Treatment of CML Transplant or Imatinib?

1
Treatment of CMLTransplant or Imatinib?

• Mark B Juckett MD
• Section of Hematology/BMT
• University of Wisconsin

2
CML - Age specific incidence
BMT Candidates
3
Clinical Course Phases of CML
Advanced phases
Chronic phase Median 56 yearsstabilization
Accelerated phase Median duration69 months
Blast crisis Median survival36 months
4
Cytogenetic Response and Survival With IFN-?
Major response
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0
P lt .001
CCR 70 OS at 10 yrs
Proportion Surviving
Minor or no response
0.0 12 24 36 48 60
Months After Treatment
Guilhot F et al. N Engl J Med. 1997337223-229.
5
Cytogenetic Abnormality of CMLThe Philadelphia
Chromosome

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

6
Mechanism of Action of Imatinib Mesylate
Goldman JM, Melo JV. N Engl J Med. 3441084-1086.
7
Imatinib for Chronic Phase CMLCytogeneic and
Hematologic Responses

• Median time on treatment was 17.5 months

NEJM 346645, 2002
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Accelerated Disease Study ResponsesTalpaz, et
al, 2002
Blood 99 1928, 2002
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Blast Crisis Study Responses

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

10
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

OBrien S.G. N Engl J Med. 348994.
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Design
RANDOMIZE
Imatinib
Crossover
IFN-a Ara-C

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

OBrien S.G. N Engl J Med. 348994.
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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

OBrien S.G. N Engl J Med. 348994.
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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

OBrien S.G. N Engl J Med. 348994.
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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)
OBrien S.G. N Engl J Med. 348994.
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Complete Hematologic Responses
96
plt0.001
67
OBrien S.G. N Engl J Med. 348994.
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Best Cytogenetic Response
plt0.001
OBrien S.G. N Engl J Med. 348994.
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Major Cytogenetic Responses
O'Brien, S. G. et al. N Engl J Med
2003348994-1004
84
85
plt0.001
30
22
18
Patients Without Progression
Estimated rate at 12 months Imatinib 97.2
(plt0.001) IFNAra-C 80.3
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Summary of 18 Month Data
lt0.001
lt0.001
OBrien S.G. N Engl J Med. 348994.
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Quality of Life
Imatinib vs. INF/ARAC
Hahn, E.A. et al. JCO 2003212138-46
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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. 1032873, 2004.
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Results After High Dose Imatinib
Complete Cytogenetic response
Complete Molecular Response
Kantarjian H. Blood. 1032873, 2004.
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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

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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

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SURVIVAL AFTER ALLOGENEIC TRANSPLANTS FOR CML IN
CHRONIC PHASE 1994-1999
100
80
HLA-identical sibling, lt1y (N 2,876)
60
HLA-identical sibling, ³1y (N 1,391)
PROBABILITY,
Unrelated, lt1y (N 613)
40
Unrelated, ³1y (N 936)
20
P 0.0001
0
0
1
2
3
4
6
5
YEARS
SUM02_3.ppt
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100-DAY MORTALITY AFTER HLA-IDENTICAL SIBLING
TRANSPLANTS 1999-2000
100
CR1 CR2 Other
CP AP BP
80
60
MORTALITY,
173
40
464
67
437
212
20
258
359
386
952
433
1,267
90
0
AML
ALL
CML
MDS
AplasticAnemia
ImmuneDeficiency
Numbers on bars numbers of patients evaluable
SUM02_39.ppt
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100-DAY MORTALITY AFTER UNRELATED DONOR
TRANSPLANTS 1999-2000
100
CR1 CR2 Other
CP AP BP
80
60
152
53
MORTALITY,
40
301
241
348
157
113
258
204
189
558
20
83
0
AML
ALL
CML
MDS
AplasticAnemia
ImmuneDeficiency
Numbers on bars numbers of patients evaluable
SUM02_40.ppt
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Oral BU/CY vs. CY/TBI
Clift RA. Blood. 943960, 1999.
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BMT With tBU/cy and Matched Sibling
Radich JP. Blood. 10231, 2003.
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BMT With tBU/cy and Matched Sibling
Radich JP. Blood. 10231, 2003.
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Non-myeloablative transplant for Chronic Myeloid
Leukemia
N 24
Disease Free Survival
Chronic GVHD
Or, Blood 101441, 2003
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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?)

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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

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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

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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

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Reduction of BCR-ABL Transcript On Treatment
All patients On IRIS study
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Reduction of BCR-ABL Transcript After CCR
Patients In CCR Only
Hughes, T. P. et al. N Engl J Med
20033491423-1432
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Imatinib Is Superior in Reducing Transcript Level
Estimated log-reduction of BCR-ABL transcripts
after 12 months of first-line therapy by
treatment arm.
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PFS After 12 Months of Imatinib
Hughes, T. P. et al. N Engl J Med
20033491423-1432
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Correlation between Cytogenetics and qRT-PCR
Branford, S. et al. Leukemia 172401, 2003
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Probability of Achieving 3-log Reduction
Branford, S. et al. Leukemia 172401, 2003
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Patient Responses to Imatinib
Branford, S. et al. Leukemia 172401, 2003
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P-loop Mutations Predict Short Survival
Branford, S. et al. Blood 102, 276, 2003
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Clonal Evolution Predicts Short Survival
Cortes, J.E. et al. Blood 1013794, 2003
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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

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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 (lt30, 30-40, gt40)
• Donor-recipient gender (F?M, other)
• Interval (lt1 yr vs. ?1 yr)
• Performance Status (KPS gt 80)
• Late stage disease
• Always poor risk

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CML-CP Risk Score
Donor type
Matched Sib 0
Matched Unrelated 2
Age
lt30 0
30 40 1
gt40 2
Donor recipient gender
Female ? Male 1
Other 0
Interval from Diagnosis
lt 1 year 0
gt 1 year 1
Performance Status
KPS gt 85 0
other 1
Passweg, J.R. et al. BJH 125613, 2004
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Survival after BMT for CML by CML-CP score


Passweg, J.R. et al. BJH 125613, 2004
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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