1. Great Debates and Updates in Hematologic Malignancies 2014
Q: Can we safely stop TKI therapy after achieving a CMR for >2 years? A: Sure, you can always restart TKI therapy if relapse
Michael J. Mauro, MD
Leader, Myeloproliferative Disorders Program
Memorial Sloan Kettering Cancer Center, New York, NY

2. As a result of treatment success the prevalence of CML is increasing steadily
Number of Cases
10x greater
steady state number
of CML patients in US
by 2050
Year
Huang et al. Cancer. 2012;118:

3. Reality: Lifelong CML therapy is not financially feasible
CML patients with higher copayments were 1.7x more likely to stop and 42% more likely to be nonadherent with TKI therapy in the first 180 days Dusetzina S, JCO 2014
Median cost RIC SCT in Mexico: $18,000 USD = to cost of 3mo of imatinib Giralt S, Bone Marrow Transplant 2008
Kantarjian H. Blood 121: , 2013
Pollack A, NY Times, Published 4/25/13
Hall S, New York Magazine, Published 10/20/13

4. We need to try discontinuation
Point 1:
We need to try discontinuation

5. Cumulative Incidence %
Achievement of deep molecular response and subsequent treatment free remission: Frontline imatinib, dasatinib, or nilotinib (postulated) 10 20 30 40 50 60 70 80 90
100
Cumulative Incidence %
Deep molecular
remission (‘CMR’)
60-80%
24-32%
40%
16% 1 2 3 4 5 7 6
Treatment free
remission (‘TFR’)
Years after commencing 2nd gen TKI
Adapted with permission from Hughes T et al, ASH 2013 Education Book

6. Original STIM study design (Bordeaux) N=100
Q- RT-PCR from peripheral blood every month in the first year and every 2 months thereafter
STOP
Start Imatinib
CMR
Sustained CMR
for ≥ 2 years
Molecular recurrence: positivity of BCR–ABL transcript in Q-RT-PCR confirmed by a second analysis point indicating the increase of one log in relation to the first analysis point, at two successive assessments, or loss of MMR at one point.
Five BCR–ABL analyses by Q-RT-PCR during these 2 years
Sixth datapoint checked in centralized laboratory
Mahon FX et al. The Lancet Oncology, 2010;11(11):

7. STIM: Cumulative incidence of molecular relapses
At 60 months 61% ( 95% CI: 52-70)
Cumulative incidence function, accounting for competing events (death in CMR without any relapse n = 1, MI 9mo after imatinib cessation)
Mahon FX et al. The Lancet Oncology, 2010;11(11):
5 extra-hematological deaths were observed:
1 case in DMR after 9 months of imatinib cessation (due to myocardial infarction)
4 cases in the molecular relapse group (due to stroke, mesothelioma, and gastric carcinoma respectively).

8. STIM: Treatment-free survival
At 60 months 40% ( 95% CI: 30-49)
Mahon FX et al. The Lancet Oncology, 2010;11(11):
Author’s estimate of cost savings, taking into account the cost of imatinib and the number of months without treatment, for STIM1 : 4,587,500 €

9. Parallel Australian Study: the TWISTER trial
N=40; 53% prior IFN, 47% IM only
CML8 trial
Molecular relapse was defined as any single sample with a value of >0.1% (i.e. loss of MMR), or two consecutive positive samples at any value
Median follow-up of 42 months (range 15 – 72 months)
No pts have progressed or developed KD mutations
22 pts retreated were sensitive to IM retreatment
Ross DM et al. Blood Jul 25;122(4):

10. Point 2:
There is consistent and growing data regarding treatment free remission

11. STIM: Molecular Relapse according to SOKAL score
At 60 months 73% ( 95 %CI: 61-84)
High and Intermediate Sokal risk
p =
Low Sokal risk
At 60 months 47% ( 95 %CI: 34-62)
Mahon FX et al. The Lancet Oncology, 2010;11(11):
You can predict subsets of patients for whom discontinuation may carry substantially higher risk of molecular relapse and need for retreatment .

12. TKI discontinuation: factors potentially associated with outcome
Study
Factors
French prospective STIM study1
Sokal risk group
Imatinib treatment duration
Australian prospective CML8 study2
IFN treatment duration prior to imatinib therapy
Japanese survey3
Duration of undetectable BCR-ABL transcripts
Imatinib dose intensity
Prior exposure to IFN
Korean retrospective study4
Time to undetectable BCR-ABL transcripts
1Mahon et al. Blood (ASH) 2011; 118: Abstract 603
2Ross et al. Haematologica 2012; abstract
3Takahashi et al. Haematologica 2012; 97:
4Yhim et al. Leukemia Research 2012; 36:

13. Point 3:
You currently can predict (to a degree) which patients will be more successful and not need re-treatment

14. Loss of MMR as criteria for re-initiation of Imatinib
A-STIM Study:
Loss of MMR as criteria for re-initiation of Imatinib
Some patients with CP-CML and an extended CMR on imatinib can discontinue treatment and maintain CMR (undetectable BCR-ABL with sensitivity of 40,000 copies) while others do not
Patients remaining in MMR
n = 51
BCR-ABL negativity
23 (45%)
BCR-ABL positivity (one occasional positive value)
12 (24%)
BCR-ABL fluctuations (≥ 2 consecutive positive values)
16 (31%)
Rousselot P, et al. ASH Abstract 381
Rousselot P, et al. J Clin Oncol [epub ahead of print]

15. Loss of MMR as criteria for re-initiation of Imatinib
A-STIM Study:
Loss of MMR as criteria for re-initiation of Imatinib
A-STIM (N = 80) evaluated loss of MMR (BCR-ABLIS > 0.1%) as a threshold to define relapse and re-start imatinib therapy
BCR-ABL after imatinib (or TKIs) stop
100 10 1
Molecular Relapse
BCR-ABLIS%
MMR
MR4
0.001
The grey zone
Undetectable 12 24 36
Months
Rousselot P, et al. ASH Abstract 381
Rousselot P, et al. J Clin Oncol [epub ahead of print]

16. Molecular Relapse defined as loss of MMR
and Impact of CMR stability on TFR
100
CIF: loss of CMR (STIM criteria) CIF: loss of MMR
100
Stable cCMR before stop Unstable cCMR before stop 80 80 60 60
Cumulative Incidence (%)
Molecular Relapse-Free Survival (%) 40 40 20 20 12 24 36 48 60 72 84 12 24 36 48 60 72 84
Time (months)
Time (months)
Greater ‘success’ by defining relapse in practical terms
28 of 55 pts in MMR after discontinuation had detectable BCR-ABL transcripts
16 pts with ≥ 2 consecutive positive results
Stability of CMR did not impact TFR success
Rousselot P, et al. ASH Abstract Rousselot P, et al. J Clin Oncol. 2013;Dec 9:[epub ahead of print]

17. Therapy discontinuation after nilotinib/dasatinib: Stop-2GTKI trial
TKI therapy ≥ 3 years; 2G-TKI frontline or after imatinib intolerance/resistance
STOP Entry: sustained CMR (≥4.5 log reduction in Bcr-Abl) ≥ 24 months
median f/u 17mo; ‘Success’= transcripts remaining ≤ MMR; 16/39 lost MMR
6 month: 72.8% (95% CI: )
100
12 month: 61.1% (95% CI: ) 80
3 different patterns of MRD off therapy: 60
Survival without loss of MMR % 40
Sustained undetectable BCR-ABL
~30%
detectable BCR-ABL on >2 tests
35% 20
Occasionally detectable BCR-ABL
35% 6 12 18 24 30
Months since 2G-TKI cessation
Kaplan-Meier estimate of stable MMR after 2G-TKI cessation
Rea D et al, ASH 2012

18. *disclaimer: I do not entirely agree with this statement
Points 3 and 4:
Patients in ongoing ‘CMR’ are more likely ‘nonproliferative’ than disease-free and may not differ from others in stable deep remission
MMR loss may be a pragmatic and accepted endpoint for defining failure and need for retreatment*
*disclaimer: I do not entirely agree with this statement

19. Hypothesis for Variability in Deep Molecular Response Duration After Imatinib Discontinuation
Imatinib eradicates all LICs or
Some LICs remain after imatinib treatment
Mahon FX, Etienne G. Clin Cancer Res. 2013

20. Defining a standard in TKI Discontinuation Studies
Study Name
Minimum Requirements for Eligibility
Definition of Relapse MR
Duration of MR
STIM1
MR5
2 years
Loss of MR5
Korean discontinuation study2
MR4.5
Loss of MMR on 2 consecutive assessments
French CML3
Undetectable BCR-ABL
Loss of MMR
French pilot study of MRD4
MR4.5 or undetectable BCR-ABL
Loss of MMR or MR4.5 or undetectable BCR-ABL
Hammersmith survey5
MR4 or better
Loss of MR
Japanese “KEIO STIM”6
Negative BCR-ABL in bone marrow
Detection of ≥ 100 copies of BCR-ABL
Retrospective survey of discontinuation in Japan7
“CMR” (no definition provided)
No minimum requirement
Loss of CMR (study identified patients potentially eligible for discontinuation based on STIM criteria)
STIM 28
MR4.5
2 years
Loss of MMR (MR3)
MR4, molecular response ≥ 4-log reduction; MR4.5, molecular response ≥ 4.5-log reduction.
1Mahon FX, et al. Lancet Oncol. 2010(11): ; 2Goh H-G, et al. Blood. 2011;118(21). Abstract 2763; 3Rea D, et al. Blood. 2011;118(21). Abstract 604; 4Rousselot P, et al. Blood. 2011;118(21). Abstract 3781; 5Milojkovic D, et al. Blood. 2011;118(21). Abstract 605; 6Matsuki E, et al. Blood. 2011;118(21). Abstract 3765; 7Takahashi Blood. 2011;118(21). Abstract 3759; 8ClinicalTrials.gov. Available at: Accessed June 2012.

21. Next-gen Discontinuation Study: visible disease (MR4)
Relapse defined as BCR-ABL > 0.1% (loss of MMR) on the IS at one time point

22. *Personal communication, F-X Mahon, Bordeaux
Concluding Points:
Current approaches, even imatinib, offer potential for treatment free remission (TFR); 2nd gen TKIs offer greater opportunity
TFR success can be predicted with old tools (Sokal); newer tools will give greater clarity
Failure and need for retreatment noted nearly always within 6mo
Non-proliferative state is likely reality of TFR
Retreatment, by all reports in discontinuation studies, has been successful
Single exception of transformation in a patient months after retreatment*
Retreatment opportunities have increased (alternate TKIs) and will continue with experimental approaches (PD-1, other immunotherapies, etc)
*Personal communication, F-X Mahon, Bordeaux

23. Thank you! maurom@mskcc.org 212-639-3107