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