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Abstract
Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S158

Type: Oral Presentation

Session title: Treatment and monitoring in CML

Background
The Canadian tyrosine kinase inhibitor (TKI) discontinuation (DISC) trial evaluated if Dasatinib (DA) therapy can lead to a successful second treatment-free remission (TFR2) after failing a Imatinib (IM) DISC for first TFR (TFR1) attempt. We previously reported that 1) The 12-month molecular relapse free survival (mRFS) rate for TFR1 was 58.0%; 2) doubling time (DT) at 2 months after IM DISC correlates with TFR1 failure. 

Aims
Here, we report the final result of TFR2 rate after DA DISC. The null hypothesis was a TFR2 rate of 17.5% while the alternative hypothesis was a TFR2 rate of 35.0%, and the study was designed to reject our null hypothesis if > 28% of pts remain in TFR2 after DA DISC.

Methods
This prospective clinical trial (BMS CA180-543, NCT#02268370) had 3 phases: 1) IM DISC phase, 2) DA rechallenge phase, 3) DA DISC phase. Key inclusion criteria included: 1) CML in chronic phase at original diagnosis, 2) total duration of IM therapy of minimum 3 years, 3) total duration of MR4.5 or deeper response over 2 years. Molecular relapse was defined as an increase in BCR-ABL qPCR > MR4 on 2 consecutive occasions, or a single increase in BCR-ABL qPCR > MR3. DA treatment was started at 100mg once daily after molecular relapse was confirmed, and continued for at least 12 months after achieving ≥ MR4 until DISC for TFR2. 

Results

The study was launched on March 2015 and completed all participants’ planned visits as of Feb 2022 with a median follow-up duration of 27.5 months (range 2-51 months).

1) In the IM DISC phase, 58 of 131 pts (44.3%) experienced molecular relapse with a median onset of 3.53 months, thus the remaining 73 pts achieved TFR1 (55.7%): The mRFS rate at 12 months was 56.8% (95% CI, 47.8-64.8 %). Distribution of monthly DT in 6 months is presented in Fig A.

2) In the DA rechallenge phase, out of the 58 pts who failed TFR1, 51 pts received DA. At 3 months, 98.0%, 87.9%, and 75.4% of pts achieved MMR, MR4 and MR4.5. The halving time (HT) after DA re-therapy is summarized in Fig B. Notably, HT at 2 and 3 months was 10.6 and 10.7 days, consistent with rapid reduction of BCR-ABL qPCR in first 3 months.

3) In the DA DISC phase, 35 pts who attained MR4 or deeper response for ≥ 12 months discontinued DA for a TFR2 attempt. Out of 35 pts, only 4 pts (11.4%) has maintained the molecular response at last follow-up, while the remaining 31 pts lost the molecular response with a median 3.65 months. The actuarial mRFS rate at 6 and 12 months was 22.9% (10.8-37.6%) and 10.0% (2.7-23.1%). Monthly DT within 6 months after DA DISC is presented in Fig C. Based on the final result of 11.4% TFR2 rate, we conclude that 12 months’ DA re-therapy could not improve TFR2 rate significantly.

4) For DT after IM DISC, average DT at 2/3 months was much shorter in those lost molecular response (10.6 / 10.7 days) than those who did not (23.5 / 30.1 days). For DT after DA DISC, while average DT was 7.6 and 14.3 days at 2/3 months in overall population, it was much shorter in those lost molecular response within 6 months (3.2 and 13.3 days at 2/3 months).

Conclusion
The final result indicates that re-challenge with DA after TFR1 failure with IM DISC is effective in restoring deep molecular response as most cases rapidly regained at least MR4. However, 12 months’ DA re-therapy does not significantly improve TFR2 rate. Further studies should consider increasing MR4 duration before TFR2 attempt, adding other therapeutics and refining risk factor for TFR2 failure. 

Keyword(s):

Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S158

Type: Oral Presentation

Session title: Treatment and monitoring in CML

Background
The Canadian tyrosine kinase inhibitor (TKI) discontinuation (DISC) trial evaluated if Dasatinib (DA) therapy can lead to a successful second treatment-free remission (TFR2) after failing a Imatinib (IM) DISC for first TFR (TFR1) attempt. We previously reported that 1) The 12-month molecular relapse free survival (mRFS) rate for TFR1 was 58.0%; 2) doubling time (DT) at 2 months after IM DISC correlates with TFR1 failure. 

Aims
Here, we report the final result of TFR2 rate after DA DISC. The null hypothesis was a TFR2 rate of 17.5% while the alternative hypothesis was a TFR2 rate of 35.0%, and the study was designed to reject our null hypothesis if > 28% of pts remain in TFR2 after DA DISC.

Methods
This prospective clinical trial (BMS CA180-543, NCT#02268370) had 3 phases: 1) IM DISC phase, 2) DA rechallenge phase, 3) DA DISC phase. Key inclusion criteria included: 1) CML in chronic phase at original diagnosis, 2) total duration of IM therapy of minimum 3 years, 3) total duration of MR4.5 or deeper response over 2 years. Molecular relapse was defined as an increase in BCR-ABL qPCR > MR4 on 2 consecutive occasions, or a single increase in BCR-ABL qPCR > MR3. DA treatment was started at 100mg once daily after molecular relapse was confirmed, and continued for at least 12 months after achieving ≥ MR4 until DISC for TFR2. 

Results

The study was launched on March 2015 and completed all participants’ planned visits as of Feb 2022 with a median follow-up duration of 27.5 months (range 2-51 months).

1) In the IM DISC phase, 58 of 131 pts (44.3%) experienced molecular relapse with a median onset of 3.53 months, thus the remaining 73 pts achieved TFR1 (55.7%): The mRFS rate at 12 months was 56.8% (95% CI, 47.8-64.8 %). Distribution of monthly DT in 6 months is presented in Fig A.

2) In the DA rechallenge phase, out of the 58 pts who failed TFR1, 51 pts received DA. At 3 months, 98.0%, 87.9%, and 75.4% of pts achieved MMR, MR4 and MR4.5. The halving time (HT) after DA re-therapy is summarized in Fig B. Notably, HT at 2 and 3 months was 10.6 and 10.7 days, consistent with rapid reduction of BCR-ABL qPCR in first 3 months.

3) In the DA DISC phase, 35 pts who attained MR4 or deeper response for ≥ 12 months discontinued DA for a TFR2 attempt. Out of 35 pts, only 4 pts (11.4%) has maintained the molecular response at last follow-up, while the remaining 31 pts lost the molecular response with a median 3.65 months. The actuarial mRFS rate at 6 and 12 months was 22.9% (10.8-37.6%) and 10.0% (2.7-23.1%). Monthly DT within 6 months after DA DISC is presented in Fig C. Based on the final result of 11.4% TFR2 rate, we conclude that 12 months’ DA re-therapy could not improve TFR2 rate significantly.

4) For DT after IM DISC, average DT at 2/3 months was much shorter in those lost molecular response (10.6 / 10.7 days) than those who did not (23.5 / 30.1 days). For DT after DA DISC, while average DT was 7.6 and 14.3 days at 2/3 months in overall population, it was much shorter in those lost molecular response within 6 months (3.2 and 13.3 days at 2/3 months).

Conclusion
The final result indicates that re-challenge with DA after TFR1 failure with IM DISC is effective in restoring deep molecular response as most cases rapidly regained at least MR4. However, 12 months’ DA re-therapy does not significantly improve TFR2 rate. Further studies should consider increasing MR4 duration before TFR2 attempt, adding other therapeutics and refining risk factor for TFR2 failure. 

Keyword(s):

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