Treatment of CMLTransplant or Imatinib?

Mark B Juckett MDSection of Hematology/BMT

University of Wisconsin

CML - Age specific incidence

BMT Candidates

Clinical Course: Phases of CML

Chronic phase

Median 5–6 yearsstabilization

Accelerated phase

Median duration6–9 months

Blast crisis

Median survival3–6 months

Advanced phases

Cytogenetic Response and Survival With IFN-

Guilhot F et al. N Engl J Med. 1997;337:223-229.

Major response

Pro

po

rtio

n S

urv

ivin

g

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0.0 12 24 36 48 60

Minor or no response

P < .001

Months After Treatment

CCR – 70% OS at 10 yrs

Cytogenetic Abnormality of CML:The Philadelphia Chromosome

•Discovered in 1960 by Nowell and Hungerford•First consistent genetic “lesion” in human cancer

Mechanism of Action of Imatinib Mesylate

Goldman JM, Melo JV. N Engl J Med. 344:1084-1086.

Imatinib for Chronic Phase CMLCytogeneic and Hematologic Responses

All Patients Patients intolerantto interferon

CytogeneticResponse Complete 41% 47% Partial 19% 19%

HematologicResponse

95% 93%

NEJM 346:645, 2002

•Median time on treatment was 17.5 months

Accelerated Disease Study: ResponsesTalpaz, et al, 2002

400mg dose 600 mg dose

Cytogenetic Response

Complete 11% 19% Partial 5% 5%

Complete Hematologic Response

27% 37%

Blood 99: 1928, 2002

Blast Crisis Study: Responses

Sawyers et al Blood 99:3530

Kantarjian et al Blood 99:3547

Cytogenetic Response

N = 260 N = 75

Complete 7% 7% Partial 9% 4%

Any Hematologic Response ( 4 wks)

31% 46%

•Median time to major cytogenetic response was 3 months•Most patients treated with 600mg

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.

Design

IFN- +

Ara-C

Imatinib

Crossover for:• Lack of response• Loss of response• Intolerance of treatment

Crossover

RANDOMIZEO’Brien S.G. N Engl J Med. 348:994.

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.

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.

Patient Status

Imatinib IFN + Ara-C

Randomized 553 553

Continued initial treatment

474 (86%) 60 (11%)

Discontinued initial treatment

68 (12%) 175 (32%)

Crossed Over 11 (2%) 318 (58%)

O’Brien S.G. N Engl J Med. 348:994.

Complete Hematologic Responses

96%

67%

p<0.001

ImatinibIFN+Ara-C

% re

spon

ding

0

10

20

30

40

50

60

70

80

90

100

Months since randomization0 3 6 9 12 15 18 21

O’Brien S.G. N Engl J Med. 348:994.

Response Imatinib

N=553

IFN+Ara-C

N=553

Major ( 35 Ph+) 85% 22%

Complete (0% Ph+) 74% 9%

Partial (1-35% Ph+) 11% 13%

Best Cytogenetic Response

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

Major Cytogenetic Responses

84%

30%

ImatinibIFN+Ara-C

% re

spon

ding

0

10

20

30

40

50

60

70

80

90

100

Months since randomization0 3 6 9 12 15 18 21

p<0.001

22%

85%

O'Brien, S. G. et al. N Engl J Med 2003;348:994-1004

Patients Without Progression

Estimated rate at 12 monthsImatinib 97.2% (p<0.001)IFN+Ara-C 80.3%

ImatinibIFN+Ara-C

= Censored observations

% w

ithou

t pro

gres

sion

0

10

20

30

40

50

60

70

80

90

100

Months since randomization0 3 6 9 12 15 18 21

Summary of 18 Month Data

92

74

97 95

3.38.5

76

15

0

20

40

60

80

100

FFP OS AP/BC CCR

Imatinib

INF/ARAC

<0.001

<0.001

O’Brien S.G. N Engl J Med. 348:994.

Quality of Life

Hahn, E.A. et al. JCO 2003;21:2138-46

Imatinib vs. INF/ARAC

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.

Results After High Dose Imatinib

Complete Cytogenetic response Complete Molecular Response

Kantarjian H. Blood. 103:2873, 2004.

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

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

SURVIVAL AFTER ALLOGENEIC TRANSPLANTS FOR CML IN CHRONIC PHASE 1994-1999

PR

OB

AB

ILIT

Y,

%

100

0

20

40

60

80

0

YEARS

1 2 3 4 6

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

100-DAY MORTALITY AFTER HLA-IDENTICAL SIBLING TRANSPLANTS 1999-2000

SUM02_39.ppt

MO

RT

AL

ITY

, %

100

0

20

40

60

80

464

3591,267

90

67

952

AML ALL CML MDS AplasticAnemia

ImmuneDeficiency

Numbers on bars = numbers of patients evaluable

CR1CR2+Other

386

173

212433

437258

CPAPBP

100-DAY MORTALITY AFTER UNRELATED DONOR TRANSPLANTS 1999-2000

SUM02_40.ppt

MO

RT

AL

ITY

, %

100

0

20

40

60

80

301

348

55883

53

189

AML ALL CML MDS AplasticAnemia

ImmuneDeficiency

Numbers on bars = numbers of patients evaluable

CR1CR2+Other

204

152

157 113241

258

CPAPBP

Oral BU/CY vs. CY/TBI

Clift RA. Blood. 94:3960, 1999.

BMT With tBU/cy and Matched Sibling

Radich JP. Blood. 102:31, 2003.

Radich JP. Blood. 102:31, 2003.

BMT With tBU/cy and Matched Sibling

Non-myeloablative transplant for Chronic Myeloid Leukemia

Disease Free Survival Chronic GVHD

Or, Blood 101:441, 2003

N = 24

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?)

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

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

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%

Reduction of BCR-ABL Transcript On Treatment

All patientsOn IRIS study

Reduction of BCR-ABL Transcript After CCR

Hughes, T. P. et al. N Engl J Med 2003;349:1423-1432

PatientsIn CCROnly

Imatinib Is Superior in Reducing Transcript Level

Estimated log-reduction of BCR-ABL transcripts after 12 months of first-line therapy by treatment arm.

Hughes, T. P. et al. N Engl J Med 2003;349:1423-1432

PFS After 12 Months of Imatinib

Correlation between Cytogenetics and qRT-PCR

Branford, S. et al. Leukemia 17:2401, 2003

Probability of Achieving 3-log Reduction

Branford, S. et al. Leukemia 17:2401, 2003

Patient Responses to Imatinib

Branford, S. et al. Leukemia 17:2401, 2003

P-loop Mutations Predict Short Survival

Branford, S. et al. Blood 102, 276, 2003

Clonal Evolution Predicts Short Survival

Cortes, J.E. et al. Blood 101:3794, 2003

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

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 (<30, 30-40, >40)• Donor-recipient gender (FM, other)• Interval (<1 yr vs. 1 yr)• Performance Status (KPS > 80%)

Late stage disease• Always poor risk

CML-CP Risk Score

Donor type

Matched Sib 0

Matched Unrelated 2

Age

<30 0

30 – 40 1

>40 2

Donor recipient gender

Female Male 1

Other 0

Interval from Diagnosis

< 1 year 0

> 1 year 1

Performance Status

KPS > 85 0

other 1

Passweg, J.R. et al. BJH 125:613, 2004

Survival after BMT for CML by CML-CP score

Passweg, J.R. et al. BJH 125:613, 2004

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