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TKI discontinuation in CML
- 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
Editor's Notes
- The success of imatinib and second-generation tyrosine kinase inhibitors (TKIs) has dramatically changed the outcome for CML patients. Bosutinib Ponatinib identifying patients who can safely stop TKI therapy may reduce long-term medical costs.
- In recent years, almost 1,000 patients have officially stopped TKI around the world for molecular efficacy in clinical trials. Pharma study
- Discontinuation of imatinib in pts. after 1–3 yrs led to a rapid increase of leukemic cells to levels at or beyond pretreatment baseline. We conclude that leukaemic stem cells, which drive CML disease, are not depleted by imatinib therapy. The rapid upslope of 0.09 ^ 0.05 per day corresponds to a doubling time of roughly 8 days, which characterizes the rate at which differentiated leukaemic cells are regenerated from leukemic stem cells. a multicenter study entitled “Stop Imatinib” (STIM) trial and three cases of late relapse were observed at months 19, 20, and 22, respectively. Most patients who experienced molecular relapse did so within 6 months of imatinib cessation and remained responsive to re-treatment with imatinib.
- CMR was defined by undetectable molecular response (UMR) with PCR sensitivity between 4.5 and 5 log. Molecular relapse, which was arbitrarily defined as two positiveRQ-PCR results over a period of 1month showing a significant rise (1 log) in BCR-ABL transcripts, was a trigger for imatinib treatment again.
- STIM1: Fifty-one percent of the patients had been previously treated with IFN, and the other half were treated with imatinib only. We still do not know the threshold of residual disease, which will allow us to safely stop TKI with the lowest rate of molecular recurrence. It is one the aims of the EURO-SKI study. (EURO-SKI) trial from the European LeukemiaNet (ELN) that is currently in progress in ten countries. The criteria for discontinuation are less strict than in the STIM studies: the duration of TKI treatment before enrolment must be at least 3 years and no PCR-results >0.01 % within the last year, i.e., a sustained deep molecular response (DMR) of 4 log have to be confirmed.
- A nationwide survey in Japan identified 50 patients who had discontinued imatinib Takahashi et al. reported that a significant difference in the estimated molecular relapse-free survival rates at 5 years following discontinuation between patients in whomCMRwas sustained for more than 24months prior to imatinib discontinuation and those sustaining a CMR for less than 24 months (78 vs. 15 %, p=0.0002)
- STIM1: Fifty-one percent of the patients had been previously treated with IFN, and the other half were treated with imatinib only. We still do not know the threshold of residual disease, which will allow us to safely stop TKI with the lowest rate of molecular recurrence. It is one the aims of the EURO-SKI study. (EURO-SKI) trial from the European LeukemiaNet (ELN) that is currently in progress in ten countries. The criteria for discontinuation are less strict than in the STIM studies: the duration of TKI treatment before enrolment must be at least 3 years and no PCR-results >0.01 % within the last year, i.e., a sustained deep molecular response (DMR) of 4 log have to be confirmed.
- A multicenter observational study (A-STIM [According to Stop Imatinib]) evaluating MMR persistence was conducted in 80 patients with CP-CML who had stopped imatinib after prolonged CMR. One patient diagnosed in 1996 (15 years ago) experienced lymphoid blast crisis 8.5 months after restarting imatinib while in MMR
- Fluctuation of BCR-ABL transcript levels below the MMR threshold (greater than or equal to two consecutive positive values) was observed in 31 % of patients after imatinib discontinuation.
- It should be noted that leukemic cells may still be present even if RQ-PCR results are negative. Current RQ-PCR methods can reliably detect up to a 5-log reduction in BCR-ABL, but newer techniques, such as DNA-based PCR, RNA-based digital PCR, and replicated PCR, have demonstrated increased sensitivities and may enable the assessment of even deeper levels of molecular response. However, it should be noted that using an ultrasensitive PCR technique, a low level of BCR-ABL transcripts has been found in the blood of normal individuals, suggesting that a complete absence of transcripts may not be required to eradicate the disease. In the TWISTER study using PCR on DNA which is a non routine technique increasing the sensitivity as compared to classical RQ-PCR (decimal logarithm twice) to analyze patient which were considered in the so- called undetectable UMRD, leukemic cells were exhibited in all cases.
- Two independent studies have been reported that low NK cell numbers may predict early disease relapse after TKI discontinuation. These studies suggest that NK cell-based immune surveillance may contribute to CML control after TKI cessation. That is why John Goldman proposed some years ago the definition of “operational cure”