TKI Discontinuation in CML

Udomsak BunworasateKing Chulalongkorn Memorial Hospital

Chulalongkorn University

BCR/ABL Tyrosine Kinase Inhibitors (TKI)

ImatinibGlivec, STI-571 Dasatinib

Sprycel, BMS-354825

NilotinibTasigna, 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.)

Discontinuation Studies in CML-CP • Imatinib N

– STIM 100– STIM2200– 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

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]

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 yrsor 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=DasatinibMahon et al. Ann Hematol 2015,94:S187-93

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

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

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 yrsor 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=DasatinibMahon et al. Ann Hematol 2015,94:S187-93

“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

Perc

ent R

elap

se-fr

ee (%

)

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

• 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

BCR-ABL DNA evidence of residual disease in patients with UMRD

Ross DM et al. Blood 2013;122(4):515-22.

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