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

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– 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

Allogeneic Stem Cell Transplantation

Shlomchik WD, Nature Reviews Immunology 7, 340-352 (May 2007)

Allogeneic Transplantation

Benefits

• Potential Cure– Graft versus Leukaemia

effect

• Avoid long term therapy– Side effects of TKIs– Lack of efficacy

Risks

• Toxicity of conditioning– Immediate– Late

• Infection• Graft versus host disease

• Relapse

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

Tra

nsp

lants

2,000

3,000

1,000

500

0

1,500

2,500

Number of allogeneic transplants, Number of allogeneic transplants, by disease, registered with CIBMTR by disease, registered with CIBMTR

1998-20081998-2008

1999 2000 2001 2002 2003 2004 2005 2007 20082006 * *

* Data incomplete

AMLALLCMLAALYM / MM / CLL

Changing trends in the characteristics of patients transplanted since 1980

1980–1990 (N=2628)

1991–1999 (N=7770)

2000–2003 (N=3018)

Median age (years) 33 37 37 Donor type HLA ident. sib. Unrelated donor

85% 7%

62% 29%

56% 36%

Stem cell source Bone marrow PBSC

100%

–

79% 21%

47% 53%

Conditioning Standard RIC

99% 1%

94% 6%

83% 17%

• 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%)

2007-2008(N=627)

45%55%

74%26%

EBMT Registry data

Overall Survival of CML by disease stage and type of donor (1997-2008)

HLA-id sib (N=3931)

MUD (N=1806)

p<0.001

HLA-id sib (N=936)

MUD (N=719)

p<0.001

HLA-id sib (N=236)

MUD (N=150)

p=0.55

CP1 CP2/AP

BC

EBMT Registry data

Years

Probability of survival after HLA-matched Probability of survival after HLA-matched sibling donor transplant for CML, by disease sibling donor transplant for CML, by disease

status and transplant year, 1998-2008status and transplant year, 1998-2008

0 2 61 3 4 5

CP, 1998-2000 (N=2,302)

0

20

40

60

80

100

10

30

50

70

90

0

20

40

60

80

100

10

30

50

70

90

Pro

babili

ty o

f Surv

ival, %

CP, 2001-2008 (N=2,412)

AP, 2001-2008 (N=314)

AP, 1998-2000 (N=301)

P < 0.0001

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

Overall survival and progression free survival

for RIC SCT in CML

Time (months)

Su

rviv

al p

rob

abili

ty

OS

PFS

Su

rviv

al p

rob

abili

tyTime (months)

CP (n=144)

AP/BC (n=42)

Effect of disease phase on overall survival with RIC

SCT for CML

• 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

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

12

CP1

• 10 patients• 2 deaths due to TRM• 2 relapse – 1 rescued

with donor lymphocytes

CP2, AP, BC

• 16 patients• 6 deaths due to TRM• 5 relapse – 1 rescued

with donor lymphocytes

13

UHW experience since 2000

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

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.

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

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

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

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