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The role of transplant for CML in the imatinib era

The role of transplant for CML in the imatinib era. Dr Wendy Ingram Consultant Haematologist University Hospital of Wales. What is Haematopoietic Stem Cell Transplantation?. Deliver high dose chemotherapy +/- radiotherapy Eradicate tumour cells

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The role of transplant for CML in the imatinib era

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  1. The role of transplant for CML in the imatinib era Dr Wendy Ingram Consultant Haematologist University Hospital of Wales

  2. What is Haematopoietic Stem Cell Transplantation? • Deliver high dose chemotherapy +/- radiotherapy • Eradicate tumour cells • Destroys haematopoietic stem cells in bone marrow • Autologous transplant • Infuse stored stem cells from the patient • Allogeneic transplant • Replace with alternative donor stem cells • New blood cells • New immune system – survey the body and aim to prevent tumour cells from returning

  3. Allogeneic Stem Cell Transplantation Shlomchik WD, Nature Reviews Immunology 7, 340-352 (May 2007)

  4. Allogeneic Transplantation Benefits Risks Toxicity of conditioning Immediate Late Infection Graft versus host disease Relapse • Potential Cure • Graft versus Leukaemia effect • Avoid long term therapy • Side effects of TKIs • Lack of efficacy

  5. Absolute numbers of allogeneic and autologous SCT performed for CML in Europe from 1990–2004 • Reduction in alloSCT for CML in 1st CP preceded demonstration of survival benefit for imatinib • AlloSCT now ‘second-line’ or ‘third-line’ strategy for patients failing imatinib

  6. Number of allogeneic transplants, by disease, registered with CIBMTR 1998-2008 3,000 AML ALL CML AA LYM / MM / CLL 2,500 2,000 Transplants 1,500 1,000 500 0 * * * Data incomplete 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

  7. Changing trends in the characteristics of patients transplanted since 1980 2007-2008 (N=627) 45% 55% 74% 26% • Proportion of patients age >40 years increased from 22% to 41% between first and last cohort • Increased transplant of patients with EBMT risk score 5 (from 5% up to 12%) EBMT Registry data

  8. Overall Survival of CML by disease stage and type of donor (1997-2008) CP1 CP2/AP HLA-id sib (N=3931) MUD (N=1806) HLA-id sib (N=936) MUD (N=719) p<0.001 p<0.001 BC MUD (N=150) HLA-id sib (N=236) p=0.55 EBMT Registry data

  9. 100 100 90 90 80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 Probability of survival after HLA-matched sibling donor transplant for CML, by disease status and transplant year, 1998-2008 CP, 2001-2008 (N=2,412) CP, 1998-2000 (N=2,302) Probability of Survival, % AP, 2001-2008 (N=314) AP, 1998-2000 (N=301) P < 0.0001 1 3 0 2 4 5 6 Years

  10. Reduced Intensity SCT in CML • Percentage of patients undergoing RIC SCT for CML has risen from 1% in 1990 to 31% in 2004 • Highly immunosuppressive • Relies more on graft-versus-leukaemia (GvL) effect than myeloablation for anti-tumour activity

  11. Overall survival and progression free survival for RIC SCT in CML Effect of disease phase on overall survival with RIC SCT for CML CP (n=144) OS Survival probability Survival probability PFS AP/BC (n=42) Time (months) Time (months) • Analysis of outcomes stratified to risk group suggest that PFS and OS at 3 years equivalent to those of standard alloSCT • BUT – short follow-up • Standard alloSCT survival continues to improve Crawley et al, Blood 2005; 106: 2969–2976

  12. UHW experience since 2000 • 9 Chronic Phase 1 • Median age 44 yrs (17-63 yrs) • Median time from diagnosis to transplant 589 days • 3 sibling, 6 unrelated • 2 standard, 7 RIC • 10 Chronic Phase 2 • 4 AP, 2 Blast crisis • Median age 50 yrs (26-65 yrs) • Median time from diagnosis to transplant 589 days • 7 sibling, 9 unrelated • 4 standard, 12 RIC

  13. UHW experience since 2000 CP1 CP2, AP, BC 16 patients 6 deaths due to TRM 5 relapse – 1 rescued with donor lymphocytes • 10 patients • 2 deaths due to TRM • 2 relapse – 1 rescued with donor lymphocytes

  14. Relapse post Allogeneic SCT • Occurs in 16–33% of patients post SCT • Decision on how to treat based on risk of GvHD and how fast BCR-ABL levels are rising • Unrelated donor versus sibling donor • Previous GvHD • Mismatched donor • Age • Choice lies between either Donor Lymphocyte Infusion (DLI) or imatinib or both • Rarely will consider second alloSCT from different donor

  15. Donor lymphocyte infusions can be used to manage relapse • Patients relapsing after SCT for CML are very sensitive to DLI • 60–90% response rate/remission • >90% response in patients transplanted in early CP • Further benefit in subsequent relapse • Incremental dosing reduces risk of GvHD Guglielmi et al, Blood 2002; 100: 397–405.

  16. Imatinib for relapse post SCT: What is the evidence for efficacy? • Imatinib also effective post SCT with benefits in all stages of disease • Hammersmith study (n=128)1 • CP = 51; AP = 31; BC = 46 • 50 patients failed DLI prior to imatinib • Overall haematologic response 84%; 98% for patients relapsing in CP • CCyR: CP, 58%; AP, 48%; BC, 22% • 25 patients achieved complete molecular remission • However, response may be less durable than DLI • Higher incidence of relapse and inferior leukaemia-free survival (6/10 patients relapsed on Imatinib)2 • DLI and imatinib may be synergistic3 • However majority of patients now being transplanted are imatinib-resistant or intolerant 1Olavarria et al, Leukaemia 2003; 17(9): 1707–1712; 2Weisser et al, Haematologica 2006; 91: 663–666; 3Savani et al, Lancet Oncology 2005;6:809-812

  17. The impact of newer TKIs on SCT • Limited data • Likely to have a role in patients relapsing post SCT who were resistant to / intolerant of imatinib • Often patients have already failed second generation TKI prior to transplant • For patients who are resistant to or intolerant of imatinib as first-line therapy, choice lies between alloSCT (if available donor) and second generation TKI

  18. SummaryWho is a candidate for SCT? • High Sokal score and low EBMT score at presentation • Discuss choice of alloSCT versus imatinib • Consider trial of Imatinib in these high-risk patients • Decision to transplant may be based on response • Intolerance to imatinib and second generation TKI • Consider alloSCT, IFN or experimental therapy • Choices after failure of or suboptimal response to imatinib 400 mg: • Dose escalation • Second generation TKI • For T315I BCR-ABL kinase domain mutation consider SCT or clinical trial • For patients with blast crisis, consider imatinib or other TKI followed by alloSCT and restart TKI when counts recover post transplant

  19. Acknowledgments • Dr Mhairi Copland, University of Glasgow • Dr Keith Wilson BMT Programme Director, University Hospital of Wales • Dr Andy Goringe • Dr Jonathan Kell • Dr Steve Knapper • Referring clinicians

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