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Role of Transplant in CML Imatinib Era

Understand Haematopoietic Stem Cell Transplantation in treating CML focusing on benefits, risks, statistics, and post-transplant relapse management with DLI and Imatinib.

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Role of Transplant in CML 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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