1) Several studies have evaluated discontinuing tyrosine kinase inhibitor (TKI) treatment in chronic myeloid leukemia patients who have achieved a deep molecular response. 2) These studies found that 40-60% of patients were able to remain in treatment-free remission for varying periods of time after stopping TKI treatment. 3) Sustaining a complete molecular response for at least 2 years before discontinuing treatment appears important for treatment-free remission success rates. Close molecular monitoring after stopping treatment is also needed.

1. TKI Discontinuation in CML
Udomsak Bunworasate
King Chulalongkorn Memorial Hospital
Chulalongkorn University

2. BCR/ABL Tyrosine Kinase Inhibitors (TKI)
Imatinib
Glivec, STI-571 Dasatinib
Sprycel, BMS-354825
Nilotinib
Tasigna, AMN-107
• Survival of CML pts. who respond to treatment is close to
the healthy population.
• TKI discontinuation in responded pts. has been proposed
due to
- Economic impact of treating patients during lifetime
- Quality of life, long-term tolerability/toxicity (esp. in younger pts.)

3. Discontinuation Studies in CML-CP
• Imatinib N
– STIM 100
– STIM2 200
– ALLG CML8 (TWISTER) 40
– A-STIM 80
– EUROSKI 200 (planned 700)
• Nilotinib/Dasatinib N
– STOP 2G-TKI 50
– ENESTfreedom 175
– ENESTop 117
– ENESTpath 1058
– DASFREE ~74
Mahon et al. Ann Hematol 2015,94:S187-93

4. To stop imatinib, it is necessary to achieve and
sustain very low level of residual disease
Michor F et al. Nature 2005, 435:1267-70 Mahon et al. ASH 2013 [abstract 255]

6. Study Rx before Response for Definition of relapse TFR %
discontinuation discontinuation (median f/U)
STIM1 IFN->I* for MR4.5 for ≥2 yrs Loss ofMMR or ≥1-log 40 % (55mos)
≥3 yrs or increase in BCR-ABL
STIM2 I for ≥3 yrs MR4.5 for ≥2 yrs Loss ofMMR or ≥1-log 46 %at 2 yrs
or increase in BCR-ABL
ALLG CML8 I for ≥3 yrs MR4.5 for ≥2 yrs Loss of MMR or confirmed 42.7 % (42 mos)
(TWISTER) loss of MR4.5
A-STIM I for ≥3 yrs MR4.5 for ≥2 yrs Loss of MMR 64 % (23 mos)
EUROSKI I, N*, D* MR4 for ≥1 yr Loss of MMR 61 % at 6 mos.
(in progress)
STOP 2G-TKI N, D CMR for median Loss of MMR 61.1 %
29 mos (preliminary)
Discontinuation Studies in CML-CP
I=Imatinib, N=Nilotinib, D=Dasatinib
Mahon et al. Ann Hematol 2015,94:S187-93

7. TWISTER
FREQUENT AND SUSTAINED DRUG-FREE
REMISSION IN THE AUSTRALASIAN CML8 TRIAL OF
IMATINIB WITHDRAWAL
Median follow-up of 42 months (range 15 – 72)
Ross et al. Blood 2013;122(4):515-22

8. Sustained CMR for at least 2 yrs is of
major importance in TKI discontinuation
78%
15%
p = 0.0002
Takahashi et al. Haematologica 2012; 97(6): 903-6

9. Study Rx before Response for Definition of relapse TFR %
discontinuation discontinuation (median f/U)
STIM1 IFN->I* for MR4.5 for ≥2 yrs Loss ofMMR or ≥1-log 40 % (55mos)
≥3 yrs or increase in BCR-ABL
STIM2 I for ≥3 yrs MR4.5 for ≥2 yrs Loss ofMMR or ≥1-log 46 %at 2 yrs
or increase in BCR-ABL
ALLG CML8 I for ≥3 yrs MR4.5 for ≥2 yrs Loss of MMR or confirmed 42.7% (42 mos)
(TWISTER) loss of MR4.5
A-STIM I for ≥3 yrs MR4.5 for ≥2 yrs Loss of MMR 64 % (23 mos)
EUROSKI I, N*, D* MR4 for ≥1 yr Loss of MMR 61 % at 6 mos.
(in progress)
STOP 2G-TKI N, D CMR for median Loss of MMR 61.1 %
29 mos (preliminary)
Discontinuation Studies in CML-CP
I=Imatinib, N=Nilotinib, D=Dasatinib
Mahon et al. Ann Hematol 2015,94:S187-93

10. “According to STIM” (A-STIM)
Loss of MMR As a Trigger for Restarting Imatinib
• Enrolled patients with MR4.5 or UMRD for ≥ 2 years on imatinib
• After discontinuation, loss of MMR was used as the criteria for
restarting imatinib
• All patients who re-initiated imatinib therapy after a loss of MMR
regained MR4.5 after a median of 7.3 months of treatment
Relapse-free Survival by Relapse Criteria
50
25
0
PercentRelapse-free(%)
0 6 12 18 24 30 36 42 48
Months
54 60 66 72 78 84 90 96
100
75
P < .0001
Without loss of MMR: 63.7%
STIM criteria*: 38.1%
Without loss of CMR: 26.5%
*Two consecutive increasing values of detectable
MRD
Rousselot et al. Haematologica. 2012;97(s1): 77 [abstract 194].
Rousselot et al . J Clin Oncol 2014;32:424-430

11. • In the STIM study, a fluctuation in BCR-ABL transcript was
detected in 5 of the 39 without confirmed molecular relapse.
Mahon et al. Lancet Oncol 2010; 11: 1029–35
Fluctuation of BCR-ABL detection after
discontinuation

12. BCR-ABL DNA evidence of residual disease
in patients with UMRD
Ross DM et al. Blood 2013;122(4):515-22.

14. Conclusion
• Around 40% of CML pts. with stable deep
molecular response for at least 2 yrs. are likely to
remain in prolonged TFR after treatment
discontinuation
• The rate is around 60% if the loss of MMR is the
criteria of molecular recurrence
• In most cases, TKI discontinuation needs to be
done under a clinical trial with close molecular
monitoring
• A long-term follow-up of the discontinuation
studies will be necessary to affirm cure