic responseComplete Molecular Response Kantarjian H. Blood. 103:2873, 2004.

23. Summary of Imatinib for CML Well tolerated treatment compared to INF/ARAC Improved QOL Decreased progression, improved CCR rates 18 mo rate of AP/BC 3.3% 18 mo rate of CCR 76% Limited activity in AP/BC Higher dose may improve cytogenetic and molecular responses

24. Transplantation for CML Curative Treatment for most patients High rate of morbidity and mortality Problems of: Toxicity of preparative regimen Graft-vs-Host disease Relapse Regimens differ in toxicity Cy/TBI tBU/CY “Mini” transplants

25. SURVIVAL AFTER ALLOGENEIC TRANSPLANTS FOR CML IN CHRONIC PHASE 1994-1999 PROBABILITY, % 100 0 20 40 60 80 0 YEARS 123 46 SUM02_3.ppt P = 0.0001 HLA-identical sibling,  1y (N = 2,876) HLA-identical sibling,  1y (N = 1,391) Unrelated,  1y (N = 613) Unrelated,  1y (N = 936) 5

26. 100-DAY MORTALITY AFTER HLA-IDENTICAL SIBLING TRANSPLANTS 1999-2000 SUM02_39.ppt MORTALITY, % 100 0 20 40 60 80 464 359 1,267 90 67 952 AMLALLCMLMDSAplastic Anemia Immune Deficiency Numbers on bars = numbers of patients evaluable CR1 CR2+ Other 386 173 212 433 437 258 CP AP BP

27. 100-DAY MORTALITY AFTER UNRELATED DONOR TRANSPLANTS 1999-2000 SUM02_40.ppt MORTALITY, % 100 0 20 40 60 80 301 348 558 83 53 189 AMLALLCMLMDSAplastic Anemia Immune Deficiency Numbers on bars = numbers of patients evaluable CR1 CR2+ Other 204 152 157 113 241 258 CP AP BP

28. Oral BU/CY vs. CY/TBI Clift RA. Blood. 94:3960, 1999.

29. BMT With tBU/cy and Matched Sibling Radich JP. Blood. 102:31, 2003.

30. BMT With tBU/cy and Matched Sibling

31. Non-myeloablative transplant for Chronic Myeloid Leukemia Disease Free SurvivalChronic GVHD Or, Blood 101:441, 2003 N = 24

32. Choosing BMT vs. Imatinib Assumption Imatinib is a preferred initial treatment IF long term outcome is unchanged. – Less early risk – Good QOL – Cost ?? Consider transplantation for those who are not responding appropriately (who are those?)

33. Choosing BMT vs. Imatinib Recommend BMT to some patients: Those who are likely to do well with transplant Those who are likely to do badly with Imatinib

34. Who will do badly with Imatinib? Majority of patients will enter complete cytogenetic remission Some will: Fail to enter CCR Progress to AP/BC Become resistant to imatinib Conventional cytogenetics is insensitive to predicting these events Risk scores are helpful (Sokal, etc.) but not validated on Imatinib patients

35. Molecular Monitoring Real-Time Quantitative PCR seems best Compares amplification of BCR-ABL transcript to control gene – usually BCR or ABL Baseline transcript quantity varies between labs Log change in transcript seems to be consistent between labs. Does not identify other clonal abnormalities May detect disease down to 0.01 – 0.001%

36. Reduction of BCR-ABL Transcript On Treatment All patients On IRIS study

37. Reduction of BCR-ABL Transcript After CCR Hughes, T. P. et al. N Engl J Med 2003;349:1423-1432 Patients In CCR Only

38. Imatinib Is Superior in Reducing Transcript Level Estimated log-reduction of BCR-ABL transcripts after 12 months of first-line therapy by treatment arm.

39. Hughes, T. P. et al. N Engl J Med 2003;349:1423-1432 PFS After 12 Months of Imatinib

40. Correlation between Cytogenetics and qRT-PCR Branford, S. et al. Leukemia 17:2401, 2003

41. Probability of Achieving 3-log Reduction Branford, S. et al. Leukemia 17:2401, 2003

42. Patient Responses to Imatinib Branford, S. et al. Leukemia 17:2401, 2003

43. P-loop Mutations Predict Short Survival Branford, S. et al. Blood 102, 276, 2003

44. Clonal Evolution Predicts Short Survival Cortes, J.E. et al. Blood 101:3794, 2003

45. Who will do well with Imatinib? Patients who: Enter a CCR Have large reduction in BCR-ABL transcript (3-log ?) Have an early response Patients who do not: Have point mutations within the P-loop Additional clonal abnormalities Still no long-term survival information

46. Who will do well with BMT? Sokal and Hasford scores not helpful in predicting success after BMT CML-CP Risk Score (only chronic phase) Donor type (Matched Sib vs. MUD) Age ( 40) Donor-recipient gender (F  M, other) Interval (<1 yr vs.  1 yr) Performance Status (KPS > 80%) Late stage disease Always poor risk

47. CML-CP Risk Score Donor type Matched Sib0 Matched Unrelated2 Age <300 30 – 401 >402 Donor recipient gender Female  Male 1 Other0 Interval from Diagnosis < 1 year0 > 1 year1 Performance Status KPS > 850 other1 Passweg, J.R. et al. BJH 125:613, 2004

48. Survival after BMT for CML by CML-CP score Passweg, J.R. et al. BJH 125:613, 2004

49. Deciding between BMT and Imatinib Patient issues: Psychosocial (chronic vs. cured disease) Perception of immediate vs. future risk Tolerance of medical care (a lot vs. a little) Doctor issues: Tolerance/efficacy of imatinib Availability of BMT Comorbid diseases Future issues: Combinations (endless possibilities) Novel Transplant approaches